Mesomelic and Acromesomelic Dysplasias

Mesomelic and rhizo-mesomelic dysplasias (including Robinow syndrome) and acromesomelic dysplasias

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

1. Introduction

The class concept: the limb segment as the diagnostic key

The dysplasias in this class are defined by the most affected limb segment. In a child with short limbs, clinical assessment begins by measuring height or length, arm span (the distance between the tips of the middle fingers with the arms in horizontal abduction) and the ratio between the upper and lower segments, which is about 1.0; once limb shortening is confirmed, the predominant segment is identified: proximal (rhizomelia), middle (mesomelia) or distal (acromelia), terms that give their names to many dysplasias [59]. In mesomelia, the forearm and lower leg are disproportionately short relative to the upper arm and thigh; in acromesomelia, short hands and feet with brachydactyly are added, and the shortening worsens from proximal to distal [13, 15]. The Oxford Desk Reference also recommends measuring the hands (total length and middle-finger length), recording a pedigree of at least three generations, paying attention to variable expressivity, and the parents' stature, and distinguishing true brachydactyly from small but structurally normal hands, as in Prader-Willi syndrome, Smith-Magenis syndrome or maternal uniparental disomy of chromosome 14 [60].

The class is heterogeneous in its molecular basis, but is organised around a few signalling pathways. Robinow syndrome (RS) and the omodysplasias result from disturbances of the non-canonical WNT pathway of planar cell polarity (PCP), in which the ligand WNT5A, the receptors ROR2 and FZD2, the dishevelled proteins (DVL1, DVL3) and nucleoredoxin (NXN) act in sequence [5, 11]. The acromesomelic dysplasias of the Maroteaux type and PRKG2-related type result from loss of function of the axis formed by C-type natriuretic peptide (CNP), its receptor B (NPR-B, encoded by NPR2) and cyclic guanosine monophosphate (cGMP)-dependent protein kinase type II (cGKII, encoded by PRKG2) [61, 62]. The Grebe, Hunter-Thompson and Du Pan spectrum results from loss of function of the GDF5–BMPR1B pair, of the transforming growth factor beta (TGF-β) superfamily [63]. The rare mesomelic dysplasias depend mainly on structural changes that dysregulate limb development genes: duplications of the HOXD cluster, microdeletions or inversions at 6p22.3 with dysregulation of ID4, microdeletions at 8q13 involving SULF1 [1, 64].

Historical overview

Meinhard Robinow, F. N. Silverman and H. D. Smith described in 1969 a dwarfism syndrome with mesomelic shortening, hemivertebrae, genital hypoplasia and a face reminiscent of that of a fetus, the origin of the name «fetal face syndrome» [65–67]. The original family had the dominant form, and the WNT5A variant identified in 2010 was found in all its living affected members [68]. According to OMIM, this family had affected members in six generations, without male-to-male transmission, and vaginal delivery was possible in affected women; Person and colleagues found the variant in seven affected individuals and found no WNT5A variants in another 23 patients with a clinical diagnosis of dominant RS, the first indication of the genetic heterogeneity of the dominant form [33]. Bain and colleagues (1986) described a father and two children with the typical face and normal limbs, but Robinow himself (1991) considered that some cases attributed to the dominant form, including these, were Maroteaux omodysplasia [33]. Giedion and colleagues consolidated in 1975 the radiological diagnosis of «fetal face = Robinow syndrome» [51]. The recessive form, more severe and with costovertebral anomalies, was first called COVESDEM; in 2000, two groups simultaneously identified biallelic ROR2 variants, one in 11 families, many of them Turkish, and the other in families from Oman, also establishing that recessive RS is allelic to dominant brachydactyly type B [69–71]. Then came WNT5A in 2010, DVL1 in 2015, with the simultaneous description of the osteosclerotic form, DVL3 in 2016 and, in 2018, FZD2 and NXN, in a cohort of 21 families studied when about 70% of dominant forms still lacked a molecular diagnosis; in that cohort, targeted Sanger sequencing and exome sequencing provided a plausible molecular explanation for 20 of the 21 probands, including alternative diagnoses and candidate genes [12, 68, 72–74]. In 2015, dominant omodysplasia was attributed to FZD2, and in 2018 its phenotype was recognised as similar to RS [75, 76].

P. Maroteaux, B. Martinelli and E. Campailla described «nanisme acromésomélique» in 1971 [52, 77]. Langer and colleagues summarised 19 patients in 1977, and more than 40 cases had been published by the time of the 8th edition of Smith's Recognizable Patterns of Human Malformation [53]. The locus was mapped to chromosome 9 in 1998, a mild form not linked to 9p13–q12 suggested heterogeneity in 2000, and Bartels and colleagues identified NPR2 in 2004 in 21 families [61, 78, 79]. In 2022, Díaz-González and colleagues described a new acromesomelic dysplasia due to biallelic PRKG2 variants [62]. In 2026, the first patient with acromesomelic-type short stature due to biallelic variants in NPPC, the gene for CNP itself, was reported [80], as was a case of NPR2-related acromesomelic dysplasia in 12,000-year-old ancient DNA [81].

Grebe described in 1952 the chondrodysplasia that bears his name and, in 1953, siblings with the intermediate form, later called Hunter-Thompson, and siblings with the Du Pan variant [82]. The name «Brazilian achondrogenesis» comes from a 1964 report by Quelce-Salgado on a new type of dwarfism with bony aplasias and hypoplasias of the extremities, according to the bibliography of the Bone Dysplasias atlas [82]. Up to the 9th edition of McKusick's catalogue (1990), Grebe dysplasia was called «achondrogenesis type II», a name abandoned because it also applied to the lethal Langer-Saldino achondrogenesis, which is unrelated to it [37]. In 1996, the Hunter-Thompson form was the first human disease attributed to a mutation in a member of the TGF-β superfamily, cartilage-derived morphogenetic protein 1 (CDMP-1, now GDF5); Grebe dysplasia followed in 1997, with a dominant-negative mechanism on the secretion of other bone morphogenetic proteins (BMPs) [83, 84]. BMPR1B was linked in 2005 to an acromesomelic chondrodysplasia with genital anomalies (Demirhan type) and, in 2014–2015, to Grebe dysplasia and the Du Pan form [63, 85, 86]. In 2016, a review counted three genes in isolated recessive acromesomelic dysplasias (GDF5, NPR2 and BMPR1B) and described syndromic forms with cardiac, respiratory, neurological and genital anomalies [87].

Among the mesomelic dysplasias, Nievergelt published in 1944 an article whose title translates as «positive proof of paternity based on hereditary malformations of the extremities»; the woman known as «Das Bärenweib» (Alice Vance) was retrospectively diagnosed with Nievergelt dysplasia [88]. Langer described in 1967 the «hypoplastic ulna, fibula, mandible» type, now Langer dysplasia [89]. The molecular basis of the rare forms emerged between 2008 and 2015: 2q31.1 microduplication in Kantaputra (2010), 8q13 microdeletion involving SULF1 in the dysplasia with acral synostoses (2010), variants and duplications of the ZRS regulatory sequence in Werner dysplasia and Laurin-Sandrow syndrome (2010) and 6p22.3 microdeletions in Savarirayan (2015) [88, 90–92].

Nomenclature and reclassifications

GeneReviews considers the name COVESDEM abandoned, because it was confused with other vertebral defect syndromes and because ROR2-related RS has acromesomelia and not only mesomelia [5]. Orphanet lists as synonyms of RS «acral dysostosis with facial and genital abnormalities», «fetal face syndrome», «mesomelic dwarfism-small genitalia syndrome», «Robinow dwarfism» and «Robinow-Silverman-Smith syndrome» [4]. Three Orphanet entities bearing the Robinow name are not RS: Robinow-Sorauf syndrome (ORPHA:3106), «Robinow-like syndrome» (ORPHA:3105) and osteopathia striata with cranial sclerosis, synonym «Robinow-Unger syndrome» (ORPHA:2780) [4].

The 2023 Nosology (11th revision; 771 entries associated with 552 genes, in 41 groups) adopted dyadic nomenclature, which combines phenotype and gene («Robinow syndrome, DVL1-related») [1]. Several reclassifications relevant to this class follow from this. Reinhardt-Pfeiffer dysplasia (MIM 191400) is now included in SHOX-related dyschondrosteosis; the Hunter-Thompson form and acromesomelic dysplasia with genital anomalies are included in «Grebe dysplasia, GDF5-related»; Kantaputra dysplasia is grouped with the Korean (Kim) and Fryns types in «Mesomelic dysplasia, HOXD-related»; Werner dysplasia (tibial hemimelia–polysyndactyly–triphalangeal thumb, ZRS-related) is in group 38 («Limb hypoplasia – reduction defects group», NOS 38-0150) and is only cross-listed from group 15 [1]. Dominant omodysplasia (FZD2) and FZD2-related RS appear as two entries for the same gene; Zhang and colleagues discuss whether these variants should be called dominant RS, omodysplasia 2 or both, and in the phenotypic analysis the 16 patients with FZD2 cluster with RS and not with the omodysplasias [1, 11]. Brachydactyly B1, allelic to recessive RS, belongs to group 18 («Brachydactylies (isolated)») [1].

Current classifications

In the 2023 Nosology, group 15 has 17 entries and group 16 has seven [1]. The following table reproduces group 15 with the Nosology entry number (NOS), the OMIM MIM number and the Nosology notes.

Group 15 also cross-refers to ZRS-related tibial hemimelia–polysyndactyly–triphalangeal thumb and mentions mesomelic dysplasia, Camera type (MIM 611886), whose status remains to be established [1]. In OMIM, the Camera form is a metaphyseal chondrodysplasia with upper-limb mesomelia and normal stature, described in two sporadic 5-year-old boys (Camera and Camera 2003; Becerra-Solano 2008, the latter with oesophageal atresia and nail hypoplasia) [93]. Group 16 is as follows.

The 2023 Nosology replaces the 2019 and 2010 revisions; the latter (Warman and colleagues) is the only one cited in the local clinical reference sources, the Oxford Desk Reference, which also refers to the European Skeletal Dysplasia Network and the UK Skeletal Dysplasia Group [1, 59]. Bell's 1951 classification is still used for the isolated brachydactylies, most of them dominant, in seven groups (A to E, with subtypes), to which genes are now assigned: IHH in A1, BMPR1B and GDF5 in A2, ROR2 in B1, GDF5 in C and HOXD13 in D/E [60].

Orphanet uses broader clinical groups. The «Mesomelic and rhizo-mesomelic dysplasia» group (ORPHA:93438; International Classification of Diseases, 11th revision, ICD-11, LD24.A) includes, in addition to the Nosology entities, cleidorhizomelic syndrome, fibrochondrogenesis, upper-limb mesomelic dysplasia Fryns type, Reinhardt-Pfeiffer dysplasia, Patterson-Lowry rhizomelic dysplasia, Urbach-type rhizomelic syndrome, atelosteogenesis II, Chassaing-Lacombe X-linked dominant chondrodysplasia (HDAC6), SAMS syndrome (GSC), colobomatous microphthalmia with rhizomelic dysplasia (MAB21L2), the AD syndrome of myopia, midface retrusion, sensorineural deafness and rhizomelic dysplasia (COL11A1), QRICH1 syndrome, EN1 dorsoventral syndrome and AFF3 syndrome [2]. The «Acromesomelic dysplasia» group (ORPHA:93437; ICD-11 LD24.9) includes AMDM, Hunter-Thompson, Grebe, mesomelia-synostoses syndrome, the Du Pan form and brachydactyly A6/Osebold-Remondini [3]. Orphanet divides RS into AR (ORPHA:1507; ROR2 and NXN) and AD (ORPHA:3107; WNT5A, DVL1, DVL3 and FZD2) and classifies Werner dysplasia separately, as tibial hemimelia–polysyndactyly–triphalangeal thumb syndrome (ORPHA:988) [4, 94]. Searches of Orphadata for OMIM numbers 609441 (Grebe/BMPR1B, Demirhan type) and 619636 (AMDP) returned no dedicated entity [3].

The bone dysplasia atlas of Spranger and colleagues (Bone Dysplasias, 4th edition, 2018) organises the material into two chapters: chapter 12, on the rhizo-mesomelic dysplasias (AR omodysplasia, RS, dyschondrosteosis, Langer, Kantaputra, Werner, Reardon-Kozlowski, Nievergelt-Savarirayan and mesomelic dysplasia with acral synostoses), and chapter 13, on the acromesomelic and acromelic dysplasias and dysostoses (AMDM, Grebe with Hunter-Thompson and Du Pan, brachydactylies, trichorhinophalangeal dysplasias, acrocapitofemoral dysplasia, Albright hereditary osteodystrophy, acrodysostosis, geleophysic and acromicric dysplasias, Myhre syndrome and SOFT syndrome) [6]. The acromelic dysplasias fall outside the scope of this article, except in the differential diagnosis, such as Weill-Marchesani syndrome and the geleophysic and acromicric dysplasias.

There is one divergence in inheritance that should be stated. AR inheritance has been attributed to WNT5A-related RS; the 2023 Nosology, GeneReviews, OMIM 180700 cited in the sources and the published series classify it as AD [1, 7, 95]. Both modes exist, but with very different weight: Smith reports a severe «Robinow-like» case with biallelic loss-of-function WNT5A variants (Birgmeier 2018), and Zhang and colleagues record a single patient with a biallelic frameshift variant, p.Tyr188Metfs*31 (published designation, without a c. notation that would allow it to be mapped on NM_003392.7), with unaffected carrier parents [11, 67]. WNT5A-related RS is treated here as AD, and the recessive form as exceptional.

Definition of the entities within the scope

This class article covers Robinow syndrome in all its genetic forms, the omodysplasias, the rare mesomelic dysplasias of the Kantaputra, Werner and Laurin-Sandrow, Kozlowski-Reardon, Nievergelt, Savarirayan, KINSSHIP, Verloes-David-Pfeiffer, Reinhardt-Pfeiffer and Fryns types, and the acromesomelic dysplasias of the Maroteaux, PRKG2, Grebe and Hunter-Thompson, Du Pan, Demirhan and Osebold-Remondini types. Léri-Weill dyschondrosteosis and Langer dysplasia, both SHOX-related, appear here only in the classification and the differential diagnosis. Short stature due to a heterozygous NPR2 variant, achondroplasia and the CNP analogues enter the differential diagnosis and the therapeutic discussion.

2. Molecular Genetics and Pathophysiology

Table of all types and genes in the class

The table brings together all the entities within the scope, with the test that distinguishes them and the related entity where there is one. For the entities caused by microduplications or microdeletions, the test method indicated derives from the mechanism described in the sources and not from a formal recommendation [88, 90, 91].

Sources for the table: [1–3, 5–7, 11, 14, 16, 51–53, 64, 82, 88, 90–92, 96–101]. The OMIM numbers, inheritance and designations in the table were checked in the OMIM entries [17–20, 22, 27, 28, 32, 33, 35–42, 102–109].

Non-canonical WNT pathway and Robinow syndrome

The RS genes converge on the WNT/PCP pathway [11]. The WNT pathway has a canonical, β-catenin-dependent branch and non-canonical branches independent of it; WNT5A acts in both and is critical for cell migration [7]. WNT5A is a known ligand and co-receptor of ROR2, which explains the phenotypic overlap between the WNT5A and ROR2 forms; ROR2 interacts with FZD2, and the signal is relayed to the dishevelled proteins DVL1 and DVL3, stabilised by NXN, which activate c-Jun N-terminal kinase (JNK) signalling, responsible for cytoskeletal reorganisation and cell polarity [5, 7]. A WNT5A gradient in the limb bud controls its elongation, and in the mouse Wnt5a controls steps of gonadal development, which relates to the genital hypoplasia [7]. Murine ROR2 is expressed early in the developing face, in proliferating chondrocytes, the genital tubercle, heart, lungs, kidney and thymus [5].

ROR2 (9q22.31; OMIM 602337) encodes a single-pass receptor tyrosine kinase, with an extracellular protein–protein interaction portion (Frizzled-like and kringle domains) and an intracellular portion with kinase activity; it has 9 exons, the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript is NM_004560.4 (GeneReviews uses NM_004560.3) and the protein has 943 amino acids [5, 54, 110]. In recessive RS the variants are missense, nonsense or frameshift, biallelic, distributed across the extracellular and intracellular domains, and there are homozygous exonic deletions (exons 6–7; exons 4–5) [5, 54]. The mechanism is loss of function: truncating variants undergo nonsense-mediated mRNA decay (NMD), and missense variants are retained in the endoplasmic reticulum, with no receptor at the membrane, which was confirmed for R108Q, R366W, P692T and R736Q in HeLa cells [54]. Of the 36 single-nucleotide variants of recessive RS analysed by Lima and colleagues, 22 occur at CpG dinucleotides; there are no hotspots, and the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) PM1 criterion is not useful for ROR2 [54].

Brachydactyly B1 results from heterozygous truncating ROR2 variants that produce an abnormal but stable receptor retained at the membrane, consistent with gain of function [5, 60]. According to Lima and colleagues, no recessive RS variant affects the interdomain regions, and variants in those regions cause brachydactyly B; Schwarzer and colleagues attributed the difference between the two phenotypes to the degree of ROR2 retention or degradation and to the amount of mutant protein reaching the plasma membrane [5, 54]. For this reason, the heterozygous parents of patients with recessive RS are usually asymptomatic, although GeneReviews allows for findings of brachydactyly B1 in heterozygotes [5]. According to OMIM, the first brachydactyly B1 variants (Oldridge 2000) were concentrated in a 7-amino-acid segment immediately after the tyrosine kinase domain, and Schwabe and colleagues (2000) described truncations in two regions, before and after that domain, with a more severe phenotype in the distal ones; in one of those families, a child of consanguineous parents who both had brachydactyly B1 had a phenotype reminiscent of RS, with aplasia or hypoplasia of the phalanges, metacarpals and metatarsals [103].

NXN (17p13.3; OMIM 612895) encodes nucleoredoxin, an oxidoreductase of the thioredoxin superfamily that acts as a redox-dependent brake on the WNT pathway: it binds the dishevelled proteins and limits the ubiquitination of DVL3 [9]. NXN-related RS was described in three individuals from two families and confirmed in a patient with the variant NM_022463.5:c.817C>T p.(Gln273Ter) in trans with a terminal 17p deletion of about 1 Mb [12, 110, 111]. In the original report, a 5-year-old Turkish girl, the daughter of consanguineous parents and without ROR2 variants, was homozygous for NM_022463.5:c.625C>T p.(Arg209Ter); two sisters from another family, identified through GeneMatcher, were compound heterozygous for NM_022463.5:c.1234_1236del p.(Glu412del), an in-frame deletion of one amino acid inherited from the mother, and for an 84 kb intragenic deletion encompassing the whole of exon 1, inherited from the father [12, 45, 46, 110]. OMIM describes the sisters' parents as consanguineous, but the clinical table of the original article indicates consanguinity only in the Turkish family [12, 46]. The paternal deletion (GRCh37 chr17:805,043–889,090) is mediated by recombination between two Alu elements in direct orientation (AluSx and AluSx1, with 81% identity) flanking the first coding exon; 17p13.3 has a high density of Alu elements, and the first and last exons of multi-exon genes are particularly prone to these deletions, so NXN CNV analysis is part of the diagnosis [11, 12]. In the frog Xenopus laevis, nucleoredoxin acts as a negative regulator of the WNT/PCP pathway, inhibiting Dvl-induced c-Jun phosphorylation via Rac and blocking the ubiquitination and degradation of Dvl, and two Nxn−/− mouse models have a short snout and cleft palate, which partly reproduces the RS face (preclinical evidence) [12].

WNT5A (3p14.3; OMIM 164975) has 5 exons and alternative splicing [7]. In dominant RS the variants are mainly missense in exons 3 and 4: 13 of 14 (93%) introduce or remove a cysteine, and four unrelated patients had different changes of residue Cys83 (Gly, Ser, Trp, Tyr) [11]. The activity of mutant WNT5A was reduced in zebrafish and Xenopus assays; homology modelling with WNT8 places the variants on one side of the protein, where they may disrupt complex formation or intraprotein bonds, and the exact mechanism has not been clarified [7, 68]. In the expression assays in zebrafish embryos summarised by OMIM, the p.Cys182Arg and p.Cys83Ser proteins behaved as hypomorphic alleles and not as dominant negatives [26]. Up to 2018, fewer than 10 patients with WNT5A variants had been published, and in that year's cohort the gene explained 2 of 21 probands (about 9.5%): a private missense variant, NM_003392.7:c.479C>G p.(Ser160Cys), in an adopted patient, with no parental study possible, and a de novo 6 bp in-frame duplication, NM_003392.7:c.487_492dup p.(Gly163_Cys164dup), present in 16 of 70 reads (23%), consistent with mosaicism in blood; the coding regions of WNT5A were visually inspected in all exomes to ensure complete coverage [12, 110].

DVL1 (1p36.33; OMIM 601365) and DVL3 (3q27.1; OMIM 601368) have 15 exons [7]. All DVL1 variants associated with RS are frameshifts in exons 14 and 15 (penultimate and last), and those of DVL3 are frameshifts in the same exons or variants of the intron 14 acceptor site, all with a −1 frameshift [7, 74, 112]. The premature termination codon lies in the last exon, the mRNA escapes NMD (the normal and mutant alleles are expressed in leucocytes), and the protein acquires a new C-terminal tail, highly basic and proline-rich [11, 72]. In the White series (2015), six de novo truncating DVL1 variants were found in eight patients, including the monozygotic twins of Portuguese descent described by Saraiva and colleagues (1999), three by exome sequencing and the others in a cohort of 62 patients with a similar phenotype; Bunn and colleagues (2015) showed that the mutant protein is stable and that its co-expression with normal DVL1 increases canonical WNT activity in cell assays [27]. The DVL3 variants of White (2016) arose de novo or were inherited from an affected parent [28]. In the 2018 cohort (21 probands with a clinical diagnosis of RS or a similar phenotype, previously screened for ROR2 and therefore biased towards the dominant form), sequencing of the penultimate and last exons identified likely pathogenic DVL1 variants in six probands and a DVL3 variant in one (7/21, 33%); the DVL1 variants lay in a GC-rich 116-nucleotide segment of the penultimate exon, and half of the DVL1 variants then published (9/17) clustered in a region where the repeated sequence «GCTGCCC» favours recurrent 13 bp deletions by secondary-structure mutagenesis [12]. The authors confirmed each frameshift allele by cloning and allele-specific sequencing [12]. White and colleagues (2016) sequenced the last two exons of DVL1, DVL2 and DVL3 in a cohort of 34 patients with a possible clinical diagnosis of RS (one DVL3 variant) and in 17 cases from an in-house database (four probands with DVL3, two with 1 bp deletions and two with splicing variants, and one with DVL1); the phenotypes of the DVL1 and DVL3 forms were largely concordant, but only 2 of the 4 patients with DVL3 and clinical data had macrocephaly, and all 4 had short stature, which points to head circumference and stature as discriminating features [43, 44]. The proposed mechanism is gain of function or a dominant-negative effect, not haploinsufficiency: a whole-gene deletion or an early truncation subject to NMD does not fit the mechanism and should not be reported as a cause of RS merely because it is truncating [113]. Bunn and colleagues showed that the mutant allele alone is less active in a canonical pathway reporter assay, but that co-expression with the normal allele doubles canonical WNT activity, an allelic interaction proposed as the explanation for the osteosclerosis; the residual non-canonical deficit would explain the mesomelia and face shared with WNT5A and ROR2 [73, 113]. In 2026, Tophkhane and colleagues showed in the chick embryo that DVL1 1519ΔT widens the frontonasal process and inhibits skeletogenesis, that the protein localises to the nucleus and that, in Drosophila, only the form with the new tail alters morphogenesis: the abnormal C-terminal tail, and not mere truncation, is pathogenic (preclinical evidence) [114]. In the mouse, absence of Dvl3 causes outflow tract defects, unlike that of Dvl1, which is consistent with the heart disease of DVL3-related RS [11].

FZD2 (17q21.31; OMIM 600667) encodes a seven-transmembrane-domain receptor for WNT and is a single-exon gene, with no predictable NMD [10, 11]. The variants are monoallelic, recurrent, missense (six unrelated patients with a change at Gly434) or C-terminal truncating (seven with p.Trp548* or p.Ser547*), which remove the dishevelled-binding region but produce protein; according to GeneGuidance, the missense variants p.Gly434Val and p.Pro142Lys behaved as dominant negatives in functional assays [10, 11]. In the 2018 cohort, FZD2 explained 3 of 21 probands (14%), and a fourth family was identified through GeneMatcher; three families had changes at the same residue, Gly434 (NM_001466.4:c.1301G>T and c.1301_1302delinsTT, both p.(Gly434Val), and c.1300G>A p.(Gly434Ser), de novo), conserved in all vertebrates and located at the boundary of a transmembrane domain, next to the third intracellular loop required for DVL1 binding [12, 110]. The fourth family had the nonsense variant NM_001466.4:c.1130G>A p.(Trp377Ter), inherited from a mother with a mild form, upstream of the C-terminal truncating variants and, because the gene has a single exon, probably with stable mRNA; in the same proband, the paternal missense variant in trans NM_001466.4:c.425C>T p.(Pro142Leu) was classified as a variant of uncertain significance (VUS), because the father and two carrier siblings had only short stature, in a family with short stature on both sides (familial target height 162 cm, below the 2nd centile) [12, 110]. GeneGuidance designates this position as p.Pro142Lys; the substitution c.425C>T produces p.(Pro142Leu) in VariantValidator, and the original article neither classifies it as pathogenic nor attributes a dominant-negative effect to it [10, 12, 110]. A de novo 17.4 kb deletion encompassing only FZD2, in a boy with anterior congenital diaphragmatic hernia, omphalocele, VSD and cryptorchidism (Wat 2011), is associated with a phenotype different from omodysplasia [29]. The p.(Trp548*) protein is produced, but interacts less with DVL and responds poorly to canonical signalling [75].

DVL2 is a candidate gene with a single patient: a de novo variant c.2105dupC, p.Pro703Serfs*103, with a +1 frameshift predicting a C-terminal tail equivalent to that of the −1 frameshifts in DVL1 and DVL3; «screw-tail» dogs homozygous for a 1 bp deletion in Dvl2 have a phenotype similar to RS [11]. GPC4 was reported in a single individual with a clinical diagnosis of RS; the Bone Dysplasias atlas allows for an X-linked form due to GPC4, but the 2023 Nosology and GeneGuidance associate GPC4 with Keipert syndrome (nasodigitoacoustic, X-linked, MIM 301026) and not with RS [1, 7, 51, 100]. RAC3, also proposed in 2018, was later reclassified as a distinct neurodevelopmental disorder [11, 12]. In the 2018 report, the GPC4 patient was an 8-year-old boy hemizygous for NM_001448.3:c.1235G>A p.(Arg412Lys), inherited from an unaffected heterozygous mother, with macrocephaly, soft-palate cleft, patent ductus arteriosus and delayed tooth eruption; GPC4 promotes the accumulation of dishevelled at the membrane and positively regulates the WNT/PCP pathway [12, 110]. RAC3, a GTPase of the Rac subfamily that interacts with DVL and activates JNK and c-Jun phosphorylation, was proposed on the basis of a 13-year-old girl with the de novo missense variant NM_005052.3:c.176C>G p.(Ala59Gly), without mesomelia or brachydactyly but with genital hypoplasia; the authors presented the two genes as candidates awaiting confirmation in other patients [12, 110].

Reference variants and normalisation

The historical nomenclature of the GeneReviews chapters uses transcripts that are not the MANE Select ones. The following table presents the reference variants normalised with VariantValidator (GRCh38, queried on 27 October 2026; rows for the 2018 and 2021 cohorts queried on 28 October 2026) [110].

Two practical observations follow from this normalisation. In DVL1, the MANE transcript NM_001330311.2 has numbering shifted by +75 nucleotides and +25 amino acids relative to the NM_004421 used in the literature, and NM_001330311.2:c.1519del is a different variant, p.(Leu507Ter); the report should therefore always state the transcript [110]. In DVL3, the protein change assigned by GeneReviews to c.1585delG (p.Ala592ProfsTer139) contains a digit transposition, and the correct description is p.(Ala529ProfsTer139), identical in NM_004423.3 and NM_004423.4 [7, 110]. The Omani founder ROR2 nonsense variant has no HGVS nomenclature in the abstract of the original article; OMIM describes it as Q502X in exon 9, and the only single-nucleotide substitution producing that stop codon, NM_004560.4:c.1504C>T p.(Gln502Ter), corresponds to ClinVar record VCV000007307, confirmed in VariantValidator [25, 110, 117]. The ZRS variant of Werner dysplasia, described as «c.404G>A; c.404G>C» in the ZRS's own numbering, without correspondence on a coding transcript, remains unnormalised [71, 92].

Recessive omodysplasia (GPC6)

GPC6 encodes glypican 6, a heparan sulfate proteoglycan; the variants interfere with WNT signalling [6]. The severe alleles are truncating, removing the heparan sulfate binding site and the glycosylphosphatidylinositol anchor domain, with total loss of function; in a family with five siblings homozygous for NM_005708.5:c.511C>T p.(Arg171Trp), short stature and rhizomelia were mild, with coxa breva and ulna minus, and the protein retained residual Hedgehog-stimulating activity [125].

Mesomelic dysplasias due to regulatory and structural changes

Kantaputra dysplasia is linked to 2q31.1, the HOXD cluster; no point variant has been identified in HOXD genes, and dysregulation of the cluster's control region is probably responsible, with families carrying 2q31.1 or 2q31.1–q31.2 microduplications (1.0 Mb) and an Italian family with a balanced translocation t(2;8)(q31;p21) [90]. The 2023 Nosology groups these duplications under «HOXD-related» and notes a variable phenotype even within families [1]. According to OMIM, the original Thai family has two separate microduplications at 2q31.1–q31.2, of about 481 kb and 507 kb, the more centromeric including the entire HOXD cluster, EVX2 and MTX2, which segregated with the phenotype in nine further relatives; the locus was first linked to 2q24–q32, a designation OMIM retains as the cytoband of the entry [20]. In 2024, Pagnamenta and colleagues found in the Danish family of Shears (2004), without copy-number change, a de novo 22.9 kb inversion within the cluster (HOXD11–HOXD13) in the mother, transmitted to her affected son, overlapping the smaller duplication of the Thai family; the canonical transcripts of HOXD11, HOXD12 and HOXD13 remained intact, and the authors propose a position effect [20]. A normal microarray therefore does not exclude a balanced structural rearrangement of the HOXD cluster [20].

The ZRS (ZPA Regulatory Sequence) is the limb-specific SHH enhancer, located in intron 5 of LMBR1 at 7q36.3, about 1 Mb from SHH; a specific point variant causes the tibial hypoplasia with polydactyly of Werner dysplasia, and ZRS duplications cause Laurin-Sandrow syndrome, in a spectrum that includes triphalangeal thumb with polysyndactyly, preaxial polydactyly type 2 and syndactyly type 4 [92]. Lohan and colleagues (2014) detected in three families with Laurin-Sandrow different heterozygous ZRS microduplications, of 16 to 75 kb, segregating with the disease; the family with the shortest duplication had the most complex phenotype, with complete syndactyly of the hands, aplasia of the patella and tibia and duplication of the fibula [105].

In Savarirayan dysplasia (Flottmann 2015, de novo microdeletions according to OMIM), three individuals had heterozygous microdeletions of about 2 Mb at 6p22.3 (MBOAT1, E2F3, CDKAL1, SOX4), close to ID4; as patients with much larger overlapping deletions had no skeletal changes, it was proposed that the phenotype results from abnormal ID4 expression in the limb bud [88]. In 2026, a 5th case with a normal microarray had a de novo inversion at 6p22.3, identified by genome sequencing, with disruption of a topologically associating domain (TAD) and probable adoption of limb enhancers by ID4, which reinforces this mechanism [64]. A «Nievergelt-like» syndrome was associated with a heterozygous 353 kb intragenic deletion in AFF3 (LAF4) at 2q11.2; homozygous knockout in the mouse does not alter the skeleton, but mice with the deletion partially recapitulate the phenotype [88]. KINSSHIP syndrome results from de novo missense variants in the nine-amino-acid degron of AFF3 or from de novo deletions of that region, with a mechanism of AFF3 excess; knock-in mice have mesomelic deformities of the lower limbs [101].

Mesomelic dysplasia with acral synostoses is a contiguous gene syndrome due to heterozygous microdeletions of 582–732 kb at 8q13 (582–738 kb in OMIM, in five patients from four families, non-recurrent in the two families with sequenced breakpoints) [108] that include SULF1, which encodes a heparan sulfate 6-O-endosulfatase, and SLCO5A1; SULF1 haploinsufficiency is probably responsible for the skeletal anomalies [91].

The CNP–NPR2–PRKG2 axis and the acromesomelic dysplasias

NPR2 (9p13.3; OMIM 108961) encodes NPR-B, a transmembrane receptor with guanylyl cyclase activity that produces cGMP when it binds CNP, a potent stimulator of endochondral growth [52, 61]. In the discovery series (21 families) there were 4 nonsense, 4 frameshift, 2 splicing and 11 missense variants, and the three missense variants tested had markedly deficient guanylyl cyclase activity [61]. The predominant mechanism of the missense variants is defective cellular trafficking: 11 of 12 mutants were retained in the endoplasmic reticulum and non-functional, and the only one at the surface (D176E) had greatly reduced ligand binding [126]. In a study of eight missense variants, four had defective trafficking, three behaved close to normal and one, in the active site, p.Arg932Cys, had normal trafficking but deficient cGMP, which underlies the difference in severity between homozygosity (AMDM) and heterozygosity (short stature) [127]. In a Turkish series of 23 patients from 20 families, the 22 distinct NPR2 variants (14 missense, 5 nonsense, 2 intronic and one single-amino-acid deletion; 15 novel) were homozygous in 19 patients and compound heterozygous in 4; 11 lay in the extracellular binding domain, 5 in the catalytic domain, 2 in the kinase homology domain and 2 in the interdomain region, and none was shared by more than two families, with no founder variant; at that time ClinVar listed 102 pathogenic or likely pathogenic NPR2 variants, about 40 of them associated with AMDM [128]. In 2026 it was shown that a homozygous synonymous variant, NM_003995.4:c.2484C>T, creates aberrant splicing with a frameshift and predicted NMD, a mechanism that only RNA analysis reveals [124]. The Npr2 pwe/pwe mouse, a model of AMDM, has disproportionate dwarfism, reduced proliferative and hypertrophic zones of the growth plate and greater activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2); inhibitors of the MEK1/2 kinases, which activate ERK1/2, corrected the growth deficit in fetal tibial explants (preclinical evidence) [129].

In the Turkish series of Simsek-Kiper and colleagues, the 22 distinct NPR2 variants are distributed as in the following table (transcript NM_003995; MANE and GRCh38 normalisation with VariantValidator on 28 October 2026; Varsome classification and gnomAD frequency as reported by the authors in 2020) [110, 128].

Of the 22 variants, 6 were classified as pathogenic, 4 as likely pathogenic and 12 as VUS, including 10 of the 14 missense variants, although all were homozygous or compound heterozygous in patients with the typical phenotype; neither of the two intronic variants had RNA studies, and the three variants of patient 21, without parental studies, have unknown phase [128]. This spectrum shows that, in AMDM, a biallelic NPR2 variant classified as a VUS in a patient with a characteristic radiological phenotype requires family segregation and, if possible, functional or RNA studies before being used for prenatal diagnosis [128].

NPR2 illustrates three phenotypes that depend on dose and the direction of the effect: biallelic loss of function causes AMDM; heterozygous loss of function causes short stature with non-specific skeletal changes (OMIM 616255); heterozygous gain of function causes tall stature with long halluces (epiphyseal chondrodysplasia, Miura type, OMIM 615923), also produced by rearrangements that overexpress NPPC [1, 13, 130]. In the three-generation family described by Miura and colleagues, the variant NM_003995.4:c.2647G>A p.(Val883Met) made the receptor constitutively active, with raised blood cGMP [131]. Heterozygous carriers of AMDM variants are shorter: on average 5.7 cm below matched controls in Smith, and a height z-score of −1.8 ± 1.1 versus −0.4 ± 0.8 in 23 non-carriers in a 39-member family [53, 132].

PRKG2 (4q21.21; OMIM 601591) encodes cGKII, activated by cGMP downstream of CNP and NPR-B; cGKII phosphorylates Raf-1 at Ser43 and reduces ERK1/2 activation induced by fibroblast growth factor 2 (FGF2) [14, 62]. Nonsense and frameshift alleles subject to NMD fail to reduce ERK1/2 and dysregulate COL10A1 and COL2A1 via SOX9, so AMDP is a downstream phenocopy of the NPR2 defect [14, 62]. The variant NM_006259.3:c.1705C>T p.(Arg569Ter), at a CpG dinucleotide, was found in homozygosity in a Moroccan girl and in an Iranian girl with no shared haplotype, which suggests independent recurrence; OMIM designates the entity «acromesomelic dysplasia 4» (MIM 619636) and the allelic form «spondylometaphyseal dysplasia, Pagnamenta type» (MIM 619638), described in three Pakistani siblings homozygous for a 1 bp duplication, with a genotype–phenotype relationship that is still provisional [22, 110]. By 2024, four variants had been described in five families; the first missense variant, p.Val470Gly, failed to repress FGF2-induced mitogen-activated protein kinase (MAPK) pathway signalling [133]. A combination of a frameshift variant with a missense variant creating a cryptic splice site produced an attenuated phenotype, through partial loss of function [134]. In the same pathway, NPPC is the most recent candidate gene: biallelic variants in a patient with acromesomelic short stature, after monoallelic variants had been described in idiopathic short stature; it is not included in the 2023 Nosology [80].

The GDF5–BMPR1B pair

GDF5 (20q11.22; OMIM 601146) signals through the BMPR1B receptor and the SMAD1/5/8 axis; a systematic review linked 49 pathogenic variants to 8 phenotypes, with dominant and recessive transmission, ordered by residual activity [15]. In OMIM, GDF5 is associated with nine phenotypes: acromesomelic dysplasias 2A (Grebe), 2B (Du Pan) and 2C (Hunter-Thompson), brachydactylies A1 with C (AD and AR), A2 and C, multiple synostoses syndrome 2, proximal symphalangism 1B and susceptibility to osteoarthritis 5 [23]. At the severe recessive end are the Grebe, Du Pan and Hunter-Thompson dysplasias; mild heterozygous loss of function causes brachydactyly C or A2; at the gain-of-function end are proximal symphalangism 1B and multiple synostoses syndrome 2, with conductive deafness due to stapes fixation [15, 60]. The Grebe dysplasia variant described in 1997 replaces with tyrosine the first of seven conserved cysteines of the mature domain; the protein is not secreted and has a dominant-negative effect on the secretion of other BMPs [84]. It corresponds to NM_000557.5:c.1199G>A p.(Cys400Tyr) (1199G-A, C400Y in OMIM), homozygous in the affected members of the original family from Bahia, in which 13 of 14 carrier chromosomes shared the same haplotype [37, 110]. The original Hunter-Thompson form resulted from a homozygous 22 bp tandem duplication [83].

BMPR1B (4q22.3; OMIM 603248) gives brachydactyly A2 and A1D with heterozygous missense variants in the kinase domain, and acromesomelic dysplasia with biallelic variants [16]. In the Demirhan family, a homozygous 8 bp deletion caused loss of function, distinct from the dominant-negative missense variants of brachydactyly A2 [85]. Graul-Neumann and colleagues described two families with Grebe dysplasia and the homozygous variants NM_001203.3:c.157T>C p.(Cys53Arg) and NM_001203.3:c.657G>A p.(Trp219*), with heterozygous parents with mild brachydactyly or no signs [86]. The Du Pan form may result from the homozygous hypomorphic variant NM_001203.3:c.91C>T p.(Arg31Cys), which loses less function than the p.Cys53Arg of Grebe dysplasia: severity is proportional to the functional deficit of the GDF5–BMPR1B pair [63].

Inheritance, penetrance and allelic disorders

The recessive forms (RS due to ROR2 and NXN, omodysplasia 1, AMDM, AMDP, the GDF5–BMPR1B spectrum) are concentrated in consanguineous families, with homozygosity in most [5, 54, 128]. The dominant forms of RS due to DVL1 and DVL3 are mostly de novo, and DVL1 and DVL3 variants occur independently in about one third of patients with a diagnosis of RS [11, 72, 74]. In Werner dysplasia and Laurin-Sandrow syndrome, incomplete penetrance is common, with significant intra- and interfamilial variability [92]. OMIM assigns two inheritance patterns to Werner dysplasia: AD, in most families, and AR, because in a five-generation Mexican family (VanderMeer 2014), with 31 members with triphalangeal thumb only and 14 with preaxial polydactyly, the most severely affected daughter, with tibial and radioulnar hypoplasia, was homozygous for the ZRS variant 402C>T, for which her parents, with abnormal thumbs, were heterozygous, which suggests a dosage effect [19]. In a three-generation Thai family, lower-limb severity increased from generation to generation (Norbnop 2014) [19]. In families with dominant isolated brachydactyly there is variable expressivity and sometimes incomplete penetrance [60]. The allelic disorders of the class are brachydactyly B1 (ROR2), heterozygous short stature and tall stature with long halluces (NPR2), brachydactyly C, A2 and the synostoses (GDF5), brachydactylies A2 and A1D (BMPR1B) and, for PRKG2, spondylometaphyseal dysplasia, Pagnamenta type [1, 14–16].

3. Clinical Spectrum and Manifestations by System

Robinow syndrome: common description

RS is present at birth, and the severe skeletal manifestations are identifiable from 13–14 weeks of gestation [51]. The major findings described by the Bone Dysplasias atlas are the fetal-like face, genital hypoplasia, growth retardation with short stature and mesomelic brachymelia, which may be absent or very mild in some dominant types; occasionally there is umbilical hernia, congenital heart disease, craniosynostosis, dental anomalies (hypodontia, supernumerary teeth), macrocephaly and deafness when there is osteosclerosis and cranial thickening [51]. Smith summarises the syndrome as a flat facial profile, short forearms and hypoplastic genitalia [67].

In the craniofacial region, the face in early childhood resembles that of an eight-week fetus: macrocephaly, a broad and prominent forehead, marked hypertelorism, prominent eyes with apparent exophthalmos due to deficiency of the lower eyelid, midface hypoplasia, a short upturned nose with a depressed bridge and anteverted nares, a large triangular mouth with the upper lip in an «inverted V» exposing the incisors and gingiva, micrognathia and simple, low-set ears [5]. The face becomes less marked with age and growth of the nose in adolescence normalises it, but the broad forehead, broad nasal bridge and hypertelorism persist in adults [5, 7]. Cleft lip or palate is occasional, and there is an unusual form of lower-lip cleft; the tongue may be bifid or bilobed [5, 7]. Dental anomalies are common and persistent: a broad retromolar ridge, alveolar ridge deformation, malocclusion, crowding, hypodontia, delayed eruption of the permanent dentition and gingival hyperplasia that may interfere with eruption and orthodontics; one case of persistent deciduous dentition required extractions at 18 years [5, 7].

In the skeleton, birth length is reduced or normal and falls below the normal range in the first year; shortening is mesomelic or acromesomelic, mainly of the forearms, with brachydactyly affecting mostly the distal phalanges of the 2nd and 5th fingers and a cleft distal phalanx of the thumb [5, 51]. On radiographs, the first metacarpal is relatively shorter than the first proximal phalanx, the middle phalanx of the 5th finger is short, the radius and ulna are broad, with radial bowing and radioulnar dislocation, and the metacarpophalangeal pattern differs between types [51]. Elbow mobility is reduced [51]. Thoracic hemivertebrae with vertebral fusions and fused or absent ribs, which result in often severe kyphoscoliosis, are characteristic of the recessive form; primary lung function is normal, but chest wall changes may impair coughing and predispose to respiratory infections [5].

In the genital tract, boys have a micropenis, with a normal scrotum and testes or with cryptorchidism; girls have a hypoplastic clitoris and labia majora [5]. Wilcox and colleagues showed by computed tomography (CT) and magnetic resonance imaging (MRI) that the penile anomaly is due to abnormal insertion of the corpora cavernosa (crura) on the inferior and posterior medial aspect of the ischial tuberosity, instead of the anteromedial aspect of the pubis, with a gap between the symphysis and the dorsum of the penis; a normal-sized penis thus appears shorter and low-set [135]. Gerber and colleagues assessed nine men with RS (mean age 19.9 years): mean penile length 32.5 mm (53 mm stretched), penoscrotal transposition in 9 of 9, buried penis in 7 of 9, hypospadias in 5 of 8, a large penopubic gap in 5 of 6, cryptorchidism in 4 of 10 and testicular atrophy in 5 of 9; 78% reported reduced sexuality, sexual function and self-image, and the genital phenotype did not correlate with the gene [136]. Endocrine assessment is usually normal, although Soliman and colleagues described low basal testosterone and a low response to human chorionic gonadotrophin (hCG) in boys; puberty is usually normal [5]. According to OMIM, Soliman and colleagues (1998) described in the recessive form an empty sella turcica in all the children studied, partial Leydig cell insensitivity to hCG, low basal testosterone in prepubertal boys and a defect of the sex steroid feedback mechanism [35]. Smith records documented partial primary hypogonadism, with normal pubertal virilisation in most [67]. This observation originates from Lee and colleagues (1982), who observed in four patients normal pubertal virilisation with persistence of the micropenis, raised FSH and an exaggerated LH response to gonadorelin in postpubertal males, suggestive of partial primary hypogonadism, with normal 5-alpha-reductase and androgen receptor activity in genital skin fibroblasts; two of these men measured 170 and 161.7 cm [33]. In girls the anomalies are generally subtle; vaginal atresia with haematocolpos is rare [50, 67].

Congenital heart disease occurs in about 15% in the ROR2 form and is the main cause of early death: pulmonary stenosis or atresia, atrial septal defect (ASD), ventricular septal defect (VSD), coarctation of the aorta, tetralogy of Fallot and tricuspid atresia [5]. As early as 1990, five of seven published cases with heart disease had right ventricular outflow tract obstruction, and in 1993 there were 9 among at least 67 cases [137, 138]. Renal anomalies (mainly hydronephrosis; cystic renal dysplasia) are frequent in the ROR2 form [5]. Two adults with ROR2-related RS showed that renal disease may progress: one had hydronephrosis, nephrocalcinosis and renal failure; the other had severe vertebral involvement and raised gonadotrophins [139].

Intellect is usually normal [5, 7]. Schwartz and colleagues assessed 13 participants aged 4 to 51 years (5 DVL1, 3 WNT5A, 2 NXN, 2 ROR2, 1 GPC4): intellectual functioning was generally average, visuomotor skills low average, adaptive functioning average in the recessive form and low average in the dominant form; there was executive or attentional dysfunction and learning difficulties in 4 of 8 children, 3 of them with DVL1, and peer problems in most, which suggests a specific risk of neurodevelopmental disorder in the dominant DVL1 form [140]. Smith records developmental delay or intellectual disability in 18%, with frequencies without a denominator [67].

Growth may be associated with growth hormone (GH) deficiency: Castells and colleagues documented it in one boy and in 3 of 4 patients with RS and available tests in Genentech's National Cooperative Growth Study, and Kawai and colleagues in a 10-year-old girl with partial deficiency [141, 142].

Frequency of findings: recessive and dominant forms

The table compares the three series with known denominators. Mazzeu and colleagues classified 88 patients (38 of their own and 50 from the literature) into 37 recessive and 51 dominant on the basis of rib fusions or inheritance; Lima and colleagues described 22 patients with ROR2-related RS from 21 families of diverse origins, with a strong Brazilian component; Zhang and colleagues analysed 68 patients with dominant or NXN forms (23 DVL1, 1 DVL2, 9 DVL3, 17 FZD2, 14 WNT5A, 4 NXN) [11, 54, 143].

Lima and colleagues also recorded, at frequencies of 75% to 99%, a broad nasal bridge, downturned corners of the mouth, bifid tongue, dental anomalies, short palms and clinodactyly; at 50% to 74%, proptosis, long eyelashes, triangular mouth, micrognathia, retrognathia, low-set ears, short neck, limited pronation–supination, broad thumbs and cryptorchidism (50%); tongue hypoplasia (35%) is a new feature, and hearing loss affected 14% [54]. Three patients without rib fusions, previously considered pathognomonic of the recessive form, led the authors to recommend that, in their absence, other diagnoses be considered [54]. Scoliosis worsens with age and vertebral severity ranges from a single hemivertebra to all vertebrae, with a major impact on prognosis [54]. Brunetti-Pierri and colleagues (2008) found thoracic syringomyelia in a patient with low back pain at 17 years, homozygous for a deletion of exons 6 and 7 of ROR2, in an extended family with intrafamilial variability of cleft lip and palate and heart disease [35]. Beiraghi and colleagues (2011) compared 9 patients with the dominant form and 3 with the recessive form: craniofacial dysmorphism was more severe in the recessive form and intraoral changes (broad retromolar ridge, alveolar ridge deformation, malocclusion, gingival hyperplasia, crowding and hypodontia) in the dominant form, and the face became less marked with age in both [35]. Patients with biallelic missense variants had more cryptorchidism, broad halluces and thumbs, heart disease and renal anomaly, and those with biallelic loss of function more low-set ears, retrognathia, pectus excavatum and limited pronation–supination; no patient with loss of function had cryptorchidism, heart disease, inguinal hernia or renal anomaly [54]. Malik and colleagues proposed that homozygous truncations originating at residues 441–452 of ROR2 cause severe autopod reduction, on the basis of a Pakistani family with tetramelic transverse deficiency [116]. Apart from this observation, GeneReviews recognises no genotype–phenotype correlations in the ROR2 form [5].

The Smith frequencies (for example, hypertelorism and upturned nose in 100%, short forearms in 100%, thoracic hemivertebrae in 70%, hypoplastic genitalia in 94%, cryptorchidism in 65%, renal anomalies in 29% and heart disease in 13%) combine the dominant and recessive forms and give neither a denominator nor a population [67].

Recessive Robinow syndrome due to ROR2

The recessive form is distinguished by severe mesomelic and acromelic short stature, multiple rib and vertebral anomalies, radioulnar dislocation, severe hypoplasia of the proximal radius and distal ulna and a more triangular mouth [67]. On radiographs, at 6 months there is severe costovertebral missegmentation, short and thick radii and ulnae and markedly short first metacarpals; at 12 years, scoliosis due to thoracic missegmentation and an anteriorly dislocated radial head [51]. The face is very marked in early childhood and becomes less so in adults; the final height of five adults was 128 to 145 cm, below the 3rd centile [54]. At birth the penis may be extremely small and buried, with cryptorchidism in half, which requires chromosomal confirmation of sex; the adult men followed reported normal erection and significant penile growth after puberty [54].

Dominant Robinow syndrome: common and gene-specific features

In the dominant form the skeleton is less affected and the teeth more so: vertebral anomalies and radial head dislocation are rare (<25%), final height is at −2 standard deviations (SD) or slightly below in most, and short stature may already be visible on fetal ultrasound at 20 weeks [5, 7]. Occasional prenatal macrocephaly persists; renal anomalies, cleft lip or palate, nail dysplasia and heart disease occur in less than 25% [7]. Puberty and fertility are normal according to the GeneReviews authors; affected women carry pregnancies to term, and delivery may require caesarean section because of cephalopelvic disproportion [7].

In the osteosclerotic DVL1 form, final height is at the lower limit of normal, with macrocephaly of +2.5 to more than +6 SD, increased bone mineral density (BMD), osteosclerosis of the skull, bilateral mixed or conductive deafness and umbilical hernia [7]. In the Zhang cohort, macrocephaly occurred in 95% (21/22), triangular mouth in 82% and increased bone density in 82% (9/11), and only 38% had short stature [11]. Of the eight patients of White (2015), all had macrocephaly, frontal bossing, a high forehead, midface hypoplasia, hypertelorism, a short nose and dental anomalies, and only two had short stature [43]. Eijkenboom and colleagues (2012) documented in a 17-year-old girl, with chronic otitis media with effusion in childhood, low-frequency conductive deafness due to narrowing of the tympanic cavity and of the oval and round window niches, with thickened and fixed ossicles, over a thick, sclerotic calvaria; Bunn and colleagues (2014) described two patients with generalised osteosclerosis of the skull and of the axial and appendicular skeleton, long bones with deficient tubulation and thick cortices, hypoplastic distal phalanges and normal cognition, one of them with raised serum alkaline phosphatase [43]. Hu and colleagues described a 3-month-old infant with a de novo DVL1 variant (c.1620delC, p.(Ser542Valfs*107) in the publication; in MANE, NM_004421.3:c.1620del p.(Ser542Valfs*107)) with bilateral hip dislocation, shortening of the radius, thoracolumbar kyphosis, deafness, severe global delay, patent ductus arteriosus and thinning of the corpus callosum; the article contains internal inconsistencies regarding sex and inheritance, which limits its interpretation [144]. At 7 years, the Bone Dysplasias atlas describes generalised osteosclerosis, thick calvaria, bifid thumbs, brachymesophalangy and «angel-shaped» middle phalanges, without mesomelic shortening of the arm [51]. Shayota and colleagues studied seven patients by dual-energy X-ray absorptiometry (DEXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT): cranial osteosclerosis appeared in the four patients with DVL1 and in the patient with GPC4, and not in the patients with WNT5A or ROR2; in the DVL1 group cortical BMD was low and trabecular BMD increased, with fewer and thicker trabeculae; one case had choanal atresia, bilateral conductive deafness and palsies of cranial nerves III, VI and VII [145].

In the DVL3 form, congenital heart disease affected 78% (7/9), with complex defects (hypoplastic right or left heart, pulmonary atresia, aberrant subclavian artery), and there was a tendency to omphalocele (3/7) and cleft lip or palate (6/9); osteosclerosis was not reported [7, 11]. ASD and VSD are the most common defects across RS [11].

In the WNT5A form, dental anomalies and genital hypoplasia were constant (7/7; 5/5 boys and 3/3 girls), without camptodactyly, renal anomalies, deafness or omphalocele; the phenotypes were the most variable [11]. The two WNT5A patients in the 2018 cohort had hemivertebrae and marked mesomelic shortening, a more severe phenotype than previously described, one of them with the variant in probable mosaicism in blood [12]. In 2026, a 10-month-old infant with the WNT5A variant p.(Cys182Arg) was initially managed as congenital adrenal hyperplasia because of microphallus, impalpable testes, hyponatraemia, hyperkalaemia and mildly raised 17-hydroxyprogesterone [146].

In the FZD2 form the phenotype is the mildest: dental anomalies in 58%, no hypoplastic phalanges or nail dysplasia, less hypertelorism (60%) and brachydactyly (67%), male genital hypoplasia in 67%, long philtrum in 92% and uterine anomalies in 4 of 11 women; missense variants cluster with the more severe phenotype of the DVL genes, and truncating variants with the milder one [11]. In the six affected individuals with FZD2 variants in the 2018 cohort (5 to 47 years at last observation), all had mesomelia or micromelia, 4 had brachydactyly and 5 significant short stature (down to −3.5 SD), with a high, broad forehead, flat face, low-set ears, broad nasal tip and anteverted nares; genital hypoplasia was present in 3 of the 5 people assessed, one had a renal anomaly and none had heart disease, and the mesomelia of the boy with p.(Trp377Ter) became less marked with age, clinically and radiologically [12]. Only three of these six patients met strict clinical criteria for dominant RS, and the authors proposed that dominant omodysplasia, with predominant short humeri and radial head dislocation, is a point on the RS spectrum rather than a distinct syndrome [12]. The description of omodysplasia 2 includes normal stature, rhizomelic shortening of the humerus with restricted elbow movement, dislocation or hypoplasia of the radial head, short first metacarpal, normal legs, facial dysmorphism and variable genitourinary anomalies; GeneReviews notes the absence of hypertelorism, whereas GeneGuidance includes it [7, 10]. In the Venditti family (2002), the mother had been diagnosed with RS and her son had delayed humeral ossification on ultrasound at 13–14 weeks and short humeri with ambiguous genitalia at 20 weeks; at birth he had a micropenis, bifid scrotum and cryptorchidism [102]. A woman followed from 9 to 48 years of age (Gordon 2014) needed extraction of 6 to 8 permanent teeth at 11 years because of crowding in a small maxilla and mandible and had a bicornuate uterus; in the Saal family (2015), the mother had bilateral cleft lip and palate, hypoplastic genitalia and a didelphic uterus [102]. In a boy followed up to 16 years of age, the undermodelling of the humeri and femora became less marked; on radiographs, the humerus is much shorter than the femur, the proximal ulna and distal radius are broad and the radial head is dislocated [10, 51]. In 2026, a prenatal case with short upper limbs, cleft lip and palate and suspected genital hypoplasia was described [147].

In the NXN form (four patients), there was short stature (2/2), a high forehead, long philtrum, triangular mouth and clinodactyly (4/4), hypoplastic phalanges and omphalocele (2/2) and mesomelia in 2 of 4, without scoliosis; phenotypically it clusters with the DVL forms and cannot be distinguished from the dominant forms [11]. The Turkish girl in the original report also had omphalocele and ventral hernia, a bicuspid aortic valve with dilatation of the ascending aorta, an anomalous course of the right coronary artery and developmental delay (walking at 36 months, sentences at 5 years); in the two sisters, aged 3 years and 6 months, development appeared normal, and all three had relative macrocephaly, mesomelia, brachydactyly and broad thumbs and great toes [45]. In the clinical table of the original article, all three also had hypertelorism, prominent eyes, anteverted nares, long philtrum, triangular mouth, gingival hyperplasia, micrognathia and clinodactyly; the uvula was absent in the Turkish patient and in the younger sister, the latter with a soft-palate cleft, the Turkish patient had a renal anomaly in addition to heart disease, and the older sister's mesomelia became less marked with age [12]. In that table, the last observation of the sisters was at 2 years and 5 months and at 4 weeks, ages different from those given by OMIM [12, 45]. In a cohort of 13 patients that included recessive forms, limb shortening was present in all, mainly mesomelic but also rhizomelic or micromelic [9].

Recessive omodysplasia (GPC6)

Omodysplasia 1 gives rhizomelic short stature with hands and feet of normal length, frontal bossing, a glabellar cutaneous haemangioma, a short upturned nose with a depressed bridge and reduced mobility of the elbows and, later, of the knees and hips; the short limbs are detected by ultrasound at 13 weeks [6]. The humerus and femur are short and distally tapered, the elbows are dislocated and the axial skeleton is normal; height is below the 1st centile, motor development may be delayed and mental development is apparently normal [6]. OMIM describes cryptorchidism, hernias, congenital heart disease and cognitive delay as variable findings; Baxová and colleagues (1994) reported two siblings with intellectual disability, one with heart disease, so cognitive normality is not constant [17]. By 2004, fewer than 20 cases had been published, with a male predominance; the recessive patients lacked the metacarpal shortening seen in the dominant form [17]. Recurrence was detected by ultrasound at 13 weeks (Tan 2005), and the growth plate has an expanded proliferative zone, with small, tightly packed chondrocytes (Borochowitz 1998) [17]. Campos-Xavier and colleagues (2009) linked the disease to 13q31.1–q32.2 in five families and found biallelic GPC6 variants in all affected individuals, all predicted to result in absence of functional protein [17].

Léri-Weill and Langer dysplasias (SHOX)

In Léri-Weill dyschondrosteosis, Madelung deformity, mesomelic short stature and a muscular habitus become apparent in late childhood, with greater severity in females; in Langer dysplasia, the biallelic expression of SHOX deficiency, the mesomelic micromelia is severe, with hypoplasia of the distal ulna, proximal fibula and mandible, and adult height is around 130 cm, 5.5 to 8.9 SD below the mean according to the GeneReviews chapter on SHOX deficiency cited by GeneGuidance [96, 97, 148, 149].

HOXD-related mesomelic dysplasia (Kantaputra type)

At birth, the forearms are very short and radially bowed, with ulnar deviation of the hands, flexion contractures of the interphalangeal joints, slightly short legs and ankylosis of the ankles with the hindfoot and midfoot fixed in extreme equinus [90]. On radiographs, the ulna is disproportionately short, the wrist is V-shaped, and there is complex distal tibiofibular, fibulocalcaneal and tibiotalar fusion, with the tarsus aligned with the axis of the leg [90]. There are no anomalies other than skeletal ones; the most severely affected patients walk on tiptoe, and in the original Thai family mean adult height was 152 cm in men and 135 cm in women [90]. OMIM describes 15 affected members in three generations in this family, including identical twins and several instances of male-to-male transmission; it considers prominence of the ventral aspect of the distal fibula a characteristic sign, together with a dumbbell-shaped distal humerus in all adults, a small or absent calcaneus, fibulocalcaneal synostosis and tiptoe walking, in a «ballerina» position [20]. In the follow-up of a 21-year-old man, the radii became progressively bowed and flexion contractures of the proximal interphalangeal joints of the 4th and 5th fingers and fusion of the tibia with the talus and distal fibula developed [20]. Kantaputra considered the Danish family of Shears (2004), with less affected radii and ulnae and without the fibular prominence or the «ballerina» position, a distinct entity, probably allelic, whereas Kwee and colleagues (2004) described a third family with the Kantaputra phenotype, seven affected members in three generations, with co-segregation with markers at the locus [20].

Werner dysplasia and Laurin-Sandrow syndrome (ZRS)

Preaxial hemimelia predominates in the lower limb, with tibial hypoplasia or fibular duplication, preaxial polysyndactyly with «mirror feet» and triphalangeal thumb; Laurin-Sandrow syndrome adds mild nasal dysmorphism, and cryptorchidism, heart disease or Hirschsprung disease are rare [92]. Knee instability and ankle deformity hamper walking, and the absence of functional thumbs limits dexterity [92]. According to Norbnop and colleagues (2014), the first digits of the hand have the character of a finger rather than a thumb, without thenar muscles, without a first web space and without opposition [19]. Congenital heart disease (Pratt 1971), bilateral cryptorchidism and Hirschsprung disease (Goldenberg 2003; Hall 1981) have been described, and the phenotype ranges from isolated triphalangeal thumb to bilateral aplasia of the tibia, sometimes with fibular duplication [19]. OMIM advises against the name «Werner syndrome» because of confusion with the progeroid syndrome of the same name (MIM 277700) and uses «tibia, hypoplasia or aplasia of, with polydactyly» (THYP) [19]. Orphanet records 94 cases of Werner and 14 of Laurin-Sandrow [94]. A 2022 review (Buzea and Boulanger), summarised by OMIM, brought together 27 cases of Laurin-Sandrow in 17 English-language articles; the most frequent nasal anomalies were a flat nasal bridge and a bulbous nasal tip, with a groove or cleft of the columella in several reports, and the typical limb findings were complex polysyndactyly, mitten or mirror hands, absent thumb, mirror feet and clubfoot [105]. Ten of these patients underwent surgery, mainly on the nose, to ease breathing, or on the hands, for functional and cosmetic reasons [105]. There are segmental forms, with mirror hand and ulnar duplication in a single limb and without nasal anomalies, attributed to somatic mosaicism (Innis and Hedera 2004) [105]. The Orphanet and review counts differ in criteria and date and do not measure population frequency.

Mesomelic dysplasia, Kozlowski-Reardon type

It combines micrognathia with cleft palate, a crumpled ear, mesomelic shortening predominantly of the forearm, bowing of the forearm and lower leg with a skin dimple at the apex and bony spurs, femoral bowing and camptodactyly [98]. There are only two reports (1993), of siblings born to a consanguineous couple, in one of which the younger sister died in the perinatal period; Orphanet reports a fatal course due to cardiorespiratory arrest and no new description since 1993 [34, 98]. In the OMIM entry («mesomelic limb shortening and bowing», without a molecular basis), the siblings of Reardon and colleagues were children of Pakistani second cousins; the sister died a few hours after birth from cardiorespiratory arrest, and the brother was alive at 4 years; the radiographs were incompatible with campomelic dysplasia and different from those of Langer dysplasia [40].

Nievergelt and Savarirayan dysplasias

At birth there is marked shortening and deformity of the legs with a bony prominence and skin dimple, atypical clubfoot with an equinus component, mild to moderate shortening of the forearms and restricted elbow mobility; hip dislocation, patellar dislocation, oligosyndactyly or polydactyly («Nievergelt-like» cases), psychomotor delay and seizures may be associated [88]. The tibiae are short, triangular or rhomboid, and there is radioulnar synostosis; in the Savarirayan phenotype the fibulae may be unossified in the neonatal period and later appear as broad triangular or rudimentary bones [88]. In Nievergelt's original family, the affected men measured 147–156 cm; Alice Vance measured 110 cm and walked on her femoral condyles [88]. Orphanet defines Savarirayan dysplasia on the basis of two sporadic cases with moderate upper-limb mesomelia, proximal widening of the ulna, pelvic anomalies and marked bilateral glenoid hypoplasia; the 5th case, from 2026, was a 9-year-old girl with severe mesomelic shortening of the lower limbs [34, 64]. Whether the two entities are allelic remains under debate [88]. OMIM keeps Nievergelt syndrome without a known molecular basis: the man described by Nievergelt in 1944 transmitted it to three children by three different women; Tüysüz and colleagues (2002) described an infant with agenesis of the cerebellar vermis and cataracts, and Nakamura and colleagues (2007) a father and son with features overlapping those of the Savarirayan form (severely deformed tibia, rudimentary fibula) and the Nievergelt form (broad trapezoidal radius in the father) [106]. The rhomboid shape of the tibia and fibula distinguishes it from Grebe dysplasia and Langer dysplasia, and some cases published as Nievergelt were other mesomelic dysplasias [106]. In the Savarirayan dysplasia entry, OMIM adds the patients of Yasui (2000), with partial deficiency of the tibia and fibula, cartilaginous remnants visible on ultrasound and MRI, teratological dislocation of the hips and subluxation of the radial head, and a patient with a larger deletion including ID4 who had intellectual disability without skeletal anomalies [107].

KINSSHIP syndrome (AFF3)

In the 18 patients described, the syndrome combines horseshoe kidney, mesomelic dysplasia similar to Nievergelt or Savarirayan dysplasia, seizures or epileptic encephalopathy, hypertrichosis, intellectual disability and pulmonary involvement, with partial overlap with CHOPS syndrome (AFF4) [101]. In 2026, a Mexican patient with congenital distal contractures (arthrogryposis) and neurodevelopmental delay was described, and the authors propose including AFF3 in the differential diagnosis of arthrogryposis with central nervous system involvement [150]. Despite the name, the Nosology considers it quite different from the Nievergelt and Savarirayan dysplasias [1].

The phenotype was delineated in stages. Steichen-Gersdorf and colleagues (2008) described a female infant with bilateral fibular agenesis, short triangular tibiae, slightly short forearms with subluxation of the radial heads, equinovalgus feet, cortical and subcortical atrophy with ventricular dilatation, apnoeas and myoclonus, horseshoe kidney, intestinal malrotation and ambiguous genitalia, who died at 4 months; she had a de novo deletion at 2q11.2, which Kraft and colleagues (2015) showed to remove exons 4 to 12 of AFF3 (LAF4) in frame [30]. Shimizu and colleagues (2019) described a Japanese girl with the de novo missense variant p.Ala258Thr (historical numbering, = NM_001386135.1:c.697G>A p.(Ala233Thr)) in the ALF domain, hypoplastic kidneys, syndactyly of the 4th and 5th toes of the left foot and 11 pairs of ribs; at 2.5 years she measured 73.1 cm (−4.9 SD) and weighed 7.4 kg (−3.5 SD), without head control or single words [30]. In the Voisin series (2021), 15 of the 16 patients had de novo missense variants in the 9-amino-acid degron of the ALF domain, which mediates binding to the SIAH ubiquitin ligases, 12 of them at codon Ala258, and one had a de novo 469 kb deletion removing exons 3 to 12 [30]. Of the 18 patients then known, all had severe developmental and epileptic encephalopathy, with mesomelic dysplasia in 12/18, faltering growth in 14/18, microcephaly in 9/18, cerebral atrophy or ventriculomegaly in 13/15, fibular hypoplasia in 12/16, horseshoe or hypoplastic kidney in 13/17, tone abnormalities in 12/16, gastro-oesophageal reflux in 6/16, hypertrichosis in 12/15 and dental and gingival changes in 12/15 [30]. In the mouse, the equivalent intragenic deletion reproduces the mesomelia, triangular tibia and fibular hypoplasia, and the p.Ala258Thr allele introduced by gene editing was not transmitted to offspring, which suggests lethality; for the deletion, Kraft and colleagues proposed a dominant-negative effect of the truncated protein (preclinical evidence) [30].

Mesomelic dysplasia with acral synostoses (Verloes-David-Pfeiffer)

It combines an expressionless face, downslanting palpebral fissures, ptosis, hypoplasia of the soft palate with absent uvula and hypernasal voice, short stature of −3 to −5 SD, mesomelic shortening with elbow dislocation, postaxial brachydactyly, genu valgum, restricted ankle movement and umbilical anomalies (hernia, excess skin, short cord), sometimes with heart disease and urinary anomalies [91]. There is postaxial carpometacarpal and intertarsal fusion; upper-limb function is preserved through compensation, but the genu valgum is progressive and the ankle deformity impairs walking [91]. In the follow-up of three of the five published patients, Isidor and colleagues (2009) described a slowly progressive course at least into adulthood, with severe limb deformities despite repeated corrective surgery; OMIM also records hydronephrosis due to ureterovesical junction stenosis, coarctation of the aorta, hypoplastic left ventricle in one case, and normal intellectual development in the boy of Leroy (2003) [108].

Other rare mesomelic dysplasias

Reinhardt-Pfeiffer dysplasia is a mild, dominant ulnofibular dysplasia without dwarfism [2, 97]. Upper-limb mesomelic dysplasia, Fryns type, has 4 cases recorded in Orphanet [2]. OMIM adds the available clinical detail. Reinhardt-Pfeiffer dysplasia was described in a family with 14 affected members in a regular AD pattern, with shortening and characteristic dysplasia of the ulna and fibula and changes of the radius, tibia and neighbouring areas of the skeleton; OMIM allows that it may be allelic to dyschondrosteosis, as the Nosology came to classify it [41]. The Fryns form (1988) was described in a father and daughter with ulnar hypoplasia and severe radial bowing, without other skeletal changes and with normal tibiae and fibulae; the father measured 179 cm, with an arm span of 144 cm, and the daughter was on the 5th centile for length at 6 months; Mégarbané and Ghanem (2005) described a Lebanese father and son with normal stature, bowed and thickened radii, subluxation of the radial heads and limited elbow movement, milder in the father; vertical transmission in both families suggests AD inheritance with variable expressivity [42].

MAB21L2-related microphthalmia or coloboma with skeletal dysplasia syndrome (4q31.3; OMIM 615877) is mainly ocular. Rainger and colleagues (2014) described 8 patients from 5 families with microphthalmia and coloboma or clinical anophthalmia, with or without rhizomelic skeletal dysplasia: in a family with 9 affected members in three generations, only the proband, a 13-year-old boy, had skeletal involvement (bowed legs since infancy, knee and hip contractures, hypoplastic femoral condyles and pes cavus); a 10-year-old Norwegian girl and a 24-year-old man, both with clinical anophthalmia, had severe rhizomelia, contractures of all large joints and moderate intellectual disability [31]. The monoallelic variants are concentrated at codons Glu49 and Arg51, a restricted repertoire that the authors interpreted as a sign of a mechanism other than simple loss of function; two siblings born to first cousins, homozygous for NM_006439.5:c.740G>A p.(Arg247Gln), had the mildest phenotype, with bilateral coloboma and unilateral microphthalmia only in the younger, who was also the only one with mild shortening of the long bones [31]. Deml and colleagues (2015) described a three-generation family with coloboma, microcornea, cataracts and rhizomelic shortening of all four limbs due to NM_006439.5:c.151C>G p.(Arg51Gly), in which the proband's unaffected mother appeared to have low-level mosaicism, a finding relevant to recurrence risk [31].

Acromesomelic dysplasia, Maroteaux type (NPR2)

Birth weight may be normal, and radiographs are often normal in the neonatal period; the linear growth deficit becomes evident in the first year and the changes are diagnostic by 2 years [52, 53]. The head is disproportionately large, with relative frontal prominence, midface hypoplasia and a small nose; the upper limbs are more affected than the lower, the forearms are bowed and shorter than the upper arms, elbow extension is limited, with subluxation or dislocation of the radial head, and the fingers are short, with short non-dysplastic nails and redundant skin [52, 53]. There is low thoracic kyphosis, lumbar hyperlordosis, prominent buttocks and joint laxity, especially of the fingers [52, 53]. On radiographs, the tubular bones of the hand shorten progressively from 6 months, with cone-shaped epiphyses and early epiphyseal fusion; the hallux is less short; the humerus, radius and ulna shorten from the first year, with a disproportionately shorter radius and ulna; the vertebral bodies, oval in infancy, develop posterior hypoplasia and anterior central protrusion by 24 months; the basilar portion of the ilium is hypoplastic [52]. Intelligence is normal, motor milestones may be delayed and sexual development may be delayed; adults develop degenerative changes of the spine with lumbar disc and foraminal narrowing [52]. Occasionally there is corneal opacification, hydrocephalus or mild intellectual disability [53].

Adult height varies between sources: 94–123 cm in the Bone Dysplasias atlas, 96.5–124.5 cm in nine adults in Smith, below 120 cm in the Orphanet definition and about 120 cm on average according to Arya and colleagues [34, 52, 53, 151]. In a Turkish series of 26 patients from 22 families with a clinical diagnosis of AMDM (a tertiary centre in Ankara), 23 patients from 20 families had biallelic NPR2 variants (13 female and 10 male); parental consanguinity was present in 18, almost always between first cousins (16), and the mean age was 34.5 months at clinical diagnosis (6 to 123 months) and 126.4 months at molecular diagnosis (12 to 272 months), with a mean age of 149.1 months (20 to 272) at the last assessment [128]. At birth, mean weight was 2,860 ± 439 g (2,000 to 3,600 g) and mean length 46.3 ± 2.9 cm (42 to 50 cm); of the 11 patients with recorded birth length, 8 were between −2 and +2 SD and 2 below −2 SD [128]. At the first visit, at a mean of 34 ± 34.9 months, height was −4.52 ± 1.90 SD (−7.34 to −1.16), head circumference −0.37 ± 1.63 SD (−3.69 to +4.48) and body mass index +0.57 ± 1.48 SD, reflecting severe short stature with normal head circumference and proportionally preserved weight [128]. There were prenatal findings in 11 of the 23, preterm birth in 3 and neonatal respiratory distress in 6; many newborns have a length within 2 SD, but a term boy measured 43 cm (−2.67 SD), and a girl born at 32 weeks measuring 42 cm (0.28 SD) measured 57 cm (−4.08 SD) at 8 months; adults typically fall below −5 SD, and the oldest patient in the series, at 99 cm (−6.6 SD) at the first visit aged 10 years and 3 months, was at −8.1 SD at 22 years and 7 months [128]. On radiographs, the most common findings were osteopenia (20/21), shortening of the long tubular bones (22/23), radial bowing (20/23) and radial head dislocation (19/23); the vertebral bodies, oval in infancy, develop relative posterior protrusion by 2 years, and anterior wedging of one or more bodies at the thoracolumbar junction produces kyphosis, with increased lordosis; one 17-year-old patient had Madelung deformity, and long, broad halluces with a sandal gap and sometimes hallux valgus were common [128]. Only the skeleton was consistently affected; the extraskeletal anomalies found — motor delay (11/23), global developmental delay or intellectual disability (5/23), spinal canal stenosis (2/23), atlantoaxial dislocation (1/23), nephrolithiasis (2/23), renal cyst (2/23), pelvic ectasia or dilatation (2/23), mitral regurgitation (2/23), mild obstructive sleep apnoea (2/23), sensorineural deafness (1/23) or mild bilateral conductive deafness (1/23), hypospadias with hydrocele, afebrile seizure, patent foramen ovale, hypomyelination or ventriculomegaly on magnetic resonance imaging and oligodontia, each in one patient — were probably attributed to other variants, given the high consanguinity, although no second diagnosis was identified [128]. Spinal canal stenosis caused spastic tetraparesis in a patient homozygous for p.(Arg388Ter) and upper-limb weakness in another, compound heterozygous for p.(Arg141His) and p.(Gln715Ter); two preterm siblings homozygous for p.(Ile558Thr) were discordant for development, normal in one and severely delayed in the other, despite normal metabolic studies, karyotype, microarray and fragile X testing; in a patient with microcephaly and global delay, the mother had untreated phenylketonuria during pregnancy, which may explain these findings [128]. Between patients with missense variants (n=11) and with loss-of-function variants (n=6) there was no genotype–phenotype correlation [128]. Other series confirm intra- and interfamilial variability and the extreme shortening of the upper limbs [122, 152]. Neuraxial complications have been described: a 10-year-old boy with symptomatic thoracic kyphoscoliosis, mild hydrocephalus, Chiari type 1 malformation and cervical syringomyelia, and an adult with obstructive sleep apnoea and hereditary myopathy [153, 154]. The AMDM proband studied by Olney and colleagues had low insulin-like growth factor 1 (IGF-1), signs of GH resistance and markedly raised plasma CNP and N-terminal pro-CNP (NT-proCNP) [132].

PRKG2-related acromesomelic dysplasia

The form described in two girls combines severe short stature due to acromesomelic shortening, brachydactyly, mild to moderate platyspondyly and progressive metaphyseal changes [62]. In two siblings followed annually from 5 to 20 years of age, short stature worsened with age, the platyspondyly and anterior vertebral beaking became less evident, and the older sibling was clinically rhizomelic, with limited elbow movement and cubitus varus [14, 155]. Akgun-Dogan and colleagues proposed recognisable facial features [133]. Intelligence and other systems are not affected [14]. The two girls of Díaz-González (2022) were a 12-year-old Moroccan girl without facial dysmorphism, with mesomelic shortening, short, thick fingers, early fusion of the growth cartilages with advanced bone age and femoral and humeral lengthening procedures, who also had congenital complete atrioventricular block, with a pacemaker since the age of 1 year, and an 11-year-old Indian girl with a triangular face, synophrys, generalised hirsutism, hypertelorism, moderate platyspondyly with anterior beaking and normal bone age; PRKG2 screening in 298 patients with short stature found no other variants [47]. Atrioventricular block is a unique finding in the sources consulted, with no established causal relationship with PRKG2. Pagnamenta and colleagues (2022) added a 9-year-old Iranian girl with generalised brachydactyly, mild mesomelic shortening and synophrys, and described in three Pakistani siblings, children of double first cousins, homozygous for NM_006259.3:c.2282dup p.(Asp761GlufsTer34), a spondylometaphyseal dysplasia phenotype (OMIM 619638, provisional relationship): stature between −2.5 and −4.9 SD without limb disproportion, mild platyspondyly with small anterior projections, long, slender femoral necks and mild metaphyseal changes, without brachydactyly at 11 years; one of the siblings also had osteogenesis imperfecta type I due to a de novo COL1A1 variant [22, 47, 48, 110]. The protein produced by this allele, which extends the C-terminus, had a level about 80% lower than normal and failed to repress the FGF2-induced MAPK pathway [22].

The Grebe, Hunter-Thompson and Du Pan spectrum (GDF5 and BMPR1B)

The spectrum presents at birth, with variable shortening of the digits; in severe cases the digits are globular appendages without flexion or extension, there is no pronation or supination, knee flexion is limited and there are dislocations, absent toes and foot deformities; severity is greatest in Grebe, intermediate in Hunter-Thompson and mild in Du Pan [82]. The proximal and middle phalanges are absent or dysplastic, the metacarpals short, the carpus fused, the femora short and the tibiae and fibulae even shorter, with fibular aplasia in some; the axial skeleton is normal, which distinguishes the spectrum from AMDM [63, 82]. Intelligence is normal, patients are ambulant and, in the original series, were independent, handling objects between their thumbs [82]. The Hunter-Thompson form has an adult height of about 120 cm, more affected lower limbs and large joint dislocations; Du Pan has near-normal stature with absent fibula [34, 82]. The Hunter-Thompson family described by Langer and colleagues (1989) and studied by Thomas and colleagues (1996) was from the Chocó district of Colombia; it had dislocations of the ankles, hips, elbows and knees, in variable number, and ball-shaped, non-functional 3rd to 5th toes [38]. In the Du Pan form, described by Du Pan in 1924 in a boy with complex brachydactyly and bilateral absence of the fibula, there is also Volkmann deformity (tibiotalar dislocation) and, in some patients, hypoplasia of the distal ulna with bowing of the radius; psychomotor development is normal [32]. Clarke and colleagues (1994) described bilateral central corneal opacities in a child with acromesomelic dysplasia, treated with keratoplasty [38]. Heterozygotes may have brachydactyly C, with marked intrafamilial variability and obligate carriers with normal hands [82, 156]. The BMPR1B form in the Demirhan family combined fibular aplasia, severe brachydactyly, ulnar deviation of the hands, carpal and tarsal fusions and uterine hypoplasia with ovarian dysfunction and hypergonadotrophic hypogonadism [85]. In OMIM, the BMPR1B form is «acromesomelic dysplasia 3» (Demirhan type); the genital anomalies (absent ovaries, hypoplastic uterus, primary amenorrhoea) occur only in some patients: the three patients of Graul-Neumann and the 38-year-old Moroccan woman of Stange (2015), homozygous for p.(Arg31Cys), with a mild Du Pan form, had a normal uterus and ovaries and normal gonadotrophins and oestradiol [39]. In 2024, a 2-year-old boy with a homozygous BMPR1B variant also had postaxial polydactyly, a finding already known in the GDF5 forms [157].

Acromesomelic dysplasia, Osebold-Remondini type

It is known from a single family with brachymesophalangy, mesomelia and carpal and tarsal anomalies (7 cases in Orphanet) [1, 3]. In the family of Osebold and colleagues (1985), the seven affected members spanned three generations, with male-to-male transmission, which supports AD inheritance; the middle phalanges of the hands and feet were hypoplastic or absent, the distal phalanges of the index fingers deviated radially, the hamate and capitate were fused and, in the younger members, the bipartite calcanei showed late coalescence; stature was slightly short and intelligence normal [109]. Opitz and Gilbert described the autopsy of a female stillborn infant with the syndrome, and Sheffield and colleagues pointed out similarities with the mild form of chondrodysplasia punctata, which Osebold disputed in 1987 [109].

Natural history and treated disease

The frequency and stature data above describe natural history, without disease-modifying treatment. The documented exceptions are isolated cases treated with GH (RS with GH deficiency; two siblings with AMDM treated with high-dose GH), presented in section 7 [141, 142, 151].

4. Clinical Recognition and Warning Signs

When to suspect, by age

In the prenatal period, ultrasound may show short limbs at 13 weeks in omodysplasia, short long bones (−2 SD), macrocephaly and the typical face at about 20 weeks in dominant RS, and increased nuchal translucency, short humerus and femur, short forearms, frontal bossing, hypertelorism, reduced thoracic circumference and thoracic hemivertebrae in ROR2-related RS [5–7]. In a fetus with ROR2-related RS, ultrasound at 24 weeks and 3 days showed macrocephaly, brachycephaly, flat face, prominent forehead, low thoracic hemivertebrae, digital anomalies and micropenis [115]. In Langer dysplasia the short limbs are visible in the second trimester, and in the Grebe spectrum the deformities were recognised at 21 weeks in a fetus studied because of parental consanguinity [82, 97]. In AMDM, ultrasound may show short limbs (26 weeks in the case of Dong and colleagues), but length may be normal at birth [121].

In the newborn and infant, RS should be considered in the presence of the triad of fetal face (prominent forehead, hypertelorism, short nose with anteverted nares, midface hypoplasia, triangular mouth, gingival hyperplasia), short limbs with mesomelia or brachydactyly and genital hypoplasia, which affects 93–100% of boys [11, 54, 143]. A very small, buried penis with cryptorchidism requires confirmation of chromosomal sex and, if there are electrolyte abnormalities, distinction of RS from congenital adrenal hyperplasia [54, 146]. Rib fusions and hemivertebrae suggest the recessive ROR2 form; macrocephaly, cranial osteosclerosis and normal stature suggest DVL1; complex heart disease suggests DVL3 [11, 143]. In hypertelorism, the Oxford Desk Reference gives as clues to RS stature and proportions, gingival hypertrophy, genital anomalies (micropenis, versus hypospadias in Opitz syndrome) and the skeletal survey [158].

In the young child, AMDM should be considered in the presence of progressive disproportionate short stature from the second year, with short hands and feet, redundant skin of the fingers, a large head and normal intelligence [53, 121, 128]. The dysplasia table of the Oxford Desk Reference places the acromesomelic dysplasias in the group «short limbs, normal trunk», alongside achondroplasia, hypochondroplasia and pseudoachondroplasia [59, 159]. In the older child and adolescent, Madelung deformity with mesomelic short stature points to dyschondrosteosis [96].

At any age, recurrence of an undiagnosed condition with parental consanguinity suggests recessive inheritance [59]. Limb malformations with tibial hypoplasia, mirror-image preaxial polysyndactyly and triphalangeal thumb suggest Werner dysplasia; triangular tibiae with equinus foot suggest Nievergelt or Savarirayan; very short forearms with tarsal synostoses and extreme equinus suggest Kantaputra [88, 90, 92].

Warning and emergency signs

Warning signs in RS are congenital heart disease (especially right ventricular outflow tract obstruction, the main cause of early death), kyphoscoliosis with chest deformity and respiratory infections, hydronephrosis and genital ambiguity in the newborn [5, 137, 139]. In the DVL1 form, choanal atresia, deafness and cranial nerve palsies should be sought [145]. In AMDM, symptoms of neuraxial compression (Chiari type 1, syringomyelia), symptomatic kyphoscoliosis and obstructive sleep apnoea warrant urgent assessment, especially before anaesthesia [153, 154]. In Kozlowski-Reardon dysplasia, a fatal course due to cardiorespiratory arrest has been reported [34].

Newborn screening

No entity in the class has newborn screening; the sources consulted describe no population screening programmes.

5. Diagnosis: Criteria, Tests and Algorithms

Criteria

There are no validated formal clinical criteria. GeneReviews establishes the diagnosis of ROR2-related RS by suggestive findings and biallelic ROR2 variants, and that of dominant RS by suggestive findings or a heterozygous pathogenic or likely pathogenic variant in DVL1, DVL3 or WNT5A [5, 7]. A variant of uncertain significance (VUS) in these genes neither establishes nor excludes the diagnosis [7]. Lima and colleagues consider mesomelia, brachydactyly, rib fusions and hemivertebrae the most important diagnostic findings of the recessive form, which makes complete radiological documentation essential [54].

Imaging

The radiological skeletal survey is the central investigation and should include the skull, spine, chest, pelvis, limbs and hands [7, 113]. The discriminating patterns are the metacarpophalangeal profile and the cleft distal phalanx of the thumb in RS, the ribs and vertebrae in the recessive form, cranial osteosclerosis in the DVL1 form, the humerus–femur relationship and the radial head in omodysplasia, the shape of the tibiae and fibulae in the Nievergelt, Savarirayan, Langer and Kantaputra dysplasias, cone-shaped epiphyses and posterior vertebral hypoplasia in AMDM, platyspondyly and metaphyses in AMDP and the normal axial skeleton in the Grebe spectrum [6, 51, 52, 62, 82, 88]. In AMDM, neonatal radiographs may be normal and should be repeated in the second year [53]. In DVL1-related RS, DEXA and HR-pQCT show increased cranial and total-body BMD with characteristic trabecular microarchitecture [113, 145]. In the initial phase, echocardiography, renal ultrasound and audiometry should also be performed [5, 113].

Molecular tests and yield

In ROR2-related RS, sequencing detects more than 95% of variants; if only one variant or none is found, targeted deletion and duplication analysis follows, with an unknown yield but with exonic deletions reported [5]. Lima and colleagues used multiplex ligation-dependent probe amplification (MLPA, kit P179) and array comparative genomic hybridisation (aCGH) when there was only one variant, none or apparent homozygosity without consanguinity, because a deletion on the other allele produces false homozygosity on next-generation sequencing (NGS) [54]. In dominant RS, DVL1 and DVL3 are sequenced first, with WNT5A simultaneously or reflexively; all DVL1 and DVL3 variants lie in exons 14 and 15, which the panel must cover well; sequencing detects more than 99%, and deletion and duplication analysis is of little use, because the mechanism is gain of function and no large intragenic rearrangements have been reported [7]. The recommended panel includes DVL1, DVL3, WNT5A, FZD2, ROR2, NXN and the genes of the differential diagnosis; Zhang and colleagues propose exome sequencing as first line and add FGD1 to the panels [7, 11].

In the Baylor College of Medicine in-house database (82 patients with a clinical diagnosis of RS, October 2021), 75.6% had a variant in a known RS gene, 14.6% in a gene of the differential diagnosis and 9.8% remained unresolved or with candidate genes; in the 2018 cohort (21 patients) the proportions were 61.5%, 24% and 14.5% [11]. In the original article on that cohort, DVL1 (6), DVL3 (1), WNT5A (2), FZD2 (3) and NXN (1) explained 13 of the 21 probands, 5 had alternative diagnoses, 2 had variants in candidate genes (RAC3 and GPC4) and 1 remained unexplained; the exome was analysed with two variant-calling pipelines in parallel, because the programs diverge mainly for indels, and with detection of CNVs and regions of absence of heterozygosity from the exome data themselves [12]. The strategy used by these authors combined Sanger sequencing of the penultimate and last exons of DVL1 and DVL3 and of the whole of FZD2 with exome or genome sequencing and CNV detection [11].

In the other entities, the discriminating test depends on the mechanism. The dysplasias due to microduplication or microdeletion (Kantaputra, Savarirayan, Verloes-David-Pfeiffer) require chromosomal microarray, rather than sequencing of the genes in the region, because no HOXD point variant has been identified in Kantaputra [88, 90, 91]. When the microarray is normal in a Savarirayan phenotype, genome sequencing may reveal a balanced inversion at 6p22.3 [64]. Werner dysplasia requires analysis of the ZRS, which is not in the coding region and is missed by many panels and exomes, and Laurin-Sandrow syndrome requires testing for the duplication [92]. In AMDM, NPR2 identifies the cause in most families (20 of 22 in a Turkish series), but synonymous or intronic variants with an effect on splicing may require RNA analysis [124, 128]. In that series, Sanger sequencing of NPR2 in 23 patients from 19 families found biallelic variants in 20 patients from 17 families, and exome sequencing, used as first line in three patients, also revealed them; in three patients from two consanguineous families, with a typical phenotype, neither Sanger nor exome sequencing (with analysis of 251 skeletal dysplasia genes) found the cause, which suggests locus heterogeneity, and the two intronic variants had no RNA studies [128]. In the Oxford Desk Reference, the genes in the acromesomelic row of the table of dysplasias with short limbs and normal trunk are GDF5, NPR2 and BMPR1B, to which PRKG2 is now added [1, 159].

Biomarkers

There is no biochemical test for RS [160]. In AMDM, serum NT-proCNP is significantly increased (three Korean patients) and plasma CNP and NT-proCNP were markedly raised in Olney's proband and normal in carriers; it is a potential biomarker of CNP resistance, not yet clinically standardised [132, 161]. There is no clinical assay of cGKII activity [14]. In the differential diagnosis of Kozlowski-Reardon dysplasia, low alkaline phosphatase identifies hypophosphatasia [98].

Limitations of testing

A negative result does not exclude the diagnosis. Exome sequencing may miss exonic deletions of ROR2 and NXN, the ZRS and balanced inversions; false homozygosity due to a deletion on the other allele is a described pitfall in ROR2-related RS [11, 54, 64]. In the dominant forms, the parent in whom the variant arose may have somatic mosaicism and be mildly affected [7]. For DVL1 and DVL3 variants, early truncation subject to NMD or whole-gene deletion does not fit the mechanism and should not be reported as a cause of RS [113]. For synonymous NPR2 variants, interpretation depends on RNA studies [124].

Report content

The report should state the gene, the transcript with version (for DVL1, specify NM_004421.3 or the MANE NM_001330311.2, whose numbering differs), the coding and protein HGVS (Human Genome Variation Society) nomenclature, the zygosity (and, in the recessive forms, whether the variants are in trans), the ACMG/AMP class and, for DVL1 and DVL3, the mechanism (−1 frameshift in exons 14–15 escaping NMD) [110, 113]. A VUS should be investigated by family segregation, especially in the dominant de novo forms [7].

Diagnostic algorithm

In the presence of short limbs, the first step is to measure and classify the predominant segment and obtain a skeletal survey [59]. If there is a fetal face and genital hypoplasia, the phenotype is RS: with rib fusions and hemivertebrae, request ROR2 with CNV analysis or exome with CNV (including NXN); without them, request a panel with good coverage of exons 14–15 of DVL1 and DVL3, WNT5A and FZD2, or an exome; if negative, exome or genome with CNV and reassessment of the differentials, including FGD1 [5, 7, 11]. If the shortening is acromesomelic, with altered vertebrae and normal radiographs at birth, request NPR2 and PRKG2; with a normal axial skeleton and globular digits, GDF5 and BMPR1B [14, 52, 82]. If the pattern is mesomelic without the RS face, look for Madelung deformity and tibiofibular changes and request PAR1 and SHOX MLPA, microarray for HOXD, 6p22.3 and 8q13, and ZRS analysis if there is preaxial polydactyly [90, 92, 96].

Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible in the recessive and dominant forms; in the dominant forms, testing does not predict severity [5, 7]. High-resolution ultrasound can detect skeletal and cardiac anomalies in high-risk pregnancies [5]. Without a prior diagnosis, trio fetal exome sequencing on amniocytes identified ROR2-related RS in the case of Yang and colleagues; autopsy confirmed mesomelic shortening, hemivertebra, S3–S4 fusion, fused rib heads and a short buried penis [115].

6. Differential Diagnosis

Comparative table of differentials outside the class

Differential diagnosis within the class

Main differentials

Aarskog-Scott syndrome is the closest differential of RS. In a series of 22 patients with a clinical diagnosis of RS, 6 (27%) had variants in other genes, and FGD1 was the most frequent (4 patients, 3 from the same family) and the most phenotypically similar according to the Human Phenotype Ontology (HPO); the authors therefore recommend including FGD1 in RS panels [11]. Smith notes that the face is much more characteristic in RS than in Aarskog syndrome [67]. In the 2018 cohort, 5 of the 21 probands had alternative diagnoses: two boys hemizygous for FGD1 frameshift variants (NM_004463.3:c.892dup p.(Cys298LeufsTer5) and NM_004463.3:c.527dup p.(Leu177ThrfsTer40)), a patient with the pathogenic PTPN11 variant NM_002834.5:c.836A>G p.(Tyr279Cys) (Noonan syndrome), a child of consanguineous parents with a dual diagnosis, homozygous for NM_001017995.3:c.969del p.(Arg324GlyfsTer19) in SH3PXD2B (Frank-ter Haar syndrome) and for the missense variant NM_001567.4:c.1636G>A p.(Val546Ile) in INPPL1 (opsismodysplasia), in distinct segments of absence of heterozygosity, and a boy with a probable unbalanced translocation 46,XY,der(X)t(X;6)(p22.31;q25.3), with a deletion of about 8.3 Mb of Xp, including SHOX, and a duplication of about 13 Mb of 6q, detected from the exome and confirmed by aCGH [11, 12, 110]. The dual diagnosis (1 in 21, 4.8%) and the large CNVs show that an exome with CNV analysis resolves some Robinow-like phenotypes that no targeted panel would explain [12].

Isolated brachydactyly is the second major differential axis. Hypoplastic distal phalanges occur in numerous syndromes (acrodysostosis, Christian, Coffin-Siris, Hajdu-Cheney and Keutel syndromes, mandibuloacral dysplasia, Albright osteodystrophy, Zimmermann-Laband syndrome), in the acro-osteolyses and in acquired causes such as frostbite, electrical injury or maternal phenytoin exposure [99]. The Oxford Desk Reference lists, among the dysplasias to consider in brachydactyly, achondroplasia, acrodysostosis, the acromesomelic dysplasias, geleophysic dysplasia, hypochondroplasia, pseudoachondroplasia, RS and Ter Haar syndrome [60].

Short stature due to a heterozygous NPR2 variant may mimic Léri-Weill dyschondrosteosis, with disproportionate short stature but without Madelung deformity [148]. Isolated or partial cases of Werner dysplasia are distinguished from split-hand/foot malformation with long-bone deficiency (SHFLD) and from the syndrome of absence or hypoplasia of the tibia with polydactyly and retrocerebellar arachnoid cyst (MIM 601027) by the morphology of the digits [92].

7. Treatments and Risk Management Strategies

General principles and guidelines

No entity in the class has an approved disease-modifying treatment, nor a guideline from a scientific society or from ERN BOND [8, 58]. The ERN BOND guideline list (page updated on 8 May 2026) brings together documents on osteogenesis imperfecta, X-linked hypophosphataemia, fibrodysplasia ossificans progressiva, achondroplasia and vosoritide, and announces guides for the ultra-rare skeletal dysplasias without a timetable; the only cross-cutting documents applicable to the class are the lifelong care roadmap for skeletal dysplasias by Nijhuis and colleagues (Eur J Med Genet, 2023) and the consensus recommendation of the European Calcified Tissue Society (ECTS) rare bone disease group on transition to adult care by Grasemann and colleagues (Calcif Tissue Int, 2025) [58]. Management relies on the case-based GeneReviews recommendations and on case series and reports [5, 7]. The Robinow Syndrome Foundation publishes a care guide for families («Robinow Syndrome Complete Care Guide», 12 pages, July 2025 version), compiled from GeneReviews, the National Organization for Rare Disorders (NORD), the Cleveland Clinic, a case review and non-scientific sources (including a parents' forum), with no consensus method described; it is a patient association document and not a guideline [166]. Its recommendations coincide with those of GeneReviews for the initial assessment (echocardiography, renal ultrasound, hearing, imaging of the spine and rib cage, endocrinological assessment of the micropenis) and add practical intervals: dental assessment every 6–12 months from early childhood, orthodontic assessment by 7 years and orthodontics at around 8–12 years; developmental assessments every 3 months in the first year and every 6–12 months in early childhood; influenza and pneumococcal vaccination in children with chest deformity or scoliosis; orchidopexy at around 1 year; repair of cleft lip at 3–6 months and of cleft palate before 1 year; a thoracolumbosacral orthosis for moderate scoliosis during growth and surgery (growing rods or arthrodesis) for severe or progressive curves; somatropin only by decision of paediatric endocrinology; and, in a pregnant woman with RS, consideration of planned caesarean section because of short stature and a narrow pelvis [166]. These intervals are guidance from a patient association, with no study supporting them in RS. There is therefore no divergence between societies to report; the existing divergences are between series and author opinions and are indicated in each subsection.

Initial assessment after a diagnosis of Robinow syndrome

GeneReviews recommends, after diagnosis, assessment of cleft lip or palate and the need for surgery by a craniofacial team; orthodontics (malaligned teeth, persistent deciduous dentition); the spine and rib cage, clinically and radiologically, because of the risk of postural and respiratory complications; radioulnar synostosis, forearm shortening and brachydactyly; hearing; the heart by echocardiography; the kidney by ultrasound; in girls, the pelvis by ultrasound (Müllerian anomalies); in boys, penile insertion, penoscrotal position and cryptorchidism in urology, and micropenis in endocrinology; development, with neuropsychological testing if there is delay; and a genetics clinic appointment [5, 7]. Atalay and colleagues and Webber and colleagues, on the basis of the case series with right ventricular outflow tract obstruction, recommend echocardiography in all patients [137, 138]. In the DVL1 form, cranial osteosclerosis warrants monitoring of hearing, choanal patency and the cranial nerves [145].

Treatment of the manifestations of Robinow syndrome

The corrective surgeries described are those for syndactyly, severe scoliosis due to hemivertebrae and rib anomalies, cleft lip or palate and abnormal penile insertion or penoscrotal transposition [5]. Wilcox and colleagues were unable to detach the crura, but improved the appearance by transposing the scrotum downwards [5]. Cryptorchidism is treated by orchidopexy, deafness and heart disease by standard treatment [7]. Orthodontics is usually necessary; in one adult, gingival hyperplasia, caries and multiple impacted teeth were treated with periodontal and restorative therapy, without surgery for the asymptomatic impacted teeth [5, 167]. In a 17-year-old man, correction of the midface deficiency with zygomatic augmentation, closed rhinoplasty, labial muscle release and lingual frenotomy, followed by orthodontics, improved the face with a positive psychological impact [168]. Lima and colleagues recommend psychological follow-up for male genital anomalies, and Schwartz and colleagues neuropsychological screening and educational and psychosocial support, especially in the dominant DVL1 form [54, 140].

Micropenis: androgens and gonadotrophins

GeneReviews reports that injection of hCG and testosterone improved penile length and testicular volume in three boys with severe micropenis (Soliman 1998) and advises that hormone therapy be monitored by paediatric endocrinology, without giving doses [5, 7]. There is no guideline or consensus on the dose, route or duration of testosterone in micropenis, and no source gives an RS-specific dose [169]. The reference dose adopted is that of the literature on congenital micropenis reviewed by Stancampiano and colleagues; the testosterone label dose appears only for comparison, because micropenis is not an approved indication and all use is off-label [169, 170].

The Charmandari series, cited by Stancampiano, includes a 1.9-year-old boy with RS treated with 2.5% DHT gel, 0.15–0.33 mg/kg/day for 2.5–4 months (2.5 mg/day below 3 years and 5.0 mg/day above), with a gain of 0.5 cm in stretched penile length according to the alignment of the extracted table [169]. The adverse effects of testosterone are rare and include temporary growth acceleration with transient advancement of bone age, with no effect on final stature reported; those of DHT include a transient fall in the ratio of high-density lipoprotein (HDL) cholesterol to total cholesterol, a rise in alkaline phosphatase and genital rash or itching [169]. Management consists of limiting the duration to the courses described and monitoring bone age, as the label requires [170]. The Portuguese SmPC of Testoviron Depot® adds that the oily solution is injected strictly intramuscularly and very slowly, with observation during and immediately after each injection, because of the rare risk of pulmonary oil microembolism (cough, dyspnoea, chest pain, syncope), and that the medicine contains castor oil and benzyl benzoate (342.0 mg per 1 mL ampoule) [171]. In Portugal, the marketed injectable enanthate presentation is 250 mg/mL, so the 25 mg micropenis dose corresponds to 0.1 mL of the solution; the sources consulted do not describe the method of measurement or dilution used in the paediatric series [169, 171].

There is a divergence between expert opinions on timing. GeneReviews and Smith allow early hormone treatment to enlarge the penis [5, 67]. Gerber and colleagues propose postponing lengthening interventions until puberty, to allow maximal natural phallic growth, and Lima and colleagues observed normal erection and significant penile growth after puberty in the men followed [54, 136]. Stancampiano and colleagues note that, with normal gonadal function, penile length increases at puberty with or without hormone treatment, and that the long-term efficacy of early therapy remains to be demonstrated [169]. In RS gonadal function is usually normal, although Soliman described low basal testosterone [5].

Growth hormone

Somatropin has no approved indication in RS or in the acromesomelic dysplasias; the FDA label of Humatrope® includes SHOX deficiency, idiopathic short stature and GH deficiency [172]. In RS, the data are cases with documented GH deficiency. Castells and colleagues described a significant increase in growth velocity in the index patient and in three patients from the National Cooperative Growth Study, with no doses in the abstract [141]. Kawai and colleagues, in a girl with partial deficiency, observed a marked improvement in growth velocity, but an even greater acceleration of bone maturation, without improvement of the height score for bone age after adding a gonadotrophin-releasing hormone analogue (gonadal suppression); they concluded that the indication for GH in RS requires careful consideration [142]. Goitia-Cárdenas and colleagues treated a boy with WNT5A-related RS and GH deficiency from 4 years of age with «0.7 U/kg/week», with stature rising from below the 1st centile to the 44th centile at 13 years, in use consistent with the GH deficiency indication [173].

In AMDM, Arya and colleagues treated two siblings with relatively high GH stimulation tests and IGF-1 of about −2 SD (relative GH resistance) with high-dose somatropin of 0.075 mg/kg/day, adjusted to keep IGF-1 close to +3 SD; growth velocity rose from 3.7 and 4.5 cm/year to 7.0 and 9.4 cm/year in the first year, and final stature, after 8.5 years, was 130.5 cm (−6.57 SD) and 134 cm (−4.58 SD), against a published mean of about 120 cm [151]. Dong and colleagues cite a Chinese series of three patients with AMDM treated from 6.5 ± 1.8 years, with a gain of 1.59 ± 0.10 SD in two years [121]. This is off-label use, in minimal series and without controls. Arya's dose is equivalent to 0.525 mg/kg/week, above the doses on the FDA label of Humatrope®: 0.18–0.3 mg/kg/week in GH deficiency, up to 0.37 mg/kg/week in idiopathic short stature and 0.35 mg/kg/week in SHOX deficiency [172]. In short stature due to heterozygous NPR2 variants, the Dutch registry described a median gain of 1.2 SD (prepubertal) and 0.5 SD (pubertal) after two years [174]. In Langer dysplasia, Smith found no benefit from GH, unlike in dyschondrosteosis [148].

The Humatrope® label contraindicates somatropin in paediatric patients with closed epiphyses, active neoplasia or acute critical illness, and warns of intracranial hypertension (fundoscopy before and during treatment; stop if there is papilloedema), glucose intolerance, hypothyroidism, slipped capital femoral epiphysis (assess limp or hip or knee pain), pancreatitis and progression of pre-existing scoliosis [172]. This last warning carries particular weight in recessive RS and in AMDM, in which scoliosis and kyphosis are frequent [52, 54].

C-type natriuretic peptide analogues

Vosoritide (Voxzogo®) and navepegritide (Yuviwel®) are agonists of NPR-B, the receptor encoded by NPR2, and require a functional receptor [13, 175]. In AMDM, biallelic loss of function of NPR2 leaves the receptor absent or non-functional, which is a pharmacological argument against efficacy; patients homozygous for NPR2 variants were expressly excluded from the phase 2 basket trial NCT04219007 [176, 177]. In AMDP, the cGKII defect lies downstream of NPR-B and cGMP, and vosoritide is not expected to be effective [14]. In RS and the GDF5–BMPR1B spectrum, the pathway is not the CNP pathway and there is neither a rationale nor trials [13]. A ClinicalTrials.gov search (API v2, 27 October 2026) found no trials for «acromesomelic» or «Robinow» [176].

For achondroplasia, the vosoritide dose on the FDA label is adjusted to actual weight, subcutaneously once daily (for example, 0.24 mg between 8 and 11 kg, 0.4 mg between 22 and 32 kg, 0.8 mg from 90 kg), with intake of 240–300 mL of fluid in the preceding hour because of the risk of hypotension; the most frequent adverse effects are injection-site reactions, rash, vomiting, arthralgia and a fall in blood pressure (hypotension in 13% versus 5% with placebo) [55]. These data serve only as a reference; the class has no indication.

Regulatory status

In Brazil, the professional package insert of Genotropin® published by the marketing authorisation holder (Pfizer Brasil, text approved by the Agência Nacional de Vigilância Sanitária, ANVISA, on 11/12/2025) indicates somatropin in GH deficiency, Turner syndrome, children born small for gestational age without catch-up by 4 years, Prader-Willi syndrome and idiopathic short stature (up to 0.067 mg/kg/day), without SHOX deficiency or skeletal dysplasias; the dose in GH deficiency is 0.025–0.035 mg/kg/day, divided into 6–7 subcutaneous injections per week, and the insert warns of progression of pre-existing scoliosis during rapid growth and of slipped capital femoral epiphysis [180]. The Brazilian indication of idiopathic short stature, absent from the European SmPC, does not cover RS or AMDM, which are identified causes of short stature. In Portugal, the SmPC of Genotropin® (Infomed, INFARMED) coincides with the European SmPC of Omnitrope® in the paediatric indications (GH deficiency, Turner syndrome, chronic renal insufficiency, small for gestational age and Prader-Willi syndrome) and does not include idiopathic short stature or SHOX deficiency, so use in RS without GH deficiency and in AMDM is off-label, as in Brazil and the USA [178, 179]. For testosterone, the Infomed listing of 18/10/2026 shows as marketed presentations the enanthate (Testoviron Depot® 250 mg/mL), the undecanoate (Nebido® 1000 mg/4 mL), the ester combination (Sustenon® 250 mg/mL) and transdermal gels (Testavan® and Testogel®); the SmPC of Testoviron Depot® indicates it only in confirmed male hypogonadism and excludes children and adolescents [171]. The Portuguese Summaries of Product Characteristics (SmPC) of chorionic gonadotrophin and vosoritide were not consulted; for testosterone and chorionic gonadotrophin no package insert published by the Brazilian holder was found, and use in micropenis is in any case off-label.

Relevant trials and studies

These studies have limitations that constrain their interpretation. The basket trial is open-label, single-arm, with the observation period as the comparator, and measures growth velocity at 12 months, a surrogate outcome; the absolute height gain (+0.65 SD) is smaller than the relative change in AGV suggests, and there are no final-height data [177]. The NPR2 subgroup has seven patients, all heterozygous; nothing can be transposed to AMDM, which was excluded [177]. There were discontinuations due to adverse effects in five patients (three slipped epiphyses and four genu valgum), mainly with ACAN [177]. The results of the SHOX deficiency arm, relevant to Langer dysplasia, have not been published [177]. The Arya series has two patients without a control and with historical comparison, and the navepegritide and vosoritide trials in achondroplasia cannot be compared indirectly or transposed to this class [55, 151, 175]. There are no negative trials in the class, because there are no trials.

Developments in the last 6 to 12 months

Between the end of 2025 and October 2026, the developments were preclinical, case reports or regulatory, with no therapeutic impact on the class. On the regulatory front, navepegritide was approved by the FDA in February 2026 and received a positive CHMP opinion in October 2026, both for achondroplasia only (authorisation and opinion) [57, 175]. The vosoritide basket trial published results for heterozygous NPR2 (phase 2 open-label trial) and a series of slipped epiphyses (case series) [177, 181]. In biology, the abnormal C-terminal tail of DVL1 was identified as the determinant of the facial phenotype (preclinical) [114]. In genetics, the following were described: an inversion at 6p22.3 reinforcing ID4 dysregulation in Savarirayan dysplasia, a synonymous NPR2 variant with aberrant splicing, the first biallelic NPPC variants in acromesomelic short stature, an attenuated AMDP phenotype, a patient with KINSSHIP and arthrogryposis, a prenatal case of omodysplasia 2 and a case of WNT5A-related RS mimicking congenital adrenal hyperplasia (case reports) [64, 80, 124, 134, 146, 147, 150]. There is a narrative review of Langer dysplasia [182].

At the preclinical level, in addition to DVL1, there are two findings with remote therapeutic potential: MEK1/2 inhibitors corrected the growth deficit in tibial explants from the AMDM mouse model, and the DKK inhibitor IIIC3a, administered in utero, normalised limb length in Fzd2 mutant mouse embryos [10, 129]. There are no human studies.

Management of the other entities

In AMDM, management is supportive and orthopaedic, without established pharmacotherapy: monitoring of growth and proportions, the spine (thoracolumbar kyphosis, foraminal stenosis in adults), the radial head and motor development [13, 52]. A patient with AMDM and a geminated tooth with supernumeraries required orthodontic treatment [183]. In AMDP, monitoring of growth and proportions, orthopaedic assessment (cubitus varus, limited elbow movement) and vertebral surveillance are recommended [14]. In the GDF5 spectrum there is no disease-modifying therapy; in the gain-of-function phenotypes, conductive deafness due to stapes fixation is progressive and warrants active audiological assessment [15]. In the Werner, Kantaputra, Nievergelt and acral synostoses dysplasias, the dominant problems are walking (knee instability, equinus, ankle deformity) and hand function; the sources consulted describe no surgical series specific to these entities, nor of limb lengthening or correction of Madelung deformity in the class [88, 90–92].

Anaesthesia and perioperative care

In RS, GeneReviews recommends preoperative radiological assessment of the vertebrae and ribs because of the risk of respiratory complications and cardiac assessment because of the possibility of congenital heart disease, and warns that endotracheal intubation may be difficult because of midface hypoplasia [5]. In AMDM, reports describe posterior fossa decompression under general anaesthesia in the prone position in a boy with Chiari type 1 and syringomyelia, the management of obstructive sleep apnoea and myopathy, and anaesthetic difficulties during vitreoretinal surgery; kyphoscoliosis, Chiari malformation, syringomyelia, obstructive apnoea and the airway should be considered, without formal recommendations [153, 154, 184]. In recessive omodysplasia, an uncomplicated general anaesthetic in a 5-year-old child has been published (Di Luca and Mitchell 2001) [17].

Agents and circumstances to avoid

In DVL1- and DVL3-related RS, a gene deletion or early truncation should not be interpreted as diagnostic, which avoids misdiagnosis [113]. Androgens should not be used without monitoring of bone age, and somatropin requires monitoring of scoliosis [170–172, 179]. CNP analogues should not be used in AMDM outside a trial, given the unfavourable rationale and the explicit exclusion from the only trial [176]. In a newborn with RS and electrolyte abnormalities, the hypothesis of congenital adrenal hyperplasia led to unnecessary glucocorticoids, later stopped [146].

Pregnancy and lactation

In women with dominant RS, pregnancy generally proceeds without complications; for an affected fetus, caesarean section may be necessary because of abnormal presentation or cephalopelvic disproportion, and a breech presentation with caesarean section has been reported [7]. Zhang and colleagues described a 26-year-old woman with ROR2-related RS (homozygous deletion of exons 6–7), 132.1 cm tall, with three pregnancies: a loss at 20 weeks due to a short cervix and premature rupture of membranes; a pregnancy with progesterone (17-hydroxyprogesterone caproate, weekly, intramuscular) and cerclage at 16 weeks, planned caesarean section under general anaesthesia at 36 weeks and symptomatic anaemia requiring transfusion; and a third with elective cerclage at 12 weeks, intrahepatic cholestasis of pregnancy, caesarean section at 36 weeks and transfusion [50]. The authors, extrapolating from achondroplasia, recommend preconception counselling and genetic testing, early antenatal anaesthetic assessment (difficult neuraxial block with kyphoscoliosis; difficult airway), an individualised mode of delivery, not bringing delivery forward routinely (around 39 weeks unless otherwise indicated), monitoring of respiratory function and considering a lower transfusion threshold because of reduced blood volume [50]. The sources consulted do not address lactation.

Transition and adult care

In adults with RS, the face (attenuated), dental problems, scoliosis and renal anomalies persist, and the latter may progress to renal failure; men may have testicular atrophy and an impact on sexuality and self-image [5, 136, 139]. Fertility is not always compromised, puberty is spontaneous with normal luteinising hormone (LH) and follicle-stimulating hormone (FSH), and there are men and women with dominant RS who have children [50]. In AMDM, adults have degenerative lumbar changes [52]. Transition should maintain renal, orthopaedic, dental and hearing surveillance and include reproductive counselling.

8. Reproductive Options and Family Counselling

Autosomal recessive forms

In ROR2-related RS, and by extension in the recessive forms due to NXN, GPC6, NPR2, PRKG2, GDF5 and BMPR1B, the parents of a patient are obligate heterozygotes; molecular testing of the parents confirms carrier status and prepares for prenatal diagnosis [5]. Siblings have a 25% risk of being affected, 50% of being heterozygotes, usually asymptomatic, and 25% of being neither affected nor carriers; the proband's children are obligate heterozygotes, with a small risk of disease unless the partner is consanguineous or has a family history; the parents' siblings have a 50% risk of being carriers [5]. Carrier testing is possible once the familial variants have been identified, and counselling should be offered before pregnancy to affected, carrier or at-risk young adults [5]. In recessive RS the recurrence risk is 25% [54].

Heterozygotes are not always clinically normal, and this must be taken into account in counselling. ROR2 carriers may have findings of brachydactyly B1 [5]. NPR2 carriers are shorter than non-carriers, with normal proportions [53, 128, 132]. In the Turkish series, heterozygous mothers measured 150.1 ± 7.9 cm and fathers 163.8 ± 7.5 cm, against 165 cm and 178.2 cm in non-Hispanic white controls from the US NHANES survey matched for age and sex (p<0.001; parents of 14 patients from 12 families, with segregation studied in 9); the reference is not Turkish, which limits the interpretation of the difference [128]. Individually, the nine heterozygous mothers measured between 142 and 168 cm (−3.27 to +0.72 SD) and the nine fathers between 148.5 and 174 cm (−3.92 to −0.4 SD); the parents of the two siblings homozygous for p.(Ile558Thr) had normal stature (168 and 174 cm), and those of a compound heterozygous patient measured 142.5 and 148.5 cm [128]. In Table 4 of the article the paternal mean is 166 ± 7.5 cm, but the text gives 163.8 ± 7.5 cm, a value that matches the mean of the nine individual heights (163.9 cm) [128]. GDF5 heterozygotes may have brachydactyly C, with marked intrafamilial variability, and BMPR1B heterozygotes mild brachydactyly or no signs [82, 86]. The Du Pan form has two inheritance patterns in OMIM: AR in most families, including a highly consanguineous Pakistani family with at least nine affected members (Ahmad 1990) and the family of Faiyaz-Ul-Haque (2002), homozygous for a GDF5 missense variant; and AD in a Polish mother and daughter (Szczałuba 2005) heterozygous for three GDF5 variants on the same allele, to which a dominant-negative effect in cis was attributed; in this scenario, the risk to the children of an affected individual is 50% [32]. In a compound heterozygous boy (Douzgou 2008), the father carrying one of the variants had only very mild radiological brachymesophalangy and the mother carrying the other had no signs [32]. Apparent homozygosity without consanguinity should prompt testing of the parents, because it may be a variant in trans with a deletion [54].

Autosomal dominant forms

In dominant RS (DVL1, DVL3, WNT5A), some patients have an affected parent, and the proportion of de novo cases is unknown, although DVL1 and DVL3 variants were de novo in all families with tested parents in the discovery series [7, 72, 74]. Parents should have a full examination and testing for the variant; if it is not present in the leucocytes of either, it is probably de novo, but there may be germline mosaicism, and the parent in whom the variant arose may have somatic mosaicism and be mildly affected [7]. Siblings have a 50% risk if a parent is affected, with unpredictable severity; if the variant is not detected in the parents, the risk is slightly above that of the population, below 1%, because of germline mosaicism; each child of a patient has a 50% risk, also with unpredictable severity [7]. The possibility of misattributed paternity or maternity and of undisclosed adoption should be considered, and DNA should be stored when the molecular diagnosis has not been confirmed [7]. The same rules apply to FZD2-related RS (one father-to-son and one mother-to-daughter transmission documented) and to the dominant mesomelic dysplasias [11, 75]. In the 2018 cohort, RS was sporadic in all families except two, both with a mother and son or daughter affected by FZD2 variants, and one patient with WNT5A had the variant in 23% of blood reads, consistent with somatic mosaicism in the proband himself [12]. In Werner dysplasia and Laurin-Sandrow syndrome, incomplete penetrance makes it necessary to examine apparently unaffected relatives [92]. In a case reported by OMIM, a clinically and radiologically normal man, married to an unrelated woman, had a daughter with bilateral aplasia of the tibia, triphalangeal thumbs and polydactyly (Canún 1986); in Werner dysplasia, a child of two heterozygous carriers may be homozygous and more severely affected [19].

Pseudoautosomal inheritance

In Léri-Weill dyschondrosteosis and Langer dysplasia, inheritance is pseudoautosomal, and a couple in which both partners have LWD may have children with Langer dysplasia; the parents of a patient with Langer dysplasia may have mild signs of dyschondrosteosis [97].

Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible in all the monogenic forms; in the dominant forms testing does not predict severity [5, 7]. High-resolution ultrasound can detect the skeletal and cardiac anomalies, and trio fetal exome sequencing identified ROR2-related RS without a prior diagnosis [5, 115]. In isolated brachydactyly, prenatal diagnosis is technically possible with the known variant, but is usually neither requested nor appropriate; syndromic forms are counselled according to the syndrome [60].

Counselling of minors

The sources consulted do not specifically address carrier testing in minors; GeneReviews recommends offering carrier counselling to affected, carrier or at-risk young adults, which implies postponing carrier testing until adulthood, unless the family and team decide otherwise [5].

9. Special Considerations: Population Diversity and Epidemiology

Prevalence: what each source measures

There are no population prevalence studies for any entity in the class. Orphanet classifies AR RS and AD RS as <1/1,000,000, a prevalence class that is an upper limit and not an estimate, with about 100 published cases each, and estimates about 200 cases of RS in total by expert opinion, with unknown point prevalence [4, 8]. GeneReviews counts more than 100 published cases of the ROR2 form and fewer than 80 families with the dominant form up to 2018–2019 [5, 7]. The estimate of 1:500,000 for RS is cited without a dedicated study, and the Robinow Syndrome Foundation repeats it («about 1 in 500,000 births») without stating the source [50, 166]. The Orphanet clinical page (text from May 2011, reviewed by Juliana Mazzeu) refers to about 200 published cases, mainly from the United States, Arab countries, Turkey, the Czech Republic and Slovakia, the Indian subcontinent and Brazil, with a sex ratio of 1:1; this distribution reflects the places of publication and not the relative frequency by region [4]. For AMDM, Orphanet records <1/1,000,000 and about 50 cases, and Dong and colleagues cite 1:1,000,000 without a primary source [34, 121]. Olney and colleagues, assuming 1 carrier of an NPR2 variant in every 700 people, estimated that about 1 in 30 children with idiopathic short stature would be a carrier; this is an assumption of the authors and not a measurement [132]. The numbers of cases recorded by Orphanet for the other entities are given in the table.

Source for the table, unless otherwise indicated: Orphadata, files of 23 June 2026 [2, 3, 34, 94].

There is a divergence regarding the relative frequency of the forms of RS. Orphanet defines AD RS as «the more common type» and AR RS as «the less common type», whereas the GeneReviews chapter on the ROR2 form states that the dominant form is rarer than the recessive [4, 5]. The available figures do not resolve the question: Orphanet attributes about 100 cases to each form; GeneReviews counts more than 100 recessive cases and fewer than 80 dominant families; the series of Mazzeu and colleagues classified 37 patients as recessive and 51 as dominant [4, 5, 7, 143]. The counts depend on the classification criterion (clinical or molecular) and on publication, and do not measure population frequency.

Founder populations and consanguinity

Recessive RS is common in consanguineous families, for example of Turkish and Omani origin, and also in non-consanguineous populations with a founder effect [5]. In Oman, 14 patients from 7 consanguineous families shared the same ROR2 nonsense variant, NM_004560.4:c.1504C>T p.(Gln502Ter) (Q502X), which removed the tyrosine kinase domain, and autozygosity mapping in these families located the gene [70, 71]. The mapping used five consanguineous Omani families and confirmed the same 4 cM locus in a Brazilian family and a British family, with no evidence of heterogeneity [35]. Aksit and colleagues (1997) counted 19 patients of Turkish couples among the 80 cases of RS then published [35]. The recessive form is «particularly frequent in Turkey», with a haplotype shared by three Turkish families [69]. According to OMIM, six of the ten Turkish families of van Bokhoven had four homozygous nonsense variants, including p.(Arg205Ter) in three families from eastern Turkey and p.(Trp720Ter) in a family from the Black Sea coast [25, 35]. An Omani child with RS and complex brachysynpolydactyly of the hands was homozygous for p.(Arg441Ter) (Schwarzer 2009), at the same position as the 5 bp deletion that, in homozygosity, gave RS with severe autopod reduction in a Turkish family with brachydactyly B1 [25, 35]. Robinow (1991), cited by OMIM, mentioned 14 Turkish patients of Balci and colleagues, all but one children of consanguineous marriages, recessive cases in Saudi Arabia and Kuwait, and Baxová's observation that the recessive form was not rare in the former Czechoslovakia, where all cases occurred in children of consanguineous Roma parents [33]. However, Lima and colleagues counted 13 different variants described in Turkish patients, which is incompatible with a single founder effect and favours the «Clan Genomics» hypothesis, in which rare, recent alleles are revealed through homozygosity by descent; all families with reported consanguinity were homozygous [54]. In Pakistan, a consanguineous family with atypical RS and severe autopod reduction and a Punjabi family with 34 individuals with brachydactyly B1 have been described [116, 185].

In AMDM, the series come mainly from populations with high consanguinity: 26 patients from 22 families and 9 patients from 8 families in Turkey, a consanguineous family from southern Punjab in Pakistan, and cases in Vietnam (the first in South-East Asia), India, Taiwan and Iran [123, 128, 152, 186]. In the Turkish series of 23 patients with molecular confirmation, the most frequent regions of origin were Central Anatolia, South-Eastern Anatolia and the Mediterranean region (5 patients each, with consanguinity in 4, 5 and 4 of them), followed by the Black Sea (3; consanguinity in 1), Eastern Anatolia and Marmara (2 each, all consanguineous) and the Aegean (1, without consanguinity); overall consanguinity was 78.2% (18/23), and the diversity of variants, with no founder variant shared by more than two families, points to consanguinity, rather than a founder effect, as the explanation for the local frequency [128]. Grebe dysplasia has been described in consanguineous families from Oman and Pakistan [156, 187]. An NPR2-related acromesomelic dysplasia was identified in an individual from 12,000 years ago [81]. According to OMIM, this is the skeleton of an Upper Palaeolithic adolescent girl from the Romito cave in Italy (Romito 2), homozygous for NM_003995.4:c.1801C>T p.(Arg601Cys) (R601C), in the kinase homology domain; an adult woman from the same burial, a first-degree relative, with short stature only, was heterozygous [21, 36, 110]. On the island of Saint Helena, a population of about 5,500 people descended from a few founders, the dysplasia described in 1970 as «pseudobrachydactylous dwarfism» in six relatives was reclassified as acromesomelic dysplasia and linked to the pericentromeric region of chromosome 9, where NPR2 is located, which suggests allelism with AMDM without molecular demonstration in the sources read [36].

Portugal and Brazil

The sources consulted contain no epidemiological data from Portugal. Saraiva and colleagues (1999) described monozygotic twins of Portuguese descent with RS: frontal bossing with a wide anterior fontanelle, prominent eyes, hypertelorism, a small upturned nose, triangular mouth, gingival hyperplasia, mesomelic shortening of the upper limbs, short fingers and toes, small penis and cryptorchidism; at 14 years, growth and development were normal and the facial features less marked; the authors proposed AD inheritance, and White and colleagues (2015) identified a de novo truncating DVL1 variant in the twins, which classifies them as dominant RS type 2 [43]. OMIM records a Portuguese family with brachydactyly type B studied by Oldridge and colleagues in 1999, with atypical features (short thumbs and absent or hypoplastic nails on the thumb and hallux) and without linkage to 9q22, which demonstrated the genetic heterogeneity of brachydactyly B; it is an entity of the differential diagnosis and not of the class [103]. Elsewhere, OMIM refers, citing Lv and colleagues (2009), to a Portuguese family with brachydactyly B1 and cutaneous syndactyly carrying NM_004560.4:c.2249del in ROR2, the variant described by Oldridge and colleagues (2000); the sources consulted do not clarify whether this is the same family [25, 110]. Brazil has clinical and molecular series of RS from the University of São Paulo and the University of Brasília: the 38 patients examined by Mazzeu and colleagues in 2007 and the international cohort of 22 patients with ROR2-related RS of Lima and colleagues in 2022, with a strong Brazilian component [54, 143]. The first NPR2 series (Bartels and colleagues, 2004) included a consanguineous Brazilian family with AMDM, homozygous for NM_003995.4:c.94C>A p.(Pro32Thr) (P32T in OMIM), and Vasques and colleagues (2013) described three Brazilian boys with short stature due to heterozygous NPR2 variants [21, 110]. The name «Brazilian achondrogenesis» for Grebe dysplasia derives from a report by Quelce-Salgado, according to the Bone Dysplasias atlas; the sources consulted do not describe the current frequency of Grebe dysplasia in Brazil [82]. OMIM places the original series in Bahia: Costa and colleagues (1998) re-studied 10 affected members of five families from Bahia described by Quelce-Salgado in 1964, with a normal axial skeleton, a proximodistal gradient of severity, constant absence of the proximal and middle phalanges with distal phalanges present and postaxial polydactyly in several, and heterozygotes with polydactyly, brachydactyly, hallux valgus or metatarsus adductus; Thomas and colleagues (1997) studied 20 members of the original family and found a haplotype shared in 13 of 14 chromosomes, consistent with a founder effect [37]. OMIM also cites a 1968 paper by Quelce-Salgado on the radiographs of a patient's parents, which explains the two dates found in the literature [37]. Werner dysplasia also has Brazilian families: Vargas and colleagues (1995) described 10 affected members in three generations, with five triphalangeal digits and a non-opposable thumb, in whom Wieczorek and colleagues (2010) identified the ZRS variant 404G>C, and Richieri-Costa and colleagues (1990) three members of another Brazilian family with a picture that OMIM likens to that of Al-Awadi (hypoplastic, bowed tibiae with postaxial polysyndactyly), with radioulnar synostosis in two [19]. A Brazilian boy, born to consanguineous parents, with recessive omodysplasia has also been published (Albano 2007) [17]. In group 38 of the Nosology, LMBR1-related acheiropodia has a Brazilian founder allele, a deletion of exon 4 of LMBR1 that probably affects the activity of the ZRS, the same enhancer as in Werner dysplasia [1].

Special populations, ERN and associations

The European Reference Network for rare bone diseases is ERN BOND, which has a case discussion platform and uses the 2023 Nosology as its reference [58]. Patient associations and resources cited in the sources: Robinow Syndrome Foundation (United States), Little People of America, Human Growth Foundation, MAGIC Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Restricted Growth Association (United Kingdom), Contact a Family (United Kingdom), European Skeletal Dysplasia Network and UK Skeletal Dysplasia Group [5, 7, 59, 60, 166]. The sources do not identify Portuguese or Brazilian associations specific to the class.

10. Illustrative Clinical Case

Acromesomelic dysplasia, Maroteaux type, due to compound heterozygous NPR2 variants

Dong and colleagues published in 2025 the case of a boy aged 8 years and 8 months, the fourth child of non-consanguineous parents (mother 160 cm, father 168 cm, maternal uncle 158 cm, −2.4 SD), admitted in July 2023 for growth retardation [121]. Ultrasound at 26 weeks had shown short limbs; he was born at term weighing 3150 g and measuring 46 cm, and motor and cognitive development were normal, with excellent school performance [121]. On examination he measured 99.3 cm (−6.0 SD) and weighed 17.5 kg (−3.0 SD), with an arm span of 85 cm and upper and lower segments of 51.3 and 48 cm; he had a prominent forehead, pectus carinatum, short limbs, cubitus valgus and genu varum [121].

25-Hydroxyvitamin D was low (26.7 ng/mL), IGF-1 normal (141 ng/mL) and the peak GH on the insulin tolerance test normal (20.7 ng/mL); thyroid and adrenal function were normal, bone age was about 8 years and MRI showed a small pituitary (2.6 mm) [121]. Radiographs (Figure 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC12186393/figure/Fig1/) showed short, irregular phalanges and metatarsals, widened metaphyses of the humerus, ulna, radius, femur and tibia, an increased anteroposterior diameter of the skull, irregular, flattened and wedged vertebrae with widened intervertebral spaces, a discontinuous sacral canal, poorly defined sacroiliac joints and irregular acetabular margins [121].

Exome sequencing identified compound heterozygosity in NPR2: NM_003995.4:c.2965C>T p.(Arg989Ter), of maternal origin, previously described in AMDM, and c.2291T>C p.(Leu764Pro), of paternal origin, novel, absent from gnomAD and classified as a VUS by the authors; segregation was confirmed by Sanger sequencing (Figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC12186393/figure/Fig2/) [110, 121, 122]. In the discussion, the authors stress that limb length may be normal at birth, with marked deceleration from the second year, and consider in the differential diagnosis osteogenesis imperfecta, Albright hereditary osteodystrophy, PIEZO2-related arthrogryposis and osteopathia striata with cranial sclerosis [121]. They also cite the response to GH in a Chinese series of three patients and in the Arya series, without describing any treatment instituted in this patient [121].

The case illustrates three points: prenatal ultrasound may be abnormal even when birth length is normal; a normal GH–IGF-1 axis does not exclude a dysplasia as the cause of severe short stature; and a VUS in trans with a known pathogenic variant, in a typical phenotype, supports the clinical diagnosis, although classification of the novel variant depends on additional evidence [121]. GH, if considered, would be off-label use, with the limited evidence described in section 7.

WNT5A-related Robinow syndrome mistaken for congenital adrenal hyperplasia

Sridharan and colleagues described in 2026 a 10-month-old infant, born preterm, weighing 2.2 kg at birth, referred for genital ambiguity, with microphallus, impalpable testes, hyponatraemia, hyperkalaemia and mildly raised 17-hydroxyprogesterone, initially treated with glucocorticoids for suspected congenital adrenal hyperplasia [146]. Examination showed a depressed nasal bridge, widely spaced eyes, a large anterior fontanelle, a broad nose, low-set ears, micropenis with a penoscrotal web, penoscrotal meatus, hypoplastic scrotum and bilateral inguinal testes; the karyotype was 46,XY and exome sequencing identified WNT5A c.544T>C p.(Cys182Arg) in the heterozygous state (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC12747829/figure/luaf311-F1/) [146]. Adrenal reassessment after weaning was normal; the patient received hCG for 6 months and then underwent orchidopexy [146]. The use of hCG in this report does not correspond to a guideline recommendation, which does not exist for RS (section 7).

11. Prognosis and Long-Term Follow-Up

Prognosis

In RS general health is good in most patients, and heart disease is the main cause of early morbidity and mortality [5, 7, 51]. In the ROR2 form, adult stature is 128–145 cm, scoliosis progresses with age in 69% and its impact depends on the number of vertebrae affected, the face becomes less marked and adult men report normal erection and post-pubertal penile growth; adults may develop renal disease [54, 139]. In the dominant form final height is at −2 SD or slightly below, and in the DVL1 form stature is usually normal or low-normal; heart disease determines the prognosis in the DVL3 form [7, 11]. Cognition is generally average, with a risk of learning and attention difficulties in the DVL1 form [140].

In AMDM, untreated adult height is between 94 and 124.5 cm, with a mean of about 120 cm; with high-dose GH, two siblings reached 130.5 and 134 cm [52, 53, 151]. Intelligence is normal, but adults develop degenerative lumbar changes and foraminal stenosis, and there may be symptomatic kyphoscoliosis, Chiari type 1 or syringomyelia [52, 153]; in a Turkish series of 23 patients with molecular confirmation, 2 had spinal canal stenosis with neurological signs and 1 atlantoaxial dislocation [128]. In AMDP short stature worsens with age [155]. In the Grebe spectrum patients are ambulant and, in the original series, were independent; the Hunter-Thompson form reaches about 120 cm and Du Pan near-normal stature [34, 82]. In Langer dysplasia adult height is around 130 cm with no major complications reported; in Kantaputra, 152 cm in men and 135 cm in women of the original family; in Nievergelt, 147–156 cm in the men of the original family [88, 90, 97]. In the Werner, Nievergelt and acral synostoses dysplasias, functional prognosis depends on walking, compromised by knee instability, equinus and ankle deformity [88, 91, 92].

Surveillance table

The sources consulted do not define specific intervals for the rare mesomelic dysplasias or for the Grebe spectrum; surveillance of these entities is orthopaedic and functional, guided by the problems described [82, 92].

12. Summary and Final Considerations

The mesomelic and acromesomelic dysplasias are grouped by the shortest limb segment and separated by molecular pathway. Robinow syndrome results from disturbances of the non-canonical WNT pathway: the recessive form, due to ROR2 and, rarely, NXN, has severe short stature, hemivertebrae, rib fusions and scoliosis; the dominant forms, due to WNT5A, DVL1, DVL3 and FZD2, have a less affected skeleton and gene-specific features, such as the macrocephaly with cranial osteosclerosis and deafness of DVL1, the heart disease of DVL3 and the milder phenotype, close to omodysplasia, of FZD2. DVL1 and DVL3 variants are −1 frameshifts in the last exons that escape mRNA decay, a gain-of-function mechanism that makes it necessary to cover these exons well and not to interpret gene deletions as causal. The fetal face and genital hypoplasia are common to all forms; the micropenis results partly from an abnormal insertion of the corpora cavernosa, and its hormone treatment, always off-label, relies on regimens from the micropenis literature, with a divergence between experts regarding timing.

The acromesomelic dysplasias are divided between the CNP axis (NPR2 in AMDM and PRKG2 in AMDP), with vertebral involvement and normal radiographs at birth in AMDM, and the GDF5–BMPR1B pair (Grebe, Hunter-Thompson and Du Pan), with a normal axial skeleton and severity proportional to the functional loss. The CNP analogues approved for achondroplasia have no rationale in AMDM, in which the receptor is absent, and homozygotes were excluded from the only trial; high-dose somatropin has data in two patients. The rare mesomelic dysplasias result mainly from structural or regulatory changes (HOXD duplications, microdeletions or inversions at 6p22.3, microdeletions at 8q13, ZRS variants and duplications), which require microarray, ZRS analysis and, sometimes, genome sequencing. Léri-Weill dyschondrosteosis, Langer dysplasia and short stature due to heterozygous NPR2 variants enter the differential diagnosis.

Throughout the class, management is supportive and multidisciplinary, without formal guidelines, and surveillance focuses on the heart, kidney, spine, teeth, hearing and development. Prevalences are known only as case counts, with a divergence between Orphanet and GeneReviews regarding the most frequent form of Robinow syndrome.

13. References

1. Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164-1209. doi:10.1002/ajmg.a.63132. PMID: 36779427. PMC10081954.
2. Orphanet. Mesomelic and rhizo-mesomelic dysplasia (ORPHA:93438; clinical group) and members (incl. 2632, 2633, 85170, 1836, 2634, 2631, 2733, 93328, 93329, 240). https://www.orpha.net/en/disease/detail/93438
3. Orphanet. Acromesomelic dysplasia (ORPHA:93437; clinical group) and members (40, 968, 2098, 2496, 2639, 93382). https://www.orpha.net/en/disease/detail/93437
4. Orphanet. Robinow syndrome (ORPHA:97360); subtypes Autosomal recessive Robinow syndrome (ORPHA:1507) and Autosomal dominant Robinow syndrome (ORPHA:3107). https://www.orpha.net/en/disease/detail/97360 [clinical page updated May 2011; accessed 27 Oct 2026]
5. Bacino CA. ROR2-Related Robinow Syndrome. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2005 Jul 28 [updated 2018 Jul 26; revised 2019 Sep 12]. PMID: 20301418. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1240/
6. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 409–11 (12.1 Omodysplasia, autosomal recessive).
7. Roifman M, Brunner H, Lohr J, Mazzeu J, Chitayat D. Autosomal Dominant Robinow Syndrome. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2015 Jan 8 [updated 2018 Aug 9; revised 2019 Oct 3]. PMID: 25577943. Available from: https://www.ncbi.nlm.nih.gov/books/NBK268648/
8. GeneGuidance. ROR2: clinical gene curation (Robinow syndrome AR; brachydactyly B1).
9. GeneGuidance. NXN: clinical gene curation (Robinow AR 2).
10. GeneGuidance. FZD2: clinical gene curation (omodysplasia 2 / Robinow AD).
11. Zhang C, Jolly A, Shayota BJ, Mazzeu JF, Du H, Dawood M, et al. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability. HGG Adv. 2022;3(1):100074. doi:10.1016/j.xhgg.2021.100074. PMID: 35047859. PMC8756549.
12. White JJ, Mazzeu JF, Coban-Akdemir Z, Bayram Y, Bahrambeigi V, Hoischen A, et al. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. Am J Hum Genet. 2018;102(1):27-43. doi:10.1016/j.ajhg.2017.10.002. PMID: 29276006. PMC5777383.
13. GeneGuidance. NPR2: clinical gene curation (AMDM; SNSK1; epiphyseal chondrodysplasia, Miura type).
14. GeneGuidance. PRKG2: clinical gene curation (AMD PRKG2 type; spondylometaphyseal dysplasia, Pagnamenta type).
15. GeneGuidance. GDF5: clinical gene curation (AMD Grebe/Du Pan/Hunter-Thompson; brachydactylies; SYM1B/SYNS2).
16. GeneGuidance. BMPR1B: clinical gene curation (brachydactyly A2/A1D; AMD3 Demirhan).
17. OMIM® Online Mendelian Inheritance in Man. #258315 OMODYSPLASIA 1; OMOD1. Johns Hopkins University; last edited 19/07/2021. https://omim.org/entry/258315. Accessed 27 October 2026.
18. OMIM® Online Mendelian Inheritance in Man. #127300 LERI-WEILL DYSCHONDROSTEOSIS; LWD. Johns Hopkins University; last edited 31/07/2019. https://omim.org/entry/127300. Accessed 27 October 2026.
19. OMIM® Online Mendelian Inheritance in Man. #188740 TIBIA, HYPOPLASIA OR APLASIA OF, WITH POLYDACTYLY; THYP. Johns Hopkins University; last edited 28/08/2026. https://omim.org/entry/188740. Accessed 27 October 2026.
20. OMIM® Online Mendelian Inheritance in Man. #156232 MESOMELIC DYSPLASIA, KANTAPUTRA TYPE; MMDK. Johns Hopkins University; last edited 30/10/2024. https://omim.org/entry/156232. Accessed 27 October 2026.
21. OMIM® Online Mendelian Inheritance in Man. *108961 NATRIURETIC PEPTIDE RECEPTOR 2; NPR2. Johns Hopkins University; last edited 04/08/2026. https://omim.org/entry/108961. Accessed 27 October 2026.
22. OMIM® Online Mendelian Inheritance in Man. *601591 PROTEIN KINASE, cGMP-DEPENDENT, TYPE II; PRKG2. Johns Hopkins University; last edited 14/10/2022. https://omim.org/entry/601591. Accessed 27 October 2026.
23. OMIM® Online Mendelian Inheritance in Man. *601146 GROWTH/DIFFERENTIATION FACTOR 5; GDF5. Johns Hopkins University; last edited 01/07/2024. https://omim.org/entry/601146. Accessed 27 October 2026.
24. OMIM® Online Mendelian Inheritance in Man. *603248 BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IB; BMPR1B. Johns Hopkins University; last edited 06/04/2022. https://omim.org/entry/603248. Accessed 27 October 2026.
25. OMIM® Online Mendelian Inheritance in Man. *602337 RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTOR 2; ROR2. Johns Hopkins University; last edited 04/03/2024. https://omim.org/entry/602337. Accessed 27 October 2026.
26. OMIM® Online Mendelian Inheritance in Man. *164975 WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 5A; WNT5A. Johns Hopkins University; last edited 05/04/2016. https://omim.org/entry/164975. Accessed 27 October 2026.
27. OMIM® Online Mendelian Inheritance in Man. *601365 DISHEVELLED SEGMENT POLARITY PROTEIN 1; DVL1. Johns Hopkins University; last edited 10/08/2026. https://omim.org/entry/601365. Accessed 27 October 2026.
28. OMIM® Online Mendelian Inheritance in Man. *601368 DISHEVELLED SEGMENT POLARITY PROTEIN 3; DVL3. Johns Hopkins University; last edited 10/08/2026. https://omim.org/entry/601368. Accessed 27 October 2026.
29. OMIM® Online Mendelian Inheritance in Man. *600667 FRIZZLED CLASS RECEPTOR 2; FZD2. Johns Hopkins University; last edited 29/10/2025. https://omim.org/entry/600667. Accessed 27 October 2026.
30. OMIM® Online Mendelian Inheritance in Man. #619297 KINSSHIP SYNDROME; KINS. Johns Hopkins University; last edited 12/05/2021. https://omim.org/entry/619297. Accessed 28 October 2026.
31. OMIM® Online Mendelian Inheritance in Man. #615877 MICROPHTHALMIA/COLOBOMA AND SKELETAL DYSPLASIA SYNDROME; MCSKS. Johns Hopkins University; last edited 30/07/2019. https://omim.org/entry/615877. Accessed 28 October 2026.
32. OMIM® Online Mendelian Inheritance in Man. #228900 ACROMESOMELIC DYSPLASIA 2B; AMD2B. Johns Hopkins University; last edited 07/12/2023. https://omim.org/entry/228900. Accessed 27 October 2026.
33. OMIM® Online Mendelian Inheritance in Man. #180700 ROBINOW SYNDROME, AUTOSOMAL DOMINANT 1; DRS1. Johns Hopkins University; last edited 29/10/2025. https://omim.org/entry/180700. Accessed 27 October 2026.
34. Orphanet. Acromesomelic dysplasia, Maroteaux type (ORPHA:40). https://www.orpha.net/en/disease/detail/40
35. OMIM® Online Mendelian Inheritance in Man. #268310 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 1; RRS1. Johns Hopkins University; last edited 02/03/2026. https://omim.org/entry/268310. Accessed 27 October 2026.
36. OMIM® Online Mendelian Inheritance in Man. #602875 ACROMESOMELIC DYSPLASIA 1; AMD1. Johns Hopkins University; last edited 06/02/2026. https://omim.org/entry/602875. Accessed 27 October 2026.
37. OMIM® Online Mendelian Inheritance in Man. #200700 ACROMESOMELIC DYSPLASIA 2A; AMD2A. Johns Hopkins University; last edited 04/04/2024. https://omim.org/entry/200700. Accessed 27 October 2026.
38. OMIM® Online Mendelian Inheritance in Man. #201250 ACROMESOMELIC DYSPLASIA 2C; AMD2C. Johns Hopkins University; last edited 21/03/2023. https://omim.org/entry/201250. Accessed 27 October 2026.
39. OMIM® Online Mendelian Inheritance in Man. #609441 ACROMESOMELIC DYSPLASIA 3; AMD3. Johns Hopkins University; last edited 11/02/2025. https://omim.org/entry/609441. Accessed 27 October 2026.
40. OMIM® Online Mendelian Inheritance in Man. 249710 MESOMELIC LIMB SHORTENING AND BOWING. Johns Hopkins University. https://omim.org/entry/249710. Accessed 27 October 2026.
41. OMIM® Online Mendelian Inheritance in Man. 191400 ULNA AND FIBULA, HYPOPLASIA OF. Johns Hopkins University; last edited 02/11/2009. https://omim.org/entry/191400. Accessed 27 October 2026.
42. OMIM® Online Mendelian Inheritance in Man. %191440 ULNAR HYPOPLASIA. Johns Hopkins University; last edited 13/08/2012. https://omim.org/entry/191440. Accessed 27 October 2026.
43. OMIM® Online Mendelian Inheritance in Man. #616331 ROBINOW SYNDROME, AUTOSOMAL DOMINANT 2; DRS2. Johns Hopkins University; last edited 29/10/2025. https://omim.org/entry/616331. Accessed 28 October 2026.
44. OMIM® Online Mendelian Inheritance in Man. #616894 ROBINOW SYNDROME, AUTOSOMAL DOMINANT 3; DRS3. Johns Hopkins University; last edited 04/04/2016. https://omim.org/entry/616894. Accessed 28 October 2026.
45. OMIM® Online Mendelian Inheritance in Man. #618529 ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 2; RRS2. Johns Hopkins University; last edited 15/11/2023. https://omim.org/entry/618529. Accessed 28 October 2026.
46. OMIM® Online Mendelian Inheritance in Man. *612895 NUCLEOREDOXIN; NXN. Johns Hopkins University; last edited 08/08/2019. https://omim.org/entry/612895. Accessed 28 October 2026.
47. OMIM® Online Mendelian Inheritance in Man. #619636 ACROMESOMELIC DYSPLASIA 4; AMD4. Johns Hopkins University; last edited 14/10/2022. https://omim.org/entry/619636. Accessed 28 October 2026.
48. OMIM® Online Mendelian Inheritance in Man. #619638 SPONDYLOMETAPHYSEAL DYSPLASIA, PAGNAMENTA TYPE; SMDP. Johns Hopkins University; last edited 14/10/2022. https://omim.org/entry/619638. Accessed 28 October 2026.
49. Binder G, et al. SHOX Deficiency Disorders. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Initial posting 2005 Dec 12. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1215/
50. Zhang Y, Casanova M, Shanahan M, Sutton VR, Fox K. Obstetrical Challenges in Robinow Syndrome. Case Rep Obstet Gynecol. 2022;2022:6481517. doi:10.1155/2022/6481517. PMID: 35909981. PMC9337944.
51. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 412–8 (12.2 Robinow syndrome).
52. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 443–6 (13.1 Acromesomelic dysplasia, Maroteaux type).
53. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 498–501 (Acromesomelic dysplasia, Maroteaux type).
54. Lima AR, Ferreira BM, Zhang C, Jolly A, Du H, White JJ, et al. Phenotypic and mutational spectrum of ROR2-related Robinow syndrome. Hum Mutat. 2022;43(7):900-918. doi:10.1002/humu.24375. PMID: 35344616. PMC9177636.
55. BioMarin Pharmaceutical Inc. VOXZOGO (vosoritide) for injection, for subcutaneous use. Prescribing information. NDA 214938. Revised 2025 (openFDA effective_time 20251125, set id 228e8560-04a4-4bb1-a81f-29531a9e4d27, version 16). Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=228e8560-04a4-4bb1-a81f-29531a9e4d27
56. European Medicines Agency. Voxzogo (vosoritide): EPAR — medicine overview. EMEA, authorised 26/08/2021; revision 9; latest EC decision 11/06/2026. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/voxzogo
57. U.S. Food and Drug Administration. Drugs@FDA: YUVIWEL (navepegritide), NDA 219164, Ascendis Pharma; original approval 27/02/2026. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=219164
58. European Reference Network on Rare Bone Diseases (ERN BOND). Guidelines [Internet]. Updated 2026 May 8 [accessed 27 Oct 2026]. Available from: https://ernbond.eu/guidelines/
59. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 316–9 (Skeletal dysplasias).
60. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 78–81 (Brachydactyly).
61. Bartels CF, Bükülmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet. 2004;75(1):27-34. doi:10.1086/422013. PMID: 15146390. PMC1182004.
62. Díaz-González F, Wadhwa S, Rodriguez-Zabala M, Kumar S, Aza-Carmona M, Sentchordi-Montané L, et al. Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia. J Med Genet. 2022;59(1):28-38. doi:10.1136/jmedgenet-2020-107177. PMID: 33106379.
63. Stange K, Désir J, Kakar N, Mueller TD, Budde BS, Gordon CT, et al. A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia. Orphanet J Rare Dis. 2015;10:84. doi:10.1186/s13023-015-0299-5. PMID: 26105076. PMC4482310.
64. Lucas-Castro E, Ramos-Mejía R, Sánchez-Gaya V, Rada-Iglesias Á, Caíno S, Fano V, et al. Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type. Eur J Hum Genet. 2026;34(6):880-884. doi:10.1038/s41431-026-02124-8. PMID: 42069959. PMC13246906.
65. Robinow M, Silverman FN, Smith HD. A newly recognized dwarfing syndrome. Am J Dis Child. 1969;117(6):645-51. doi:10.1001/archpedi.1969.02100030647005. PMID: 5771504.
66. Patton MA, Afzal AR. Robinow syndrome. J Med Genet. 2002;39(5):305-10. doi:10.1136/jmg.39.5.305. PMID: 12011143. PMC1735132.
67. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 166–9 (Robinow syndrome).
68. Person AD, Beiraghi S, Sieben CM, Hermanson S, Neumann AN, Robu ME, et al. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn. 2010;239(1):327-37. doi:10.1002/dvdy.22156. PMID: 19918918. PMC4059519.
69. van Bokhoven H, Celli J, Kayserili H, van Beusekom E, Balci S, Brussel W, et al. Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome. Nat Genet. 2000;25(4):423-6. doi:10.1038/78113. PMID: 10932187.
70. Afzal AR, Rajab A, Fenske C, Crosby A, Lahiri N, Ternes-Pereira E, et al. Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22. Hum Genet. 2000;106(3):351-4. doi:10.1007/s004390051049. PMID: 10798366.
71. Afzal AR, Rajab A, Fenske CD, Oldridge M, Elanko N, Ternes-Pereira E, et al. Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat Genet. 2000;25(4):419-22. doi:10.1038/78107. PMID: 10932186.
72. White J, Mazzeu JF, Hoischen A, Jhangiani SN, Gambin T, Alcino MC, et al. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum Genet. 2015;96(4):612-22. doi:10.1016/j.ajhg.2015.02.015. PMID: 25817016. PMC4385180.
73. Bunn KJ, Daniel P, Rösken HS, O'Neill AC, Cameron-Christie SR, Morgan T, et al. Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. Am J Hum Genet. 2015;96(4):623-30. doi:10.1016/j.ajhg.2015.02.010. PMID: 25817014. PMC4385193.
74. White JJ, Mazzeu JF, Hoischen A, Bayram Y, Withers M, Gezdirici A, et al. DVL3 Alleles Resulting in a -1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome. Am J Hum Genet. 2016;98(3):553-561. doi:10.1016/j.ajhg.2016.01.005. PMID: 26924530. PMC4800044.
75. Saal HM, Prows CA, Guerreiro I, Donlin M, Knudson L, Sund KL, et al. A mutation in FRIZZLED2 impairs Wnt signaling and causes autosomal dominant omodysplasia. Hum Mol Genet. 2015;24(12):3399-409. doi:10.1093/hmg/ddv088. PMID: 25759469. PMC4834928.
76. Nagasaki K, Nishimura G, Kikuchi T, Nyuzuki H, Sasaki S, Ogawa Y, et al. Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes. Am J Med Genet A. 2018;176(3):739-742. doi:10.1002/ajmg.a.38623. PMID: 29383834.
77. Maroteaux P, Martinelli B, Campailla E. [Acromesomelic dwarfism]. Presse Med (1893). 1971;79(42):1839-42. PMID: 5000841.
78. Kant SG, Polinkovsky A, Mundlos S, Zabel B, Thomeer RT, Zonderland HM, et al. Acromesomelic dysplasia Maroteaux type maps to human chromosome 9. Am J Hum Genet. 1998;63(1):155-62. doi:10.1086/301917. PMID: 9634515. PMC1377238.
79. Faivre L, Le Merrer M, Megarbane A, Gilbert B, Mortier G, Cusin V, et al. Exclusion of chromosome 9 helps to identify mild variants of acromesomelic dysplasia Maroteaux type. J Med Genet. 2000;37(1):52-4. doi:10.1136/jmg.37.1.52. PMID: 10633136. PMC1734441.
80. Amalnath D, Rajagopal S, Akkadka C. First Report of Biallelic NPPC Variants Causing Acromesomelic Type of Short Stature. Am J Med Genet A. 2026 [Epub ahead of print]. doi:10.1002/ajmg.a.70331. PMID: 42888861.
81. Fernandes DM, Llanos-Lizcano A, Brück F, Oberreiter V, Özdoğan KT, Cheronet O, et al. A 12,000-Year-Old Case of NPR2-Related Acromesomelic Dysplasia. N Engl J Med. 2026;394(5):513-515. doi:10.1056/NEJMc2513616. PMID: 41604646.
82. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 447–52 (13.2 Grebe dysplasia).
83. Thomas JT, Lin K, Nandedkar M, Camargo M, Cervenka J, Luyten FP. A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Nat Genet. 1996;12(3):315-7. doi:10.1038/ng0396-315. PMID: 8589725.
84. Thomas JT, Kilpatrick MW, Lin K, Erlacher L, Lembessis P, Costa T, et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet. 1997;17(1):58-64. doi:10.1038/ng0997-58. PMID: 9288098.
85. Demirhan O, Türkmen S, Schwabe GC, Soyupak S, Akgül E, Tastemir D, et al. A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies. J Med Genet. 2005;42(4):314-7. doi:10.1136/jmg.2004.023564. PMID: 15805157. PMC1736042.
86. Graul-Neumann LM, Deichsel A, Wille U, Kakar N, Koll R, Bassir C, et al. Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe. Eur J Hum Genet. 2014;22(6):726-33. doi:10.1038/ejhg.2013.222. PMID: 24129431. PMC4023204.
87. Khan S, Basit S, Khan MA, Muhammad N, Ahmad W. Genetics of human isolated acromesomelic dysplasia. Eur J Med Genet. 2016;59(4):198-203. doi:10.1016/j.ejmg.2016.02.011. PMID: 26926249.
88. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 435–8 (12.8 Mesomelic dysplasia, Nievergelt-Savarirayan type).
89. Langer LO. Mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type. Radiology. 1967;89(4):654-60. doi:10.1148/89.4.654. PMID: 6059604.
90. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 425–8 (12.5 Mesomelic dysplasia, Kantaputra type).
91. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 439–42 (12.9 Mesomelic dysplasia with acral synostoses).
92. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 429–31 (12.6 Mesomelic dysplasia, Werner type).
93. OMIM® Online Mendelian Inheritance in Man. 611886 MESOMELIC DYSPLASIA, CAMERA TYPE. Johns Hopkins University; last edited 16/01/2021. https://omim.org/entry/611886. Accessed 27 October 2026.
94. Orphanet. Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (ORPHA:988); Laurin-Sandrow syndrome (ORPHA:2378). https://www.orpha.net/en/disease/detail/988
95. Roifman M, Marcelis CL, Paton T, Marshall C, Silver R, Lohr JL, et al. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype. Clin Genet. 2015;87(1):34-41. doi:10.1111/cge.12401. PMID: 24716670.
96. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 419–21 (12.3 Dyschondrosteosis).
97. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 422–4 (12.4 Mesomelic dysplasia, Langer type).
98. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 432–4 (12.7 Mesomelic dysplasia, Reardon-Kozlowski type).
99. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 455–6 (13.4 Brachydactyly B).
100. GeneGuidance. GPC4: clinical gene curation (Keipert syndrome; SGBS1).
101. Voisin N, Schnur RE, Douzgou S, Hiatt SM, Rustad CF, Brown NJ, et al. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. Am J Hum Genet. 2021;108(5):857-873. doi:10.1016/j.ajhg.2021.04.001. PMID: 33961779. PMC8206167.
102. OMIM® Online Mendelian Inheritance in Man. #164745 OMODYSPLASIA 2; OMOD2. Johns Hopkins University; last edited 03/04/2024. https://omim.org/entry/164745. Accessed 27 October 2026.
103. OMIM® Online Mendelian Inheritance in Man. #113000 BRACHYDACTYLY, TYPE B1; BDB1. Johns Hopkins University; last edited 04/02/2020. https://omim.org/entry/113000. Accessed 27 October 2026.
104. OMIM® Online Mendelian Inheritance in Man. #249700 LANGER MESOMELIC DYSPLASIA; LMD. Johns Hopkins University; last edited 09/09/2016. https://omim.org/entry/249700. Accessed 27 October 2026.
105. OMIM® Online Mendelian Inheritance in Man. #135750 LAURIN-SANDROW SYNDROME; LSS. Johns Hopkins University; last edited 01/03/2024. https://omim.org/entry/135750. Accessed 27 October 2026.
106. OMIM® Online Mendelian Inheritance in Man. %163400 NIEVERGELT SYNDROME. Johns Hopkins University; last edited 04/01/2018. https://omim.org/entry/163400. Accessed 27 October 2026.
107. OMIM® Online Mendelian Inheritance in Man. 605274 MESOMELIC DYSPLASIA, SAVARIRAYAN TYPE. Johns Hopkins University; last edited 12/05/2021. https://omim.org/entry/605274. Accessed 27 October 2026.
108. OMIM® Online Mendelian Inheritance in Man. #600383 MESOMELIA-SYNOSTOSES SYNDROME. Johns Hopkins University; last edited 31/05/2017. https://omim.org/entry/600383. Accessed 27 October 2026.
109. OMIM® Online Mendelian Inheritance in Man. 112910 OSEBOLD-REMONDINI SYNDROME. Johns Hopkins University; last edited 18/11/2021. https://omim.org/entry/112910. Accessed 27 October 2026.
110. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. doi:10.1002/humu.23348. PMID: 28967166. Ferramenta: https://rest.variantvalidator.org (consulta GRCh38/MANE Select 27/10/2026)
111. Zhang C, Mazzeu JF, Eisfeldt J, Grochowski CM, White J, Akdemir ZC, et al. Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome. Am J Med Genet A. 2021;185(12):3593-3600. doi:10.1002/ajmg.a.61908. PMID: 33048444. PMC8445516.
112. GeneGuidance. DVL3: clinical gene curation (Robinow AD 3).
113. GeneGuidance. DVL1: clinical gene curation (Robinow AD 2, osteosclerotic).
114. Tophkhane SS, Akarsu G, Gignac SJ, Xie X, Fu K, Verheyen EM, et al. The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes. Hum Mol Genet. 2026;35(14):ddag053. doi:10.1093/hmg/ddag053. PMID: 42424595. PMC13349050.
115. Yang L, Shannon P, Silver R, Roifman M, Yates C, Chitayat D. Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities. Prenat Diagn. 2024;44(5):653-656. doi:10.1002/pd.6543. PMID: 38504427.
116. Malik S, Nalbant G, Noreen M, Afzal M, Tolun A. A homozygous ROR2 variant in a family with atypical Robinow syndrome and tetramelic transverse deficiency of autopods. Am J Med Genet A. 2022;188(1):343-349. doi:10.1002/ajmg.a.62514. PMID: 34569147.
117. National Center for Biotechnology Information. ClinVar; VCV000007307: NM_004560.4(ROR2):c.1504C>T (p.Gln502Ter) [Internet]. Bethesda (MD): NCBI [accessed 28 Oct 2026]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/7307/
118. National Center for Biotechnology Information. ClinVar; VCV000007310: NM_004560.4(ROR2):c.613C>T (p.Arg205Ter) [Internet]. Bethesda (MD): NCBI [accessed 28 Oct 2026]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/7310/
119. National Center for Biotechnology Information. ClinVar; VCV000007309: NM_004560.4(ROR2):c.2160G>A (p.Trp720Ter) [Internet]. Bethesda (MD): NCBI [accessed 28 Oct 2026]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/7309/
120. National Center for Biotechnology Information. ClinVar; VCV000029819: NM_003392.7(WNT5A):c.544T>C (p.Cys182Arg) [Internet]. Bethesda (MD): NCBI [accessed 28 Oct 2026]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/29819/
121. Dong Y, Pei S, Yang Z, Xue Y, Wang H. A novel variant in NPR2: C.2291T > C (p.Leu764Pro) identified in a patient with acromesomelic dysplasia Maroteaux type. Ital J Pediatr. 2025;51(1):199. doi:10.1186/s13052-025-02050-3. PMID: 40551241. PMC12186393.
122. Ain NU, Iqbal M, Valta H, Emerling CA, Ahmed S, Makitie O, et al. Novel variants in natriuretic peptide receptor 2 in unrelated patients with acromesomelic dysplasia type Maroteaux. Eur J Med Genet. 2019;62(9):103554. doi:10.1016/j.ejmg.2018.10.006. PMID: 30359775.
123. Mustafa S, Akhtar Z, Latif M, Hassan M, Faisal M, Iqbal F. A novel nonsense mutation in NPR2 gene causing Acromesomelic dysplasia, type Maroteaux in a consanguineous family in Southern Punjab (Pakistan). Genes Genomics. 2020;42(8):847-854. doi:10.1007/s13258-020-00955-3. PMID: 32506268. PMC7374443.
124. Acikgoz NB, Kılıç HB, Urel Demir G, Utine GE, Simsek Kiper PO, Kocaefe YC. A synonymous NPR2 variant causes acromesomelic dysplasia through aberrant pre-mRNA splicing. Differentiation. 2026;151:100978. doi:10.1016/j.diff.2026.100978. PMID: 42442044.
125. GeneGuidance. GPC6: clinical gene curation (omodysplasia 1).
126. Hume AN, Buttgereit J, Al-Awadhi AM, Al-Suwaidi SS, John A, Bader M, et al. Defective cellular trafficking of missense NPR-B mutants is the major mechanism underlying acromesomelic dysplasia-type Maroteaux. Hum Mol Genet. 2009;18(2):267-77. doi:10.1093/hmg/ddn354. PMID: 18945719. PMC2638773.
127. Badawi S, Varghese DS, Raj A, John A, Al-Musafir HS, Al-Ghamari AJ, et al. Unveiling the pathogenic mechanisms of NPR2 missense variants: insights into the genotype-associated severity in acromesomelic dysplasia and short stature. Front Cell Dev Biol. 2023;11:1294748. doi:10.3389/fcell.2023.1294748. PMID: 38078000. PMC10702138.
128. Simsek-Kiper PO, Urel-Demir G, Taskiran EZ, Arslan UE, Nur B, Mihci E, et al. Further defining the clinical and molecular spectrum of acromesomelic dysplasia type maroteaux: a Turkish tertiary center experience. J Hum Genet. 2021;66(6):585-596. doi:10.1038/s10038-020-00871-0. PMID: 33288834.
129. Geister KA, Brinkmeier ML, Hsieh M, Faust SM, Karolyi IJ, Perosky JE, et al. A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type. Hum Mol Genet. 2013;22(2):345-57. doi:10.1093/hmg/dds432. PMID: 23065701. PMC4817088.
130. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 826–8 (22.4 CNP-overexpression overgrowth syndrome).
131. Miura K, Namba N, Fujiwara M, Ohata Y, Ishida H, Kitaoka T, et al. An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS One. 2012;7(8):e42180. doi:10.1371/journal.pone.0042180. PMID: 22870295. PMC3411678.
132. Olney RC, Bükülmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab. 2006;91(4):1229-32. doi:10.1210/jc.2005-1949. PMID: 16384845.
133. Akgun-Dogan O, Díaz-González F, de Lima Jorge AA, Onenli-Mungan N, Menezes Andrade NL, de Polli Cellin L, et al. Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant. Eur J Hum Genet. 2024;32(10):1250-1256. doi:10.1038/s41431-023-01472-z. PMID: 37789084. PMC11500347.
134. Akimova D, Markova T, Orlova M, Kenis V, Skoblov M. Case Report: Dual pathogenic mechanism of a PRKG2 missense variant underlies an attenuated phenotype of acromesomelic dysplasia. Front Genet. 2025;16:1708985. doi:10.3389/fgene.2025.1708985. PMID: 41574272. PMC12823036.
135. Wilcox DT, Quinn FM, Ng CS, Dicks-Mireaux C, Mouriquand PD. Redefining the genital abnormality in the Robinow syndrome. -004. J Urol. 1997;157(6):2312-4. PMID: 9146662.
136. Gerber JA, Sheth KR, Austin PF. Robinow syndrome: Genital analysis, genetic heterogeneity, and associated psychological impact. Am J Med Genet A. 2021;185(12):3601-3605. doi:10.1002/ajmg.a.61981. PMID: 33277809.
137. Webber SA, Wargowski DS, Chitayat D, Sandor GG. Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome? Am J Med Genet. 1990;37(4):519-21. doi:10.1002/ajmg.1320370418. PMID: 2260599.
138. Atalay S, Ege B, Imamoğlu A, Suskan E, Ocal B, Gümüş H. Congenital heart disease and Robinow syndrome. Clin Dysmorphol. 1993;2(3):208-10. PMID: 8287182.
139. Tufan F, Cefle K, Türkmen S, Türkmen A, Zorba U, Dursun M, et al. Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome. Am J Med Genet A. 2005;136(2):185-9. doi:10.1002/ajmg.a.30785. PMID: 15952209.
140. Schwartz DD, Fein RH, Carvalho CMB, Sutton VR, Mazzeu JF, Axelrad ME. Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome. Am J Med Genet A. 2021;185(12):3576-3583. doi:10.1002/ajmg.a.61854. PMID: 32954672. PMC13619162.
141. Castells S, Chakurkar A, Qazi Q, Bastian W. Robinow syndrome with growth hormone deficiency: treatment with growth hormone. J Pediatr Endocrinol Metab. 1999;12(4):565-71. doi:10.1515/jpem.1999.12.4.565. PMID: 10417975.
142. Kawai M, Yorifuji T, Yamanaka C, Sasaki H, Momoi T, Furusho K. A case of Robinow syndrome accompanied by partial growth hormone insufficiency treated with growth hormone. Horm Res. 1997;48(1):41-3. doi:10.1159/000185369. PMID: 9195209.
143. Mazzeu JF, Pardono E, Vianna-Morgante AM, Richieri-Costa A, Ae Kim C, Brunoni D, et al. Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome. Am J Med Genet A. 2007;143(4):320-5. doi:10.1002/ajmg.a.31592. PMID: 17256787.
144. Hu R, Qiu Y, Li Y, Li J. A novel frameshift mutation of DVL1-induced Robinow syndrome: A case report and literature review. Mol Genet Genomic Med. 2022;10(3):e1886. doi:10.1002/mgg3.1886. PMID: 35137569. PMC8922971.
145. Shayota BJ, Zhang C, Shypailo RJ, Mazzeu JF, Carvalho CMB, Sutton VR. Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form. Am J Med Genet A. 2020;182(11):2632-2640. doi:10.1002/ajmg.a.61843. PMID: 32888393. PMC13619164.
146. Sridharan A, Kumar S, Guddeti A, Hari Kumar KVS. Robinow Syndrome Mimicking Congenital Adrenal Hyperplasia. JCEM Case Rep. 2026;4(1):luaf311. doi:10.1210/jcemcr/luaf311. PMID: 41477475. PMC12747829.
147. Jurk S, Schröck K, Biskup S, Stepan H, Springer C. [Omodysplasia Type II - first publication of de novo Mutation in FZD2 Gene]. Z Geburtshilfe Neonatol. 2026;230(1):51-54. doi:10.1055/a-2689-2624. PMID: 41022130.
148. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 622–5 (Léri-Weill dyschondrosteosis).
149. GeneGuidance. SHOX: clinical gene curation (LWD; Langer).
150. Ordaz-Robles T, Ramírez-García D, Dahan-Oliel N, Tavukcu S, Giampietro PF, Ríos-Ruíz JG, et al. Arthrogryposis With CNS Involvement in AFF3-Related KINSSHIP Syndrome: A Detailed Phenotypic Characterization From a Mexican Patient and Review of the Literature. Am J Med Genet A. 2026 [Epub ahead of print]. doi:10.1002/ajmg.a.70257. PMID: 42499216.
151. Arya VB, Raj M, Younes M, Chapman S, Irving M, Kapoor RR, et al. Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings. Horm Res Paediatr. 2020;93(5):335-342. doi:10.1159/000511874. PMID: 33238275.
152. Kılıç E, Çavdarlı B, Büyükyılmaz G, Kılıç M. Acromesomelic dysplasia-Maroteaux type, nine patients with two novel NPR2 variants. J Pediatr Endocrinol Metab. 2021;34(9):1115-1121. doi:10.1515/jpem-2021-0055. PMID: 34162036.
153. Haldar R, Gyanesh P, Samanta S. Anesthesia for a patient of acromesomelic dysplasia with associated hydrocephalus, Arnold Chiari malformation and syringomyelia. J Anaesthesiol Clin Pharmacol. 2013;29(4):555-7. doi:10.4103/0970-9185.119153. PMID: 24249999. PMC3819856.
154. Huang PC, Chang JH, Shen ML, Chen KB. Management of general anesthesia for a patient with Maroteaux type acromesomelic dysplasia complicated with obstructive sleep apnea syndrome and hereditary myopathy. J Anesth. 2012;26(4):640-1. doi:10.1007/s00540-012-1389-3. PMID: 22526432.
155. Mollaoğlu E, Uludağ Alkaya D, Yıldız CA, Kasap B, Tüysüz B. Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2. Clin Genet. 2023;103(5):574-579. doi:10.1111/cge.14277. PMID: 36504352.
156. Al-Yahyaee SA, Al-Kindi MN, Habbal O, Kumar DS. Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family. Am J Med Genet A. 2003;121A(1):9-14. doi:10.1002/ajmg.a.20256. PMID: 12900894.
157. Abdelrazek IM, Knaus A, Javanmardi B, Krawitz PM, Horn D, Abdalla EM, et al. Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding. Mol Genet Genomic Med. 2024;12(10):e70023. doi:10.1002/mgg3.70023. PMID: 39441036. PMC11497645.
158. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 258–9 (Ocular hypertelorism).
159. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 853–5 (Skeletal dysplasia charts).
160. GeneGuidance. WNT5A: clinical gene curation (Robinow AD 1).
161. Wang W, Song MH, Miura K, Fujiwara M, Nawa N, Ohata Y, et al. Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports. Am J Med Genet A. 2016;170A(2):426-434. doi:10.1002/ajmg.a.37463. PMID: 26567084.
162. OMIM® Online Mendelian Inheritance in Man. #301026 KEIPERT SYNDROME; KPTS. Johns Hopkins University; last edited 21/11/2022. https://omim.org/entry/301026. Accessed 27 October 2026.
163. OMIM® Online Mendelian Inheritance in Man. 601027 TIBIA, ABSENCE OR HYPOPLASIA OF, WITH POLYDACTYLY, RETROCEREBELLAR ARACHNOID CYST, AND OTHER ANOMALIES. Johns Hopkins University; last edited 12/10/2010. https://omim.org/entry/601027. Accessed 27 October 2026.
164. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 371–4 (10.7 Chondrodysplasia punctata, tibia-metacarpal type).
165. OMIM® Online Mendelian Inheritance in Man. #211350 KYPHOMELIC DYSPLASIA; KMD. Johns Hopkins University; last edited 13/02/2025. https://omim.org/entry/211350. Accessed 27 October 2026.
166. Robinow Syndrome Foundation. Robinow Syndrome Complete Care Guide [Internet]. 2025 Jul [accessed 27 Oct 2026]. Available from: https://www.robinow.org/RobinowCareGuide.pdf ; website: https://www.robinow.org/
167. Basman A, Akay G, Peker I, Gungor K, Akarslan Z, Ozcan S, et al. Dental management and orofacial manifestations of a patient with Robinow Syndrome. J Istanb Univ Fac Dent. 2017;51(2):43-48. doi:10.17096/jiufd.86251. PMID: 28955595. PMC5573473.
168. Mossaad AM, Abdelrahman MA, Ibrahim MA, Al Ahmady HH. Surgical Management of Facial Features of Robinow Syndrome: A Case Report. Open Access Maced J Med Sci. 2018;6(3):536-539. doi:10.3889/oamjms.2018.129. PMID: 29610615. PMC5874380.
169. Stancampiano MR, Suzuki K, O'Toole S, Russo G, Yamada G, Faisal Ahmed S. Congenital Micropenis: Etiology And Management. J Endocr Soc. 2022;6(2):bvab172. doi:10.1210/jendso/bvab172. PMID: 35036822. PMC8754418.
170. Eugia US LLC. Testosterone enanthate injection, USP. Prescribing information (openFDA effective_time 20260612, set id 82a98132-9d5f-40a5-8c4f-f52f2a5de60e). Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82a98132-9d5f-40a5-8c4f-f52f2a5de60e
171. Bayer Portugal, Lda. Testoviron Depot 250 mg/ml solução injetável (enantato de testosterona): Resumo das Características do Medicamento [Internet]. Lisboa: INFARMED, Infomed [accessed 18 Oct 2026]. Available from: https://extranet.infarmed.pt/INFOMED-fo/
172. Eli Lilly and Company. HUMATROPE (somatropin) for injection. Prescribing information (openFDA effective_time 20260820, set id a774e1ae-3997-49ee-8b0e-99a2b315d409; sections 1, 2, 4 and 5). Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a774e1ae-3997-49ee-8b0e-99a2b315d409
173. Goitia-Cárdenas M, Azotla-Vilchis CO, Miranda-Lora AL. Robinow syndrome and its response to growth hormone treatment: a case report and review of the literature. Bol Med Hosp Infant Mex. 2023;80(Supl 1):040-046. doi:10.24875/BMHIM.22000101. PMID: 36917807.
174. Renes JS, Reedijk AMJ, Hokken-Koelega ACS, Hendriks YMC, Bakker B, Boot AM, et al. Clinical Characteristics and Response to Growth Hormone Treatment in 27 Children With Heterozygous NPR2 Variants: Real-World Data. J Clin Endocrinol Metab. 2025;111(1):e166-e174. doi:10.1210/clinem/dgaf309. PMID: 40424589.
175. European Medicines Agency. Yuviwel (navepegritide): summary of opinion — CHMP positive opinion adopted 15/10/2026 (EMEA/H/C/006627). Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/yuviwel
176. Dauber A (Children's National Research Institute). Vosoritide for Selected Genetic Causes of Short Stature. ClinicalTrials.gov ID NCT04219007. Updated 18/03/2026. Available from: https://clinicaltrials.gov/study/NCT04219007
177. Dauber A, Zhang A, Shafaei N, Seaforth R, Pitner K, Dham N, et al. A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency. J Clin Endocrinol Metab. 2026;111(9):2416-2425. doi:10.1210/clinem/dgag157. PMID: 41967490. PMC13466934.
178. European Medicines Agency. Omnitrope (somatropin): EPAR – Product Information (Summary of Product Characteristics) [Internet]. Amsterdam: EMA [accessed 27 Oct 2026]. Available from: https://www.ema.europa.eu/en/documents/product-information/omnitrope-epar-product-information_en.pdf
179. Laboratórios Pfizer, Lda. Genotropin 5,3 mg/1 ml e 12 mg/1 ml pó e solvente para solução injetável (somatropina): Resumo das Características do Medicamento [Internet]. Lisboa: INFARMED, Infomed [accessed 27 Oct 2026]. Available from: https://extranet.infarmed.pt/INFOMED-fo/
180. Pfizer Brasil Ltda. Genotropin® (somatropina): bula para o profissional de saúde [Internet]. Text approved by ANVISA on 11/12/2025 [accessed 27 Oct 2026]. Available from: https://www.pfizer.com.br/files/Genotropin_Profissional_de_Saude_22.pdf
181. Kanakatti Shankar R, Oetgen ME, Martin BD, Shafaei N, Pitner K, Dauber A. Slipped Capital Femoral Epiphysis during Vosoritide Therapy for Short Stature: A Case Series. Horm Res Paediatr. 2026:1 [Epub ahead of print]. doi:10.1159/hrp/adaag011. PMID: 42678892.
182. Piwar H, Pawlasek J, Sielaff P, Sztachelska M, Ordak M. Langer mesomelic dysplasia as a rare manifestation of SHOX deficiency: a narrative review. Front Genet. 2026;17:1876732. doi:10.3389/fgene.2026.1876732. PMID: 42553923. PMC13436952.
183. Chang J, Azami N, Chen PJ, Yadav S. Management of a geminated tooth and supernumeraries in a patient with Acromesomelic Dysplasia, Maroteaux type. J Clin Orthod. 2025;59(8):518-526. PMID: 41109857.
184. Sinha R, Valecha B, Savithri HG, Garg H. Anaesthetic challenges in a patient with acromesomelic dysplasia posted for vitreoretinal surgery - A case study. Indian J Anaesth. 2023;67(Suppl 4):S305-S307. doi:10.4103/ija.ija_405_23. PMID: 38187968. PMC10768913.
185. Habib R, Amin-Ud-Din M, Ahmad W. A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B. Clin Dysmorphol. 2013;22(2):47-50. doi:10.1097/MCD.0b013e32835c6c8c. PMID: 23238279.
186. Tran TH, Cao MH, Luong LH, Le PT, Vu DC, Ta TD, et al. Acromesomelic dysplasia Maroteaux-type in patients from Vietnam. Am J Med Genet A. 2019;179(8):1420-1422. doi:10.1002/ajmg.a.61192. PMID: 31077548.
187. Faiyaz-Ul-Haque M, Ahmad W, Wahab A, Haque S, Azim AC, Zaidi SH, et al. Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia. Am J Med Genet. 2002;111(1):31-7. doi:10.1002/ajmg.10501. PMID: 12124730.