ACAN- and NPR2-Associated Short Stature

Literature and regulatory information updated: 17 October 2026.

Aggrecan (ACAN) disorders: short stature with advanced bone age and early-onset osteoarthritis or osteochondritis dissecans, familial osteochondritis dissecans, spondyloepiphyseal dysplasia, Kimberley type, and spondyloepimetaphyseal dysplasia, aggrecan type. Natriuretic peptide receptor B (NPR2) disorders: short stature due to heterozygous loss-of-function variants, acromesomelic dysplasia, Maroteaux type, and epiphyseal chondrodysplasia, Miura type, due to gain of function.

0. Initial Reference Table

This article brings together the entities caused by variants in the ACAN and NPR2 genes, two components of the growth plate whose heterozygous deficiency presents, in most cases, as apparently idiopathic short stature. SHOX deficiency (Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia), which shares the phenotype of mild disproportionate short stature, is included only in the differential diagnosis. The remaining acromesomelic and mesomelic dysplasias (Grebe, Hunter-Thompson, du Pan, PRKG2, Langer, Nievergelt and Robinow types) belong to the group of mesomelic and acromesomelic dysplasias and appear here only in the differential diagnosis. Overexpression of C-type natriuretic peptide (CNP) due to 2q37 translocations (NPPC), heterozygous NPPC variants and biallelic loss of function of NPR3 are treated as differentials within the same signalling pathway.

0.1. Identification of the entities

Sources: Orphanet [1–7], the nosology of genetic skeletal disorders of the International Skeletal Dysplasia Society (ISDS), 2023 revision [8], OMIM for numbers 616255 and 615923 [9, 10] and the international consensus on children born small for gestational age [11]. AD, autosomal dominant; AR, autosomal recessive; OMIM, Online Mendelian Inheritance in Man; MIM, OMIM entry number. Number 615923 corresponds to epiphyseal chondrodysplasia, Miura type, due to heterozygous NPR2 variants [10]; the atlas of bone dysplasias assigns it to the CNP overexpression syndrome [12], but the 2023 nosology links overexpression due to translocation to the NPPC gene (MIM 600296) and 619543 to NPR3 [8]. A search of the GeneReviews catalogue identified no chapter for ACAN or for NPR2 [13].

0.2. Reference clinical data

SD, standard deviation (equivalent to the standard deviation score, SDS, of the sources); ERN, European Reference Network; Endo-ERN, network for rare endocrine conditions, which includes growth disorders [32]; ERN BOND, network for rare bone diseases [33]. Orphanet prevalence classes derive from the number of published families and not from population screening; frequencies in cohorts of children with short stature measure diagnostic yield in a selected population and not prevalence in the general population.

1. Introduction

1.1. "Idiopathic" short stature as a provisional category

In general clinical practice, short stature is defined as a height more than two standard deviations (SD) below the mean for sex, age and population, which corresponds to a value below the 2.3rd percentile [34]; the Oxford Desk Reference uses the 0.4th percentile as the threshold for investigation in the British setting [35]. The 2025 French PNDS (French National Diagnosis and Care Protocol) on aggrecanopathies accepts two alternative criteria: height below the 3rd percentile on the French reference charts or a distance of more than 1.5 SD below the parental target height, together with a significant slowing of growth velocity [36]. When the history, examination, endocrine studies and biochemistry identify no cause, the child is labelled as having idiopathic short stature (ISS). For decades, most of these children were placed in the categories of familial short stature and constitutional delay of growth and puberty, which the Oxford Desk Reference estimates to account for 75% of cases of short stature in the United Kingdom, against about 1% for skeletal dysplasias [35]. Exome sequencing and multigene panels have shown that some of these children have a monogenic cause acting on the growth plate, and ACAN and NPR2 are among the most frequently involved genes. The 2026 international guideline on genetic testing in short stature includes both in the minimum list of genes with the strongest evidence of association with isolated short stature, together with COL2A1, FBN1, FGFR3, GH1, GHR, GHSR, IGF1R, IHH, NF1, PTPN11 and SHOX [16].

1.2. Historical milestones for aggrecan

The first human disease attributed to the aggrecan gene was spondyloepiphyseal dysplasia, Kimberley type. In 1990, Anderson and colleagues described a South African family with mild dominantly inherited spondyloepiphyseal dysplasia and showed that it was not due to defects of type II collagen [37]. In 2005, Gleghorn and colleagues identified in this multigenerational family, previously mapped to 15q26.1, a single base-pair insertion in the variable repeat region of exon 12 of the gene then called AGC1, which shifts the reading frame over 212 amino acids, with 22 cysteines, before a premature stop codon, and linked it to severe premature degenerative arthropathy [38]. In 2009, Tompson and colleagues described the recessive form, spondyloepimetaphyseal dysplasia, aggrecan type, in a nuclear family with three severely affected children; homozygosity mapping defined a 17.4 Mb interval containing 296 genes on chromosome 15, and prioritisation by selective expression in cartilage led to a homozygous missense variant in the C-type lectin domain [39]. In 2010, Stattin and colleagues linked a heterozygous variant in the same domain to dominant familial osteochondritis dissecans in a five-generation family [19].

The phenotype that is now most frequent was defined in 2014. Using exome sequencing in three families with dominant short stature, advanced bone age and early cessation of growth, Nilsson and colleagues found novel heterozygous ACAN variants and documented adult heights between −2.3 and −4.2 SD, childhood heights between −1.9 and −3.5 SD and a normal endocrine evaluation [40]. In 2015, Quintos, Guo and Dauber described the first diagnosis by targeted ACAN sequencing in a boy with three affected generations [41], and in 2016 Gibson and Briggs grouped the entities under the term "aggrecanopathies", a non-lethal spectrum ranging from spondyloepimetaphyseal dysplasia to short stature with accelerated maturation [42]. The international cohort of Gkourogianni and colleagues, published in 2017 with 103 individuals from 20 families, established the reference natural history [15].

1.3. Historical milestones for NPR2

Acromesomelic dysplasia was recognised by Maroteaux, Martinelli and Campailla in 1971 as "nanisme acromésomélique" [43], and Langer and colleagues summarised in 1977 the manifestations in 19 patients in childhood [28, 44]. In 1998, Kant and colleagues mapped the Maroteaux form to chromosome 9, with a LOD score of 5.1 in four families, in a 6.9 cM interval distinct from the locus of the Hunter-Thompson and Grebe forms on chromosome 20 [45]. In 2000, Faivre and colleagues described mild variants not linked to chromosome 9, evidence of genetic heterogeneity [46]. In 2004, Bartels and colleagues identified biallelic variants of NPR2, the gene for natriuretic peptide receptor B (NPR-B, also called guanylyl cyclase B), in 21 families, and observed that obligate carriers were shorter than matched controls [47]. Olney and colleagues quantified this effect in 2006 in an extended family [48], and Vasques and colleagues showed in 2013, in São Paulo, that heterozygous NPR2 variants accounted for a fraction of children classified as having ISS [23]. In 2015, Hisado-Oliva and colleagues described the phenotype resembling Léri-Weill dyschondrosteosis without Madelung deformity [26].

The opposite effect was identified in 2012, when Miura and colleagues described a three-generation Japanese family with tall stature, scoliosis and macrodactyly of the great toes due to a gain-of-function NPR2 variant [49]. In 2013, Hannema and colleagues described an extremely tall man without skeletal deformities carrying an activating variant in the kinase homology domain [50], and in 2014 Miura and colleagues proposed the category of "overgrowth CNP/NPR2 signalopathy", which includes CNP overproduction due to translocations [31]. The latter had been described in 2007 by Bocciardi and colleagues in a balanced t(2;7) translocation [51] and by Moncla and colleagues in a cluster of breakpoints at 2q37 with NPPC overexpression [52].

1.4. Current nomenclature and definition of the entities

The 2023 ISDS nosology names the three ACAN entities ACAN-related spondyloepiphyseal dysplasia (dominant, Kimberley type), ACAN-related spondyloepimetaphyseal dysplasia (recessive, aggrecan type) and ACAN-related short stature with advanced bone age, the latter with the note that some cases have osteochondritis dissecans and others only short stature, without skeletal signs and with normal bone age [8]. The Kimberley designation is historical, and the heterozygous form may be underdiagnosed because its manifestations are not distinctive compared with other mild spondyloepiphyseal dysplasias [20]. For NPR2, the nosology keeps acromesomelic dysplasia, Maroteaux type, in group 16 and tall stature with long great toes due to monoallelic gain-of-function variants in group 31, with the note that it corresponds to OMIM epiphyseal chondrodysplasia, Miura type [8]. Short stature due to heterozygous NPR2 variants has no entry of its own in the nosology or in Orphanet; OMIM calls it "short stature with nonspecific skeletal abnormalities 1" (SNSK1, MIM 616255), a designation also used by the consensus on children born small for gestational age [9, 11]. OMIM recognises genetic heterogeneity in this category: SNSK2 corresponds to brachydactyly type A1 due to heterozygous IHH variants (MIM 112500) [9].

The entities in this article are defined as follows. Heterozygous aggrecan deficiency (SSOAOD) is a primary bone dysplasia with proportionate or mildly disproportionate short stature, early cessation of growth, accelerated skeletal maturation, variable presence of early-onset osteoarthritis and osteochondritis dissecans and a normal endocrine evaluation [1]. Familial osteochondritis dissecans is the form in which multiple osteochondral lesions with disproportionate short stature predominate [2]. SEDK is the dominant spondyloepiphyseal dysplasia with premature degenerative arthropathy [3], and SEMD-ACAN is the biallelic form with extreme short stature [4]. On the NPR2 side, haploinsufficiency produces short stature without endocrine abnormality, sometimes with delayed bone age [13]; biallelic loss of function produces AMDM, a severe dwarfism with shortening of the middle and distal segments of the limbs and of the vertebrae, with normal face and intelligence [5]; and gain of function produces ECDM, an early proportionate overgrowth with scoliosis, arachnodactyly, macrodactyly of the great toes, coxa valga and susceptibility to slipped capital femoral epiphysis [6].

2. Molecular Genetics and Pathophysiology

2.1. The ACAN gene and aggrecan

The ACAN gene (aliases AGC1, CSPG1, CSPGCP, MSK16; MIM 155760; HGNC:319; UniProt P16112) is located at 15q26.1 and encodes the core protein of aggrecan, the main aggregating chondroitin sulphate proteoglycan of the cartilage extracellular matrix [13, 20]. The gene has 19 exons, and the protein is organised into three globular domains (G1, G2 and G3), an interglobular domain and a central glycosaminoglycan attachment region; G3 consists of two epidermal growth factor-like repeats, a C-type lectin domain and a complement regulatory protein module [36]. The N-terminal globular region (G1 domain) binds hyaluronic acid and forms large hydrated aggregates that give articular cartilage, the growth plate and the intervertebral disc the ability to resist compression [13]. The C-terminal globular domain (G3) contains a C-type lectin module that interacts with matrix proteins: the SEMD-ACAN variant alters the binding and kinetics of the interaction with tenascin-C [39], and the familial osteochondritis dissecans variant abolishes the interaction with fibulin-1, fibulin-2 and tenascin-R [19]. Exon 12 contains a 57-nucleotide variable number tandem repeat (VNTR) region whose length is polymorphic in the population and is associated with height in the general population [53]; the Kimberley family insertion lies in this region [38], which is also technically difficult to sequence [17].

Reduced functional aggrecan shortens the period of linear growth, accelerates skeletal maturation and makes articular and disc cartilage prone to early degeneration, which explains the association of short stature with osteoarthritis, osteochondritis dissecans and degenerative disc disease [13]. In the Acan+/− mouse (cmd, 7 bp microdeletion), normal at birth and with postnatal growth arrest, the growth deficit results mainly from reduced extracellular matrix and deficient chondrocyte hypertrophy, with little effect on proliferation; single-cell RNA sequencing showed suppression of Akt signalling in prehypertrophic and hypertrophic chondrocytes, associated with increased Camk1D [54]. Ovariectomised Acan+/− mice treated with estradiol cypionate 0.15 µg/g/week for 4 weeks showed no greater susceptibility to oestrogen-induced growth plate senescence, which points to intrinsic cartilage abnormalities as the cause of early growth cessation and argues against the hypothesis of oestrogen hypersensitivity [55]. In a chicken model of aggrecan deficiency, increased levels of activated mitogen-activated protein kinase (MAPK) were described in the growth cartilage, a finding used as the rationale for testing vosoritide [18]. These results are preclinical.

The proposed mechanisms are haploinsufficiency and a dominant-negative or neomorphic effect [42]. Truncating variants and deletions act through haploinsufficiency; for the G3 domain missense variants associated with osteochondritis dissecans, neither the recombinant proteins nor full-length aggrecan extracted from the cartilage of heterozygous patients are secreted at wild-type levels, and binding to matrix ligands is reduced [56]. The protein carrying the V2303M variant (historical numbering, probably = NM_001369268.1:c.7363G>A p.(Val2455Met)) of the original family is produced and is present in the patient's cartilage [19]. Gene dosage explains the phenotypic continuum: the same p.(Ala171Val) variant has been described in the homozygous state in siblings with SEMD-ACAN and in the heterozygous state in a 15-year-old boy with short stature, advanced bone age and dysmorphic features, and the siblings' heterozygous mother had severe short stature [21]. A heterozygous de novo variant in the G3 domain, NM_001369268.1:c.7492G>A p.(Gly2498Arg) (published as NM_013227.3:c.7378G>A p.Gly2460Arg), produced a phenotype intermediate between SEDK and SEMD-ACAN, with greater metaphyseal involvement [57].

2.2. The NPR2 gene and the CNP–NPR-B pathway

The NPR2 gene (aliases GUCY2B, GC-B, NPRB, ANPRB; MIM 108961; HGNC:7944; UniProt P20594) is located at 9p13.3 and encodes natriuretic peptide receptor 2 (NPR-B), a transmembrane guanylyl cyclase with an extracellular binding domain, a kinase homology domain (KHD), a helical oligomerisation hinge and a C-terminal guanylyl cyclase catalytic domain [13]. NPR-B is the primary receptor for C-type natriuretic peptide (CNP), encoded by NPPC at 2q37.1; CNP binding increases the production of cyclic guanosine monophosphate (cGMP), stimulates chondrocyte proliferation and endochondral growth at the growth plate and inhibits the MAPK pathway downstream of fibroblast growth factor receptor 3 (FGFR3) signalling [12, 13]. The pathway connects with the other genes in this article: SHOX has been described as a regulator of the FGFR3, CNP/NPR2 and BMP4 pathways and interacts with SOX5 and SOX6 to activate the aggrecan gene enhancer [58].

NPR2 activity determines height in an approximately dose-proportional manner. Biallelic loss of function causes AMDM; heterozygous loss of function causes short stature; gain of function causes tall stature with skeletal deformities [13]. A high-throughput reporter assay, combined with a second functional assay and published data, assigned an activity score to 245 NPR2 missense variants: 47 were classified as loss of function, 34 as partial loss and 14 as gain of function; activity was associated almost linearly with height (R² = 0.438; p = 5.8 × 10⁻¹⁰), with an additive effect on the polygenic background, and a phenome-wide association study showed association only with height and related traits [59]. The authors describe NPR2 as a growth "dimmer switch" and use the result as the rationale for NPR-B agonists [59].

Several heterozygous missense variants act through a dominant-negative effect demonstrated by 1:1 co-transfection with the wild-type allele: NM_003995.4:c.226T>C p.(Ser76Pro), c.788G>C p.(Arg263Pro) and c.2455C>T p.(Arg819Cys) suppressed cGMP production in response to CNP [23]; c.328C>T p.(Arg110Cys) is retained in the endoplasmic reticulum and c.1249C>G p.(Gln417Glu) reaches the cell surface, both with a dominant-negative effect [22]; c.2905G>C p.(Val969Leu) behaved in the same way [60]. In AMDM, the variants NM_003995.4:c.1231T>C p.(Tyr411His) and c.2761C>T p.(Arg921Ter) are retained in the endoplasmic reticulum, with complete loss of function, whereas c.2762G>A p.(Arg921Gln) reaches the surface with limited function, and serum NT-proCNP is increased in all patients [61]. In the AMDM proband studied by Olney, IGF-I was low, there was evidence of growth hormone (GH) resistance and plasma CNP and NT-proCNP were markedly elevated, whereas in carriers they were normal [48]. In gain-of-function variants, the receptor produces cGMP even without ligand (NM_003995.4:c.2647G>A p.(Val883Met)) [49], is hyperactive under basal conditions and with ligand (c.1462G>C p.(Ala488Pro)) [31] or shows an increased response to CNP and to the stimulatory effect of ATP, forming stable heterodimers with the wild type with a dominant-positive effect (c.1963C>T p.(Arg655Cys)); in this last patient plasma NT-proCNP was reduced [50].

2.3. Reference transcripts and variant normalisation

The MANE Select transcript of ACAN is NM_001369268.1 (transcript variant 3), not NM_013227.3/.4 (variant 1) used in most of the literature nor NM_001135 cited in curation databases [13, 62]. Up to exon 12 the c. numbering coincides in the two transcripts; downstream, in the C-terminal exons, the MANE transcript has 114 more nucleotides and 38 more amino acids, so NM_013227.3:c.7064T>C corresponds to NM_001369268.1:c.7178T>C [62]. The founder variants of 2009 and 2010 were published in a historical numbering that does not correspond to any current transcript: the SEMD-ACAN variant "D2267N" corresponds in ClinVar to NM_001369268.1:c.7255G>A p.(Asp2419Asn), with the alias D2267N [63]; the familial osteochondritis dissecans variant "V2303M" is returned in ClinVar as NM_001369268.1:c.7363G>A p.(Val2455Met), but the alias field does not display the historical designation, so the correspondence is probable and not confirmed [63]. The MANE Select transcript of NPR2 is NM_003995.4; NM_001378923 cited in curation databases is not the MANE transcript [62].

Normalisation sources: VariantValidator (GRCh38) and ClinVar [62, 63]. The Kimberley family insertion [38] and the exon 12 frameshift variant described by genomic coordinate in the case of Ruiz and colleagues [69] have no c. description in the sources and were not normalised. The heterozygous NPR2 loss-of-function variants from the Brazilian, Japanese and Czech cohorts are kept in the published nomenclature [22, 23, 70]. The repeat length of the exon 12 VNTR is not a monogenic cause of ISS: in a comparison of 128 Japanese patients with ISS, 63 of whom were born small for gestational age, with 100 controls, the repeat distribution was similar and did not correlate with height [53].

2.4. Variant spectrum and genotype–phenotype correlations in ACAN

In a review of 190 individuals with ACAN variants cited by Ruiz and colleagues, missense variants accounted for 35.71%, nonsense 26.53%, splicing 4.08%, in-frame deletions 3.06%, translocations 1.02% and start codon loss 1.02%; median height was −3.23 SD with truncating variants and −2.94 SD with missense variants, with no difference between sexes [69]. In the Dutch registry of children treated with GH, truncating variants were associated with lower baseline height than non-truncating variants (−2.8 versus −2.1 SD; p = 0.002) [71]. In the 20-family cohort of Gkourogianni there was no apparent correlation between variant type and the presence of joint complaints [15]. The variants associated with familial osteochondritis dissecans cluster in the G3 domain [56].

The French PNDS summarises the trends described without giving them individual predictive value: truncating variants (nonsense, frameshift and splicing) are associated with more marked short stature, early growth cessation and disabling joint destruction from adolescence or early adulthood; missense variants have a heterogeneous phenotype, from early joint involvement to moderate short stature without joint complications; and those in the G3 domain are more often associated with severe joint complications, with early disc degeneration and severe joint deterioration before the age of 40 [36]. The same document stresses that there is no strict genotype–phenotype correlation, and the 20-family cohort found no relationship between variant type and joint complaints [15, 36].

Deletions are a fraction of the spectrum that requires specific detection methods. In 2020 the first intragenic ACAN deletion (6.082 kb) was described in Slovenia, detected by array comparative genomic hybridisation and exome analysis; a carrier relative had normal height (−0.5 SD), a demonstration of intrafamilial variability [72]. A European series from Spain, Portugal and the Netherlands brought together 15 individuals from 6 families with ACAN deletions (3 complete and 3 intragenic), when until then only one multiexon deletion had been described; the patients had moderate to severe short stature, mildly disproportionate growth, mild dysmorphic features and, in most cases, joint involvement with early surgery [73].

2.5. Variant spectrum and genotype–phenotype correlations in NPR2

In AMDM, Bartels and colleagues found in 21 families 4 nonsense, 4 frameshift, 2 splicing and 11 missense variants, and the 3 missense variants tested had markedly deficient guanylyl cyclase activity [47]. In a Turkish series of 26 patients from 22 families with AMDM, a molecular diagnosis was obtained in 20 families, with 22 distinct variants (14 missense, 5 nonsense, 2 intronic and 1 single amino acid deletion), 15 of them novel; 19 patients were homozygous and 4 compound heterozygous, reflecting high consanguinity [74]. Synonymous variants can be pathogenic: c.2643G>A causes skipping of exon 17 and a premature stop codon [75], and the homozygous variant NM_003995.4:c.2484C>T creates a splice donor site with partial truncation of the exon, frameshift and premature termination, probably with nonsense-mediated mRNA decay (NMD); heterozygotes express both the normal and the aberrant transcript [29].

In heterozygotes, the Dutch registry of 27 children identified 18 variants (5 truncating, 11 non-truncating and 2 splicing), mainly in the binding domain or the KHD; truncating variants were associated with lower height than non-truncating variants (−3.3 versus −2.5 SD; p = 0.02) and KHD variants with lower height than those in other domains (−3.2 versus −2.5 SD; p < 0.01) [25]. In a Chinese cohort with a literature review up to August 2020, the height gain with GH was greater with variants in the guanylyl cyclase catalytic domain than in the extracellular binding domain (median 1.9 versus 0.6 SD; p = 0.019) [76]. The variant NM_003995.4:c.1579C>T p.(Leu527Phe) makes the receptor almost insensitive to the stimulatory effect of ATP on CNP-dependent activity [75]. In gain of function, the same p.(Val883Met) variant was found in two independent families, in Japan and Russia [30, 49], and the KHD variant p.(Arg655Cys) produced extremely tall stature without skeletal deformities [50]. Wang and colleagues found, in 4 cohorts, 8 loss-of-function variants in short individuals and 1 gain-of-function variant in a tall individual, and suggested that NPR2 gain of function may be a more common cause of tall stature than previously thought [77].

2.6. Inheritance, penetrance and expressivity

The heterozygous forms of ACAN (SSOAOD, familial osteochondritis dissecans, SEDK) and of NPR2 (short stature and ECDM) are transmitted in an autosomal dominant manner; SEMD-ACAN and AMDM are autosomal recessive [8]. Penetrance for short stature is incomplete and expressivity is variable for both genes. Healthy Chilean children with normal height, advanced bone age and pathogenic ACAN variants have been described [78], as well as a carrier of an intragenic deletion with −0.5 SD [72] and, in a Chinese family with 18 short individuals, 4 carriers of an NPR2 variant without marked short stature [79]. In NPR2-related short stature, the mean height of adult obligate carriers of AMDM was 5.7 cm lower than that of matched controls [28], and in a 39-member family the 16 carriers had a height of −1.8 ± 1.1 SD, compared with −0.4 ± 0.8 SD in the 23 non-carriers (p < 0.0005), with no difference in body proportions [48]. The height of NPR2 heterozygotes decreases progressively with age: in a multigenerational North American family, the height SD of heterozygotes (−2.06 ± 0.97) fell significantly with age, whereas that of siblings with the wild-type genotype (−1.37 ± 0.59) remained constant [80]. The same pattern of SD loss with age is seen in aggrecan deficiency, with a median of −3.05 SD in adults versus −2.25 SD in children [81].

2.7. Allelic disorders, related entities and gene–disease validity

ACAN has four recognised allelic phenotypes (SSOAOD, familial osteochondritis dissecans, SEDK and SEMD-ACAN), which form a continuum of severity dependent on dosage and on the location of the variant [21, 42, 57]. NPR2 has three phenotypes that depend on dosage and on the direction of the effect (AMDM, heterozygous short stature and ECDM) [13]. In the same pathway, heterozygous variants in the CNP ring encoded by NPPC cause autosomal dominant short stature with small hands: in a screen of 668 patients (357 with disproportionate short stature and 311 with dominantly inherited ISS) and of 29 families by exome sequencing, 2 variants with a significant reduction in cGMP were identified, one of them already linked to the lbab mouse mutant [82]. CNP overexpression due to rearrangements involving the NPPC locus and biallelic loss of function of NPR3 (Boudin-Mortier syndrome) produce overgrowth with long great toes [8, 12]. In the GenCC database, the association of NPR2 with AMDM is classified as definitive and the associations with the two dominant phenotypes are classified as moderate to strong; ClinGen had no validity assertion for NPR2 in September 2026 [13].

3. Clinical Spectrum and Manifestations by System

3.1. Heterozygous aggrecan deficiency (SSOAOD): growth pattern

The central feature of heterozygous aggrecan deficiency is short stature that worsens with age because skeletal maturation advances and growth ends early. In the international cohort of 103 individuals (57 female and 46 male) from 20 families, with patients from the United States, several European countries (Spain, the Czech Republic, Sweden) and Brazil, the variant co-segregated with the phenotype in all families; median adult height was −2.8 SD (range −5.9 to −0.9), with a history of early growth cessation, whereas children's height was less affected (median −2.0 SD; −4.2 to −0.6) and the median difference between bone age and chronological age was +1.3 years (0.0 to +3.7) [15]. The spectrum ranges from mild proportionate short stature to mild skeletal dysplasia with disproportion and brachydactyly [15]. Advanced bone age is not obligatory: in a series of atypical forms, a 6-year-old boy with −1.75 SD had a bone age advanced by 3 years and a de novo variant with no family history, and a 12-year-old boy with −3.9 SD had a bone age about 1 year below chronological age and a dominant history with early-onset osteoarthritis [64]. In an English series of 9 individuals from 4 families, bone age by the TW3 method was delayed in 3 children and advanced in 1, and one child had short long bones on prenatal ultrasound [83]. In the literature compilation cited by the French PNDS, about 92% of heterozygous carriers had a height below −2 SD, with values between −5.5 and +1.1 SD in children and between −6.5 and −0.9 SD in adults, and marked height differences within the same family were described; absence of the pubertal growth spurt is suggestive, and overweight and obesity are frequent, as in other constitutional bone diseases [36].

About 30–40% of children with aggrecan deficiency are born small for gestational age (SGA), with birth length always more affected than weight, and 14% of short SGA children with bone age advanced by 6 months or more have ACAN variants [11]. In the Dutch cohort of 290 SGA children treated with GH, ACAN was sequenced in the 29 with bone age advanced by at least 0.5 years, and 4 (13.8%) had a variant; midface hypoplasia (p = 0.003), joint problems (p = 0.010) and broad great toes (p = 0.003) were associated with the diagnosis, which was found in 0% of children with at most one of these features, in 50% of those with two and in 100% of those with all three [84].

3.2. SSOAOD: dysmorphic and skeletal features

The dysmorphic features are subtle and variable: mild to relative macrocephaly, frontal bossing, midface hypoplasia, flat nasal bridge, brachydactyly, broad thumbs and lordosis [1]; broad great toes and lumbar lordosis have been described repeatedly [13]. In the Dutch registry of 36 children treated with GH (23 boys and 13 girls, 25 variants), disproportion, advanced bone age, early-onset osteoarthritis in the family, midface hypoplasia and brachydactyly were present in most, but about 20% of the children had no specific features; median height at the start of GH was −2.6 SD (interquartile range −3.2 to −2.2) [71]. In a Turkish cohort of 47 individuals from 20 families (59.6% children), with height up to −2 SD or predicted adult height below −2 SD, the most frequent features were high forehead, upslanting palpebral fissures, depressed nasal bridge, low-set anteverted ears, mild pectus and brachydactyly; osteochondritis dissecans was present in 6.5%, early-onset osteoarthritis in 8.7%, advanced bone age in 28.6%, scoliosis in 19.6%, lumbar hyperlordosis in 13% and vertebral endplate changes in 10.9% [85]. In a Chinese series of 8 children with a mean height of −3.30 ± 0.85 SD, dysmorphic features were significantly less frequent than in Western populations and only 24.24% of the children in the review had significantly advanced bone age [86]. The English series described in the parents axial changes similar to those of hypochondroplasia (reduced caudal widening of the lumbar interpedicular distance and short pedicles) and a short 4th metacarpal in 4 individuals [83]. The PNDS specifies that macrocephaly is generally below +3 SD and, in its phenotype table, also records exostoses, a waddling gait in some patients and elbow involvement (swelling, pain, loss of mobility, flattening of the humeral capitellum, enlargement of the radial head, loose bodies and, rarely, ulnar nerve compression) [36].

3.3. SSOAOD: joints and spine

Joint disease is the main source of morbidity in adults. In the 20-family cohort, early-onset osteoarthritis was present in 12 families and intervertebral disc disease in 9 [15]. A targeted musculoskeletal assessment of 22 individuals from 9 families, with history, examination, gait analysis, joint-specific patient-reported outcomes and imaging, showed that children had subtle disproportion and clinically silent joint disease, with osteochondritis dissecans in 25%, whereas adults had frequent joint symptoms (declining knee function, disability from spinal complaints, reduced physical activity), osteoarthritis or osteochondritis dissecans in 90% and orthopaedic surgery in 60% [81]. In the phenotyping of 22 carriers from the Cincinnati trial (12 children and 10 adult first-degree relatives), osteochondritis dissecans was found in 3 of 12 children and in 1 of 10 adults, and osteoarthritis in 0 of 12 children and in 8 of 10 adults, by magnetic resonance imaging (MRI) or radiography of the knees [87]. Osteoarthritis and osteochondritis dissecans usually appear in late adolescence or young adulthood [18]. Genu valgum is rare in aggrecan deficiency but has been described, including a GH-treated case with progressive genu valgum that underwent surgery [18]. ACAN deletions were associated with joint involvement in most patients, with early surgery [73]. According to the PNDS, early joint deterioration is the second most frequently reported manifestation, after short stature, begins in late adolescence in most patients described and mainly affects the knee, but also the elbows, spine, ankles, hips and hands; in adults, axial deviations (genu valgum or varum) and back pain with disc disease are part of the assessment [36].

3.4. SSOAOD: other manifestations described

Some extraskeletal manifestations have been described in isolated series without demonstration of causality. In a Chinese series of 20 patients, 3 of 11 girls (27.3%) had central precocious puberty, 4 boys had intellectual disability or global developmental delay and some patients had a subnormal GH response on stimulation tests [88]. Otosclerosis was described in a Slovenian patient [72]. In a Canadian boy with multifocal osteochondritis dissecans, high-turnover osteoporosis and Chiari I malformation with syringomyelia were found, with no established association with ACAN [17]. In a Chinese hospital cohort of 37 children with ACAN variants, 78.4% had short stature and 75.7% advanced bone age, and the 13 untreated children had a final growth velocity between 0 and 6.98 cm/year over 3 to 58 months of follow-up [89]. The French PNDS, by contrast, considers that the aggrecanopathies, including the recessive form, have no neurosensory or neurodevelopmental involvement, and does not recommend specific screening for deafness, ophthalmological abnormalities or developmental disorders; the findings of the Chinese series and otosclerosis have not been shown to be part of the disease [36, 72, 88].

3.5. Familial osteochondritis dissecans

In the five-generation family described by Stattin, osteochondritis dissecans was associated with short stature and early-onset osteoarthritis [19]. Orphanet describes the entity as abnormal chondroskeletal development with disproportionate short stature and deformity mainly of the knees, hips, ankles and elbows, with onset in late childhood or adolescence [2]. Three new families with missense variants in the G3 domain were described in 2022 [56]. In OMIM the entity is grouped with SSOAOD (MIM 165800) and the ISDS nosology treats it as part of the same phenotype [8].

The French PNDS adds contextual data, but presents as the overall incidence of osteochondritis dissecans a value (about 6 cases per 100,000 people per year) that, in the source study, refers only to symptomatic knee lesions. In the Olmsted County (Minnesota) population study, with 302 patients diagnosed between 1976 and 2014, the adjusted annual incidence of symptomatic osteochondritis dissecans of the knee was 6.09 per 100,000 person-years, 8.82 in males and 3.32 in females, with the peak between 11 and 15 years of age (39.06 and 16.15 per 100,000, respectively) [90]; about two-thirds of knee lesions are located in the medial femoral condyle and one-third in the lateral condyle [36]. In the series of Stattin (2022) and Tang (2024), 38% of the ACAN variants identified were associated with familial cases of osteochondritis dissecans [36]. Most lesions heal spontaneously in children with open growth plates; when they do not heal, the osteochondral fragment may detach and form a loose body, with exertional pain, mechanical locking and stiffness [36]. In the aggrecanopathies, the lesions appear earlier than in idiopathic forms, may be multiple and are not limited to the knee; the PNDS phenotype table ranks the sites by frequency (knee, ankles, elbows, hips) and gives adult heights of 152–167 cm in men and 145–156 cm in women [36].

3.6. Spondyloepiphyseal dysplasia, Kimberley type

SEDK presents in childhood with near-proportionate short stature, a stocky habitus and progressive osteoarthropathy of the weight-bearing joints [20]. In the original family, adult height ranged from 141 to 162 cm in men and from 138 to 149 cm in women, and osteoarthropathy of the large joints progressed slowly, with increasing pain and restriction of movement [20]. Radiologically there is mild platyspondyly with irregular and sclerotic endplates, flattened and irregular epiphyseal ossification, especially of the femoral heads, and mild widening of the proximal femoral metaphyses [20]. In patient 1 of the atlas, a 4-year-old boy with an affected older brother and father, there was double-curve scoliosis, femoral heads not yet ossified, flared iliac wings and coxa valga; at 7 years the distal femoral and proximal tibial epiphyses were small and flattened, and the hands were normal [20]. The French PNDS places the SEDK variants in exon 12 and associates them with the G3 domain; the variant in the original family is, however, an insertion in the variable repeat region of exon 12, which encodes the central glycosaminoglycan attachment region and not G3 [36, 38]. The PNDS adds that severe progressive joint dysplasia may require joint replacement in adulthood [36].

3.7. Spondyloepimetaphyseal dysplasia, aggrecan type

SEMD-ACAN is evident from birth [20]. The picture includes midface hypoplasia with almost absent nasal cartilage, prognathism, relative macrocephaly, hoarse voice, severe short-limbed short stature and joint laxity, especially of the hands [20], as well as a short neck, barrel chest, brachydactyly, irregular epiphyses with widened metaphyses, platyspondyly and cervical vertebral clefts [13]. Adult height in the original family ranged from 66 to 71 cm, with increased joint mobility and mild scoliosis; apart from this the patients were healthy [20]. Patient 4 of the atlas, an adult, had thoracolumbar kyphoscoliosis with flattened and anteriorly wedged vertebral bodies, mild cervical kyphosis and marked pectus excavatum [20]. In the 2024 Turkish report, two siblings born to first cousins were homozygous for p.(Ala171Val) [21]. The French PNDS describes height below −8 SD, a short neck, broad chest and mild lumbar hyperlordosis, and its phenotype table adds an upper/lower segment ratio of 1.1–1.2, mesomelia and rhizomelia, telescoping interphalangeal joints, accessory carpal ossification centres, horizontal nail beds and bronchospasm in one patient; in addition to the 3 homozygous siblings of 2009, it records 1 compound heterozygous patient described in 2019 with a milder phenotype [36]. Heterozygous carriers may have mild proportionate short stature [36]. Homozygous loss of function of ACAN has been known in veterinary medicine since the 19th century as a cause of very severe dwarfism, such as the "bulldog calf" of Dexter cattle and ACAN-related equine dwarfism [36].

3.8. Short stature due to heterozygous NPR2 variants

In the Dutch registry of 27 children (18 boys and 9 girls), median baseline height was −2.9 SD (interquartile range −3.3 to −2.4), and 89% had mild features suggestive of skeletal dysplasia, mainly mild disproportion and dysmorphic features of the hands [25]. In the review of published cases by Ke and colleagues, brachydactyly was present in 56.2%, shortening of the metacarpals or metatarsals, especially the 4th and 5th, in 26.1% and clinodactyly in 21.7%, together with facial dysmorphic features [76]. The SGA consensus describes an increased sitting height/height ratio, shortening of the metacarpals and phenotypic or radiographic indicators similar to those of SHOX deficiency, but without Madelung deformity, with normal GH, IGF-I and IGFBP-3 and a mean deviation at birth of −0.8 SD in weight and −2.3 SD in length [11]. OMIM describes in SNSK1 a height significantly lower than that of non-carrier relatives, with increased arm span/height and sitting height/height ratios, delayed bone age and shortening of the metacarpals [9]. In the three Brazilian families of Vasques, a 15-year-old boy with −2.1 SD and appropriate bone age had at 12.9 years an arm span of +3.7 SD and a sitting height/height ratio of +2.3 SD, with a carrier father (−4.55 SD) and sister (−3.8 SD); a 17-year-old boy measuring 158 cm (−2.4 SD) had a short 5th metacarpal on one hand and a carrier mother with a sitting height/height ratio of +3.3 SD; and a 20-year-old man with proportionate short stature (158 cm, −2 SD) and mildly delayed bone age had a carrier father (−2.8 SD) and grandfather (−3.7 SD) [9]. In the two Japanese families of Amano, the variants were inherited from the mother, with adult heights of the proband and mother of −2.8 and −1.3 SD in one family and −2.6 and −2.5 SD in the other [9]. Bone age may be delayed [13]. In a 5.1-year-old Brazilian boy with −3.1 SD, a prominent forehead, depressed nasal bridge, centripetal adiposity and high-pitched voice mimicked GH deficiency, with low IGF-I and a normal GH peak [60]. In a Slovenian cohort of 150 children with ISS, the growth pattern of carriers ranged from low-normal to marked short stature, and there was an increase in body mass index (BMI), with a mean gain of +1.41 SD, a finding not previously described [24]. In a 5.2-year-old Chinese proband, proportionate short stature was accompanied by delayed bone age, dysmorphic facial features, prematurity, SGA birth and hypospadias [79].

3.9. Acromesomelic dysplasia, Maroteaux type

AMDM presents at birth; the short limbs may be recognised clinically, but the distinctive radiological findings only appear during the first year [27]. Birth weight may be normal, the linear growth deficit becomes evident in the first year and the radiological changes are diagnostic by 2 years [28]. The major findings are short-limbed dwarfism, acromelic and mesomelic micromelia more marked in the upper limbs, redundant skin of the fingers in children and adults, subluxation or dislocation of the radial head, relatively large great toes and a relatively large head with midface hypoplasia, depressed nasal bridge and small nose [27]. The forearms are bowed and relatively shorter than the upper arms, elbow extension is limited, the fingers and nails are short without nail dysplasia, and there is low thoracic kyphosis, lumbar hyperlordosis and prominent buttocks [28]. Corneal clouding, hydrocephalus and mild intellectual disability have occasionally been described [28]. Intellectual development is normal; motor milestones may be delayed because of the large head and short limbs, sexual development may be delayed and, in adults, degenerative changes of the spine appear with narrow disc spaces and intervertebral foramina, especially in the lumbar region [27]. In the Turkish series, only the skeleton was consistently affected, and the extraskeletal anomalies observed (global developmental delay or intellectual disability, nephrolithiasis, renal cyst, oligodontia) were possibly attributed to other variants related to consanguinity [74]. IGF-I is around −2 SD with relatively high stimulated GH, a pattern of relative GH resistance [91]. A case of NPR2-related AMDM was identified by ancient DNA analysis in a 12,000-year-old individual [92].

Mild forms exist. A British boy of non-consanguineous parents, compound heterozygous for two missense variants, had at 11 years a height on the 2nd percentile, relative macrocephaly, mild mesomelic shortening and brachydactyly, with his father on the 2nd percentile for height without shortening [68].

3.10. Epiphyseal chondrodysplasia, Miura type (NPR2 gain of function)

Overgrowth is prenatal and postnatal, with birth length and height between +3 and +6 SD, and is accompanied by a proportionate tall or marfanoid habitus, elongated and broad great toes, long hands and feet with arachnodactyly, sometimes camptodactyly and clinodactyly, and kyphoscoliosis; arterial hypertension may appear in adulthood [12]. In mid-childhood the great toe deformity, camptodactyly and kyphoscoliosis appear, often requiring orthopaedic intervention [12]. In the four-generation Korean family with p.(Ala488Pro), with 11 affected members, the phenotype included tall stature, macrodactyly of the great toes, scoliosis, coxa valga and slipped capital femoral epiphysis [31]. In the Russian family of 5 affected members with p.(Val883Met), the mother had borderline tall stature and elongated great toes operated on in childhood, and the children had tall stature, scoliosis and elongated fingers that raised suspicion of Marfan syndrome, with progressive valgus deformities of the hip, knee and ankle treated with osteotomies, guided growth and arthrodesis of the great toes; radiologically there was coxa valga, scoliosis, multiple pseudoepiphyses of the digits with unequal elongation and ankle valgus [30]. Miura's Japanese proband, a 15-year-old boy with an affected mother and maternal grandmother, had a height above +3 SD at birth and at 15 years, elevated bone formation and resorption markers and a spinal bone mineral density of −3.9 SD corrected for height [10]. In the Korean family, the 11 affected members had coxa valga with dysplasia of the proximal femoral epiphyses, tall vertebral bodies with irregular endplates and normal echocardiography and ophthalmological examination, and 2 had slipped capital femoral epiphysis [10]. Reanalysis of the Korean proband's radiographs showed multiple extra epiphyses in the hands [10]. A mother and her two daughters with a 6 bp NPR2 deletion, activating in fibroblasts and transfected cells, had progressive macrodactyly of the great toes, ankle valgus, long thumbs and pseudoepiphyses of the middle and proximal phalanges of all digits; the mother and one daughter underwent epiphysiodesis of the great toes in childhood [10]. The Dutch patient with p.(Arg655Cys), assessed at 61 years, had +5.2 SD, long fingers, mild scoliosis, broad but not elongated great toes, mild hip dysplasia and normal echocardiography, and had undergone epiphysiodesis of the distal femur and proximal tibia and fibula [10, 50], and one patient with an NPR2 variant in the atlas lacked the distinctive elongation of the great toes [12]. Blood cGMP was elevated in the Japanese family [49], and NT-proCNP was normal with p.(Ala488Pro) [31] and reduced with p.(Arg655Cys) [50].

3.11. Natural history and treated disease

The adult height data of Gkourogianni, Nilsson and Alexandrou refer mainly to untreated individuals [15, 40, 81]. In the 2017 cohort, the 19 individuals treated with GH had a mean adult height of −2.5 SD, compared with −3.0 SD in untreated individuals, in a non-randomised comparison [69]. The AMDM adult heights in the atlas and in Smith (94–123 cm and 96.5–124.5 cm) and the mean of about 120 cm cited by Arya come from untreated patients; the two British brothers treated with high-dose GH reached 130.5 and 134 cm [27, 28, 91].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the prenatal period, aggrecan deficiency may present with short long bones on ultrasound [83], and short stature of prenatal onset generally suggests a skeletal dysplasia [35]. In AMDM the short limbs may be recognised at birth, but neonatal radiographs are often normal [27, 28]; ECDM presents with a birth length of +3 to +6 SD [12]; SEMD-ACAN is evident at birth because of severe short stature and midface hypoplasia [20].

In infants and young children, suspicion of AMDM arises with progressive shortening of the tubular bones of the hands, abnormal by about 6 months, and of the forearm from the first year [27]. Bone age is of limited use below 3 years [16], which delays recognition of the accelerated maturation of aggrecan deficiency, and interpretation is difficult below 4 years unless it is advanced [35].

At school age, the settings that should raise suspicion of ACAN are short stature with advanced bone age, especially with a dominant family history of short stature and early-onset osteoarthritis in a parent [14, 93], the SGA child without catch-up growth with advanced bone age and midface hypoplasia, broad great toes or joint complaints [11, 84] and the short child with brachydactyly, broad thumbs and lordosis [1]. The 2026 international guideline points out that most primary growth disorders have normal or delayed bone age, but that in prepubertal children with heterozygous pathogenic variants of ACAN or GNAS advanced bone age is frequent [16]. Suspicion of heterozygous NPR2 arises in the child with mildly disproportionate short stature, brachydactyly, shortening of the 4th and 5th metacarpals and an appearance similar to SHOX deficiency without Madelung deformity, especially when SHOX analysis is negative [11, 26, 76]. Madelung deformity points to SHOX [16].

In adolescence, the warning signs of ACAN are early growth cessation with a final height below that predicted, puberty with already advanced bone age and osteochondritis dissecans lesions of the knee, ankle or elbow, sometimes in atypical or multifocal locations [17, 40]. For the French PNDS, absence of the pubertal growth spurt is an indicator of constitutional bone disease, and a poor response to GH in a short child may suggest a genetic cause such as ACAN, without being a diagnostic criterion, because response data are scarce [36]. Suspicion of ECDM arises in the very tall adolescent with long great toes, arachnodactyly and scoliosis in whom the evaluation for Marfan syndrome does not confirm the diagnosis [30, 31].

In adults, osteoarthritis of the large joints or early-onset disc disease in a short individual, especially with short relatives, suggests aggrecan deficiency or SEDK [15, 20]. Identification of an affected adult at the consultation for a child with short stature is the most frequent situation, because parents with short stature similar to the child's indicate dominant inheritance [16].

4.2. Warning signs during treatment and emergency signs

Hip or knee pain or limping in a child with aggrecan deficiency on vosoritide or GH requires slipped capital femoral epiphysis to be excluded. In the phase 2 vosoritide trial, slipped epiphysis occurred in 2 of 12 participants with ACAN, all after more than 12 months of treatment and of the rare valgus type [94], and slipped epiphysis is also a rare adverse effect of GH that occurs during periods of rapid growth [18]. Progression of genu valgum or coxa valga under treatment preceded slipped epiphysis in some cases and led to discontinuation of the drug in children with ACAN [18]. In ECDM, susceptibility to slipped epiphysis is part of the natural history [6, 31]. New joint pain during GH treatment in a patient with ACAN should prompt assessment for osteochondritis dissecans; in the Canadian case, pain in the elbows, knees and ankles appeared about 6 months after the start of GH [17]. On vosoritide, transient hypotension after injection is the acute effect that requires preventive measures [95]. There is no emergency card for the aggrecanopathies, and the French PNDS considers that there is no evidence to justify creating one; therapeutic education should teach the patient and family to recognise the signs of deterioration that require urgent consultation [36]. Signs of spinal cord involvement (pyramidal syndrome, motor or sensory deficit), especially at the craniocervical junction, sought in the systematic neurological examination, require neuroradiological study [36].

4.3. Newborn screening

There is no newborn screening for any of the entities in this article in the sources consulted. Diagnosis depends on serial auxology, assessment of proportions and bone age and phenotype-driven genetic testing [16].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Absence of formal clinical criteria

None of the entities in this article has validated formal clinical criteria; the diagnosis is molecular, supported by auxology, body proportions, bone age and radiology. The only published scoring system is that of the Dutch SGA cohort, in which the presence of bone age advanced by at least 0.5 years with midface hypoplasia, joint problems and broad great toes discriminated carriers of ACAN variants (0% with at most one feature, 50% with two and 100% with three), in a set of only 29 sequenced children [84]. The Growth Hormone Research Society (GRS) states that advanced bone age in a family with dominantly inherited short stature may suggest ACAN variants and that advanced bone age with a family history of early arthritis points to the same diagnosis [93]. The French PNDS defines the diagnosis of an ACAN-related disorder by the identification of a pathogenic (class 5) or likely pathogenic (class 4) variant consistent with the observed mode of transmission, usually autosomal dominant, and points out that the somatotropic and thyroid axes and calcium-phosphate metabolism are normal in these patients [36].

5.2. Clinical and auxological assessment

The assessment includes the prenatal and perinatal history, chronic diseases, development, family history and exposures, body proportions, dysmorphic features, head circumference, BMI and pubertal stage [34]. The three-generation pedigree should record relatives' heights, consanguinity, age at puberty and the parents' final height [16, 35]. Target height is calculated, in girls, as [(father's height − 13) + mother's height]/2, with a range of ±9 cm, and in boys as [(mother's height + 13) + father's height]/2, with a range of ±10 cm, 13 cm being the mean difference between adults of the two sexes in the United Kingdom [35]. In families with ACAN or NPR2, an affected parent lowers the target height and makes the child appear to be growing in line with the familial potential. The examination measures arm span, sitting height and segment ratio, distinguishes rhizomelia from mesomelia and looks for deformities (bowing, Madelung deformity), brachydactyly, broad thumbs and shortening of the 4th and 5th metacarpals and metatarsals [35]. Table A16 of the Oxford Desk Reference includes the acromesomelic dysplasias in the group with short limbs and a normal trunk, with involvement of the hands and advanced bone maturation in the hands [96].

The laboratory evaluation, recommended in all short children [16], includes biochemistry, thyroid function, full blood count, erythrocyte sedimentation rate, urinalysis and coeliac disease antibodies [35]. In aggrecan deficiency and NPR2 haploinsufficiency, the GH/IGF-1 axis is normal, and its evaluation serves to exclude GH deficiency, not to confirm the diagnosis [11, 13]. The GRS considers the GH stimulation test unnecessary when an alternative diagnosis such as aggrecan deficiency exists, unless there is additional suspicion of GH deficiency from specific growth curves or very low IGF-I [93]. In AMDM, low IGF-I reflects relative GH resistance [48, 91].

5.3. Bone age and radiology

A radiograph of the hand and wrist for bone age is indicated in any short child [16]; in addition to maturation, it may show subtle signs of dysplasia associated with SHOX, FGFR3, NPR2 and IHH [93]. Automated bone age methods increase consistency but may miss radiological signs of dysplasia, and the Greulich and Pyle standards derive from white North American children of predominantly northern European ancestry [93]. A skeletal survey is indicated when dysplasia is suspected (disproportion, deformities, abnormal mineralisation) and includes anteroposterior and lateral radiographs of the skull and spine, anteroposterior radiographs of the pelvis and of all four limbs (unilateral if there is no asymmetry) and of the hands and feet; indicators include disproportionate short stature, brachydactyly, severe or progressive kyphoscoliosis, altered joint mobility and a waddling gait [16].

For the aggrecanopathies, the French PNDS proposes an initial survey with conventional radiographs of the thoracolumbar spine (lateral), the hands and feet (frontal), one entire upper limb (frontal), the lower limbs standing (frontal) with the pelvis (or the pelvis and both knees, frontal) and bone age; conventional radiographs are preferable to EOS imaging because they show the metaphyses and epiphyses better [36]. MRI assesses cartilage and osteochondral lesions and, in the cervical and thoracolumbar spine, degenerative disc disease, especially in the presence of persistent back pain or neurological signs; the PNDS indicates it at diagnosis and in the event of a clinical event, but not as a routine examination, also because of the difficulty of performing and interpreting it in young children [36].

5.4. Recommendations for genetic testing

The 2026 international guideline of the International Growth Genetics Guideline Consortium, developed using the GRADE methodology and endorsed by eight paediatric endocrinology and human genetics societies, including the European Society for Paediatric Endocrinology (ESPE), the Pediatric Endocrine Society (PES) and the European Society of Human Genetics (ESHG), is the current reference for patient selection [16]. In the guideline, "we recommend" corresponds to a strong recommendation and "we suggest" to a weak recommendation; good clinical practice statements are not graded.

Source: [16]. ACMG, American College of Medical Genetics and Genomics; ACGS, Association for Clinical Genomic Science; rhGH, recombinant human growth hormone. The quality of evidence ranges from ⊕○○○ (very low) to ⊕⊕⊕⊕ (high).

With disproportion, the yield increases: in single-gene studies, a sitting height/height ratio above +2 SD raised the NPR2 yield from 17.6% to 28.3%, and in short children with mild skeletal abnormalities carriers of variants in bone dysplasia genes, such as ACAN and IHH, had a significantly different sitting height/height ratio [16]. The systematic review that supported the guideline (134 studies) estimated yields of 4.4% (95% confidence interval [CI] 3.3–5.7) for single-gene testing, 21.6% (15.1–28.9) for panels, 16.3% (8.1–26.4) for chromosomal microarray and 33.3% (26.4–40.6) for exome; by phenotype, 15.1% (10.4–20.6) in isolated short stature, 50.8% (43.2–58.4) in syndromic short stature and 69.8% (61.1–77.9) in suspected skeletal dysplasia [16, 97]. ACAN was among the most recurrent genes, and facial dysmorphism and skeletal abnormalities were the factors most associated with a higher yield; yields are lower when variants of uncertain significance (VUS) are excluded [97]. Clinical enrichment weighs heavily for ACAN: in a Chinese cohort of more than 1000 children with short stature, the yield was 1.2% overall, 14.3% in children with advanced bone age and 35.7% in those with advanced bone age and a family history, although 5 of 11 carriers did not have advanced bone age [14]; in Slovenia, selection by advanced bone age and/or dominant inheritance gave a yield of 37.5% (6 of 16) [72].

Earlier guidelines play a complementary role. The 2021 ACMG focused revision document on the genetic evaluation of short stature [98] and the 2019 GRS perspective [93] predate the 2026 guideline, which supersedes them in practice for test selection; the GRS stresses that history, examination and auxology remain the most important methods and that the interpretation of rare variants requires genotype–phenotype correlation, segregation and sometimes functional studies [93]. The French PNDS, centred on ACAN, proposes as a first approach targeted ACAN sequencing or a panel of genes for growth disorders or constitutional bone diseases, reserving exome or genome sequencing for negative cases, with clinical and radiological reassessment and a medical genetics consultation to discuss the implications and the recurrence risk [36]; it does not explicitly mention CNV analysis, which the international guideline considers necessary [16].

5.5. Molecular tests and their limitations

A negative result does not exclude the diagnosis. Intragenic or complete ACAN deletions require CNV analysis by microarray, by CNV analysis of the exome or by MLPA, and the first intragenic deletion was detected by microarray and exome analysis [72, 73]. When a panel is negative with a suggestive phenotype, the report should be reviewed for coverage of ACAN exon 12 [17]. Synonymous NPR2 variants should not be excluded by default by analysis filters [29, 75]. The guideline recommends reanalysing the data when new signs appear and, periodically, resequencing samples tested before about 2018 [16]. Mosaicism is not described as a relevant mechanism in the sources consulted; the detection of de novo variants in ACAN [17, 57, 64] nevertheless makes parental testing informative for counselling.

5.6. Interpretation, reporting and variants of uncertain significance

The report should state the gene, the reference transcript with version (NM_001369268.1 for ACAN and NM_003995.4 for NPR2), the HGVS c. and p. description, zygosity and ACMG/AMP class, and should preferably mention the correspondence with the historical numbering when the variant has already been published on another transcript [62, 63]. VUS are frequent among ACAN missense variants, and segregation is hampered by incomplete penetrance and variable expressivity [66, 72, 78]. There are no validated in vitro assays that reliably assess the effect of an individual variant on aggrecan function, in the terms of the vosoritide trial protocol [18]. For NPR2, cGMP production assays in transfected cells, with co-transfection with the wild-type allele to detect a dominant-negative effect, have been used in almost all series [22, 23, 26], and the functional score of 245 variants offers an additional reference [59]. Clinical trials of targeted treatments defined strict variant criteria for ACAN: deletion of the gene or of more than one exon; truncating variant (frameshift, nonsense, splicing at positions ±2, start codon loss); missense variant with an aggregate allele frequency below 1 × 10⁻⁵ in gnomAD, deleterious in PolyPhen2 and SIFT and with segregation or de novo occurrence; in-frame insertions or deletions of more than one amino acid [18, 99].

5.7. Practical algorithm

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis is possible when the causal variant has been identified in the family, and serial fetal growth ultrasound scans follow pregnancies at risk, with the caveat that predicting dysplasias at 20 weeks has pitfalls [35]. In AMDM there are no distinctive radiological findings at birth [27], which makes ultrasound of little help and makes prenatal diagnosis dependent on molecular testing. In aggrecan deficiency a prenatal presentation with short long bones has been described [83]. The same prerequisite, prior identification of the familial variant, applies to preimplantation genetic testing.

5.9. Severity assessment and functional scales

The French PNDS proposes a multidimensional assessment of the severity of the aggrecanopathies, without a specific validated scale [36]. The clinical criteria are height and growth velocity in SD on the 2018 CRESS/INSERM French reference charts, BMI and Tanner pubertal stage; pain, mobility limitations and joint destruction; axial deviations in adults; back pain with disc disease; and the ability to carry out activities of daily living [36]. Joint ranges of motion are measured with a goniometer from a defined reference position (usually the anatomical position, with the forearm in intermediate pronosupination), with the centre of the goniometer over the centre of the joint and the arms aligned with bony landmarks, active or passive mobilisation in defined planes, stabilisation of the adjacent joints and recording according to international conventions, so that measurements are reproducible between examiners [36]. Advanced bone age indicates a higher risk of early epiphyseal fusion [36]. For quality of life, the PNDS suggests the PedsQL in children (physical, emotional, social and school domains) and the EQ-5D in adults (mobility, self-care, usual activities, pain or discomfort and anxiety or depression, with a visual analogue scale) [36]. With these elements, severity is graded as mild (minimal impact on growth and joint function, with no limitation of daily activities), moderate (noticeable reduction in height, with moderate pain and functional limitation) and severe (significant impact on stature, intense joint pain, major functional limitation and a major impact on quality of life) [36].

6. Differential Diagnosis

6.1. Comparative table

6.2. Aggrecan deficiency and other causes of short stature with advanced bone age

Advanced bone age in a short child is unusual and narrows the differential. In the 2026 guideline, heterozygous ACAN and GNAS variants are the monogenic causes cited for advanced bone age in short prepubertal children [16]. Obesity and hypothalamic hyperphagia also advance bone age, and this effect should be considered before the finding is given weight [93]. Absence of advanced bone age does not exclude ACAN: the nosology records cases with normal bone age [8], the Turkish series found advanced bone age in only 28.6% [85] and the English series found delayed bone age in 3 of 4 children [83]. Hypochondroplasia is the closest radiological differential in adults with ACAN, because of the similar axial changes [83]. The dysplasia atlas recommends excluding SHOX, ACAN and NPR2 before accepting the label of idiopathic short stature in a child with relatively short extremities without the vertebral and pelvic changes of hypochondroplasia [101]. The French PNDS compares the aggrecanopathies with the spondyloepiphyseal dysplasias: the congenital form presents from birth with a short trunk, marked platyspondyly, severe vertebral anomalies and frequent thoracic involvement, and the tarda form appears in adolescence with moderate short stature and progressive joint pain; in the aggrecanopathies, involvement is more heterogeneous, with associated metaphyseal anomalies, generally less marked vertebral involvement and facial features more frequent in some forms, whereas the joint course is often earlier and more severe in the spondyloepiphyseal dysplasias [36].

6.3. Heterozygous NPR2 and SHOX deficiency

The heterozygous NPR2 phenotype overlaps with that of SHOX deficiency. In the Spanish screen of 173 patients referred with suspected Léri-Weill dyschondrosteosis and 95 with ISS, all without defects of SHOX or its enhancers, 8 NPR2 variants were found in 9 individuals (7 from the Léri-Weill group and 2 from the ISS group); 6 altered trafficking or cGMP synthesis in response to CNP or B-type natriuretic peptide, all the pathogenic variants were in the Léri-Weill group (about 3%), and no patient had Madelung deformity [26]. The authors recommend studying NPR2 in patients with a Léri-Weill phenotype and negative SHOX testing [26]; Smith's records that none of these patients had Madelung deformity [104]. The SGA consensus describes the same pattern [11].

6.4. AMDM and other acromesomelic dysplasias

AMDM is distinguished from the GDF5 and BMPR1B forms by involvement of the skull (relative macrocephaly) and the axial skeleton (wedged vertebrae and thoracolumbar kyphosis), which the Hunter-Thompson and Grebe forms spare [68]. The Grebe form has much more severe deformities, with fused or absent skeletal elements in the hands and feet, and lacks the vertebral findings of AMDM [27]. Pseudohypoparathyroidism and acrodysostosis have similar hand changes, but without the vertebral and forearm changes [27]. Pseudoachondroplasia has more marked epiphyseal changes and an irregular carpus [27]. These entities belong to the group of mesomelic and acromesomelic dysplasias.

6.5. ECDM and other causes of tall stature with long digits

ECDM, CNP overexpression due to translocation and CATSHL syndrome share hyperactivation of the CNP–NPR-B pathway or inactivation of FGFR3, which explains the arachnodactyly, camptodactyly and kyphoscoliosis they have in common; elongation of the great toes distinguishes the first two from CATSHL [12]. Marfan syndrome and related syndromes lack disproportionate elongation of the great toe and have their own extraskeletal manifestations [12], and suspicion of Marfan syndrome was the initial hypothesis in the Russian family with ECDM [30]. CNP overexpression due to 2q37 translocation includes aortic root dilatation and umbilical hernia in the reports [7]. The NT-proCNP level was normal or reduced in NPR2 gain of function [31, 50] and is a finding that may help to distinguish ligand overproduction from receptor hyperactivity, although no validated threshold exists in the sources consulted.

7. Treatments and Risk Management Strategies

7.1. General principles

In 2026 there is no approved treatment for ACAN deficiency or for NPR2 deficiency [18], and the sources consulted identify no approved drug for any NPR2 disorder [13]. Management rests on three components: promotion of growth with somatropin within the indications of each jurisdiction or off-label, possibly combined with drugs that delay epiphyseal fusion; surveillance and treatment of joint, spinal and orthopaedic complications; and genetic counselling with testing of at-risk relatives [105]. CNP analogues are approved only for achondroplasia, and their use in the entities of this article is experimental [18, 95, 106]. For skeletal dysplasias in general, the Oxford Desk Reference states that there is no unequivocal benefit of GH in most syndromes and dysplasias and that the management plan should prevent complications, discuss the prognosis and address procedures such as limb lengthening [35]. For SEDK, SEMD-ACAN and AMDM, treatment is orthopaedic and supportive [13, 20].

The French PNDS describes the team for the aggrecanopathies. The general practitioner and the paediatrician provide routine follow-up and guide the patient; the geneticist coordinates and decides on further investigations; the paediatric endocrinologist assesses growth and the indication for GH; the rheumatologist, paediatric or adult, treats chronic pain and joint and spinal lesions; the pain specialist defines strategies for chronic pain; the orthopaedic surgeon carries out a first assessment at diagnosis and follows the forms with early joint deterioration or osteochondritis dissecans; the physical and rehabilitation medicine physician coordinates technical aids and rehabilitation; and the school doctor, psychologist, physiotherapist, occupational therapist, psychomotor therapist, adapted physical activity teacher and nurse are involved, the latter also in therapeutic education and in GH administration [36]. The paediatric endocrinologist, the rheumatologist and the orthopaedic surgeon may themselves reach the diagnosis, the orthopaedic surgeon especially in the forme fruste of adults [36]. The aims are to optimise growth and prevent overweight, prevent pain and disability, treat joint and orthopaedic complications early (early joint deterioration, osteochondritis dissecans, genu valgum, scoliosis), limit the impact on school and work and support the patient and family psychologically [36].

7.2. Somatropin: regulatory framework

Somatropin (recombinant human growth hormone, rhGH) is marketed, among others, as Norditropin®, Humatrope® and Genotropin® in the United States and as Omnitrope® under a centralised authorisation in the European Union. In the United States, idiopathic short stature is a labelled indication with its own thresholds: height below −2.25 SD associated with growth velocity that makes normal adult height unlikely (Norditropin® and Humatrope®) [107, 108], or height of −2.25 SD or below in patients with open epiphyses in whom the diagnostic evaluation has excluded other causes that should be observed or treated by other means (Genotropin®) [109]. The vosoritide trial in ACAN and NPR2 used the −2.25 SD threshold because it is the one currently approved by the FDA for GH in ISS [18]. Strictly speaking, a child with a molecular diagnosis no longer has "idiopathic" short stature, so use of the ISS indication in the United States is a practice framework and not a labelled one. In the European Union, centrally authorised somatropin has no ISS indication; the paediatric indications include GH deficiency, Turner syndrome, chronic renal insufficiency, Prader-Willi syndrome and children born SGA, with birth weight and/or length below −2 SD, current height below −2.5 SD, parent-adjusted height below −1 SD and no catch-up growth (growth velocity below 0 SD during the last year) by the age of 4 years or later [110]. In Europe, GH in a child with ACAN or NPR2 is on-label only if another indication coexists, mainly SGA; in the remaining cases it is off-label use. In France, the PNDS frames GH in the aggrecanopathies as a prescription outside the marketing authorisation (AMM), permitted in the absence of a suitable alternative, and points out that the French National Agency for Medicines and Health Products Safety (ANSM) may issue a temporary recommendation for use (RTU) based on the PNDS and that health insurance may reimburse the prescription on an exceptional basis after an opinion from the HAS [36].

SGA, small for gestational age; GHD, GH deficiency; SmPC, summary of product characteristics. In Japan, GH (Humatrope®, Norditropin®) has been approved since the 1990s for chondrodystrophies, including hypochondroplasia, at a dose of 0.35 mg/kg/week in children (Japanese open-label studies; no maximum dose defined in the source), unlike the FDA and the EMA [111].

7.3. Somatropin in aggrecan deficiency

The only prospective trial is the Cincinnati open-label single-arm study (NCT03288103, phase 1/2, 2018–2023), which enrolled 10 treatment-naive children aged at least 2 years, prepubertal, with bone age equal to or greater than chronological age and normal IGF-I, treated with Norditropin® 50 µg/kg/day adjusted according to IGF-I [87, 99, 112]. Median age was 5.6 years (2.4–9.7), 6 were girls, baseline height was −2.5 SD (−4.3 to −1.1), bone age 6.9 years (2.5–10.0) and the bone age/chronological age ratio 1.2 (0.9–1.5) [99]. Growth velocity (GV) rose from 5.2 (3.8–7.1) to 8.3 (7.3–11.2) cm/year in the first year (p = 0.004) and was 7.7 (5.9–8.8) in the second and 6.8 (4.9–8.6) cm/year in the third; the height gain was +0.62 SD (+0.35 to +1.39) after 1 year (p = 0.002) and +1.21 SD (+0.82 to +1.94) cumulatively at 3 years, with median height rising from −2.52 to −1.09 SD, and predicted adult height increased by 6.8 cm in 3 years [87, 99, 112]. Four girls entered puberty, the bone age/chronological age ratio changed by −0.1 and the response was attenuated in the older patients who entered puberty [112]. There were no GH-related adverse events; the events recorded were knee pain in 4 of 10, fever in 3, conjunctivitis in 2, hip pain in 1 and behavioural change in 1 [87].

Real-world data are concordant. In the Dutch national registry, the 36 children treated for at least 1 year gained 1.0 SD (interquartile range 0.9–1.4) in 3 years when they started treatment before puberty, whereas in those who started during puberty height SD remained relatively stable [71]. In an extended Israeli family with the p.(Arg675Ter) variant, 5 children treated from 3.2 ± 2.1 years for 6.4 ± 5.0 years went from −3.3 ± 1.0 to −2.0 ± 1.1 SD (p = 0.001), with a gain of 1.3 ± 0.3 SD and GV rising from −0.5 ± 0.6 to 2.1 ± 1.2 SD in the first year (p = 0.04), without adverse effects or significant advancement of bone age; 3 children entered puberty between 10 and 11.6 years and received an adjuvant gonadotrophin-releasing hormone analogue (GnRHa), and the response was variable within the same family [65]. In a Chinese real-world series, 17 children treated for 4 to 61 months had a GV significantly higher than baseline at 3, 6, 9, 12 and 18 months [89]; in another, 15 patients treated with GH alone or combined with GnRHa all improved in height [88]; in the Chinese review by Deng, GV with growth-promoting treatment rose from 4.52 ± 1.00 to 8.03 ± 1.16 cm/year [86]. In the Gkourogianni cohort, the 19 treated individuals showed some evidence of increased GV, and the authors concluded that the optimal strategy requires further study [15].

Adult height data are scarce. In a series cited by Ruiz and colleagues with 10 patients who reached adult height, GH alone was associated with a mean gain of +0.35 SD (pretreatment height −2.0 to −3.1 SD; adult −1.6 to −2.4 SD), GH with GnRHa with +0.05 SD (−1.6 to −3.7; adult −2.0 to −4.0) and GH with GnRHa and an aromatase inhibitor with +0.4 SD (−2.4 to −2.8; adult −1.3 to −3.1) [69]. The non-randomised comparison of the 2017 cohort gave a mean adult height of −2.5 SD in treated and −3.0 SD in untreated individuals [69]. In all the GH studies in ACAN, NPR2 and Noonan syndrome cited by the authors of the vosoritide trial, GV slowed in the years after the first [18].

The long-term joint safety of GH in aggrecan deficiency is unknown [105]. In the Canadian case of multifocal osteochondritis dissecans, pain in the elbows, knees and ankles appeared about 6 months after the start of GH, which was stopped after 1 year; the authors raise the hypothesis, not demonstrated, that GH may have triggered or worsened the lesions and recommend weighing the risks before starting it in patients with joint disease [17]. Slipped capital femoral epiphysis is a known rare adverse effect of GH, occurring during periods of rapid growth [18]. The SGA consensus recommends measuring IGF-I 3 to 6 months after the start of GH, to assess adherence and safety [11].

The French PNDS considers GH an option to be weighed case by case, outside the AMM, with moderate efficacy and a benefit–risk balance to be assessed before starting, because there are no natural history studies allowing comparison of the final height of treated and untreated patients [36]. The literature review included in the PNDS brought together 152 patients with ACAN variants treated with GH in publications from 2017 to 2024 (89 male and 63 female), with a median age of 8.05 years at the start and a median duration of 12 months; the mean gain was +0.56 SD (paired t-test; t = −12.21; p < 0.001), +0.60 SD in boys and +0.51 SD in girls (Mann-Whitney U = 2792.5; p = 0.713) [36]. The gain correlated negatively with age at onset of treatment (Spearman r = −0.573; p < 0.001), but not with duration (r = 0.123; p = 0.123); by age group, it was 0.74 SD in girls and 0.97 SD in boys aged 0 to 5 years, 0.65 and 0.61 SD from 6 to 10 years, −0.001 and 0.25 SD from 11 to 15 years and 0.23 SD in boys aged 16 to 20 years [36]. The addition of GnRHa did not appear to improve the result, and sex, type of treatment and variant type had no clear influence [36]. The doses recorded in the studies reviewed were mostly between 25 and 66 µg/kg/day [36]. The limitations are those of a retrospective aggregation of published cases with short follow-up and no adult height data: the appendix table includes at least 18 rows that repeat patients already listed from the original publication (the 6 Slovenian patients of Stavber, the 3 from the Xu family, the 3 of Liang, 2 of Lin and 4 of van der Steen reappear in the part extracted from the 2024 Tang compilation), sometimes with discordant values, which double-weights these patients and makes the denominator inaccurate [36].

Before starting GH, the PNDS requires assessment by a specialist team (growth, hormone tests and genetics) and draws attention to reports, without demonstrated causality, of slipped epiphysis or joint deterioration on GH in other conditions (obesity, as in Prader-Willi syndrome, and epiphyseal dysplasias), which justifies extra caution in families with known osteochondritis dissecans [36]. During treatment, the dose is adjusted to response and tolerance, puberty is assessed and its suppression may be discussed when height at the onset of puberty predicts a low final height; prescription is the responsibility of a paediatric endocrinologist experienced in constitutional bone diseases, within the reference centre network [36].

7.4. Somatropin in short stature due to heterozygous NPR2

In the Dutch registry, after 2 years of GH, the median height gain was 1.2 SD (0.8–1.4) in prepubertal and 0.5 SD (0.3–0.9) in pubertal children, and near-adult height improved in 5 of 6 children who reached it [25]. In a Czech centre with 747 children treated with GH, 5 of the 87 with familial short stature (height up to −2 SD in the child and in the shorter parent) had pathogenic or likely pathogenic NPR2 variants; GV increased by 3.6 to 4.2 cm/year in the first year and height improved by +1.2 to +1.8 SD in 5 years [70]. In the Chinese cohort with a literature review, median height went from −2.9 to −2.1 SD with GH (p < 0.001), with a better response in girls, in those who started earlier and with variants in the guanylyl cyclase domain; the gain correlated negatively with age at onset (r = −0.477; p = 0.034) [76]. Other small series describe +1.59 ± 0.1 SD in 2 years in 3 children who started at 6.5 ± 1.8 years [75], +1.54 ± 0.78 SD in 6 children from the same family treated for 4.68 ± 2.68 years [79], a variable response between −0.01 and +0.74 SD in Slovenia [24] and one patient with a positive response in Spain [26]. The authors of the vosoritide trial cite a real-world study with a median gain of 0.7 SD in the first year in prepubertal children [18].

The first results were not positive: the 3 Brazilian patients treated with GH 33–50 µg/kg/day had no significant change in height SD [23]. A Brazilian boy treated later went from a GV of 3.4 to 10.4 cm/year in the first year (+1.1 SD) and at 8.8 years had a GV of 6.4 cm/year and a height of −1.8 SD [60]. The SGA consensus considers the data on GH response in ACAN and NPR2 insufficient [11], and no GH trial dedicated to NPR2 was identified on ClinicalTrials.gov [113].

7.5. Somatropin in AMDM

Published experience is limited to 2 British brothers, born to consanguineous parents and homozygous for a novel NPR2 variant, with IGF-I around −2 SD, treated off-label with high-dose GH at 0.075 mg/kg/day adjusted to keep IGF-I around +3 SD [91]. GV before treatment was 3.7 and 4.5 cm/year, and in the first 3 years was 7.0, 5.4 and 4.7 cm/year in one brother and 9.4, 8.0 and 5.9 cm/year in the other; the pubertal gain was 10.6 and 5.9 cm, and final height, after 8.5 years of treatment, was 130.5 cm (−6.57 SD) and 134 cm (−4.58 SD), above the described mean of about 120 cm [91]. This is the first description of final height in GH-treated AMDM, in a series of 2 patients with no comparison group.

7.6. Drugs to delay epiphyseal fusion

The aromatase inhibitor anastrozole and GnRHa are used in aggrecan deficiency to prolong the growth period, always off-label and without a randomised trial [13, 69]. The best-documented case is that of the boy described in 2015 by Quintos, who started somatropin 0.3 mg/kg/week at 6 years and 1 month, with a predicted adult height of 142 cm by the Bayley-Pinneau method and a parental target height of 165 cm; at central puberty, at 11 years and 7 months (4 mL testes, bone age 13.5 years), anastrozole 1 mg/day was added, with GH 0.3–0.4 mg/kg/week, for 4.5 years [41, 69]. Adult height was 156.3 cm at 16 years and 1 month, 14 cm above the pretreatment prediction and 9 cm below the parental target; liver function, gonadotrophins and estradiol were monitored annually and remained normal, with no adverse effects attributed to anastrozole, and bone densitometry was not performed [69]. The authors chose anastrozole over letrozole because of the reported safety profile, stress that final height was below the last prediction (160 cm), which shows the limits of predicted height, and acknowledge that the effect of GH cannot be separated from that of the inhibitor; in a 3-year trial in children with GH deficiency, the combination increased predicted adult height by 6.7 ± 1.4 cm, compared with 1.0 ± 1.1 cm with GH alone [69].

In the Dutch SGA cohort, all carriers of ACAN variants treated with GH received GnRHa for 2 years from the onset of puberty; at adult height, one girl was 5 cm taller than her mother and one boy 8 cm taller than his father with the same variant [84]. The 2023 SGA consensus recommends considering the addition of 2 years of GnRHa when the expected adult height at the onset of puberty is below −2.5 SD, with a mean gain of 6.6 cm in adult height in SGA children [11]. The GRS considers aromatase inhibitors in pubertal boys a controversial and off-label option, considers GnRHa alone not indicated to increase adult height and accepts the addition of GnRHa to GH in children with GH deficiency, SGA or Silver-Russell syndrome with low height at the onset of puberty, in a personalised approach in reference centres or within a trial [93]. The Israeli and Chinese series used adjuvant GnRHa at puberty, whether early or normally timed [65, 88]. The sources consulted do not provide the dose or formulation of the GnRHa used in these series. The French PNDS accepts GH alone or combined with a GnRH analogue to delay bone maturation and prolong growth, but its own case review showed no additional gain with GnRHa [36].

7.7. Vosoritide: drug, label and dosing in achondroplasia

Vosoritide (Voxzogo®) is a CNP analogue that binds to NPR-B and interferes with the signalling cascade downstream of FGFR3 [93]. It acts as an agonist of the receptor encoded by NPR2, and therefore requires a functional receptor; benefit cannot be assumed in biallelic loss of function of NPR2 [13]. In the United States, the current indication is to increase linear growth in paediatric patients with achondroplasia and open epiphyses, under accelerated approval based on improvement in annualised growth velocity, with continued approval contingent on verification of clinical benefit in confirmatory trials [95]. In the European Union, the indication is the treatment of achondroplasia in patients aged 4 months and older whose epiphyses are not closed, with the diagnosis confirmed by appropriate genetic testing; it is an orphan medicine [114]. ACAN deficiency and NPR2 deficiency are not indications in either jurisdiction [115, 116].

The FDA label dose is based on actual body weight and given subcutaneously once daily: 0.096 mg for 3 kg; 0.12 mg for 4 kg; 0.16 mg for 5 kg; 0.2 mg for 6–7 kg; 0.24 mg for 8–11 kg; 0.28 mg for 12–16 kg; 0.32 mg for 17–21 kg; 0.4 mg for 22–32 kg; 0.5 mg for 33–43 kg; 0.6 mg for 44–59 kg; 0.7 mg for 60–89 kg; and 0.8 mg from 90 kg, using vials of 0.4 mg, 0.56 mg (0.8 mg/mL) and 1.2 mg (2 mg/mL) [95]. The achondroplasia GeneReviews summarises the dose as 15–30 µg/kg/day depending on age [117], and in the study in children under 5 years 30 µg/kg was used below 2 years and 15 µg/kg from 2 years [95]. Before the injection, the child should be adequately fed and should have drunk about 240 to 300 mL of fluid in the preceding hour; a missed dose may be given up to 12 hours later and, after that, should be skipped [95]. Weight, growth and development should be monitored every 3 to 6 months, and treatment is permanently discontinued upon closure of the epiphyses [95]. There are no contraindications in the FDA label; the drug is not recommended with an estimated glomerular filtration rate below 60 mL/min/1.73 m² [95].

Adverse reactions with a frequency above 10% were injection site erythema, swelling and urticaria, rash, vomiting, arthralgia, decreased blood pressure and gastroenteritis [95]. In the pivotal study (NCT03197766), in 121 children aged 5.1 to 14.9 years treated with 15 µg/kg/day, transient hypotension occurred in 13% versus 5% with placebo, with a median onset at 31 minutes (18–120) and median resolution within 31 minutes (5–90), and was symptomatic in 2 of 60 patients (3%); injection site reactions occurred in 85% versus 82% (120.4 versus 29.2 events per person-year), and alkaline phosphatase increased in 17% versus 7% [95]. Hypertrichosis was added as a postmarketing reaction [95]. In achondroplasia, the difference in growth velocity versus placebo was 1.57 cm/year at 52 weeks [95], with a 95% CI of 1.22 to 1.93 cm/year [118].

7.8. Vosoritide in ACAN and NPR2 deficiency: phase 2 trial

Trial NCT04219007 is a phase 2, open-label, single-centre basket trial (Children's National Hospital, Washington DC), investigator-initiated and funded by BioMarin, which had no role in its design, conduct or analysis; an independent data and safety monitoring board reviewed the data every 6 months [18]. The design included 6 months of observation followed by 12 months of vosoritide 15 µg/kg/day subcutaneously [18]. Eligible participants were prepubertal boys aged 3 to 11 years and girls aged 3 to 10 years with height below −2.25 SD on the Centers for Disease Control and Prevention (CDC) charts and IGF-1 above the lower limit, with groups for hypochondroplasia (published separately), RASopathies, ACAN, heterozygous NPR2, SHOX and NPPC; patients homozygous for NPR2 were excluded [18]. Enrolment took place from August 2020 to February 2024, and the last patient completed the main period in August 2025 [18]. The co-primary outcomes were adverse events, change in standardised GV and change in height SD [18].

Thirty children started treatment, aged 7.2 ± 2.2 years, 8 of them girls (27%): 12 with ACAN (40%), 7 with NPR2 (23%) and 11 with RASopathies (8 with Noonan syndrome, 2 with neurofibromatosis type 1 and 1 with Costello syndrome); 5 had previously received GH, and 28 entered the efficacy analysis [18]. Median adherence was 99.3% [18]. One child with a severe form of aggrecan deficiency had a baseline height of −8.98 SD and was removed from Figure 2C for presentation reasons, being included in Figure S1 of the supplement [18].

Source: [18]. Values as mean (SD). Mean heights went from −2.94 to −2.30 SD in the NPR2 group and from −3.38 to −2.81 SD in the ACAN group [18].

Among the secondary outcomes, the bone age/chronological age ratio did not change significantly (0.94 to 0.92; p = 0.22; in the ACAN group, 1.11 ± 0.17 to 1.06 ± 0.14), the sitting height/height ratio, +2.88 SD at baseline, changed by −0.37 (p = 0.08), the arm span−height difference changed by −0.61 SD (p = 0.01), the collagen X biomarker (CXM) rose from 20.94 to 39.43 ng/mL (difference 16.28; p = 0.001), and the QoLISSY quality-of-life questionnaire showed improvement in the parent-reported physical domain (p = 0.01) [18]. Five children entered puberty during treatment [18].

In the first year, safety was reassuring: injection site reactions in 12 of 30 children (40%; 332 occurrences, all grade 1–2), local swelling in 9 (30%), urticaria in 6 (20%), erythema in 5, bruising in 5 and pain in 4; upper respiratory tract infections in 10 (33.3%), vomiting in 8 (26.7%) and fever in 8 (26.7%); 2 unrelated serious events (status asthmaticus and appendicitis) and 1 grade 3 event (traumatic nasal fracture); no grade 4 or 5 events, no concerning echocardiographic changes and no discontinuation because of a related event [18]. In the long-term extension, 5 children discontinued treatment because of related events: one with Noonan syndrome and one with ACAN developed severe genu valgum treated with outpatient guided growth surgery, continued vosoritide after discussion with the families and orthopaedic surgeons and later had slipped capital femoral epiphysis with surgery and discontinuation on days 1078 and 1633; a third child with ACAN had slipped epiphysis on day 493, after developing coxa valga; and two others with ACAN developed significant genu valgum that led to discontinuation [18]. Four of the 5 children who discontinued had aggrecan deficiency [18].

The case series published in 2026 by the same group described slipped capital femoral epiphysis as an emerging serious adverse event in two phase 2 vosoritide trials: in the basket trial, in 2 of 12 participants with ACAN, 1 of 11 with RASopathies, 0 of 7 with NPR2 and 0 of 24 with hypochondroplasia; in the trial in girls with Turner syndrome (NCT05849389), in 2 of 5 [94]. All 5 cases occurred after more than 12 months of treatment and were of the rare valgus type [94]. The authors accept that patients with aggrecan deficiency, and perhaps with Noonan syndrome, may be predisposed to genu valgum aggravated by rapid growth, point out that slipped epiphysis is described in NPR2 hyperactivity and consider it possible that the complications are a specific effect of vosoritide [18]. They conclude that vosoritide markedly increased GV in all three conditions and may become a precision therapy for growth disorders affecting the MAPK pathway, but that prolonged use requires caution, especially in aggrecan deficiency [18].

The authors compare the first-year gain with GH data: 0.59 SD with vosoritide versus 0.62 SD with GH in aggrecan deficiency and 0.69 SD versus 0.7 SD in NPR2 [18]. The effect on GV in ACAN and NPR2, 3 cm/year or more, was greater than that described in achondroplasia (1.57 cm/year) and in hypochondroplasia (1.81 cm/year) [18]. No child had osteoarthritis or osteochondritis dissecans, so the trial provides no information on the effect of vosoritide on joint disease; vosoritide does not cross the blood–brain barrier to a substantial extent [18]. The trial registration indicates an actual enrolment of 56 participants across all groups, primary completion on 14 August 2025 and estimated completion of the extension in June 2035, with active, not recruiting status in March 2026 [119]. The supplement with the individual variants and the genu valgum cases (Tables S1–S5) was not consulted.

7.9. Navepegritide

Navepegritide (Yuviwel®) is a once-weekly CNP prodrug, approved by the FDA on 27 February 2026, under accelerated approval, to increase linear growth in paediatric patients aged 2 years and older with achondroplasia and open epiphyses, with a weekly dose by weight band (from 0.88 mg for 8–9.9 kg to 8.8 mg for 73.6–90 kg) [106]. The achondroplasia GeneReviews summarises the dose as 100 µg/kg per week [117]. A search of ClinicalTrials.gov in October 2026 found 7 navepegritide studies, all in achondroplasia, and none in ACAN or NPR2, so its use in these conditions would be exclusively experimental [113]. The European regulatory status of navepegritide was not consulted.

7.10. Comparative regulatory status

CHMP, Committee for Medicinal Products for Human Use; EC, European Commission. The design article of the phase 3 trial in hypochondroplasia states that vosoritide is approved for achondroplasia also in Japan, Brazil and Australia [111]; national access in Portugal and Brazil was not searched in INFARMED or ANVISA sources.

7.11. Treatment trials and studies

The results of these studies cannot be compared directly with one another. Only the trials in achondroplasia and hypochondroplasia have a randomised control group; in ACAN and NPR2, the vosoritide trial used each child's observation period as the comparator, and the GH studies are open-label, single-arm or observational, with different populations, ages, pubertal stages and doses. First-year GV gains are not equivalent to adult height gains, and GV slowed in the years after the first in all the GH studies cited [18]. The 2013 Brazilian series is a negative result [23]. Gains in height SD depend on age at onset and on entry into puberty [25, 71, 76, 112]. BioMarin's randomised phase 2 trial in ISS (NCT06382155; vosoritide at three doses versus placebo and, in the USA, versus GH; enrolling since 21 October 2024, about 100 participants planned) expressly excludes children with known genetic variants, including ACAN deficiency, SHOX alterations and RASopathies; the main criteria do not expressly exclude heterozygous NPR2 [121].

7.12. Orthopaedic, joint and rehabilitation management

Orthopaedic surgery intervenes as indicated [20]. In aggrecan deficiency, timely identification of joint pathology and intervention is the conclusion of Alexandrou's musculoskeletal assessment, which found orthopaedic surgery in 60% of adults [81]. Joint protection is part of the multidisciplinary approach proposed in the 2026 review [105]. In the Canadian case of multifocal osteochondritis dissecans, failure of conservative treatment led to bilateral knee arthroscopy with microdrilling, repeated at 13.5 years with fixation by absorbable implants; given high-turnover osteoporosis on biopsy, intravenous zoledronic acid was used off-label (0.0125 mg/kg for the first dose and then 0.025 mg/kg every 6 months, changing to 0.0125 mg/kg every 3 months, for a total of 0.05 mg/kg/year), with intensive pool-based physiotherapy [17]. This regimen comes from a single case and is not a recommendation.

In ECDM, the great toe deformities, camptodactyly and kyphoscoliosis of childhood often require orthopaedic intervention [12], and severe double-curve scoliosis may require surgery [12]. In the Russian family, the progressive valgus deformities of the hip, knee and ankle were treated with osteotomies, guided growth and arthrodesis of the great toes [30]. Epiphysiodeses of the distal femur and proximal tibia and fibula were performed in the 61-year-old patient with a stature of +5.2 SD [10] and bilateral percutaneous epiphysiodeses of the very long great toes in childhood in a mother and one of her daughters [10]. In AMDM, management is supportive and orthopaedic [13], and in adults the degenerative lumbar changes and thoracolumbar kyphosis are the focus [27]. In SEDK, osteoarthropathy of the weight-bearing joints progresses slowly [20].

The French PNDS makes physical and rehabilitation medicine the basis of the symptomatic treatment of pain and deformities in the aggrecanopathies, to be started from diagnosis by a team experienced in constitutional bone diseases: the individualised programme includes progressive passive and active mobilisation, gentle muscle strengthening, postural and proprioceptive re-education and adapted physical activity, to maintain ranges of motion, limit deformities and prevent stiffness, postural changes and imbalances; resting, positioning or support orthoses are reassessed regularly, and rehabilitation continues outside painful phases to maintain the gains [36]. Physiotherapy includes exercise and endurance training; occupational therapy adapts the environment with orthoses, technical aids and home adaptations, with standardised assessment and visits to the home, school or workplace, and is particularly useful when brachydactyly limits fine grip; psychomotor therapy works on coordination, balance, posture and self-esteem; no sporting activity should be systematically forbidden, and the PNDS recommends regular physical activity, preferably endurance exercise; nutritional follow-up prevents or treats obesity, which worsens joint involvement; and psychological support, individual or family, addresses body image and acceptance of the difference in stature [36]. As complements, little studied in these diseases, the PNDS cites transcutaneous electrical nerve stimulation (TENS), therapeutic education, pain self-management, cognitive behavioural therapy, balneotherapy, meditation and relaxation and joint mobilisation by professionals, coordinated by someone familiar with constitutional bone diseases in liaison with a rare disease network (filière); pain that is difficult to control justifies referral to a chronic pain service, with psychological support if necessary [36].

According to the PNDS, analgesia follows an empirical ladder, for lack of dedicated studies: paracetamol first line for mild to moderate pain; nefopam as an alternative in adolescents over 15 years and in adults when pain persists or non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated, with monitoring for nausea, dizziness and tachycardia; topical NSAIDs (diclofenac, ibuprofen) for localised joint pain, used outside the AMM in children; in the event of failure or contraindication, intra-articular corticosteroid injections, decided case by case by a rheumatologist or other trained physician, with an effect lasting a few weeks and a risk of cartilage deterioration with repetition; intra-articular hyaluronic acid, of controversial efficacy and which a recent meta-analysis did not distinguish from placebo, not reimbursed; and, finally, weak or strong opioids for severe refractory pain, for limited periods, with regular reassessment of benefit, adverse effects and the risk of use disorder [36]. The PNDS does not give doses. The doses in the French summaries of product characteristics (SmPCs) serve as a regulatory comparison; their age and duration restrictions diverge from the prolonged and paediatric use described in the PNDS, which is the clinical reference.

Pain assessment, described in the PNDS appendix, uses a validated scale suited to age, cognitive abilities and context, with a preference for self-assessment; between 4 and 6 years two tools are used together to test the ability to self-assess, below 4 years observer assessment is used, and the scale used for the first measurement remains the reference for subsequent ones [36].

Source: [36].

In osteochondritis dissecans, the PNDS describes as surgical options microdrilling, preferred for stable or large lesions after failure of conservative treatment, fragment fixation or osteochondral autograft in complex cases and arthroscopy for removal of loose bodies and joint decompression; there is no validated technique specific to carriers of ACAN variants, and the decision rests with a centre specialising in constitutional bone diseases [36]. In adults with severe joint dysplasia of the knee or hip, joint replacement may be considered case by case, according to age, functional level and the other skeletal changes [36]. No limb lengthening has been described in the aggrecanopathies, and a request of this kind should be discussed at a multidisciplinary meeting in a specialist centre [36]. The PNDS also mentions, in osteochondritis dissecans, a single observation of intravenous bisphosphonate use (pamidronate or zoledronic acid), with the rationale of strengthening the subchondral bone and preventing stress fractures; the published case used zoledronic acid, with the regimen described [17, 36].

7.13. Agents and procedures to be weighed with caution

Vosoritide should not be used outside a clinical trial in the entities of this article; in aggrecan deficiency, the signal of genu valgum and slipped epiphysis after more than 12 months of treatment justifies particular caution [18, 94]. CNP analogues have no established rationale in AMDM, because they require a functional receptor; the basket trial excluded patients homozygous for NPR2 and no trial of vosoritide or CNP in AMDM was found [13, 18, 113]. In aggrecan deficiency with established joint disease, the authors of the Canadian case recommend weighing the risks before starting GH [17].

7.14. Pregnancy, lactation, perioperative care and transition

The French PNDS recommends, in a pregnant woman with an ACAN variant, enhanced monitoring of fetal growth with reference ultrasound scans, multidisciplinary follow-up (obstetrician, geneticist and, if necessary, neonatologist) at a multidisciplinary prenatal diagnosis centre (CPDPN) and counselling on the risk of transmission [36]. The PNDS does not address delivery, lactation or anaesthesia; the other sources consulted do not describe them either, nor pregnancy in women with NPR2 variants, and there are no data on gestational exposure to vosoritide in these conditions. In SEMD-ACAN, failure of fusion of the cervical neural arches in the young patient and cervical kyphosis in the adult [20] are anatomical findings relevant to pre-anaesthetic assessment and cervical positioning, although the sources do not formulate anaesthetic recommendations. Transition to adult medicine is mainly orthopaedic and rheumatological in aggrecan deficiency, because of the high frequency of osteoarthritis, disc disease and surgery in adults [15, 81]. The PNDS asks for transition to be planned from adolescence, with assessment of the needs for pain control, mobility and musculoskeletal complications and with coordination between the paediatric and adult teams [36]. For adults with multiple pain or severe dysplasia, it recommends planning travel: accessible care at the destination, comfortable means of transport for long periods of sitting or standing and travel insurance covering pre-existing conditions [36]. In adults with ECDM, arterial hypertension may appear and should be looked for [12].

7.15. Developments in the last 12 months

The ClinicalTrials.gov search found no trials of vosoritide or CNP in AMDM and no GH trials dedicated to NPR2, which does not demonstrate that none exist [113].

7.16. Guideline recommendations and divergences between sources

There is no treatment guideline specific to ACAN or NPR2 [13, 18]. The PES, in its 2016 GRADE guidelines, maintains ISS as a controversial indication for GH [131], and the 2026 Delphi consensus redefined ISS and the elements of its assessment [34]. The FDA approves GH in ISS with the −2.25 SD threshold, and the EMA does not approve it for this indication [107, 110], which creates a practical divergence between the United States and Europe in access to GH for children with ACAN or NPR2 without another indication. The SGA consensus considers the data on GH response in ACAN and NPR2 insufficient, but recommends assessing the bone age of SGA children treated with GH at around 8 years and regularly from the onset of puberty, because advancement may signal aggrecan deficiency, and accepts GnRHa for 2 years in SGA children with a low predicted adult height at the onset of puberty [11]. The GRS considers aromatase inhibitors controversial and restricts adjuvant GnRHa to personalised situations in reference centres or within a trial [93]. The 2019 GRS accepted that CNP analogues could theoretically be useful in CNP deficiency, heterozygous NPR2 variants and ISS [93]; the 2026 trial confirmed the increase in GV, but added the musculoskeletal safety signal in aggrecan deficiency [18].

The French PNDS on the aggrecanopathies, of September 2025, is the only national document dedicated to ACAN and is based on a literature review and expert consensus; it addresses NPR2 only as a differential [36]. The divergences from the other sources are as follows.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by entity

In heterozygous aggrecan deficiency, familial osteochondritis dissecans and SEDK, each child of an affected parent has a 50% risk of inheriting the variant [8]. De novo variants have been described [17, 57, 64], and the absence of a family history does not exclude the diagnosis [64]. In such cases, the parents should be tested, because incomplete penetrance for short stature allows a carrier parent to have normal height, like the relative with −0.5 SD carrying an intragenic deletion [72] and the Chilean children with pathogenic variants and normal height [78]. In short stature due to heterozygous NPR2 and in ECDM, the risk to the offspring of a carrier is likewise 50% [8–10], with incomplete penetrance described in a Chinese family in which 4 carriers did not have marked short stature [79].

In SEMD-ACAN and AMDM, inheritance is autosomal recessive and the risk to each sibling of a patient is 25% when both parents are heterozygous [8]. The heterozygous parents and siblings of patients with AMDM are themselves at risk of short stature, with a mean height of −1.8 SD in the carriers of the family studied by Olney [48] and obligate carriers 5.7 cm shorter than matched controls [28]; in the Turkish series, the heterozygous parents were significantly shorter than controls [74]. The same dosage continuum exists for ACAN: the heterozygous mother of the Turkish siblings with SEMD-ACAN had severe short stature [21]. Assortative mating between short people, which the 2026 guideline identifies as a factor that confounds segregation [16], increases the probability of a couple consisting of two heterozygotes with short stature; in a multigenerational North American family, two sisters with AMDM were compound heterozygous for a maternal and a paternal variant, and the heterozygous relatives had proportionate short stature [80]. The French PNDS adds that, in the dominant aggrecanopathies, no recurrence has been described in siblings of unaffected parents, with a theoretical risk of germline mosaicism below 1%, and that, in SEMD-ACAN, the heterozygous parents may have moderate short stature, all the children of a patient are heterozygous carriers at risk of moderate short stature, and the risk of an affected child is very low outside unions between relatives [36].

8.2. Cascade testing and relatives

The 2026 guideline recommends testing relatives when the result may change management or counselling [16], and the 2026 review includes screening of at-risk relatives in the multidisciplinary approach [105]. In aggrecan deficiency, diagnosis in an adult parent identifies someone at risk of early-onset osteoarthritis and disc disease [81], and diagnosis in younger siblings allows surveillance of bone age and GV to start and treatment to be discussed before puberty, when the response to GH is greater [71, 112]. The guideline recommends segregation analysis when it may change the classification of a variant, with caution because of variable expressivity and lack of penetrance in the dominant forms [16]. Because of incomplete penetrance, variable expressivity, also within the same family, and underdiagnosis, the French PNDS recommends extended family enquiry after a patient has been identified, because the disease is often inherited from an undiagnosed parent; the genetic counselling consultation may be repeated during follow-up [36].

8.3. Counselling of minors

Children should be tested only when there is a potential benefit for the child, preceded by counselling [16]. In the entities of this article, the benefit usually exists, because the diagnosis changes auxological and joint surveillance and the options for growth treatment. The pre-test discussion should include the benefits and risks [16], and genetic counselling should be offered to all tested families [16]. For disclosure of the diagnosis, the French PNDS refers to the disclosure protocol of the AnDDI-Rares network: the physician who requested the test, experienced and informed about the disease, discloses it in a quiet office without interruptions, with time to answer questions, outside emergency settings and avoiding evenings and the eve of weekends; disclosure may be postponed in the presence of a pregnancy, a tragedy or a recent family conflict; a joint consultation with a psychologist is recommended; for a child, both parents should be present and the child as well, if age, maturity and emotional context allow; and the consultation ends with the plan of initial investigations, specialist follow-up and the contact details of the nearest reference or competence centre for constitutional bone diseases [36].

8.4. Prenatal diagnosis and preimplantation genetic testing

When the familial variant has been identified, prenatal diagnosis is technically possible, and serial fetal growth ultrasound scans follow the pregnancy, with the limitations of ultrasound prediction at 20 weeks [35]. In AMDM, the absence of distinctive radiological findings at birth makes ultrasound of little help [27]. In aggrecan deficiency, prenatal presentation with short long bones was described in 1 of 9 individuals in an English series [83]. Preimplantation genetic testing likewise depends on prior identification of the variant. Reproductive decisions in the mild dominant forms, with a median adult height of −2.8 SD and joint morbidity in adulthood [15], differ from decisions in the severe biallelic forms, such as SEMD-ACAN, with an adult height of 66–71 cm [20], and AMDM [27]. In France, the PNDS places prenatal diagnosis (amniocentesis or chorionic villus sampling) and preimplantation genetic diagnosis within a collegial decision of a CPDPN, at the couple's request, taking into account the personal and family history; they are reserved for diseases considered incurable and of particular severity, such as SEMD-ACAN, and are generally not accepted for isolated short stature, which does not fall under articles L2213-1 and R2131-18 of the French Public Health Code; preimplantation diagnosis and gamete donation are alternatives to avoid termination of pregnancy for medical reasons [36].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

There is no validated population prevalence estimate for the entities of this article. The Orphanet classes below 1/1,000,000 are based on the number of published families or cases (3 families for SSOAOD, 1 family for SEDK, 3 cases for SEMD-ACAN, about 50 cases for AMDM and 2 families for ECDM) [1, 3–6] and contrast with the frequency of the heterozygous forms in cohorts of short children. The SGA consensus estimates that ACAN and NPR2 each account for about 1–2% of children with short stature born SGA and of children with ISS [11], and the authors of the vosoritide trial place heterozygous NPR2 variants in 1–2% of children with ISS [18]. The NPR2 literature cites values between 2 and 6% [75, 76, 79]. Olney and colleagues estimated, on the assumption of 1 carrier in every 700 people, that about 1 in 30 individuals with ISS would carry an NPR2 variant; this is a modelled estimate, not a measured prevalence [48]. Wang and colleagues estimated a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in ISS, comparing 192 patients with 192 controls of normal height in the United States and Chile [77]. The French PNDS states that there are no incidence or prevalence data for any aggrecanopathy and records SEMD-ACAN in only 4 patients from 2 families since 2009, a count that does not include the 2024 Turkish report [21, 36]. The same document places ACAN variants in 1.1 to 1.4% of children with idiopathic short stature in sequencing studies from 2017 to 2024 and between 1 and 5% in other estimates, with 14.3% in children with advanced bone age and up to 37.5% in those with a family history of short stature; in this synthesis, ACAN is the third most frequent monogenic cause of isolated short stature, after SHOX (2–15%) and NPR2 (1.8–13.6%), and, in another passage, SHOX and NPR2 account for about 2–4% and 2% of isolated short stature [36]. The wide ranges reflect referred populations with different selection criteria.

9.2. Diagnostic yield by country and cohort

These values measure the yield in referred and selected populations, with different inclusion criteria, and not prevalence in the general population. Enrichment by advanced bone age, dominant family history and disproportion explains much of the variation between studies [14, 16, 72]. In the Brazilian panel, the diagnosis had an impact on management in 4 of the 17 children diagnosed [102].

9.3. United States, Europe and consanguineous populations

North American data come mainly from the Cincinnati and Washington centres, with the 20-family reference cohort [15], the musculoskeletal assessment of 9 families [81], the GH trial [99] and the vosoritide trial, in which 63% of participants were white [18]. In Europe, there are data from national registries in the Netherlands [25, 71, 84], cohorts from Slovenia [24, 72], the Czech Republic [70], Spain [26, 82], Germany [132] and England [68, 83, 91]. No founder variant of ACAN or NPR2 has been described; the Israeli family with p.(Arg675Ter) is an extended family and not a founder population [65]. Consanguinity explains the frequency of AMDM and SEMD-ACAN in series from Turkey, where 19 of 23 characterised patients with AMDM were homozygous [21, 74], and in British brothers born to consanguineous parents [91]. In China, dysmorphic features and advanced bone age were less frequent than in Western series [86], and in Turkey advanced bone age was present in 28.6% [85], which reduces the value of clinical criteria derived from North American and European series when applied to other populations. The GRS points out that the Greulich and Pyle bone age standards derive from white North American children and may not be applicable to all populations [93].

9.4. Portugal and Brazil

In Brazil, the São Paulo group identified the first series of heterozygous NPR2 variants in ISS [23], described the sustained response to GH in a boy [60], took part in the international ACAN cohort [15] and in the Spanish NPR2 study [26], and published the yield of a multigene panel in 102 children with ISS [102]. In Portugal, authors from Coimbra took part in the European series of ACAN deletions [73], and a 2026 case, from centres in the north and centre of the country, described an ACAN variant of uncertain significance with an incidental ALPL variant [66]. The sources consulted contain no frequency estimates for Portugal.

9.5. Special populations

Children born SGA are a population with an increased frequency of aggrecan deficiency: about 30–40% of children with ACAN are born SGA [11], and selection by advanced bone age in this population has a high yield [84]. In girls, short stature has historically been less investigated, and the GRS recommends assessing girls and boys in the same way [93]. In adulthood, joint disease predominates [81].

9.6. European Reference Networks and patient associations

Endo-ERN covers rare endocrine conditions, including growth disorders [32], and ERN BOND covers bone dysplasias, such as SEMD-ACAN, SEDK, AMDM and ECDM, and early joint complications [33]. The October 2026 search found no patient associations specific to ACAN or NPR2; generic associations include the MAGIC Foundation in the United States [133], the Child Growth Foundation in the United Kingdom [134] and the Restricted Growth Association in the United Kingdom, aimed at dysplasias with short stature [135]. In France, the reference for the aggrecanopathies is the network of reference and competence centres for constitutional bone diseases (CRMR MOC), whose coordinating centre, at Montpellier University Hospital, drew up the PNDS with the support of the OSCAR health network (rare diseases of bone, calcium and cartilage) [36]. There is no patient association specific to the aggrecanopathies, French or international; the PNDS lists the Association des Personnes de Petite Taille (APPT), the association Un défi de taille, dedicated to the spondyloepimetaphyseal dysplasias, and the Maladies Rares Info Services forum, and recommends that the physician always suggest contact, leaving the decision to the patient or family [36]. Therapeutic education is an integral part of care [36].

9.7. Social support, schooling and employment: the French model

The French PNDS describes social support, the need for which depends on the manifestations: generally unnecessary in isolated short stature and indispensable in SEMD-ACAN [36]. With the support of a social worker, families apply to the Maison départementale des personnes handicapées (MDPH): up to 20 years of age, the education allowance for a child with a disability (AEEH) and supplements or the disability compensation benefit (PCH), and, from the family allowance fund, the daily parental presence allowance (AJPP), which can be combined with the basic AEEH but not with the supplement; the mobility inclusion card (priority, parking and disability from 80%); after 20 years, recognition as a disabled worker (RQTH), to be requested 6 to 12 months in advance, and the disabled adult allowance (AAH) when the disability prevents full-time work (rate above 80%, or 50 to 80% with a substantial and lasting restriction of access to employment); applications are renewed 6 months before the end of support, with appeal and conciliation possible [36]. At school, the individualised reception plan (PAI) provides furniture adapted to height (desk, chair and footrest), access to the lift, a locker and a second set of textbooks at home to reduce the weight of the school bag, a stable stool or platform near the board and in non-adapted spaces, accessible coat hooks, access to food and the tray in the canteen, respect for walking pace on outings, extra time in examinations when writing is difficult and physical education without formal contraindication, but with adapted requirements and assessment, avoiding repeated jumping (trampoline), somersaults (risk of falling on the neck) and contact sports [36]. Human assistance (a support worker for pupils with disabilities), transport and referral to specialised establishments are requested from the MDPH, with a personalised schooling plan; during prolonged absences, there is home or hospital tuition and distance learning [36]. Professional integration usually takes place in mainstream settings, with workplace adaptations, and most adults live independently, with small adaptations of the environment [36].

10. Illustrative Clinical Case

10.1. Main case: aggrecan deficiency with multifocal osteochondritis dissecans

In 2023, Ochoa and colleagues described, at the children's hospital in Ottawa (Canada), a boy referred at 13 years to the genetics and metabolic bone disease clinic with undiagnosed short stature and osteochondritis dissecans [17]. At 5 years he measured 99 cm (−2.3 SD) and weighed 18 kg (−0.2 SD), with a GV of 6 cm/year (−1.1 SD) and a target height of 176.7 cm (+0.02 SD); IGF-1 was 176 µg/L (reference 75–469), thyroid function was normal and screening for chronic disease was negative [17]. At 10 years bone age was advanced by 2 years, and the GH stimulation test with clonidine and arginine gave a peak of 12.9 µg/L [17].

At 11 years he started rhGH for idiopathic short stature, 0.18 mg/kg/week in 6 doses, up to a maximum of 0.28 mg/kg/week; about 6 months later pain appeared in the elbows, knees and ankles, and GH was stopped after 1 year because of the pain and the lack of clear growth benefit [17]. MRI showed stable osteochondritis dissecans that failed conservative treatment, and the patient underwent bilateral knee arthroscopy with microdrilling; the pain recurred, with a daily need for non-steroidal anti-inflammatory drugs (NSAIDs), an antalgic gait and withdrawal from sport [17]. MRI at 13 years (Figure 1 of the article, whose legend was consulted) showed in the left knee lesions on the middle and lateral aspects of the medial femoral condyle and on the middle and posterior aspects of the lateral femoral condyle, and in the right knee lesions on the lateral aspect of the medial femoral condyle and in the subcortical lateral tibial plateau [17, 136]. At 13.5 years he underwent repeat arthroscopy with microdrilling and fixation with absorbable implants [17]. As an incidental finding, a Chiari I malformation with 16 mm tonsillar descent and syrinxes at C5–C7 (4 × 7 mm) and T3–T6 (8 × 7 mm) were identified, treated by posterior fossa decompression; the authors do not establish an association with ACAN [17].

At 14 years, dual-energy X-ray absorptiometry (DXA) showed a lumbar bone mineral apparent density of −3.4 SD and a total hip density of −3.1 SD, and peripheral quantitative computed tomography (pQCT) of the distal tibia gave −3.6 SD in the trabecular compartment and −2.2 SD in the cortical compartment, with 25-OH-vitamin D of 78 nmol/L; the skeletal survey showed osteopenia without fractures or evident dysplasia [17]. Transiliac biopsy revealed very thin cortices, a bone formation rate twice the mean and low trabecular bone volume, a picture of high-turnover osteoporosis [17]. The osteoporosis panel and the short stature panel were negative; in the latter ACAN was only 83% covered, without sequencing of exon 12 [17]. Trio exome sequencing identified the de novo variant NM_013227.4:c.5391dup, which on the MANE transcript is described as NM_001369268.1:c.5391dup p.(Gln1798AlafsTer17), in exon 12, classified as pathogenic [17, 62].

At around 14 years, the patient received off-label intravenous zoledronic acid: 0.0125 mg/kg for the first dose and then 0.025 mg/kg every 6 months; as pain relief lasted only 3 months, the regimen was changed to 0.0125 mg/kg every 3 months, keeping 0.05 mg/kg/year, together with intensive pool-based physiotherapy, which resolved the right knee contracture (range 30 to 140°) in 8 weeks [17]. After 1 year, biopsy showed a trabecular bone volume of 89% of the healthy mean (previously 72%) and a cortical width of 98–99% (previously 36%), and lumbar and hip density rose to −1.2 SD [17]. Two years later, mobility was normal and the patient returned to basketball; MRI at 16 years, three years after surgery and two after zoledronic acid, showed improvement of the lesions in both knees [17, 136].

The case illustrates three points: incomplete coverage of ACAN exon 12 on panels, the possibility of severe joint disease in adolescence and the uncertainty about the joint safety of GH. The authors hypothesise that GH triggered or worsened the osteochondritis dissecans, which the report does not demonstrate [17]. The zoledronic acid regimen and its combination with surgery and rehabilitation represent the management of a single case, without a comparative study, and are not provided for in guidelines; high-turnover osteoporosis is also not an established feature of aggrecan deficiency.

10.2. Complementary case: adult height after somatropin and anastrozole

The boy described by Quintos in 2015, then aged 5.5 years and with three affected generations (maternal grandfather 144.5 cm, −4.7 SD; mother 147.7 cm, −2.6 SD; index case 99.2 cm, −2.7 SD), had a bone age of 8 years, a predicted adult height of 142 cm (−5.1 SD) and the truncating variant p.Gly1797Glyfs*52, in the published nomenclature [41]. Follow-up to adult height, published in 2026, showed the combination of GH from 6 years with anastrozole 1 mg/day for 4.5 years from 11 years and 7 months, with an adult height of 156.3 cm at 16 years, 14 cm above the initial prediction and below the last prediction of 160 cm [69]. The variant was described in the 2026 article by genomic coordinate in exon 12 without a c. description, and the correspondence between the two descriptions was not established by the sources [41, 69]. This management is off-label and has not been assessed in a randomised trial.

10.3. Complementary Portuguese case: ACAN variant of uncertain significance and incidental ALPL variant

In 2026, Silva and colleagues described a 16-year-old Portuguese girl with severe disproportionate short stature and growth arrest since the age of 12, rolandic epilepsy since the age of 7 (off medication for about 2 years), mild intellectual disability and attention deficit hyperactivity disorder [66]. She was born at term weighing 2405 g (−1.56 SD) and measuring 45 cm (−1.49 SD), had menarche at 11 years and bone age advanced by about 2 years at 12; target height was 153.5 cm (−1.53 SD), with her mother measuring 147.5 cm and her father 162.9 cm [66]. At 16 years she measured 136.7 cm (−3.83 SD), with an upper/lower segment ratio of 1.24, a sitting height/height ratio of 0.55 (+2 SD), relative macrocephaly (56.5 cm, +1.51 SD) and enamel defects; alkaline phosphatase was 35 U/L (reference 50–117) and the bone fraction 6.6 µg/L (19.5–150), with the rest of calcium-phosphate metabolism, densitometry and the skeletal survey normal [66]. The exome-based dysplasia panel identified the pathogenic ALPL variant c.1426G>A p.(Glu476Lys), inherited from her 50-year-old father, who had low alkaline phosphatase and was asymptomatic, and the ACAN variant NM_001369268.1:c.511G>C p.(Ala171Pro), classified as a VUS and inherited from her mother, who had no osteoarthritis, osteochondritis or disc disease; her 22-year-old brother had both variants and measured 164 cm (−1.72 SD) [62, 66]. The authors attributed the growth phenotype mainly to ACAN and considered the ALPL variant probably coincidental [66]. Codon 171 is the same as that of the homozygous p.(Ala171Val) variant of SEMD-ACAN [21]. The case shows the difficulty of interpreting ACAN missense variants with limited segregation and variable penetrance.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

Life expectancy is not described as reduced in any of the entities of this article in the sources consulted; the prognosis depends on final height and musculoskeletal morbidity. In heterozygous aggrecan deficiency, median untreated adult height is −2.8 SD, with a range of −5.9 to −0.9 SD [15], and ranges from −2.3 to −4.2 SD in the three Nilsson families [40]. The loss of height SD with age, from a median of −2.25 SD in children to −3.05 SD in adults, reflects early growth cessation [81]. Osteoarthritis or osteochondritis dissecans is present in 90% of adults assessed in a targeted manner, and 60% have had surgery [81]; in another cohort, osteoarthritis was present in 8 of 10 adult carriers [87]. ACAN deletions are associated with moderate to severe short stature and joint involvement with early surgery [73]. Predicted adult height overestimates the outcome in treated patients, as in the case in which the last prediction was 160 cm and final height 156.3 cm [69].

In SEDK, adult height in the original family was 141–162 cm in men and 138–149 cm in women, and osteoarthropathy of the large joints progressed slowly with increasing pain and restriction [20]. In SEMD-ACAN, adult height was 66–71 cm, and the patients were otherwise healthy [20]. In short stature due to heterozygous NPR2, height declines progressively in SD with age [80], and near-adult height improved in 5 of 6 children treated with GH in the Dutch registry [25]. In AMDM, untreated adult height was 94–123 cm in the atlas [27] and 96.5–124.5 cm in 9 adults [28], with normal intelligence, degenerative lumbar changes in adulthood and possible pubertal delay [27]; the two brothers treated with high-dose GH reached 130.5 and 134 cm [91]. In ECDM, the great toe deformities, camptodactyly and kyphoscoliosis appear in mid-childhood and often require surgery, slipped capital femoral epiphysis occurred in 2 members of the Korean family, and arterial hypertension may appear in adulthood [10, 12].

11.2. Surveillance

For NPR2 there is no specific surveillance guideline. For the aggrecanopathies, the 2025 French PNDS proposes, by expert consensus, a follow-up schedule that sets intervals for growth, bone age, osteoarticular assessment and genetics and endocrinology consultations [36]; the remaining intervals come from the labels and the SGA consensus, and the assessments without a defined interval derive from the natural history described. In adults, the PNDS focuses follow-up on joint and spinal lesions, with assessment by an orthopaedic surgeon or neurosurgeon in the presence of symptoms or deterioration [36].

11.3. Prognosis with treatment

With GH started before puberty, the height gains described are about +1.0 SD in 3 years in aggrecan deficiency [71] and +1.2 SD in 2 years in NPR2 [25], with +1.21 SD at 3 years in the prospective trial [112]. Adult height data are limited to small series with mean gains of +0.05 to +0.4 SD depending on the regimen [69] and to non-randomised comparisons [69]. Vosoritide increased GV by more than 3 cm/year in the first year in ACAN and NPR2, without adult height data and with the signal of genu valgum and slipped epiphysis in the extension [18]. The effect of any of these treatments on osteoarthritis and osteochondritis dissecans is unknown [18, 105].

12. Summary and Final Considerations

Heterozygous variants of ACAN and NPR2 are monogenic causes of short stature that frequently hide under the label of idiopathic short stature or familial short stature, and each accounts for about 1–2% of children with ISS or with short stature after SGA birth [11]. The 2026 international guideline includes both genes in the minimum list for isolated short stature and recommends testing when dominant inheritance is suggested, or there is disproportion, height below −3 SD or skeletal abnormalities [16]. Aggrecan deficiency is recognised by the combination of dominantly inherited short stature, frequently advanced bone age, early growth cessation, brachydactyly and early-onset osteoarthritis in adult relatives, but advanced bone age and dysmorphic features are absent in a fraction of patients, especially outside North American and European series [15, 85, 86]. Short stature due to heterozygous NPR2 mimics SHOX deficiency without Madelung deformity and tends to worsen with age [26, 80].

Both genes have a dosage-dependent allelic spectrum: for ACAN, from SSOAOD to SEMD-ACAN with an adult height of 66–71 cm [20, 21]; for NPR2, from biallelic AMDM with an adult height of about 94–124 cm to gain-of-function ECDM with overgrowth and slipped epiphysis [12, 27, 28]. Molecular diagnosis requires attention to coverage of ACAN exon 12, to deletions, to synonymous NPR2 variants with a splicing effect and to the historical numbering of variants, which should be converted to the MANE transcripts NM_001369268.1 and NM_003995.4 [17, 29, 62, 72].

No drug is approved for these entities. Somatropin produces gains of about 1 SD in 2–3 years when started before puberty, with scarce adult height data, and its regulatory framework differs between the United States, where the ISS indication is approved, and the European Union, where it is not [25, 71, 107, 110]. Aromatase inhibitors and GnRHa are used off-label on the basis of cases and series [69, 84]. Vosoritide increased GV by more than 3 cm/year in ACAN and NPR2 in a phase 2 trial without a control group, but genu valgum and slipped capital femoral epiphysis after more than 12 months, concentrated in aggrecan deficiency, limit its use to clinical trials [18, 94]. The long-term morbidity of aggrecan deficiency is joint and spinal, present in 90% of adults assessed in a targeted manner [81], and the 2025 French PNDS proposes, by expert consensus, an osteoarticular assessment at least annually and a multidisciplinary follow-up schedule, with rehabilitation from diagnosis and stepwise analgesia [36].

13. References

1. Orphanet. Short stature-advanced bone age-early-onset osteoarthritis syndrome (ORPHA:435804). https://www.orpha.net/en/disease/detail/435804
2. Orphanet. Familial osteochondritis dissecans (ORPHA:251262). https://www.orpha.net/en/disease/detail/251262
3. Orphanet. Spondyloepiphyseal dysplasia, Kimberley type (ORPHA:93283). https://www.orpha.net/en/disease/detail/93283
4. Orphanet. Spondyloepimetaphyseal dysplasia, aggrecan type (ORPHA:171866). https://www.orpha.net/en/disease/detail/171866
5. Orphanet. Acromesomelic dysplasia, Maroteaux type (ORPHA:40). https://www.orpha.net/en/disease/detail/40
6. Orphanet. Tall stature-long halluces-multiple extra-epiphyses syndrome (ORPHA:329191). https://www.orpha.net/en/disease/detail/329191
7. Orphanet. Overgrowth syndrome with 2q37 translocation (ORPHA:498488). https://www.orpha.net/en/disease/detail/498488
8. 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.
9. Online Mendelian Inheritance in Man (OMIM). Short stature with nonspecific skeletal abnormalities 1; SNSK1. MIM 616255. Baltimore (MD): Johns Hopkins University; updated 2024 Sep 26 [accessed 2026 Oct 17]. Available from: https://www.omim.org/entry/616255
10. Online Mendelian Inheritance in Man (OMIM). Epiphyseal chondrodysplasia, Miura type; ECDM. MIM 615923. Baltimore (MD): Johns Hopkins University; updated 2021 Oct 14 [accessed 2026 Oct 17]. Available from: https://www.omim.org/entry/615923
11. Hokken-Koelega ACS, van der Steen M, Boguszewski MCS, Cianfarani S, Dahlgren J, Horikawa R, et al. International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood. Endocr Rev. 2023;44(3):539-565. doi:10.1210/endrev/bnad002. PMID 36635911. PMC10166266.
12. 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 University Press; 2018. 22.4 CNP-overexpression overgrowth syndrome. p. 826–828.
13. GeneGuidance. Gene records for ACAN, NPR2 and NPPC and library (diagnosis: short stature; management: achondroplasia). Version of 2026-09-26 (accessed 2026-10-17).
14. Lin L, Li M, Luo J, Li P, Zhou S, Yang Y, et al. A High Proportion of Novel ACAN Mutations and Their Prevalence in a Large Cohort of Chinese Short Stature Children. J Clin Endocrinol Metab. 2021;106(7):e2711-e2719. doi:10.1210/clinem/dgab088. PMID 33606014. PMC8208663.
15. Gkourogianni A, Andrew M, Tyzinski L, Crocker M, Douglas J, Dunbar N, et al. Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations. J Clin Endocrinol Metab. 2017;102(2):460-469. doi:10.1210/jc.2016-3313. PMID 27870580. PMC5413162.
16. Dauber A, Jorge AAL, Nilsson O, Dekkers OM, Argente J, Netchine I, et al. International guideline on genetic testing of children with short stature. Eur J Endocrinol. 2026;194(2):R17-R36. doi:10.1093/ejendo/lvag013. PMID 41543979.
17. Ochoa M, Yang A, Kollias C, Bakir C, Carsen S, Lazier J, et al. From "ACAN" to "I CAN": Restoring wellness in a boy with severe osteochondritis dissecans through diagnostic precision combined with optimal medical, surgical and rehabilitation management. Bone Rep. 2023;18:101663. doi:10.1016/j.bonr.2023.101663. PMID 36950254. PMC10025132.
18. 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.
19. Stattin EL, Wiklund F, Lindblom K, Onnerfjord P, Jonsson BA, Tegner Y, et al. A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans. Am J Hum Genet. 2010;86(2):126-137. doi:10.1016/j.ajhg.2009.12.018. PMID 20137779. PMC2820178.
20. 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 University Press; 2018. 7.14 Aggrecan-associated skeletal dysplasias. p. 209–213.
21. Arslan G, Hazan F, Tabanlı G, Kırkgöz T, Özkan B. A rare case of skeletal dysplasia: biallelic variant in ACAN gene. J Pediatr Endocrinol Metab. 2024;37(12):1104-1111. doi:10.1515/jpem-2024-0255. PMID 39295451.
22. Amano N, Mukai T, Ito Y, Narumi S, Tanaka T, Yokoya S, et al. Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. J Clin Endocrinol Metab. 2014;99(4):E713-8. doi:10.1210/jc.2013-3525. PMID 24471569.
23. Vasques GA, Amano N, Docko AJ, Funari MF, Quedas EP, Nishi MY, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. J Clin Endocrinol Metab. 2013;98(10):E1636-44. doi:10.1210/jc.2013-2142. PMID 24001744.
24. Stavber L, Gaia MJ, Hovnik T, Jenko Bizjan B, Debeljak M, Kovač J, et al. Heterozygous NPR2 Variants in Idiopathic Short Stature. Genes (Basel). 2022;13(6):1065. doi:10.3390/genes13061065. PMID 35741827. PMC9222219.
25. 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.
26. Hisado-Oliva A, Garre-Vázquez AI, Santaolalla-Caballero F, Belinchón A, Barreda-Bonis AC, Vasques GA, et al. Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis. J Clin Endocrinol Metab. 2015;100(8):E1133-42. doi:10.1210/jc.2015-1612. PMID 26075495.
27. 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 University Press; 2018. 13.1 Acromesomelic dysplasia, Maroteaux type. p. 443–446.
28. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Acromesomelic dysplasia (acromesomelic dysplasia, type Maroteaux). p. 498–501.
29. 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.
30. Kenis V, Melchenko E, Mazunin I, Pekkinen M, Mäkitie O. A new family with epiphyseal chondrodysplasia type Miura. Am J Med Genet A. 2021;185(1):112-118. doi:10.1002/ajmg.a.61923. PMID 33073519.
31. Miura K, Kim OH, Lee HR, Namba N, Michigami T, Yoo WJ, et al. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A. 2014;164A(1):156-163. doi:10.1002/ajmg.a.36218. PMID 24259409.
32. European Reference Network on Rare Endocrine Conditions (Endo-ERN). https://endo-ern.eu/
33. European Reference Network on Rare Bone Diseases (ERN BOND). https://ernbond.eu/
34. Linglart A, Cianfarani S, Dattani MT, Jorge AAL, Lebenthal Y, Luo X, et al. International Consensus on the Diagnosis and Clinical Management of Idiopathic Short Stature: A Modified Delphi Method. Horm Res Paediatr. 2026:1. doi:10.1159/hrp/adaag008. PMID 42658741.
35. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Short stature. p. 312–314.
36. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Aggrécanopathies. Centre de référence des maladies osseuses constitutionnelles, filière OSCAR; texte de septembre 2025. Saint-Denis La Plaine: HAS; 2025 Oct 27 [accessed 2026 Nov 6]. Available from: https://www.has-sante.fr/jcms/p_3689368
37. Anderson IJ, Tsipouras P, Scher C, Ramesar RS, Martell RW, Beighton P. Spondyloepiphyseal dysplasia, mild autosomal dominant type is not due to primary defects of type II collagen. Am J Med Genet. 1990;37(2):272-276. doi:10.1002/ajmg.1320370223. PMID 1978986.
38. Gleghorn L, Ramesar R, Beighton P, Wallis G. A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis. Am J Hum Genet. 2005;77(3):484-490. doi:10.1086/444401. PMID 16080123. PMC1226213.
39. Tompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, Rimoin DL, et al. A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. Am J Hum Genet. 2009;84(1):72-79. doi:10.1016/j.ajhg.2008.12.001. PMID 19110214. PMC2668039.
40. Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, et al. Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. J Clin Endocrinol Metab. 2014;99(8):E1510-8. doi:10.1210/jc.2014-1332. PMID 24762113. PMC4121031.
41. Quintos JB, Guo MH, Dauber A. Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene. J Pediatr Endocrinol Metab. 2015;28(7-8):927-932. doi:10.1515/jpem-2014-0450. PMID 25741789. PMC4501863.
42. Gibson BG, Briggs MD. The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases. Orphanet J Rare Dis. 2016;11(1):86. doi:10.1186/s13023-016-0459-2. PMID 27353333. PMC4924316.
43. Maroteaux P, Martinelli B, Campailla E. [Acromesomelic dwarfism]. Presse Med (1893). 1971;79(42):1839-1842. PMID 5000841.
44. Langer LO, Beals RK, Solomon IL, Bard PA, Bard LA, Rissman EM, et al. Acromesomelic dwarfism: manifestations in childhood. Am J Med Genet. 1977;1(1):87-100. doi:10.1002/ajmg.1320010110. PMID 610427.
45. 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):155-162. doi:10.1086/301917. PMID 9634515. PMC1377238.
46. 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):52-54. doi:10.1136/jmg.37.1.52. PMID 10633136. PMC1734441.
47. 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.
48. 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):1229-1232. doi:10.1210/jc.2005-1949. PMID 16384845.
49. 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.
50. Hannema SE, van Duyvenvoorde HA, Premsler T, Yang RB, Mueller TD, Gassner B, et al. An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities. J Clin Endocrinol Metab. 2013;98(12):E1988-98. doi:10.1210/jc.2013-2358. PMID 24057292.
51. Bocciardi R, Giorda R, Buttgereit J, Gimelli S, Divizia MT, Beri S, et al. Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation. Hum Mutat. 2007;28(7):724-731. doi:10.1002/humu.20511. PMID 17373680.
52. Moncla A, Missirian C, Cacciagli P, Balzamo E, Legeai-Mallet L, Jouve JL, et al. A cluster of translocation breakpoints in 2q37 is associated with overexpression of NPPC in patients with a similar overgrowth phenotype. Hum Mutat. 2007;28(12):1183-1188. doi:10.1002/humu.20611. PMID 17676597.
53. Nakamura S, Kuroki Y, Pak K, Kamimaki T, Mochizuki T, Ishiguro A, et al. ACAN Repeat Number Polymorphism in Patients with Idiopathic Short Stature. Cytogenet Genome Res. 2025;165(2):51-56. doi:10.1159/000545736. PMID 40517756. PMC12237279.
54. Bendre A, Ottosson L, Baroncelli M, Dou Z, Nilsson O. Growth failure in aggrecan deficiency is due to decreased extracellular matrix and impaired growth plate chondrocyte hypertrophy. Bone. 2025;200:117594. doi:10.1016/j.bone.2025.117594. PMID 40685060.
55. Bendre A, Hadad H, Ottosson L, Ohlsson C, Windahl SH, Nilsson O. Aggrecan deficiency does not increase susceptibility to estrogen-induced growth plate senescence. J Endocr Soc. 2026;10(9):bvag163. doi:10.1210/jendso/bvag163. PMID 42582486. PMC13457934.
56. Stattin EL, Lindblom K, Struglics A, Önnerfjord P, Goldblatt J, Dixit A, et al. Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan. Sci Rep. 2022;12(1):5215. doi:10.1038/s41598-022-09211-y. PMID 35338222. PMC8956744.
57. Ahmed HA, Elhossini R, Aglan M, Amr K. Aggrecan-related bone disorders; a novel heterozygous ACAN variant associated with spondyloepimetaphyseal dysplasia expanding the phenotypic spectrum and review of literature. J Genet Eng Biotechnol. 2024;22(1):100341. doi:10.1016/j.jgeb.2023.100341. PMID 38494255. PMC10860877.
58. Binder G, Rappold GA. SHOX Deficiency Disorders. 2005 Dec 12 [updated 2018 Jun 28; revised 2024 May 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. NBK1215. https://www.ncbi.nlm.nih.gov/books/NBK1215/
59. Jeong R, Covarrubias S, Shanghavi D, Ruhrmund D, Estrada K, Zhou D, et al. Functional analysis of NPR2 variants supports the therapeutic rationale for CNP in short stature. Am J Hum Genet. 2026;113(1):117-132. doi:10.1016/j.ajhg.2025.12.006. PMID 41512838. PMC12824620.
60. Vasques GA, Hisado-Oliva A, Funari MF, Lerario AM, Quedas EP, Solberg P, et al. Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2. J Pediatr Endocrinol Metab. 2017;30(1):111-116. doi:10.1515/jpem-2016-0280. PMID 27941173.
61. 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.
62. 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):61-68. doi:10.1002/humu.23348. PMID 28967166. https://rest.variantvalidator.org/
63. National Center for Biotechnology Information. ClinVar. VCV000014305, VCV000014306, VCV000143053, VCV000143054, VCV000143055. https://www.ncbi.nlm.nih.gov/clinvar/
64. Tatsi C, Gkourogianni A, Mohnike K, DeArment D, Witchel S, Andrade AC, et al. Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation. J Endocr Soc. 2017;1(8):1006-1011. doi:10.1210/js.2017-00229. PMID 29264551. PMC5686699.
65. Shalev-Goldman E, Asaly A, Ityel H, Pode-Shakked B, Modan-Moses D, Levy-Shraga Y. Impact of Growth Hormone Treatment in Children From an Extended Family With ACAN -Related Short Stature. Clin Genet. 2026;109(2):374-379. doi:10.1111/cge.70050. PMID 41211650. PMC12779246.
66. Silva JA, Costa ARA, Mazeda I, Mota C, Abreu M, Borges T, et al. ACAN-related short stature with an incidental ALPL variant: a case report. Clin Pediatr Endocrinol. 2026;35(3):255-259. doi:10.1297/cpe.2025-0108. PMID 42441205. PMC13337292.
67. Lin C, Pan D, Lai X, Fu S. A Novel ACAN Missense Variant in the G1 Domain Causes Short Stature, Advanced Bone Age, and Osteochondritis Dissecans: A Case Report and Literature Review. Clin Genet. 2026. doi:10.1111/cge.70241. PMID 42827044.
68. Murch O, Jain V, Offiah AC. A mild case of acromesomelic dysplasia, type Maroteaux with novel natriuretic peptide receptor B (NPR2) variants. Radiol Case Rep. 2021;16(8):2240-2243. doi:10.1016/j.radcr.2021.05.011. PMID 34178199. PMC8213897.
69. Ruiz DL, Delano A, Quintos JB. Adult Height After Growth Hormone and Aromatase Inhibitor Therapy for Short Stature due to ACAN Mutation. AACE Endocrinol Diabetes. 2026;13(4):643-648. doi:10.1016/j.aed.2026.04.004. PMID 42491490. PMC13377873.
70. Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, et al. NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy. J Clin Endocrinol Metab. 2020;105(3):dgaa037. doi:10.1210/clinem/dgaa037. PMID 31990356.
71. Renes JS, Reedijk AMJ, Losekoot M, Kant SG, Van der Steen M, Van der Kaay DCM, et al. Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data. Horm Res Paediatr. 2024;97(5):456-469. doi:10.1159/000535651. PMID 38232712.
72. Stavber L, Hovnik T, Kotnik P, Lovrečić L, Kovač J, Tesovnik T, et al. High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature. Eur J Endocrinol. 2020;182(3):243-253. doi:10.1530/eje-19-0771. PMID 31841439. PMC7087498.
73. Sentchordi-Montané L, Díaz-Gonzalez F, Modamio-Høybjør S, Nevado J, Machado-Fernandes F, Carcavilla A, et al. Moderate to Severe Short Stature and Joint Involvement in Individuals With ACAN Deletions. Clin Endocrinol (Oxf). 2025;103(2):177-184. doi:10.1111/cen.15237. PMID 40129139.
74. 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.
75. Chen H, Zhang S, Sun Y, Chen J, Yuan K, Zhang Y, et al. Novel pathogenic NPR2 variants in short stature patients and the therapeutic response to rhGH. Orphanet J Rare Dis. 2023;18(1):221. doi:10.1186/s13023-023-02757-8. PMID 37501190. PMC10375756.
76. Ke X, Liang H, Miao H, Yang H, Wang L, Gong F, et al. Clinical Characteristics of Short-Stature Patients With an NPR2 Mutation and the Therapeutic Response to rhGH. J Clin Endocrinol Metab. 2021;106(2):431-441. doi:10.1210/clinem/dgaa842. PMID 33205215.
77. Wang SR, Jacobsen CM, Carmichael H, Edmund AB, Robinson JW, Olney RC, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature. Hum Mutat. 2015;36(4):474-481. doi:10.1002/humu.22773. PMID 25703509. PMC4382411.
78. Hernández MI, Gallardo V, Unanue N, van Duyvenvoorde H, Mericq MV. Identification of pathogenic ACAN variants in healthy children with normal height and advanced bone age. J Pediatr Endocrinol Metab. 2025;38(10):1114-1116. doi:10.1515/jpem-2025-0408. PMID 40862364.
79. Wang D, Hu X, Su S, Yi Y, Zeng Y, Zhang K, et al. Novel NPR2 heterozygous variant in a familial short stature and the therapeutic response to rhGH: a case report. J Pediatr Endocrinol Metab. 2026. doi:10.1515/jpem-2025-0185. PMID 42438924.
80. Hanley PC, Kanwar HS, Martineau C, Levine MA. Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations. J Clin Endocrinol Metab. 2020;105(10):dgaa491. doi:10.1210/clinem/dgaa491. PMID 32720985. PMC7442278.
81. Alexandrou E, Dauber A, Tyzinski L, Hwa V, Andrew M, Kim H, et al. Clinical phenotype and musculoskeletal characteristics of patients with aggrecan deficiency. Am J Med Genet A. 2022;188(4):1193-1203. doi:10.1002/ajmg.a.62639. PMID 35001504.
82. Hisado-Oliva A, Ruzafa-Martin A, Sentchordi L, Funari MFA, Bezanilla-López C, Alonso-Bernáldez M, et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. Genet Med. 2018;20(1):91-97. doi:10.1038/gim.2017.66. PMID 28661490.
83. Pattani N, Page A, Barber JL, Del Rey Jimenez JC, Alsters S, Albanese A, et al. ACAN-related disorder, antenatal presentation and phenotypic variability: a case series. J Med Genet. 2026;63(7):456-462. doi:10.1136/jmg-2025-111354. PMID 41956799.
84. van der Steen M, Pfundt R, Maas SJWH, Bakker-van Waarde WM, Odink RJ, Hokken-Koelega ACS. ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment. J Clin Endocrinol Metab. 2017;102(5):1458-1467. doi:10.1210/jc.2016-2941. PMID 27710243.
85. Kolkiran A, Özdemir BS, Sezer A, Kulalı MA, Daşar T, Erdeve ŞS, et al. ACAN -Related Short Stature and Skeletal Dysplasia: Expanding the Phenotypic and Genotypic Spectrum in a 47 Patient Cohort From Turkey. Am J Med Genet A. 2026;200(11):2507-2518. doi:10.1002/ajmg.a.70282. PMID 42613584.
86. Deng S, Hou L, Xia D, Li X, Peng X, Xiao X, et al. Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese children and a review of the literature. Front Endocrinol (Lausanne). 2022;13:1015954. doi:10.3389/fendo.2022.1015954. PMID 36387899. PMC9649928.
87. ClinicalTrials.gov. Clinical Characterization and Trial of Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency. NCT03288103 (results posted). https://clinicaltrials.gov/study/NCT03288103 (last updated 2024-07-30)
88. Cai B, Chen H, Su Y, Zhang S, Wu W, Sun Y, et al. Phenotypic and genotypic diversity in patients with Chinese aggrecan gene-related short stature. Pediatr Res. 2026. doi:10.1038/s41390-026-05165-3. PMID 42277182.
89. Wu S, Cui Y, Chen Y, Zhou W, Zheng B, Wang C, et al. Phenotypic Characterization and recombinant human growth hormone Therapeutic Response in ACAN Children With Short Stature: A Real-World Study. Endocr Pract. 2026:S1530-891X(26)01081-5. doi:10.1016/j.eprac.2026.07.016. PMID 42498135.
90. Pareek A, Sanders TL, Wu IT, Larson DR, Saris DBF, Krych AJ. Incidence of symptomatic osteochondritis dissecans lesions of the knee: a population-based study in Olmsted County. Osteoarthritis Cartilage. 2017;25(10):1663-1671. doi:10.1016/j.joca.2017.07.005. PMID: 28711583.
91. 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.
92. 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.
93. Collett-Solberg PF, Ambler G, Backeljauw PF, Bidlingmaier M, Biller BMK, Boguszewski MCS, et al. Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective. Horm Res Paediatr. 2019;92(1):1-14. doi:10.1159/000502231. PMID 31514194. PMC6979443.
94. 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. doi:10.1159/hrp/adaag011. PMID 42678892.
95. BioMarin Pharmaceutical Inc. VOXZOGO (vosoritide) for injection, for subcutaneous use. Prescribing information. NDA 214938. DailyMed/openFDA set_id 228e8560-04a4-4bb1-a81f-29531a9e4d27, version 16 (effective 2025-11-25). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=228e8560-04a4-4bb1-a81f-29531a9e4d27
96. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Skeletal dysplasia charts, Table A16. p. 854.
97. Scalco RC, Schoones JW, Galetaki D, Santillan-Vasconez AM, Kim GJ, Cellin LP, et al. Diagnostic yield of genetic testing in children with short stature: a systematic review. Eur J Endocrinol. 2026;194(2):S15-S24. doi:10.1093/ejendo/lvag011. PMID 41543974.
98. Mintz CS, Seaver LH, Irons M, Grimberg A, Lozano R. Focused Revision: ACMG practice resource: Genetic evaluation of short stature. Genet Med. 2021;23(5):813-815. doi:10.1038/s41436-020-01046-0. PMID 33514815.
99. Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Andrew M, Hwa V, et al. Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human Growth Hormone: 1-Year Response. J Clin Endocrinol Metab. 2022;107(5):e2103-e2109. doi:10.1210/clinem/dgab904. PMID 34922359. PMC9432476.
100. 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 University Press; 2018. 12.3 Dyschondrosteosis. p. 419–421.
101. 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 University Press; 2018. 1.3 Hypochondroplasia. p. 12.
102. Andrade NLM, Funari MFA, Malaquias AC, Collett-Solberg PF, Gomes NLRA, Scalco R, et al. Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature. Endocr Connect. 2022;11(12):e220214. doi:10.1530/ec-22-0214. PMID 36373817. PMC9716379.
103. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Brachydactyly. p. 80.
104. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Léri-Weill dyschondrosteosis. p. 622–623.
105. Chen Y, Wu S, Gu W. Research progress of short stature and advanced bone age, early-onset osteoarthritis and osteochondritis dissecans (SSOAOD) caused by acan gene mutation. Front Endocrinol (Lausanne). 2026;17:1809260. doi:10.3389/fendo.2026.1809260. PMID 42255433. PMC13233341.
106. Ascendis Pharma. YUVIWEL (navepegritide) for injection, for subcutaneous use. Prescribing information. NDA 219164. openFDA set_id e01c1197-338f-414c-b804-808e129ebc8c, version 4 (effective 2026-03-25). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e01c1197-338f-414c-b804-808e129ebc8c
107. Novo Nordisk. NORDITROPIN (somatropin) injection. Prescribing information. BLA 021148. openFDA set_id 1058e17c-9261-459c-a3e6-fae38d196c14, version 30 (effective 2025-07-07). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1058e17c-9261-459c-a3e6-fae38d196c14
108. Eli Lilly and Company. HUMATROPE (somatropin) for injection. Prescribing information. BLA 019640. openFDA set_id a774e1ae-3997-49ee-8b0e-99a2b315d409, version 45 (effective 2026-08-20). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a774e1ae-3997-49ee-8b0e-99a2b315d409
109. Pfizer. GENOTROPIN (somatropin) lyophilized powder for injection. Prescribing information. BLA 020280. openFDA set_id ffebf88b-d257-4542-9808-74d9b7167765, version 37 (effective 2026-08-04). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffebf88b-d257-4542-9808-74d9b7167765
110. European Medicines Agency. Omnitrope (somatropin): EPAR. Authorisation 12/04/2006. https://www.ema.europa.eu/en/medicines/human/EPAR/omnitrope
111. Dauber A, Savarirayan R, Carroll R, Cheung M, Cormier-Daire V, Maghnie M, et al. A phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of vosoritide in children with hypochondroplasia: CANOPY HCH-3 study design. Ther Adv Endocrinol Metab. 2026;19:20420188261480984. doi:10.1177/20420188261480984. PMID 42694461. PMC13538998.
112. Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Hwa V, Backeljauw P. Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human GH: 3-year Response. J Endocr Soc. 2024;8(12):bvae177. doi:10.1210/jendso/bvae177. PMID 39502477. PMC11535719.
113. ClinicalTrials.gov. Searches “ACAN OR aggrecan”, “NPR2”, “acromesomelic dysplasia”, “vosoritide …”, “navepegritide OR TransCon CNP”, “C-type natriuretic peptide short stature” (API v2). https://clinicaltrials.gov/
114. European Medicines Agency. Voxzogo (vosoritide): EPAR — medicine overview/product information. EMEA/H/C/005475. Authorisation 26/08/2021. https://www.ema.europa.eu/en/medicines/human/EPAR/voxzogo
115. U.S. Food and Drug Administration. Drugs@FDA: VOXZOGO (vosoritide), NDA 214938 — original approval (2021-11-19), supplement S-002 (2023-10-20) and S-004 (2024-11-04), approval letters. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/214938Orig1s002ltr.pdf [accessed 2026 Oct 17].
116. European Medicines Agency. Voxzogo (vosoritide): EPAR — procedural steps taken and scientific information after authorisation; CHMP summary of opinion II/0006 (EMA/410364/2023, 14 Sep 2023). Available from: https://www.ema.europa.eu/en/documents/procedural-steps-after/voxzogo-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf [accessed 2026 Oct 17].
117. Legare JM, Modaff P. Achondroplasia. 1998 Oct 12 [updated 2025 Nov 20; revised 2026 Apr 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. NBK1152. https://www.ncbi.nlm.nih.gov/books/NBK1152/
118. Poskanzer SA, Peña LDM, Niu Z. Vosoritide approved for treatment of linear growth in pediatric patients with achondroplasia: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). Genet Med Open. 2023;1(1):100771. doi:10.1016/j.gimo.2023.100771. PMID 39669232. PMC11613676.
119. ClinicalTrials.gov. Vosoritide for Selected Genetic Causes of Short Stature. NCT04219007. https://clinicaltrials.gov/study/NCT04219007 (last updated 2026-03-18)
120. BioMarin Pharmaceutical. BioMarin Announces Positive Phase 3 Pivotal Study Results for VOXZOGO (vosoritide) in Children with Hypochondroplasia [press release]. 20 May 2026. https://www.biospace.com/press-releases/biomarin-announces-positive-phase-3-pivotal-study-results-for-voxzogo-vosoritide-in-children-with-hypochondroplasia
121. ClinicalTrials.gov. A Phase 2, Randomized, Controlled, Multicenter Study of Vosoritide in Children With Idiopathic Short Stature. NCT06382155. https://clinicaltrials.gov/study/NCT06382155 (last updated 2026-05-22)
122. Agence nationale de sécurité du médicament et des produits de santé (ANSM). DOLIPRANE 500 mg, comprimé (paracétamol): résumé des caractéristiques du produit. CIS 63368332; updated 25/08/2025. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/63368332/extrait
123. Agence nationale de sécurité du médicament et des produits de santé (ANSM). DOLIPRANE 2,4 POUR CENT, suspension buvable (paracétamol): résumé des caractéristiques du produit. CIS 66477582; updated 05/10/2026. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/66477582/extrait
124. Agence nationale de sécurité du médicament et des produits de santé (ANSM). ACUPAN, comprimé (néfopam 30 mg): résumé des caractéristiques du produit. CIS 68943687; updated 31/03/2026. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/68943687/extrait
125. Agence nationale de sécurité du médicament et des produits de santé (ANSM). VOLTARENACTIGO 1 POUR CENT, gel (diclofénac): résumé des caractéristiques du produit. CIS 60851678; updated 20/10/2026. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/60851678/extrait
126. Agence nationale de sécurité du médicament et des produits de santé (ANSM). IBUPROFENE ARROW 5 %, gel: résumé des caractéristiques du produit. CIS 63691015; updated 30/09/2026. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/63691015/extrait
127. Agence nationale de sécurité du médicament et des produits de santé (ANSM). HEXATRIONE 2 POUR CENT, suspension injectable (intra-articulaire) (hexacétonide de triamcinolone): résumé des caractéristiques du produit. CIS 62232169; updated 05/01/2026. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/62232169/extrait
128. Agence nationale de sécurité du médicament et des produits de santé (ANSM). CONTRAMAL 50 mg, gélule (tramadol): résumé des caractéristiques du produit. CIS 68655884; updated 30/10/2025. Base de données publique des médicaments [accessed 2026 Nov 6]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/68655884/extrait
129. BioMarin Pharmaceutical. BioMarin announces positive results of phase 3 VOXZOGO vosoritide study in hypochondroplasia published in NEJM Evidence [press release]. September 2026. https://finviz.com/news/390284/biomarin-announces-positive-results-of-phase-3-voxzogo-vosoritide-study-in-hypochondroplasia-published-in-nejm-evidence
130. Carroll RS, Olney RC, Duker AL, Coghlan RF, Schelhaas AJ, Mackenzie WG, et al. C-type natriuretic peptide and collagen X marker are aberrant in skeletal dysplasias. J Bone Miner Res. 2025;40(9):1052-1060. doi:10.1093/jbmr/zjaf085. PMID 40581356. PMC12406125.
131. Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, et al. Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr. 2016;86(6):361-397. doi:10.1159/000452150. PMID 27884013.
132. Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, et al. Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genet Med. 2018;20(6):630-638. doi:10.1038/gim.2017.159. PMID 29758562. PMC5993671.
133. MAGIC Foundation. https://www.magicfoundation.org/
134. Child Growth Foundation. https://childgrowthfoundation.org/
135. Restricted Growth Association. https://www.restrictedgrowth.co.uk/
136. Ochoa M, Yang A, Kollias C, Bakir C, Carsen S, Lazier J, et al. Fig. 1. MRIs of the patient with osteochondritis dissecans before and three years after combined therapy. Bone Rep. 2023;18:101663. doi:10.1016/j.bonr.2023.101663. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10025132/figure/f0005/