Chondrodysplasia Punctata

Group of skeletal dysplasias defined by stippled calcification of cartilage in the fetus and infant: peroxisomal rhizomelic forms (PEX7, GNPAT, AGPS, FAR1, PEX5), X-linked recessive form (ARSL), X-linked dominant Conradi-Hünermann-Happle form (EBP), CHILD syndrome (NSDHL) and acquired phenocopies, including warfarin embryopathy.

Literature and regulatory information updated: 10 October 2026; integration of the French national protocol (HAS PNDS): 6 November 2026.

0. Initial Reference Table

The term chondrodysplasia punctata (CDP) designates a radiological finding, stippled calcification of epiphyseal and extra-epiphyseal cartilage, and a heterogeneous nosological group (ORPHA:93442; group 23 of the 2023 Nosology of Genetic Skeletal Disorders) [1, 2]. Stippling results from defects of peroxisomal ether lipid metabolism, post-squalene cholesterol synthesis, arylsulfatase L or the vitamin K cycle, and from prenatal exposures such as vitamin K antagonists (VKA), maternal vitamin K deficiency and maternal autoimmune disease [3, 4]. The first table gathers the identifiers; the second, the essential clinical data for each entity and the relevant European Reference Network (ERN). Inheritance is given as autosomal recessive (AR) or autosomal dominant (AD).

Table 0A. Identifiers of the entities in this article

Sources for Table 0A: GeneReviews for each entity, GeneGuidance database (dump of 26 Sep 2026) and Orphanet (local index and Orphadata API, 10 Oct 2026) [4, 5, 7–14]. Two mapping corrections were applied: the Oxford Desk Reference table reproduced from the 2010 nosology swaps the loci of NSDHL and EBP, which are Xq28 and Xp11.23 respectively [3, 7, 8]; and GeneGuidance swaps the Orphanet codes of CHILD syndrome (ORPHA:139) and CK syndrome (ORPHA:251383), as well as those of the two forms associated with FAR1 [9, 13]. The 2023 nosology retains the symbol ARSE; the symbol approved by the HUGO Gene Nomenclature Committee (HGNC) is ARSL [2, 15].

Table 0B. Essential clinical data

The prevalences in the table measure different quantities: that of RCDP is a birth prevalence modelled from allele frequencies in population databases and not a case count; that of CDPX2 differs between sources, and the Orphanet record cites GeneReviews itself (PMID 21634086) as the source, which gives a range two to four times higher; that of CHILD syndrome corresponds to a number of published cases [7, 11, 13, 16]. For CDP as a whole, of all causes, the 2022 French national diagnosis and care protocol (PNDS) gives a birth incidence estimated at 1/110,000, without stating the population or period of the estimate [17]. The relevant ERNs are ERN BOND (rare bone diseases), MetabERN (peroxisomal and lipid disorders subnetwork), ERN-Skin (syndromic ichthyoses) and ERN ITHACA (malformation syndromes) [19–21]. In France, the 2022 PNDS of the Haute Autorité de Santé (HAS) is the only national care protocol for CDPX1, CDPX2, MEND syndrome, CHILD syndrome and Greenberg dysplasia, and it links the rare disease networks (filières) OSCAR (constitutional bone diseases), AnDDI-Rares (developmental anomalies) and FIMARAD (rare dermatological diseases) (section 9.5) [17].

1. Introduction

1.1. Founding descriptions and separation of the clinical forms

The first description of a newborn with stippled calcifications of the epiphyses is attributed to Erich Conradi, who in 1914 published the case of a “hypoplastic fetal chondrodystrophy” with premature and unusual calcification nuclei; Carl Hünermann described in 1931 “congenital calcifying chondrodystrophy” as an abortive form of chondrodystrophy [22, 23]. For decades, the Conradi-Hünermann eponym was applied to almost all newborns with epiphyseal stippling. In 1971, Spranger, Opitz and Bidder demonstrated the heterogeneity of the group and separated an autosomal recessive rhizomelic form, with a severe prognosis, from non-rhizomelic forms with a more benign course; in the same year, Spranger, Bidder and Voelz characterised the “rhizomelic type” radiologically [24, 25]. In 1976, Sheffield and colleagues described in Melbourne 23 patients, 17 of them male, with a mild and relatively common form, with almost diagnostic facies, stippled calcification of the calcaneus on lateral foot radiograph and final stature and intelligence at the lower limit of normal; some of these cases would correspond, in the light of later knowledge, to CDPX1 and maternal phenocopies [26, 27].

Rudolf Happle reviewed 35 published cases in 1979 and added a new one: all patients were female (ratio 36:0), linear or patchy skin lesions were the hallmark of the syndrome, and the author postulated an X-linked gene with a lyonisation pattern in females and lethality in the hemizygote, proposing the classification of CDP into three forms, rhizomelic, Conradi-Hünermann and X-linked dominant [28]. In 1980, Happle, Koch and Lenz brought together two new cases and 18 from the literature under the acronym CHILD, describing unilateral erythema and scaling with a sharp midline demarcation, ipsilateral limb defects and, in some cases, ipsilateral epiphyseal calcifications, with a sex ratio of 19:1 [29]. The first recognisable report of this syndrome had been that of Falek and colleagues in 1968, on two sisters with unilateral limb and skin deformities and heart disease [30, 31]. In 1989, Maroteaux described four boys with CDP, brachytelephalangy and facial dysmorphism resembling Binder maxillonasal dysostosis, proposed an X-linked recessive form related to terminal Xp deletions and noted that the distal phalangeal anomaly allows diagnosis once the stippling has already disappeared [32].

The association with warfarin was recognised in 1975, when several groups simultaneously reported infants with nasal hypoplasia and stippling exposed to coumarins in utero; earlier isolated cases were identified retrospectively [33–36]. Hall, Pauli and Wilson published in 1980 the review of 418 pregnancies exposed to coumarin derivatives that established the pattern of fetal risk, and van Driel and colleagues updated in 2002 the synthesis of cases, follow-up and pathogenesis [37, 38]. There followed the phenocopies due to maternal vitamin K deficiency and to congenital vitamin K epoxide reductase deficiency, described by Pauli and colleagues in 1987, and the association with maternal autoimmune disease, whose first report is attributed to Curry and colleagues in 1993 [39–41].

1.2. Milestones of molecular discovery

In 1985, Heymans and colleagues identified RCDP as a peroxisomal disorder [42]. In April 1997, three independent groups showed that the gene for RCDP type 1 is PEX7, which encodes the receptor for peroxisomal targeting signal type 2 (PTS2); Braverman and colleagues found the L292ter variant in 26 of 36 probands, all with the severe form, and Motley and colleagues found that 86% of patients belonged to complementation group 11 of the peroxisome biogenesis disorders [43–45]. Ofman and colleagues cloned in 1998 the cDNA of dihydroxyacetone phosphate acyltransferase (DHAPAT, gene GNPAT) and found variants in all patients with RCDP type 2 analysed; in the same year, alkyl-DHAP synthase deficiency (AGPS, RCDP type 3) was characterised [24, 46]. FAR1 deficiency (2014) and selective loss of the long isoform of PEX5 (2015) were proposed as RCDP types 4 and 5, although without the typical skeletal changes in type 4 [24, 47].

In the cholesterol pathway, Braverman and colleagues and Derry and colleagues identified in 1999 the EBP gene, which encodes 3β-hydroxysteroid-Δ8,Δ7-isomerase, as the cause of CDPX2; the second group also showed the orthologous mutation in the tattered mouse [48, 49]. Kelley and colleagues demonstrated in the same year the accumulation of 8(9)-cholestenol and 8-dehydrocholesterol in Conradi-Hünermann-Happle syndrome and in sporadic lethal cases of CDP [50]. In 2000, König and colleagues identified NSDHL as the gene for CHILD syndrome, and Grange and colleagues described a CHILD phenotype caused by an EBP variant [51, 52]. The gene for the X-linked recessive form had been identified in 1995 by Franco and colleagues, who discovered a cluster of sulfatase genes at Xp22.3, found ARSE variants in five patients and showed that the enzyme's activity is inhibited by warfarin, which suggested a common basis for CDPX1 and warfarin embryopathy [53].

1.3. Nomenclature and reclassifications

The 2023 Nosology of the International Skeletal Dysplasia Society organises group 23 with eleven entities: CDPX1 (ARSE), CDPX2 (EBP), CHILD syndrome (NSDHL), Keutel syndrome (MGP), Greenberg dysplasia (LBR, which includes HEM dysplasia and “dappled” diaphyseal dysplasia), five forms of RCDP (PEX7, GNPAT, AGPS, FAR1, PEX5) and tibia-metacarpal type CDP, with no known gene and some cases possibly secondary to maternal autoimmune disease [2]. The nosology table contains two typographical errors in the symbols (DHPAT for GNPAT and AGP5 for AGPS) and retains ARSE, which HGNC has replaced with ARSL [2, 15]. Autosomal dominant Sheffield-type CDP (ORPHA:79344) is classified as obsolete in Orphanet, because its manifestations are almost identical to those of BCDP and the phenocopies and because dominant inheritance can only be asserted after maternal factors have been excluded [1, 27]. GeneReviews has adopted gene-centred designations (PEX7-related RCDP, EBP-related X-linked CDP, NSDHL-related disorders) and treats adult Refsum disease due to PEX7 as the extreme of a continuum with RCDP [5, 7, 8]. The 2022 French PNDS groups the genetic CDPs it covers by mechanism: arylsulfatase E deficiency (CDPX1, which it calls CDP with brachytelephalangy) and cholesterol biosynthesis defects (CDPX2, MEND syndrome, CHILD syndrome and Greenberg dysplasia, also called HEM, for hydrops-ectopic calcification-moth-eaten), and leaves RCDP and the phenocopies in the differential diagnosis [17]. In 2025, an international gene- and function-based classification of disorders of epidermal differentiation replaced the 2010 ichthyosis classification and included the syndromic forms of the cholesterol pathway among the candidates for pathogenesis-based therapy [54].

1.4. Definition of the entities in this article

RCDP is an autosomal recessive peroxisomal disorder defined by plasmalogen deficiency, with or without accumulation of phytanic acid, and by symmetrical rhizomelia, stippling, vertebral coronal clefts and cataracts in the classic form; the genes are PEX7, GNPAT, AGPS, FAR1 and PEX5 [5, 55]. CDPX1 is the X-linked recessive form due to loss of function of ARSL, with brachytelephalangy and nasomaxillary hypoplasia in males; the descriptive term brachytelephalangic CDP (BCDP) covers CDPX1 and the non-genetic phenocopies [4]. CDPX2 is the X-linked dominant form due to loss of function of EBP, almost exclusive to females, with mosaic lesions in the skin, eyes and skeleton; the hypomorphic variant in non-mosaic males gives rise to MEND syndrome, without stippling [7]. CHILD syndrome is the X-linked dominant form due to loss of function of NSDHL, with unilateral skin and skeletal lesions; the hypomorphic variant in males causes CK syndrome, without stippling or skin changes [8]. Phenocopies are CDP presentations that are non-hereditary or have another genetic basis, in which cartilage calcification results from inhibition of the vitamin K cycle (VKA, maternal deficiency, congenital VKORC1 or GGCX deficiency) or from maternal autoimmune disease; warfarin embryopathy, covered in this article, is their prototype [3, 4, 33].

The Zellweger spectrum, in which patellar stippling is a frequent finding, the prenatal approach to severe and lethal dysplasias, including Greenberg dysplasia, Smith-Lemli-Opitz syndrome, X-linked ichthyosis and Xp22.3 contiguous deletions, and desmosterolosis enter only into the differential diagnosis.

2. Molecular Genetics and Pathophysiology

Stippled calcification is an aberrant mineralisation of cartilage that is eventually incorporated into growing bone, but that can disturb growth and become asymmetric when the disease is expressed in mosaic form [3]. Four pathways converge on this finding: peroxisomal ether lipid synthesis, post-squalene cholesterol synthesis, Golgi arylsulfatase L and vitamin K-dependent γ-carboxylation of cartilage matrix proteins [3, 4, 9].

2.1. RCDP: PTS2 import and plasmalogen synthesis

Plasmalogens are ether glycerophospholipids with a fatty alcohol in a vinyl-ether bond at the sn-1 position, enriched in polyunsaturated fatty acids at the sn-2 position; they are abundant in myelin and pulmonary surfactant, which relates to the white matter changes and chronic respiratory disease of RCDP [5, 9]. The first steps of their synthesis take place in the peroxisome. FAR1, an NADPH-dependent peroxisomal membrane enzyme, reduces 16- and 18-carbon acyl-CoA to fatty alcohols and constitutes the rate-limiting step, regulated by feedback inhibition from the cellular plasmalogen content. GNPAT (DHAPAT) acylates dihydroxyacetone phosphate, the first committed step. AGPS, an FAD-dependent enzyme anchored to the luminal face of the membrane, exchanges the acyl chain of acyl-DHAP for a fatty alcohol and forms the first ether bond (alkyl-DHAP), which passes to the endoplasmic reticulum (ER) to complete the synthesis [9, 55]. AGPS and GNPAT form a complex on the luminal face, full GNPAT activity depends on the presence of AGPS and the substrate is channelled between the two [56].

PEX7 is the cytosolic receptor for matrix proteins with a PTS2 signal: AGPS, phytanoyl-CoA hydroxylase (PHYH, required for α-oxidation of phytanic acid) and peroxisomal thiolase ACAA1, the latter non-essential [5]. PEX7 does not act alone: the long isoform of PEX5 (PEX5L), which has a PEX7-binding domain, stabilises the receptor and acts as a co-receptor; membrane docking (PEX13, PEX14), translocation (PEX2, PEX10, PEX12) and receptor recycling (PEX1, PEX6, PEX26) are shared with the PTS1 pathway [47, 55]. Pathogenic PEX7 variants prevent the import of PTS2 enzymes, which remain in the cytosol and are degraded, whereas PTS1 import and membrane assembly are preserved; the mechanism is loss of function, with no evidence of gain of function [5]. RCDP1 therefore has its own biochemical phenotype, the tetrad described by Motley in 1997 (deficiency of DHAPAT, of alkyl-DHAP synthase, of phytanate α-oxidation and of thiolase import), distinct from the Zellweger spectrum, in which PTS1 import is impaired and VLCFA accumulate [5, 44]. In RCDP5, variants in exon 9, exclusive to the long isoform, eliminate only PEX5L; synthesis of the short isoform and PTS1 import remain intact and the result is a selective defect of PTS2 import, as in RCDP1 [47, 55].

In RCDP2 and RCDP3, the deficiency is enzymatic and isolated: RCDP2 has no demonstrable peroxisomal abnormality other than DHAPAT, and RCDP3 is an isolated alkyl-DHAP synthase deficiency [9, 46]. In all types plasmalogen synthesis is lacking, which may be only partial in the mildest patients, up to 40% of control; phytanic acid, of exclusively dietary origin, accumulates in types 1 and 5, in which PHYH is not imported, but not in types 2, 3 and 4, and its concentration depends on age and diet [55]. Plasmalogen deficiency appears to have a direct effect on bone growth [57]. In FAR1, the direction of the defect distinguishes two diseases: biallelic loss-of-function variants lower plasmalogens and cause severe intellectual disability, early epilepsy, microcephaly, congenital cataracts and growth deficiency, with inconsistent rhizomelia and stippling; heterozygous de novo variants at residue Arg480 (NM_032228.6:c.1438C>T p.(Arg480Cys), c.1439G>A p.(Arg480His) and c.1439G>T p.(Arg480Leu)) abolish feedback inhibition, increase FAR1 protein and activity and raise plasmalogens in fibroblasts, with cataracts, spastic paraparesis and speech delay [9, 55].

The abnormal neuronal migration (polymicrogyria, pachygyria) of the Zellweger spectrum does not occur in RCDP or in other diseases with isolated plasmalogen deficiency, which led to it being attributed to VLCFA accumulation [58]. The progressive cerebellar atrophy of RCDP has two readings: in a clinical series of magnetic resonance imaging (MRI) studies, severity tracked plasmalogens and phytanic acid did not appear causal; in an allelic series of Pex7 mice (hypomorphic/hypomorphic, hypomorphic/null, null/null), the graded reduction in plasmalogens was accompanied by an increase in C26:0-lysophosphatidylcholine and phytanic acid, loss of Purkinje cells, reduction of myelin basic protein and of neurotransmitters, and the authors proposed that phytanate contributes to atrophy in older patients [59, 60]. Metabolomics of patients and deficient mice showed extensive changes in phospholipids, acylcarnitines and sphingomyelins in the cortex and cerebellum, many absent from plasma, so the plasma profile underestimates lipid remodelling in the central nervous system (CNS) [61]. In 2025 the first spontaneous large animal model was described, in Aubrac cattle, with 21 stillborn calves homozygous for a deep intronic GNPAT variant that activates cryptic splice sites, with an allele frequency of 2.6% in the breed and absent in 375,535 animals of 17 breeds [62].

2.2. CDPX2 and CHILD syndrome: the post-squalene cholesterol pathway

EBP is an integral ER membrane protein that converts Δ8 sterols into Δ7 isomers, in particular 8(9)-cholestenol into lathosterol; its deficiency causes accumulation of 8(9)-cholestenol and 8-dehydrocholesterol (8-DHC) in serum and tissues, with plasma cholesterol often normal or low-normal [7, 63]. EBP also forms, with DHCR7, the microsomal antiestrogen binding site [9]. The mechanism is loss of function, through nonsense, frameshift, splice, missense and non-coding variants, including one case of retrotransposon insertion in a girl and her mother [7]. The variability in females and the distribution of skin lesions along Blaschko's lines reflect the functional mosaicism created by X inactivation [7, 63]. In the tattered mouse, heterozygous females develop hairless hyperkeratotic patches that leave stripes in the coat, and males die before birth [49].

NSDHL (sterol-4α-carboxylate 3-dehydrogenase, decarboxylating) forms part of the C4-demethylase complex with C4-methyl oxidase (MSMO1) and 3-ketosteroid reductase (HSD17B7), is located on the ER surface and in lipid droplets and acts one step before the EBP isomerase [8, 63]. Loss of function blocks local cholesterol synthesis and causes accumulation of potentially toxic methylsterols and carboxysterols; this dual mechanism underpins the topical combination of cholesterol, which replaces the product, and a statin, which reduces production of the precursors [9, 64]. The bare patches and striated mice, with Nsdhl variants, are X-linked dominant models lethal in the male [51]. The lateralisation of CHILD syndrome was studied by Paller and colleagues: keratinocytes from lesional skin expressed exclusively the mutant allele and those from unaffected skin only the normal allele, whereas fibroblasts from the affected area expressed both; in blood, X inactivation was skewed (89 ± 2% normal allele), suggesting selection against mutant cells on the spared side [65]. Fibroblasts from clinically normal skin, on both sides, may show an abnormal sterol profile [7]. Why the CHILD phenotype is common in NSDHL deficiency and rare in EBP deficiency has not been clarified [7].

2.3. CDPX1: arylsulfatase L

ARSL encodes arylsulfatase L (ARSE), synthesised as a 60 kDa precursor and N-glycosylated into a mature 68 kDa form located in the Golgi apparatus, unique among sulfatases [66]. Like all sulfatases, it is activated by SUMF1, which converts a cysteine into Cα-formylglycine; the physiological substrate is unknown [4]. Four of five missense variants from patients abolished activity without affecting stability or localisation, and all alleles studied in the North American programme of 2008–2010 had negligible activity on the artificial substrate 4-methylumbelliferyl sulfate [66, 67]. Deletions, nonsense and missense variants produce indistinguishable phenotypes, pointing to loss of function [4]. There is an ARSL pseudogene on the Y chromosome that may hinder detection of deletions of some exons [4].

2.4. Vitamin K, Gla proteins and phenocopies

VKORC1 recycles vitamin K 2,3-epoxide to the hydroquinone, and GGCX couples γ-carboxylation of glutamate residues to vitamin K epoxidation. Deficiency of either leaves the Gla proteins undercarboxylated and inactive: factors II, VII, IX and X, proteins C, S and Z, osteocalcin and matrix Gla protein (MGP), the physiological inhibitor of mineralisation of cartilage and the vascular wall [9]. Loss of function of MGP causes Keutel syndrome, and in the Mgp-null mouse mineral deposition in cartilage and vessels is the primary event [9]. In 1987, Pauli and colleagues described a boy with bleeding from birth, deficiency of factors II, VII, IX and X partially corrected by oral vitamin K, circulating excess of vitamin K epoxide and abnormal osteocalcin, who had nasal hypoplasia, distal digital hypoplasia and stippling identical to those of coumarin embryopathy; they concluded that the embryopathy results from the primary pharmacological effect of coumarins, inhibition of γ-carboxylation of bone proteins [39]. Menger and colleagues added in 1997 a third mechanism, embryonic vitamin K deficiency due to maternal malabsorption, alongside warfarin and congenital epoxide reductase deficiency [40].

As the vitamin K-dependent coagulation factors are absent in the embryo between 6 and 9 weeks, the embryopathy must involve other carboxylated proteins; CNS anomalies are associated mainly with exposure in the second and third trimesters and have been attributed to fetal haemorrhage, although first-trimester exposure can also cause structural defects [33]. In a South African series of 13 autopsied fetuses with warfarin embryopathy, there was cerebral haemorrhage in 8, which reinforces the role of haemorrhage [68]. A 2026 review adds, based mainly on experimental models, effects of warfarin on the Gas6/TAM, PXR, Ras and Wnt/β-catenin pathways in skeletal, vascular and neural development [69]. Inhibition of ARSE by warfarin in vitro would explain the similarity between CDPX1 and the embryopathy [4, 53]. In GGCX deficiency, the p.(His587Arg) variant affects extrahepatic Gla proteins, including MGP, more than hepatic ones, which explains why oral vitamin K corrects the coagulopathy without correcting the calcifications [70].

2.5. Variant spectrum and nomenclature

Variants are described according to Human Genome Variation Society (HGVS) nomenclature, on the MANE Select transcript (Matched Annotation from NCBI and EMBL-EBI), with the historical designation in parentheses when it differs. The PEX7 allele c.875T>A p.(Leu292Ter), historically L292ter or L292X, accounts for about half of mutant alleles in North American series (50% in 44 probands and in 60 probands), and homozygotes share an identical haplotype, indicating a single origin on an ancestral chromosome of European descent [71, 72]. In the series of 60 probands from the Johns Hopkins laboratory (USA, Canada and Australia), 24 alleles accounted for 95% of mutant alleles; the splice variant designated IVS9+1G>C (historical numbering, = NM_000288.4:c.903+1G>C) accounted for 13% and occurred on at least three haplotypes [72]. GeneReviews gives 51% for p.Leu292Ter and up to 68% for p.Leu292Ter, p.(Gly217Arg) and p.(Ala218Val) combined (c.649G>A and c.653C>T; Table 2.1) [5]. In the Amsterdam series, with 78 patients and 22 variants, severity correlated with the residual activity of the alleles: eight alleles from severely affected patients did not restore import, and two alleles from mildly affected patients complemented the defect when overexpressed [73].

Variants associated with the mild form or the Refsum phenotype include surface missense variants that do not disturb the structure (in NM_000288.4: c.74C>T p.(Ser25Phe), c.854A>G p.(His285Arg), c.40A>C p.(Thr14Pro), c.733A>T p.(Ile245Phe), c.347G>T p.(Ser116Ile), c.119A>G p.(Tyr40Cys) and p.(Asp177Glu), registered in ClinVar as c.531T>G) and alleles that allow some normal protein through: c.-45C>T and c.340-10A>G, in-frame translation reinitiation of c.45_52dup p.(His18ArgfsTer35) and initiation at a downstream methionine of c.13_19dup p.(Gly7ValfsTer51) (Table 2.1) [5]. The 8-nucleotide duplication c.45_52dup predicts a frameshift at codon 17, but is associated with a mild phenotype because the reading frame is restored, which was confirmed in a luciferase assay in COS cells [73]. PEX7 sequencing should include the 5' untranslated region and intron 3, where known pathogenic variants lie [5].

In RCDP5, the original variant was published as c.722dupA p.(Val242Glyfs*33) on the long isoform NM_001131023.1; on the MANE Select transcript it corresponds to NM_001351132.2:c.677dup p.(Val227GlyfsTer33), a difference of 45 nucleotides and 15 codons [47, 74]. In CDPX1, the historical variant T481M is NM_000047.3:c.1442C>T p.(Thr481Met), classified as likely pathogenic in the 2026 report and with conflicting classifications in ClinVar (last evaluated on 24 Oct 2025) [15, 75, 76]. In total, more than 94 EBP variants and more than 33 NSDHL variants had been described at the time of the 7th edition of Saudubray [63].

Table 2.1. Variants cited in this article, normalised in VariantValidator (GRCh38, MANE Select, 10 Oct 2026) and ClinVar status [74]

The dash “—” indicates that ClinVar status was not consulted for that variant. Clinical sources for the variants: [5, 15, 43, 47, 65, 72, 73, 80–82]. Other variants mentioned in the text (AGPS c.637+1G>A, whereas c.154dupG corresponds to NM_003659.4:c.154dup p.(Ala52GlyfsTer6); EBP c.33C>A p.(Tyr11*) and c.356T>G; NSDHL c.262C>T p.(Arg88Ter), c.455G>A p.(Gly152Asp), c.696_698del p.(Lys232del) and c.1098dup p.(Arg367SerfsTer33); GGCX c.1760A>G p.(His587Arg) and c.1787del) keep the nomenclature of the publications, because the transcript was not normalised in the sources consulted; for NSDHL, GeneReviews uses NM_015922.3 [7, 8, 70, 83–85].

2.6. Genotype–phenotype correlations, penetrance and mosaicism

In RCDP1, all p.Leu292Ter homozygotes studied have the classic form; in compound heterozygosity with this allele, the second allele determines the phenotype, and p.His285Arg is the most frequent variant in the mild forms [5]. Erythrocyte plasmalogens act as an integrated measure of residual function: they are almost undetectable in the classic form, reach 43% of the control mean in non-classic forms and are 10 to 30 times higher in the mild form than in the classic form [5, 86]. In RCDP2 and RCDP3, milder forms are associated with residual function [56].

In CDPX2, null variants cause a severe phenotype in females and intrauterine lethality in males, except in mosaic form; hypomorphic variants in hemizygosity cause MEND syndrome [7]. There is no clear correlation between variant type and severity, or between sterol profile and severity, because the X-inactivation pattern dominates; skewed X inactivation explains part of the differences in Spanish and Dutch families [87–89]. Males survive when they have a 47,XXY karyotype, post-zygotic somatic mosaicism (allele fractions of 20% to 75% in blood and skin) or a hypomorphic variant; a single non-mosaic male, with a constitutional variant inherited from his mother, who survived has been described [7, 63]. Some women with a confirmed variant have no recognisable manifestations and are identified by segregation, sometimes only after having a more severely affected child [7]. Has and colleagues described a grandmother with an isolated sectoral cataract without a variant detectable in blood (somatic and gonadal mosaicism) and healthy parents with two affected daughters (gonadal mosaicism) [90]. Maternal inheritance usually results in more severe disease in the offspring, an observation that some authors have described as “anticipation”, without a demonstrated molecular mechanism [23, 63, 90].

In CHILD syndrome, variability does not correlate strictly with the predicted severity of the variants and penetrance appears complete; male conceptuses with a variant are miscarried or resorbed, and the rare affected males are post-zygotic mosaics, such as the 2-year-old 46,XY boy described by Happle in 1996 and the man mosaic for p.(Arg88Ter) [8, 91]. In CK syndrome, the alleles c.696_698del p.(Lys232del) and c.1098dup p.(Arg367SerfsTer33) are hypomorphic and temperature-sensitive and increase methylsterols in cells and cerebrospinal fluid, with normal cholesterol [85]. In CDPX1, penetrance may be incomplete: the variant NM_000047.3:c.410G>C p.(Gly137Ala) and a deletion of exons 7 to 10 were found in asymptomatic maternal grandfathers of affected probands, but, as the signs improve with age, it is not certain that this represents non-penetrance [4, 92, 93]. There is no genotype–phenotype correlation in CDPX1 [67].

2.7. Allelic disorders and related entities

Biallelic PEX7 variants also cause about 10% of cases of adult Refsum disease (the rest are due to PHYH), with retinitis pigmentosa beginning in late childhood or later, anosmia, polyneuropathy, deafness, ataxia and ichthyosis, plasma phytanate more than 20 times the upper limit and reduced or normal plasmalogens; GeneReviews describes a continuum between classic RCDP, mild RCDP and Refsum-like phenotypes [5, 6]. MEND syndrome (EBP) and CK syndrome (NSDHL) are the male hypomorphic forms of the two X-linked dominant diseases [7, 8]. A contiguous Xq28 duplication including NSDHL was described in an 8-year-old boy with autism spectrum disorder, without features of CK or CHILD [8]. Contiguous Xp22.3 deletions including ARSL combine ichthyosis due to steroid sulfatase deficiency, hypogonadotrophic hypogonadism with anosmia, cataracts, intellectual disability and autism and, when they include SHOX, SHOX deficiency with possible Madelung deformity [4, 94]. Biallelic LBR variants cause Greenberg dysplasia, a distal defect of cholesterol synthesis, and a survivable intermediate form, rhizomelic skeletal dysplasia with or without Pelger-Huët anomaly (OMIM 618019), is associated with residual activity [9]. In Greenberg dysplasia, the variants affect the sterol Δ14-reductase domain of the lamin B receptor; the sterol profile in fibroblasts cultured in cholesterol-free medium shows an increase in cholesta-8(9),14-dien-3β-ol and cholesta-8(9),14,24-trien-3β-ol, and about ten fetal cases had been described by 2022, none liveborn [17]. Other LBR variants, mainly in the chromatin organisation domain, cause Pelger-Huët anomaly (deficient nuclear segmentation of neutrophils in heterozygosity, absent in homozygosity, usually without clinical consequence) and regressive spondylometaphyseal dysplasia with Pelger-Huët anomaly, whose bone changes may improve with growth; Astley-Kendall dysplasia and “dappled” diaphyseal dysplasia have been proposed as forms related to Greenberg dysplasia [17].

3. Clinical Spectrum and Manifestations by System

Stippling is an age-dependent sign in all forms: it is present in the fetus and infant and disappears with ossification of the epiphyses, usually between the first and fourth year, leaving irregular epiphyses, vertebral deformity or non-specific sequelae [3, 22, 94]. The following description separates, for each entity, the natural history from the reported interventions.

3.1. Classic RCDP

Skeleton. Shortening is rhizomelic, bilateral and symmetrical, greater in the humerus than in the femur, with widened and cupped metaphyses, especially at the knee, stippling of the epiphyses of the knee, hip, elbow and shoulder and, sometimes, of the hyoid, larynx, costochondral junctions and vertebrae [5, 25]. Vertebral coronal clefts, unossified cartilage between the anterior and posterior centres of the vertebral body, are seen on the lateral radiograph of the infant and cease to be visible with ossification; they are not invariable, being absent in three of five patients in a 1990 series [24, 95]. The calcifications resolve in 1 to 3 years and leave abnormal epiphyses and wide, irregular metaphyses; the intervertebral discs may calcify, and cartilage involvement explains the frontal bossing and short, concave nasal bridge [5]. The iliac bones are wide, with horizontal acetabula and trapezoid dysplasia of the upper part [24, 25]. Congenital contractures make the joints stiff and painful, which manifests as irritability in the infant; they tend to improve with time and with physiotherapy [5, 25]. On spinal MRI, all children with the classic form studied had cervical stenosis, and global stenosis, cervical or thoracolumbar kyphosis and tethered cord were less frequent; in the Nemours registry (Wilmington, USA), 10 of the 11 children with sagittal cervical MRI performed between 2004 and 2015, aged 1 week to 32 months, had canal stenosis, and only one had myelomalacia [5, 96, 97]. Spinal curvature develops in most children who live more than two months [25].

Eyes. Bilateral cortical cataracts are present in virtually all patients, at birth or in the first months (usually evident by 6 months), and are progressive [5]. Bone Dysplasias gives about 72%, a figure that includes less severe forms [24].

Growth and feeding. Birth weight, length and head circumference (HC) are at the lower limit of normal (in Smith, means of 2.9 kg, 46.6 cm and 32.4 cm), followed by profound postnatal growth deficiency: at 3 years, height, weight and HC correspond to the 50th centile of a child aged 4 to 6 months; weight gain falls to 5 g/day at 6 months and to less than 2 g/day after 3 years [5, 25]. In White's series, up to 38% of children required a nasogastric tube or gastrostomy because of aspiration or difficulty with textures [5]. Delayed tooth eruption and caries are frequent [25].

Development and neurology. Developmental quotients are below 30 in all children with the classic form; smiling and recognition of voices appear late, and skills usually acquired after 6 months (sitting unsupported, walking, sentences, sphincter control) are not achieved [5, 25]. Spasticity, spastic tetraplegia and temperature instability are common [24, 95]. In the Dutch cohort of 16 patients, 14 (88%) developed epilepsy, with an age at onset paralleling clinical and biochemical severity; myoclonic seizures, followed by atypical absences, were the most frequent seizures, and all patients with seizures had interictal epileptiform activity on the electroencephalogram (EEG); visual and auditory evoked potentials were initially normal in 93% and had no individual predictive value [98]. GeneReviews gives a median age at seizure onset of 2.5 years, and Smith more than 80% of children with seizures among those who live more than two months [5, 25]. In a series of 21 MRI scans from 11 patients, the mild form showed no changes, whereas the severe forms (types 1 and 3) showed delayed myelination, ventriculomegaly, enlarged subarachnoid spaces, supratentorial white matter changes and cerebellar atrophy, with a pattern that is both developmental and regressive; spectroscopy shows reduced choline and creatine and increased mobile lipids [5, 59].

Heart. Cardiac malformations were found in 52% of patients in the Dutch cohort and in 64% of the North American cohort [5, 99]. In the Dutch series of 23 patients with a genetic diagnosis, 12 had congenital heart disease (the 52% refers to the total of 23; among the 18 with cardiac data, the proportion is 67%): all had RCDP1, 11 carried c.875T>A and 7 were homozygous; plasmalogens were lower in patients with heart disease; the lesions were septal defects (80% atrial), patent ductus arteriosus, pulmonary artery hypoplasia, tetralogy of Fallot and mitral valve prolapse, the latter mainly in older patients [100].

Respiratory, skin and other. Recurrent respiratory infections result from neurological impairment, aspiration, immobility and the small thorax, and plasmalogen deficiency in surfactant may contribute [5]. Otitis media with hearing loss is frequent [25, 95]. Eczema, mild ichthyosis and rashes occur in about half of patients in White's series, a figure that GeneReviews reproduces; Bone Dysplasias and Smith give ichthyosiform lesions in 27% and 28%, respectively, a difference reflecting different criteria (isolated ichthyosis or all skin changes) [5, 24, 25]. Calcium oxalate renal stones were observed in 3 of 24 patients from a skeletal dysplasia clinic and, in isolated patients, pelviureteric junction obstruction, cleft palate, diaphragmatic hernia, hypospadias and cryptorchidism [5].

Survival. In the series of White and colleagues (USA), with 35 new patients and 62 cases from the literature, 90% survived to 1 year and 50% to 6 years, higher than previously described; the most frequent cause of death was respiratory [101]. GeneReviews, for the 35 children older than one month from the same series, gives 90% at 1 year, 55% at 5 years and about 20% at 12 years; in a later review of 66 patients (Duker 2020), 80% survived to 5 years, 45% to 12 years and 35% reached adulthood [5, 102]. Bone Dysplasias, from 2018, still gives 16 years as the age of the oldest patient described, a figure superseded by the 2020 series [24]. Neonatal deaths, of unknown number, are associated in clinical experience with congenital heart disease or pulmonary hypoplasia [5].

3.2. Non-classic (mild) RCDP

The non-classic form is defined clinically by the ability to walk, with or without support, and to communicate, verbally or otherwise [5, 98]. In the international series of 16 patients from five countries, aged 5 to 37 years, mean age at diagnosis was 2.6 years; most had cataracts, growth deficiency, contractures and developmental delay, and there were learning difficulties in 87%, behavioural changes in 56%, seizures in 43% and heart disease in 31%; C16:0 plasmalogens were reduced, but above those of the classic form, and phytanic acid was raised in most [86]. Radiographic CDP was present in 56% at diagnosis and rhizomelia, asymmetric, in only 18% [5]. About half have flexion contractures of the elbows, knees and hips, progressive mainly at the knees, and hip deformities (coxa valga, coxa vara, dysplasia) are common and usually operated on [5]. Cataracts appear in the first two years and may be the only finding; two patients developed pigmentary retinopathy in late childhood or young adulthood [5]. Seizures begin between 4 and 24 years of age, as absences or tonic-clonic seizures, with normal MRI or white matter changes [5]. Heart defects include atrial septal defect, patent foramen ovale, patent ductus arteriosus and ventricular septal defect; two of 16 patients had heart block and mitral valve prolapse, possibly degenerative [5]. Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), obsessive-compulsive disorder, sleep disorders and anxiety are frequent at school age; vitamin D deficiency and eczema or mild ichthyosis occur in 25% [5]. Eleven of 12 patients in one series reached adulthood [5, 102].

3.3. RCDP types 2 to 5 and FAR1 deficiency

RCDP2 had about 10 patients described at the time of the 7th edition of Saudubray and is clinically indistinguishable from type 1; RCDP3 had six published patients up to 2022, when two Turkish families with AGPS NM_003659.4:c.154dup p.(Ala52GlyfsTer6) (published as c.154dupG) and c.637+1G>A were added [55, 83]. Clinically, RCDP2 and RCDP3 have no features distinguishing them from RCDP1 [5]. In RCDP4, three patients had profound growth deficiency, developmental delay, pyramidal dysfunction and seizures, without rhizomelia despite greatly reduced erythrocyte plasmalogens, possibly due to compensation by FAR2, which has a different tissue expression [55]. The dominant form due to de novo variants at Arg480 (12 patients in the 2021 series) presents with bilateral congenital or juvenile cataracts, spastic paraparesis, speech and motor delay and axial hypotonia, and may be confused with hereditary spastic paraplegia or cerebral palsy [9, 55]. RCDP5 has been described in four patients from two families, with a classic RCDP phenotype [47, 55].

3.4. CDPX1 (ARSL)

CDPX1 affects boys with stippling, brachytelephalangy and nasomaxillary hypoplasia; most have reduced morbidity and skeletal findings that improve by adulthood, but some have severe airway stenosis and cervical instability [4]. Hypoplasia of the anterior nasal spine produces a flattened nasal base, short columella, crescent-shaped nostrils and, sometimes, vertical grooves on the alae nasi [4]. The distal phalanges have an inverted triangle shape, with lateral stippling at the apex, and that of the 5th finger may be spared; the stippling is symmetrical, fine, predominant at the ankle, distal phalanges and cervical and lumbosacral spine, and disappears at 2 to 3 years [4, 94]. Table 3.1 summarises the reported frequencies.

Table 3.1. Frequency of the manifestations of CDPX1 (series of Nino 2008 and Matos-Miranda 2013, with possible ascertainment bias towards severe cases) [4]

The spectrum is broader than the designation “mild form” suggests: in a series of 16 boys there was one case with a severe presentation with early death, cataracts and respiratory distress [75]. Calcification of the entire trachea and main bronchi was first described in 2004, and respiratory failure may require choanal stents, tracheostomy or tracheal reconstruction [4, 103]. Garnier and colleagues described four cases with severe cervical narrowing confirmed by radiography, MRI or autopsy and counted nine published cases with severe cervical cord compression, a high proportion of the cases then known [104]. A 14-month-old boy presented with stridor due to tracheal calcifications, mild midface hypoplasia and brachytelephalangy, without short stature or stippling, and his maternal grandfather had the same deletion without manifestations [92]. Less frequently there are cataracts, optic nerve atrophy or hypoplasia, patent ductus arteriosus, septal defects, pulmonary artery stenosis, gastro-oesophageal reflux and feeding difficulties [4]. Life expectancy is usually normal; early mortality, when it occurs, is due to respiratory compromise and cervical stenosis or instability [4]. Heterozygous females have no described disease, although some are shorter than expected [4]; the French PNDS accepts that female carriers may have brachytelephalangy or be asymptomatic [17].

The 2022 French PNDS, which counts about 140 published cases, adds frequencies and clinical details that the GeneReviews series do not break down, all derived from published cases and not from a defined cohort [17]. Calcifications of the larynx, trachea and bronchi occur in about 25% and may give rise to progressive stenosis; cervical involvement (localised stenosis or atlantoaxial instability) is the most frequent vertebral abnormality, in 19%, and instability may cause a progressive myelopathy that becomes symptomatic around adolescence. Respiratory distress, reported in a third of patients in older series and less frequent in current practice, manifests mainly at birth, with central or obstructive apnoeas and respiratory distress that may require ventilation or tracheostomy, and has a multifactorial origin: severe nasal hypoplasia, tracheobronchial calcification with extensive stenoses, bilateral choanal stenosis or compression of the upper cervical cord and medulla; tracheobronchial involvement may appear in the first months or in early childhood and, in one patient followed up to 18 years of age, the calibre of the trachea and bronchi did not grow normally, despite disappearance of the calcifications [17]. Hearing loss, sensorineural or conductive, was described in 26%, mainly conductive due to ossicular chain fixation or intermittent serous otitis, sometimes unilateral; as newborn hearing screening may miss losses predominating at low frequencies and hearing loss may appear later, the PNDS recommends specialised audiological follow-up even with a normal screen [17]. Ophthalmological abnormalities (cataracts, optic nerve atrophy or hypoplasia, strabismus, ptosis) occurred in 16%, feeding difficulties with gastro-oesophageal reflux in 10% and urogenital anomalies (hypospadias, inguinal hernia) in less than 10%; growth is usually normal at birth, although there may be intrauterine growth restriction, and relative postnatal short stature is moderate and inconsistent in adults [17]. The nostrils are half-moon, comma-shaped or triangular, the nasal spine is usually absent, the alae nasi are preserved and there may be a submucous cleft palate; congenital contractures may affect small and large joints [17]. Development is usually normal, and the delay described is associated mainly with contiguous Xp22 deletions including ARSL and neighbouring genes such as NLGN4 [17]. According to the PNDS, complete gene deletion accounts for about a fifth of cases, and there is no biochemical diagnostic test [17].

In the fetus, a systematic review with its own series brought together 22 fetuses with ARSL variants (17 unique variants): nasal hypoplasia in 55%, stippling or bone calcifications in 41%, polyhydramnios in 32%, short long bones in 23%, spinal canal stenosis in 23%, ventriculomegaly in 18% and brachytelephalangy, clubfoot, premature rupture of membranes and intraventricular haemorrhage in 9% each; the authors described a new association with intrauterine fetal death and suggested that intracranial haemorrhage is under-recognised [105].

3.5. CDPX2 (EBP) and MEND syndrome

The female spectrum ranges from fetal death with multiple malformations to women without recognisable anomalies, diagnosed only after a more severely affected daughter or in adulthood [7, 106]. Intrafamilial variation with the same variant is wide [7, 23].

Skin and appendages. The skin is involved in more than 95% of cases [7]. In the newborn there is ichthyosiform erythroderma with scales in whorls and swirls along Blaschko's lines, sometimes total desquamative erythroderma; it resolves in the first months and leaves linear or whorled follicular atrophoderma, with dilated pores of “orange peel” appearance, and pigmentary changes that may persist [7, 23]. The hair is coarse and lustreless, with patchy cicatricial alopecia and sparse, asymmetric eyebrows and eyelashes; the nails may be flattened or split and the teeth are normal [7]. Histology shows follicular ostial hyperkeratosis with calcium deposits in the keratin [7, 23].

Skeleton. Stippling of the long bones, ribs, vertebrae and tracheal cartilage is present in almost all symptomatic infants and, in Bone Dysplasias, predominates at the ends of the long bones, in the carpus and tarsus, the vertebral processes, the ischium and the pubis [7, 22]. About 90% have asymmetric shortening, mainly of the femur and humerus [7]. Short stature is the most common skeletal manifestation, with heights between the 10th–25th centile and −6 standard deviations; Bone Dysplasias gives an adult height usually above 130 cm [7, 22]. Kyphoscoliosis, sometimes congenital, is common and may progress rapidly in infancy or early childhood, with potentially fatal secondary lung disease [7]. In a series of 20 patients with CDP and vertebral anomalies (15 female), the deformity was rarely visible on neonatal radiographs and typically appeared in the first year; 17 had rapidly progressive dysplastic kyphoscoliosis [107]. Contractures, dislocation of the patella and hips, clubfoot and postaxial polydactyly are also described [7]. Laryngotracheal calcifications with airway obstruction are rare; the first case of severe subglottic stenosis was published in 2026 [108].

Eyes. GeneReviews describes cataracts in about two thirds, at birth or early, usually unilateral, asymmetric or sectoral, with microphthalmia or microcornea; Bone Dysplasias gives about 20% [7, 22]. The difference may reflect the populations and the age at observation of the sources, which do not explain it.

Other. Intelligence is usually normal, unless there is a CNS malformation [7, 63]. Dysplastic pinnae with sensorineural hearing loss, hydronephrosis, neonatal hypoglycaemia and congenital heart disease are rare [7, 22]. Life expectancy is usually normal; severe scoliosis may compromise cardiac and pulmonary function [7]. In Smith, the first months may be marked by faltering growth and infections, but survival is good for those who get through them [23].

Data from the French PNDS. The 2022 PNDS places short stature between −1 and −6 standard deviations and adds to the skeletal description asymmetric hip dysplasia due to hypoplasia of the acetabulum and femoral heads, patellar dysplasia, talipes calcaneovalgus, brachydactyly, postaxial polydactyly of all four limbs (10%) and cutaneous syndactyly of the toes [17]. Scoliosis is often malformative (butterfly vertebrae, hemivertebrae); cervical canal stenosis with syringomyelia, C1–C2 instability and, once, spinal cord atrophy secondary to atlas hypoplasia have been described [17]. Ichthyosis is present in 95%, and skin biopsy is justified when the typical extracutaneous features do not dominate the picture; in addition to cataracts (two thirds, mainly early, unilateral and sectoral, but also obstructive and bilateral) and microphthalmia, strabismus, nystagmus, corneal opacities, glaucoma and optic atrophy are described [17]. Sensorineural hearing loss was described in about 10%, school difficulties occasionally, posterior fossa arachnoid cysts and pelvicalyceal dilatation rarely; about 90 different point variants of EBP had been published [17]. A single non-mosaic male fetus described, who died in utero, had symmetrical involvement (stippling, rhizomelia, brachydactyly, ichthyosis and cataract) [17].

Males. Males with a 47,XXY karyotype or somatic mosaicism have a phenotype within the female range of variability; hemizygotes for non-mosaic hypomorphic variants have MEND syndrome [7, 63]. MEND syndrome combines moderate to severe developmental delay, CNS malformations in almost all (Dandy-Walker variant, agenesis of the corpus callosum, gyration abnormalities), dysmorphism with a prominent nasal bridge, 2–3 toe syndactyly, postaxial polydactyly or syndactyly, cryptorchidism, hypospadias and, in many, chronic diffuse ichthyosis, without epiphyseal stippling; it overlaps with Smith-Lemli-Opitz syndrome [7]. In Saudubray, mortality of hemizygotes is high, with deaths between 1 day and 4.5 years [63]. Arnold and colleagues proposed criteria to distinguish the male with mosaic CDPX2, with a prognosis close to that of females, from the male with MEND [84]. The French PNDS, which counts about ten cases of MEND, describes the skin as inconsistent, diffuse and non-Blaschkoid, with a yellowish collodion membrane, moderate congenital ichthyosis of yellow, waxy appearance that may persist and hypopigmented patches, without nail or hair changes and without documented histology [17]. It adds epilepsy (mainly tonic-clonic), hydrocephalus and cerebellar hypoplasia to the brain malformations, unilateral or bilateral cataracts, microphthalmia, strabismus, nystagmus, ptosis and foveal hypoplasia, heart defects (atrial and ventricular septal defects, tetralogy of Fallot, valvular anomalies, aortic arch hypoplasia) that may determine the vital prognosis, a wide anterior fontanelle, short palpebral fissures, micrognathia and cleft palate, and an isolated renal ectopia [17]. Unlike GeneReviews, the PNDS states that stippling has been described rarely (two reports) in MEND syndrome [17]. Heterozygous female carriers of hypomorphic variants are usually asymptomatic, some with hypopigmented patches, and the sterol profile of these women has not been characterised [17].

3.6. CHILD syndrome and CK syndrome (NSDHL)

Skin. Erythematous, inflammatory plaques with yellowish, waxy, adherent scales occupy large regions of one half of the body, with a sharp midline boundary, usually sparing the face; they may follow Blaschko's lines and contain islands of normal skin [8, 63]. The right side is affected in about two thirds of cases; left-sided involvement is less frequent and, in Smith, more severe, and bilateral involvement is exceptional [8, 30, 31]. The lesions are present at birth or in the first weeks, and new lesions may appear until puberty or early adulthood; most improve, but intertriginous lesions persist (ptychotropism) and new lesions may appear at sites of trauma [8]. Histology shows hyperkeratosis, parakeratosis, acanthosis and foamy histiocytes in the dermal papillae (verruciform xanthoma pattern); verruciform xanthoma of clubbed fingers is the most pathognomonic form [8]. Ipsilateral alopecia, onychodystrophy with periungual hyperkeratosis and claw-like nails are frequent [8]. Heterozygous females may have only minor lesions, and the isolated “CHILD naevus” may be limited to one finger [8, 30].

Skeleton. Ipsilateral limb hypoplasia ranges from shortening of metacarpals and phalanges to amelia, with contractures, pterygia, oligodactyly and, rarely, polydactyly or syndactyly; the defects may be transverse or longitudinal and the pattern is malformative, not merely hypoplastic [8, 30, 31]. Hypoplasia may affect the vertebrae, pelvis, ribs, scapula, clavicle, mandible and skull, with progressive scoliosis and thoracic hypoplasia [8, 30]. Ipsilateral stippling of the epiphyses, sella turcica and laryngeal, nasal and thyroid cartilages disappears early, sometimes before birth, so its absence does not exclude the syndrome [8, 30]. The limb defects may be mild with exuberant skin involvement [30].

Viscera. Ipsilateral hypoplasia of the brain, spinal cord, lung, thyroid, adrenals, ovaries and fallopian tubes is described; heart disease (atrial septal defect, single ventricle, single coronary artery), pulmonary hypoplasia with potentially fatal respiratory compromise and renal anomalies from hydronephrosis to unilateral agenesis [8, 30, 31]. Intelligence is usually normal [8]. In Smith, early death is due mainly to heart disease [31]. The French PNDS, which counts about 60 published cases, estimates heart disease at 10% to 20% (atrial and ventricular septal defects, hypoplastic left heart) and ipsilateral CNS anomalies at less than 10% (cerebral hypoplasia, type II lissencephaly, dysplastic cerebellar hemisphere, cranial nerve anomalies, polymicrogyria, ventriculomegaly); sensorineural hearing loss and early respiratory distress due to a small thorax with pulmonary hypoplasia have been described without known frequency, and mild cognitive difficulties are occasional [17]. In the skin, there may be lesions on the contralateral side of the body, and the presence of xanthomatous histiocytes with lipid vacuoles (verruciform xanthoma) on biopsy of the yellowish verrucous lesions distinguishes CHILD syndrome from CDPX2 and incontinentia pigmenti, whereas the histology of the psoriasiform plaques is not very specific [17]. Up to 2022 two living males had been described, interpreted as post-zygotic mosaics [17].

Recent atypical forms. Publications from 2025 and 2026 describe molecularly confirmed CHILD syndrome without limb defects, with bilateral involvement in a 7-year-old girl, or with an appearance resembling Hailey-Hailey disease, without unilaterality or skeletal anomalies [82, 109–111].

Prognosis. Lifespan does not appear limited in patients without severe visceral malformations; one three-generation family included a woman diagnosed at 82 years of age, and adults are probably underdiagnosed [8].

CK syndrome. Males hemizygous for hypomorphic variants have mild to severe intellectual disability (most without speech), aggression, ADHD and irritability, seizures in childhood in all, cortical malformations (polymicrogyria), spasticity, microcephaly in all, a long thin face, asthenic habitus with long thin limbs and fingers, hyperextensible joints and, in some, scoliosis, optic atrophy and concentric left ventricular hypertrophy; one patient was alive at 62 years [8, 85]. Twenty-five males from three families are known [8]. Heterozygous females have normal physical examination, intelligence and MRI, with possible irritability or aggression [8, 63].

3.7. Phenocopies

Warfarin embryopathy. Exposure between 6 and 9 weeks causes nasal hypoplasia with a depressed bridge, often with a deep groove between the alae and the tip, stippling of uncalcified epiphyses mainly in the axial skeleton (vertebrae, pelvis), proximal femurs and calcanei, which disappears after the first year, hypoplastic distal phalanges and low birth weight, with catch-up in most [33]. Choanal atresia, cleft lip and palate, pulmonary hypoplasia, severe rhizomelia, scoliosis, heart disease, vertebral anomalies, asplenia, renal agenesis and brain malformations are occasionally associated [33]. Exposure between 14 and 20 weeks is associated with microcephaly, hydrocephalus, Dandy-Walker malformation, agenesis of the corpus callosum, cerebellar atrophy, seizures, spasticity, intellectual disability, optic atrophy, cataracts, microphthalmia and Peters anomaly [33]. The US warfarin label describes the embryopathy as nasal hypoplasia with or without stippled epiphyses and growth restriction, adds dorsal and ventral midline dysplasias and, after exposure in the second and third trimesters, intellectual disability, blindness, schizencephaly, microcephaly and hydrocephalus [112]. In the 13 fetuses autopsied in South Africa between 1991 and 2007, at 17 to 37 weeks, nasal hypoplasia was present in 11 and radiological stippling in only 3 [68]. Upper airway obstruction may require an oropharyngeal tube, and cervical anomalies with instability may cause severe neurological dysfunction and sudden death; most children have normal cognitive development, with persistent nasal malformation [33, 113, 114]. In a Dutch cohort of 274 school-age children exposed to coumarins in utero, compared with 231 controls, there were no major anomalies, but the risk of minor neurological dysfunction and of an intelligence quotient (IQ) below 80 increased, and the combination of two or more minor anomalies had a relative risk of 7.6; most children had no clinically significant effect on growth and development [115]. A 25-week preterm infant exposed to phenprocoumon had coagulopathy with intraventricular and parenchymal haemorrhages, midface hypoplasia, cholestatic liver disease and ocular malformations [116].

Maternal vitamin K deficiency. Menger and colleagues described three infants with stippled calcifications, nasal hypoplasia and vertebral anomalies, born to mothers with chronic malabsorption requiring parenteral nutrition (coeliac disease, short bowel after resection, jejunoileal bypass) [40]. Toriello and colleagues brought together eight patients with a Binder phenotype, with or without CDP, all with known or suspected maternal vitamin K deficiency, due to hyperemesis gravidarum or Crohn's disease, and brachytelephalangy was a common component [117]. Other maternal causes described are small bowel obstruction, pancreatitis, cholelithiasis and hepatic fibrosis due to transfusional iron overload; the deficiency was documented only indirectly in three cases and suspected in the others [4, 118, 119]. Grey matter heterotopias have been described after hyperemesis gravidarum [120].

Maternal autoimmune disease. Maternal systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) and scleroderma may cause CDP with rhizomelic shortening; Chitayat and colleagues brought together eight cases, and by 2007 nine newborns with an RCDP phenotype born to mothers with connective tissue disease had been published [4, 41, 121]. Maternal disease may be subclinical during pregnancy: in one case, the mother developed SLE eight months after delivery [121]. Some of the tibia-metacarpal type cases may have this origin [2].

Hereditary deficiency of vitamin K-dependent factors. Hereditary combined deficiency of vitamin K-dependent factors (VKCFD1 and VKCFD2) is part of the differential diagnosis. VKCFD1 (GGCX) causes bleeding from the neonatal period, from bruising to fatal intracranial haemorrhage, with prolonged prothrombin time and activated partial thromboplastin time and variable reduction of factors II, VII, IX and X and proteins C and S; it is associated with a pseudoxanthoma elasticum-like pole, skeletal involvement and, rarely, fetal CDP [9, 122]. About 50 families with VKCFD due to GGCX or VKORC1 have been described [9].

4. Clinical Recognition and Red Flags

4.1. Prenatal period

Ultrasound may show epiphyseal, costal or vertebral stippling, short long bones, rhizomelia, a flat facial profile with a hypoplastic nasal bone, polyhydramnios, spinal canal stenosis and ventriculomegaly [105, 123]. In RCDP, rhizomelia and stippling have been detected from 17 to 19 weeks, and in one case bilateral cataracts were seen at 32 weeks and stippling four weeks later [5]. In CDPX2, stippling is detectable from the second trimester; a 2026 case showed stippling of almost the entire thoracic outline at 12 weeks, with postaxial polydactyly [7, 81]. In fetal CDPX1, nasal hypoplasia is the most frequent finding (55%), and a normal prenatal ultrasound does not exclude severe complications such as tracheal stenosis [92, 105]. The isolated Binder phenotype (nasofrontal angle greater than 143° and verticalised nasal bones) was identified in seven fetuses in an Italian series from 2021–2023, with normal karyotype and microarray in the three studied [124]. In a Chinese series of five fetuses from three families, all had stippled echogenicity of the long bone epiphyses, four short long bones and three vertebral anomalies, with normal karyotype and microarray and diagnosis by exome sequencing [123].

The 2022 French PNDS states that most patients with CDPX1 are now diagnosed prenatally: in a male fetus, a variable combination of nasomaxillary hypoplasia, absent nasal spine, brachytelephalangy and vertebral anomalies (small bodies, canal stenosis) points to this form, sometimes with increased nuchal translucency, polyhydramnios, thoracic hypoplasia and short long bones [17]. Ultrasound and fetal MRI show the verticalised nasal bone, increased nasofrontal angle and narrow nostrils, but filled with fluid, which excludes arhinia; low-dose fetal bone CT, from 29 to 30 weeks, and fetal MRI confirm the diagnosis and look for prognostic factors such as canal stenosis with cord compression, deformity of the craniovertebral junction and the extent of laryngotracheal calcifications [17]. In CDPX2, with about 15 female fetuses described, second- and third-trimester ultrasound shows epiphyseal stippling with rhizomelic and asymmetric shortening, sometimes bowed long bones, increased nuchal translucency, paravertebral calcifications, wide metaphyses, hypoplastic ribs with a narrow thorax, hypoplastic nasal bones and clubfoot; the history looks for early miscarriages in the family, which may reflect male lethality, and fetal autopsy may reveal ichthyosis from the second trimester, microphthalmia and cataract [17]. In MEND syndrome, the two prenatal reports described a single kidney, a corpus callosum anomaly, ventricular septal defect, an aortic anomaly and polyhydramnios, without stippling [17]. In CHILD syndrome, ultrasound may show the limb reduction defect with absent digits, hemidysplasia and heart disease, sometimes with reduced fetal movements [17]. Greenberg dysplasia manifests early, with increased nuchal translucency, cystic hygroma, hydrops, growth restriction with severe micromelia, narrow thorax, platyspondyly, frequent postaxial polydactyly and polyhydramnios, and the diagnosis rests on autopsy, radiology (“moth-eaten” appearance of the pelvis and long bones, ectopic calcifications, hypomineralisation of the skull), histology (hypoplastic bone marrow, extramedullary haematopoiesis, disorganised cartilage and bone) and LBR [17].

4.2. Newborn and infant

Suspicion arises with stippling on a radiograph, symmetrical rhizomelia with cataracts and contractures (RCDP), severe nasal hypoplasia with short distal phalanges in a boy (CDPX1 or phenocopy), whorled ichthyosis along Blaschko's lines with asymmetric shortening in a girl (CDPX2) or unilateral ichthyosiform erythroderma with an ipsilateral limb defect (CHILD) [3–5, 7, 8]. In the approach to congenital cataract, short stature, ichthyosis and limb asymmetry in a girl point to CDP, and sterol analysis, VLCFA and a skeletal survey are part of the investigation [125]. In the approach to nasal anomalies, Binder syndrome (maxillary hypoplasia, flat and vertical nose, absent nasal spine, relative prognathism) may correspond to the adult phenotype of mild forms of CDP [3, 126]. Fetal and neonatal findings suggesting an inborn error of metabolism include stippled epiphyses and asymmetric growth [127]. The French PNDS summarises two rules of thumb: hypoplasia of the distal phalanges points to a group of non-genetic causes (VKA, phenytoin, maternal vitamin K deficiency or hyperemesis in the first trimester, maternal autoimmune disease) or genetic causes (disorders of vitamin K metabolism or, in a boy, arylsulfatase E deficiency), and stippling in a girl with an asymmetric or unilateral limb reduction defect is highly suggestive of a cholesterol biosynthesis defect, with transient ichthyosis and cataracts favouring CDPX2 and a persistent unilateral ichthyosiform naevus favouring CHILD syndrome [17]. In neonatal CDPX1, respiratory distress, apnoeas, hypotonia, growth restriction of prenatal onset and feeding difficulties with reflux may coexist [17].

The targeted history includes a three-generation pedigree with consanguinity (recessive forms), second-trimester male fetal losses (X-linked dominant form), male proband (X-linked recessive form), maternal disease (malabsorption, SLE), exposure to warfarin or phenytoin, neonatal bleeding (vitamin K deficiency), faltering growth, development and seizures [3]. Maternal autoimmune disease, VKA exposure and malabsorption should be actively asked about, because SLE may be diagnosed only after delivery [40, 41, 117, 121]. Examination includes length, arm span and segments, pattern of shortening, asymmetry, scoliosis, contractures, nasal hypoplasia, cataracts, skin, alopecia, hands (distal phalanges) and neurological signs of spinal stenosis [3].

4.3. Older child, adolescent and adult

As stippling disappears at around 2 years of age, early radiographs should always be requested when a child or adult is referred for counselling [3]. From 3 years of age, the clues are residual coronal clefts and rhizomelia (RCDP), short distal phalanges (CDPX1 and warfarin embryopathy), follicular atrophoderma, patchy alopecia and sectoral cataracts (CDPX2) and a persistent unilateral skin lesion (CHILD) [3, 7, 8]. Non-classic RCDP is diagnosed on average at 2.6 years, from cataracts, growth deficiency, contractures and developmental delay [86]. CDPX2 may be recognised only in adulthood, often in a mother with minimal signs after the diagnosis of a daughter [7, 87, 106]. CHILD syndrome may present without limb defects, bilaterally or mimicking Hailey-Hailey disease, situations in which NSDHL testing clarifies the diagnosis [82, 110, 111]. Juvenile cataracts with spastic paraparesis point to the dominant form of FAR1 disease [55].

4.4. Emergency signs

Table 4.1. Red flags and emergency signs in CDP

The French PNDS includes emergency cards, distributed by the rare disease networks, for CDPX1 (ORPHA:79345), CDPX2 (ORPHA:35173), CHILD syndrome (ORPHA:139) and MEND syndrome (ORPHA:401973), with fields for ophthalmological, auditory, skeletal (scoliosis, cervical stenosis, syringomyelia, craniovertebral instability, myelopathy, limb length discrepancy), respiratory, cardiac, dermatological and neurological involvement, allergies, treatments and advance directives; the CDPX1 card highlights airway assessment and positioning in case of surgery, and the MEND syndrome card describes the patient's comprehension and expression abilities and means of communication (pictograms, sign language, pointing) [17].

4.5. Newborn screening

There is no newborn screening for CDP. Screening for X-linked adrenoleukodystrophy by C26:0-lysophosphatidylcholine also detects the Zellweger spectrum, but RCDP has normal VLCFA [5, 9]. In the Dutch founder population with 6.1% RCDP1 carriers, targeted preconception carrier screening has been adopted in clinical practice since 2012 (section 8) [130].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria for any of the entities; diagnosis rests on the combination of suggestive findings with a biomarker or a pathogenic variant [5, 7, 8]. RCDP1 is established with suggestive findings and biallelic pathogenic or likely pathogenic variants in PEX7; CDPX1, in a male with suggestive findings and a hemizygous variant in ARSL; CDPX2, in a female with typical findings and characteristic biochemistry or a heterozygous variant in EBP, or in a 46,XY male with a mosaic variant; CHILD syndrome, in a female with a heterozygous loss-of-function variant in NSDHL; CK syndrome, in a male with a hypomorphic hemizygous variant [4, 5, 7, 8]. A non-mosaic male with a hypomorphic EBP variant has MEND syndrome and not CDPX2 [7]. Variants of uncertain significance (VUS), whether biallelic, combined with a pathogenic variant, hemizygous or heterozygous, neither establish nor exclude the diagnosis [4, 5, 7].

5.2. Algorithm

The first step is a complete skeletal survey, including a lateral view of the foot, looking for vertebral coronal clefts (RCDP), hypoplastic distal phalanges (CDPX1 and warfarin embryopathy), the pattern and symmetry of stippling and involvement of the tarsus, patellae or larynx [3]. In parallel the maternal history is taken (VKA, phenytoin, malabsorption, hyperemesis, SLE) and, if autoimmunity is suspected, antinuclear and anti-double-stranded DNA antibodies are requested in the mother [3]. Biochemistry guides: erythrocyte plasmalogens and phytanic acid with VLCFA for the peroxisomal forms, plasma sterols for CDPX2 and Smith-Lemli-Opitz syndrome (7-dehydrocholesterol), coagulation studies for vitamin K deficiencies [3, 5, 94]. Molecular testing is by multigene CDP panel or exome, reserving genome sequencing for atypical phenotypes; chromosomal microarray is the first choice when an Xp22.3 deletion or a chromosomal syndrome is suspected [3–5]. Where molecular testing is available, the CDPX2 GeneReviews recommends it first and uses biochemistry to support inconclusive variants [7]. When CHILD syndrome is suspected and NSDHL is negative, EBP should be studied [63]. In a patient with a selective PTS2 import defect, PEX7 and exon 9 of PEX5 should be sequenced [47].

Table 5.1. Phenotype-driven algorithm

Sources: [4, 5, 7–9, 67, 121].

For the forms it covers, the 2022 French PNDS recommends two complementary approaches, which may proceed simultaneously: biochemical, by the profile of cholesterol precursors, useful in EBP disorders (CDPX2 and MEND) and complex to perform in CHILD syndrome and Greenberg dysplasia; and molecular, which may come first; in CDPX1, diagnosis is molecular only [17]. The PNDS decision tree (Table 5.2) separates at the outset presentations with growth restriction or developmental anomalies suggestive of a chromosomal anomaly and lethal Greenberg dysplasia, and then uses body asymmetry as the first criterion [17].

Table 5.2. Diagnostic orientation in CDP according to the French PNDS (2022)

Source: annex 3 of the PNDS [17].

5.3. Biomarkers

Plasmalogens and phytanic acid. The combination of deficient erythrocyte plasmalogens, increased plasma phytanic acid (when the diet contains it) and normal VLCFA consistently predicts the PEX7 defect; these assays are performed reliably in few laboratories worldwide [5]. Plasmalogens are deficient in all patients with RCDP, but only partially in the mildest; phytanic acid may be normal, because it depends on age and diet and accumulates only in types 1 and 5 [55, 98]. The traditional gas chromatography–mass spectrometry (GC-MS) method measures C16:0, C18:0 and C18:1 dimethylacetals in erythrocytes and is sensitive, but does not identify molecular species; it has been extended to dried blood spots [5]. In 2023 a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was published for 18 ethanolamine plasmalogen species in erythrocytes, with age-specific reference ranges and potential for monitoring therapies [131]. Biochemistry confirms the group but not the gene: it does not distinguish RCDP1 from RCDP2 and RCDP3, and DHAPAT activity and fibroblast studies are now research tools [9, 55]. In FAR1 deficiency, plasmalogens are low in the recessive form and increased in fibroblasts in the dominant Arg480 form [9]. In Refsum disease due to PEX7, plasma phytanate exceeds 20 times the upper limit of normal (which is below 10 µmol/L) and may exceed 1000 µmol/L [5, 55].

Sterols. In CDPX2, an increase in 8(9)-cholestenol and 8-DHC in plasma, scales, lymphoblasts or cultured fibroblasts is virtually diagnostic [7, 50]. The GeneReviews reference values derive from 105 women with presumed CDPX2: plasma 8(9)-cholestenol from 0.18 to 186 µg/mL and 8-DHC from less than 0.01 to 138 µg/mL, with normal values below 0.01 µg/mL in the newborn aged 1 to 2 days [7]. In a series of 26 women with suspected CDPX2, 20 of the 22 with an abnormal sterol profile had an EBP variant (91%), and the profile identified the clinically unaffected mother of a sporadic case [87]. There are, however, patients with molecular confirmation and normal biochemistry, levels do not correlate with severity and, in the male, biochemistry does not distinguish mosaic CDPX2 from MEND syndrome [7, 88]. In CHILD syndrome, serum methylsterols and cholesterol are almost always normal; lymphoblasts cultured in cholesterol-free medium show increased methylsterols and carboxysterols, and scales from affected skin also accumulate them [8, 63]. In cultured lymphoblasts, CHILD and CDPX2 both show a paradoxical increase in lathosterol [7]. In 2018, GC-MS analysis of cholesterol precursors in plasma and urine for CHILD was available only in research laboratories [30]. In the summary table of the French PNDS, the increase in 8-DHC and 8(9)-cholestenol can be sought in plasma or in amniotic fluid supernatant in CDPX2 and MEND syndrome, and confirmed in another sample (fibroblasts) if necessary; in CHILD syndrome, Greenberg dysplasia and CDPX1, plasma biochemistry does not contribute, and the alternatives are lymphoblasts (CHILD) or fibroblasts and fetal tissues (Greenberg) [17].

Histology and other. In CDPX2, skin biopsy shows follicular ostial hyperkeratosis with calcium deposits in the keratin, a relatively specific finding useful in mild forms; trichoscopy shows loss of follicular openings, perifollicular scaling, pili torti and follicular plugs [7]. A 2025 Irish report is devoted to early skin biopsy in this disease [132]. In CDPX1, prothrombin time, activated partial thromboplastin time and factors II, VII, IX and X are normal, and arylsulfatase activity is not available clinically [4, 133].

5.4. Molecular tests, yield and limitations

Table 5.3. Yield of molecular methods and limitations

The proportion of variants detectable by a method is not the clinical sensitivity of the test: the values in Table 5.3 describe the distribution of variant types in patients who already have a molecular diagnosis, whereas the yield in patients with clinical suspicion is lower (58% in brachytelephalangic CDP, 85% in suspected CDPX2) [4, 67, 87]. Exome sequencing does not reliably detect exon deletions, deep intronic variants, low-level mosaicism or regions with pseudogenes; a negative result does not exclude the diagnosis, especially in a male with suspected mosaic CDPX2, in whom it may be necessary to study affected skin [4, 7]. The absence of stippling does not preclude ARSL testing after the neonatal period, and brachytelephalangy is not obligatory [92, 93].

5.5. Reporting, classification and segregation

The report should identify the gene, the transcript with version (for example, NM_000288.4 for PEX7, NM_000047.3 for ARSL, NM_006579.3 for EBP, NM_015922.3 for NSDHL, NM_014236.4 for GNPAT, NM_003659.4 for AGPS, NM_032228.6 for FAR1 and NM_001351132.2 for PEX5), the variant in HGVS, zygosity or the mosaic allele fraction and the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [74]. Interpretation of ARSL is difficult because there is no expert panel adapting the ACMG criteria to the gene, and the same variant may be classified as likely pathogenic in one report and have conflicting classifications in ClinVar [15, 76, 105]. Family segregation is essential: parental testing confirms the phase of the variants in RCDP, identifies heterozygous mothers with minimal signs in CDPX2 and CHILD and carrier mothers in CDPX1 [4, 5, 7, 8]. In RCDP, carrier detection is molecular only [5].

5.6. Evaluation after diagnosis

Table 5.4. Initial evaluation recommended by GeneReviews

Sources: [4, 5, 7, 8]. MRI of the whole spine in RCDP is based on the Abousamra series, in which cervical stenosis was present in 10 of 11 children [96].

The French PNDS defines the initial evaluation of the four forms it follows into adulthood, coordinated by the geneticist of a reference or competence centre, who requests the complete skeletal survey (with anteroposterior and lateral spine) and the biochemical or molecular study; the attending physician follows growth and psychomotor development (Table 5.5) [17].

Table 5.5. Initial evaluation according to the French PNDS (2022)

Source: Table 4 of annex 4 of the PNDS [17]. Compared with GeneReviews (Table 5.4), the PNDS makes cervical and spinal MRI before 3 months systematic in CDPX1 and CDPX2, as well as the electrocardiogram and echocardiogram and abdominopelvic ultrasound in all forms, and defines hearing assessment by threshold evoked potentials and ASSR [4, 7, 8, 17]. On establishing the diagnosis, the coordinating physician draws up the care protocol and, if justified, the application to the Maison départementale des personnes handicapées (MDPH), and the family is directed to social services and patient organisations [17].

5.7. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal testing by chorionic villus sampling or amniocentesis and preimplantation genetic testing (PGT) are possible [4, 5, 7, 8]. In CDPX2, genetic testing is the first choice for prenatal diagnosis [63]. Without a family diagnosis, ultrasound guides and fetal or trio exome sequencing establishes the diagnosis, as in the cases of homozygous PEX7 NM_000288.4:c.875T>A p.(Leu292Ter) and c.257G>A p.(Cys86Tyr), of EBP p.(Leu49Ter) at 16 weeks and of the 2026 Chinese series [5, 81, 123]. In pregnancies at risk because of maternal medication or SLE, ultrasound of the epiphyses with limb biometry is recommended [3]. In fetuses of mothers with autoimmune disease, in addition to the usual cardiac assessment, ultrasound and, if indicated, radiography of the newborn look for a hypoplastic nasal bone, brachydactyly, short long bones and stippling [41].

For the prenatal aetiological investigation of CDP, the French PNDS adds the sequence in Table 5.6, and for CDPX1 suspected on ultrasound it recommends maternal autoimmunity studies, a history of vitamin K deficiency and teratogens and microarray on amniotic fluid, which excludes an Xp22.3 deletion with genes neighbouring ARSL, such as NLGN4, with implications for the intellectual prognosis [17].

Table 5.6. Prenatal investigation in the differential diagnosis of CDP according to the French PNDS (2022)

Source: Table 3 of annex 4 of the PNDS [17].

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of chondrodysplasia punctata

Sources: [2–5, 7–9, 22, 24, 25, 63, 94, 134–137]. The gene for SMED short limb–abnormal calcification type is given by the 2023 nosology [2]. The rows for squalene synthase deficiency and Pacman dysplasia follow the 2022 French PNDS, whose differential diagnosis table also includes tibia-metacarpal type CDP with renal agenesis [17].

6.2. Differential between the genetic forms

RCDP is distinguished from CDPX2 by symmetry, coronal clefts, few vertebral calcifications, symmetrical cataracts, severe intellectual disability and epilepsy; in CDPX2, the vertebral anomalies are more heteromorphic, the stippling is asymmetric and scattered and development is normal [7, 22, 24]. RCDP2 and RCDP3 are clinically identical to RCDP1, and only phytanate (raised only in RCDP1 and RCDP5) and molecular testing separate them [5, 9]. Patellar stippling, considered a hallmark of Zellweger syndrome, also occurs in RCDP, but the Zellweger spectrum has no coronal clefts or rhizomelia, has abnormal brain development, often with lissencephaly, and accumulates VLCFA [22, 24]. The severe tibia-metacarpal type may have humeral shortening and coronal clefts, but has platyspondyly with marked vertebral stippling, normal iliac bones, short tibiae and normal development [24, 135]. In Greenberg dysplasia, the vertebrae are less ossified, the iliac wings have irregular outlines and the tubular bones are fragmented, whereas RCDP has more ossified vertebrae with coronal clefts and widened but not fragmented tubular ends; Astley-Kendall dysplasia, postulated to be allelic with Greenberg dysplasia, has ossification defects of the calvaria, spine and long bones [7, 134].

In CDPX1, the short inverted-triangle distal phalanges are the distinguishing element compared with autosomal dominant Sheffield-type CDP and RCDP; sparing of the 5th finger is not specific to Keutel syndrome, which has more extensive cartilage calcification, calcified pinnae and peripheral pulmonary stenosis [9, 27, 94, 136]. As CDPX1 is much more common than Keutel syndrome, Bone Dysplasias recommends testing ARSE in any boy with suspected Keutel syndrome [136]. The clinical overlap between Keutel syndrome and arylsulfatase E deficiency has been the subject of a dedicated review [138]. The French PNDS estimates the prevalence of Keutel syndrome at 1/1,000,000, with about 40 published cases, brachytelephalangy in 75% (short, broad distal phalanges of the 1st to 4th rays, sparing the 5th), calcifications of the laryngeal, respiratory, auricular, nasal, costal and arterial cartilages, pulmonary artery stenosis, ventricular septal defect or ventricular hypertrophy, sensorineural or mixed hearing loss, inconsistent and mild intellectual disability, epilepsy, short stature and respiratory complaints, with intrafamilial variability [17]. Few features distinguish molecular CDPX1 from phenocopies on examination, and about 40% of boys with brachytelephalangic CDP have neither an ARSL variant nor a known maternal cause; in Nino's series, three of four patients without a variant had a maternal condition [67, 133]. Hereditary defects of vitamin K-dependent coagulation are excluded by coagulation studies, and SLE and maternal vitamin K deficiency by the maternal history [94].

6.3. CDPX2 and CHILD syndrome

CDPX2 has bilateral, albeit asymmetric, lesions along Blaschko's lines, which improve over time and leave follicular atrophoderma in most by 2 years, with early ocular anomalies; CHILD has unilateral lesions with strict midline demarcation, which persist, more severe limb reduction defects ipsilateral to the skin, ipsilateral organ anomalies and absence of cataracts [7, 8, 51, 52]. Some patients with CDPX2 have unilateral involvement resembling CHILD, but only limb hypoplasia, whereas CHILD has transverse and longitudinal defects with a malformative pattern [22, 30]. The CHILD phenotype may be due to an EBP variant, with raised plasma 8-DHC and 8(9)-cholestenol, so EBP testing follows a negative NSDHL result [52, 63]. Schimmelpenning-Feuerstein-Mims syndrome and other epidermal naevus syndromes, due to post-zygotic HRAS, KRAS or NRAS variants, have epidermal naevi that follow Blaschko's lines and grow, involve the face and scalp and are associated with brain anomalies, colobomas and overgrowth; incontinentia pigmenti (IKBKG) evolves through vesicular, verrucous, hyperpigmented and hypopigmented stages, with hypodontia and retinal changes [8]. The differential diagnosis of CK syndrome includes other X-linked diseases with intellectual disability and asthenic habitus (ATP6AP2, ATRX, MED12, PQBP1, SKI, SLC9A6, SMS, ZDHHC9) and methylmalonic aciduria with homocystinuria cblC (MMACHC) [8]. In a male with an EBP variant, the distinction between mosaic CDPX2 and MEND has prognostic implications [84]. The French PNDS frames this distinction as follows: in a boy, a pathogenic EBP variant in somatic mosaic form, or with a 47,XXY karyotype, causes CDPX2, usually without neurodevelopmental disorder, and a constitutional hypomorphic variant causes MEND, with a usually severe neurodevelopmental disorder; as biochemistry does not separate them, the distinction is clinical [17]. The main differential of MEND syndrome is Smith-Lemli-Opitz syndrome (DHCR7; raised 7-dehydrocholesterol in blood, fibroblasts or amniocytes), which shares 2–3 toe syndactyly, postaxial polydactyly, brain, cardiac and genital malformations and cataracts (20%), without stippling in the classic phenotype; then come similar disorders, lathosterolosis (SC5D; raised plasma lathosterol, severe microcephaly, postaxial hexadactyly, cataracts and liver dysfunction) and squalene synthase deficiency (FDFT1) [17]. Schimmelpenning-Feuerstein-Mims syndrome and incontinentia pigmenti, the cutaneous differentials of CHILD syndrome, do not have stippling [17].

6.4. Phenocopies due to inhibition of the vitamin K cycle and warfarin embryopathy

Warfarin and the other coumarins cross the placenta, and fetal plasma concentrations approach maternal ones [112, 129]. The Oxford Desk Reference estimates embryopathy in 6% to 30% of fetuses exposed between 6 and 12 weeks and describes CNS malformations and fetoplacental haemorrhage after exposure in any trimester, with a risk of neonatal haemorrhage if exposure continues until near delivery [129]. The North American label gives a pattern of congenital malformations in about 5% of those exposed in the first trimester, based on data not derived from controlled studies [112]. Table 6.2 summarises the studies that quantify the risk, whose designs and populations are not comparable with one another.

Table 6.2. Studies on the fetal risk of VKA exposure

LMWH, low-molecular-weight heparin; HR, hazard ratio; CI, confidence interval; INR, international normalised ratio; OR, odds ratio.

Three observations follow from the table. The first is the window of exposure: in the ENTIS cohort, the risk of embryopathy was very low when first-trimester therapy did not extend beyond week 8 after the first day of the last menstrual period, and the authors do not recommend termination of a wanted pregnancy after early inadvertent exposure, but rather a level II ultrasound [140]; substitution with heparin up to week 6 and up to week 12 eliminated the risk in Chan's review [18]. The second is dose dependence, with fewer anomalies and more live births with warfarin at or below 5 mg/day, but without demonstrated safety, because losses and adverse events persisted [141]. The third is that embryopathy is only part of the fetal risk: miscarriage, prematurity and fetal death are more frequent with VKA in the first trimester [140, 142]. The prevention recommendations are in section 7.6.

Maternal vitamin K deficiency produces a phenotype clinically indistinguishable from warfarin embryopathy, and congenital deficiency of VKOR or GGCX produces warfarin pseudoembryopathy, with coagulopathy in the newborn [3, 39, 40]. The phenotype of the embryopathy is similar to that of CDPX1, with particularly severe nasal bone hypoplasia (Binder anomaly), but it affects both sexes [4, 5]. Maternal autoimmune disease produces changes similar to BCDP or to the tibia-metacarpal type, with rhizomelic shortening [4, 22]. A newborn with an RCDP phenotype without a plasmalogen or cholesterol defect should prompt investigation for maternal autoimmunity, including SLE that becomes manifest after delivery [121]. Brachytelephalangic CDP has also been described in VKCFD1 diagnosed prenatally [122]. The French PNDS lists as causes of maternal vitamin K deficiency inadequate intake (anorexia, hyperemesis gravidarum), malabsorption (biliary obstruction, extensive bowel resection, coeliac disease, chronic pancreatitis), alcoholism and exposure to VKA or phenytoin [17]. In alcohol embryopathy, the stippling predominates in the heels and knees, with possible brachytelephalangy; in phenytoin embryopathy, the few cases described had vertebral, epiphyseal and hand and foot stippling, rhizomelia, Binder phenotype, cleft palate and heart disease [17]. Among maternal autoimmune diseases, in addition to SLE and MCTD (Sharp syndrome), a case associated with Sjögren syndrome has been described; in maternal SLE, neonatal lupus may coexist (1% to 2%), and in maternal MCTD psychomotor development is usually normal [17].

6.5. Non-specific stippling

Stippling limited to the tarsus occurs in fetal alcohol syndrome, phenytoin toxicity, GM1 gangliosidosis, mucolipidosis II, Smith-Lemli-Opitz syndrome and trisomies 18 and 21 [22]. The French PNDS adds mucopolysaccharidosis III, galactosialidosis and free sialic acid storage disease among the lysosomal diseases, and monosomy X among the chromosomal anomalies [17]. Lysosomal diseases, trisomies 13, 18 and 21, β-glucuronidase deficiency, thyroid hormone resistance, spondyloenchondromatosis and ALG3-CDG are among the causes of stippled epiphyses in the lists of inborn errors of metabolism [25, 127]. Stickler syndrome has similar facies without stippling [3]. The Zellweger spectrum, with neonatal hypotonia, a large fontanelle and patellar stippling, and Smith-Lemli-Opitz syndrome enter the differential diagnosis [3, 145].

7. Treatments and Risk Management Strategies

7.1. General principles

For CDPX1, CDPX2, MEND syndrome, CHILD syndrome and Greenberg dysplasia there is a national protocol, the HAS PNDS (French National Diagnosis and Care Protocol) published in December 2022 and coordinated by the reference centres for developmental anomalies and for constitutional bone diseases of the Hospices Civils de Lyon; according to the authors themselves, there are very few studies with a high level of evidence, and the recommendations and monitoring schedules rest on expert consensus [17]. For RCDP there is no formal guideline, and the GeneReviews recommendations for the four forms are based on the literature and the authors' experience; searches of Europe PMC up to October 2026 did not identify any other formal consensus [4, 5, 7, 8]. Management is coordinated, in childhood and adulthood, by the multidisciplinary team of a reference or competence centre, with the centre's geneticist or paediatrician coordinating paediatric care and the geneticist in adulthood [17]. The discrepancies between the PNDS and the other sources are brought together in section 7.11. No medicinal product is authorised by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for these diseases, and there is no European orphan designation for RCDP, CDPX2, CHILD syndrome or plasmalogens [146]. Treatment is supportive, multidisciplinary and directed at complications; the only interventions with dosing described in the sources are the topical preparations for CHILD syndrome, all compounded and off-label, and the anticoagulation regimens in pregnancy that prevent warfarin embryopathy [8, 65, 147, 148]. The management of RCDP2 and RCDP3, with about eight published patients with RCDP3, is extrapolated from RCDP1 [9].

7.2. RCDP

Table 7.1. Management of RCDP according to GeneReviews

In PEX7-related Refsum disease, phytanate restriction resolves the ichthyosis, sensory neuropathy and ataxia; a high-calorie diet is recommended, avoiding fasting and sudden weight loss, which mobilise phytanate from adipose tissue, high-calorie parenteral infusion in severe illness or after surgery, and plasmapheresis or lipid apheresis in acute arrhythmia or extreme weakness; the foods to avoid are meat and dairy products from ruminants, some fish and nuts, and ibuprofen and amiodarone should be avoided [6, 9]. Testing of at-risk siblings allows phytanate to be lowered before symptoms appear [9].

Supplementation with alkylglycerol, a natural plasmalogen precursor, has been used in a few patients with the classic form, with anecdotal reports and without marked clinical benefit; in mutant mice, it corrected ether phospholipids in all tissues except the brain [5, 55]. The synthetic precursors are described in section 7.9.

7.3. CDPX1

Respiratory distress requires ENT and respiratory medicine, with nasal stents and oxygen when needed, and extensive tracheobronchial calcifications may require tracheostomy or tracheal reconstruction [4, 103]. Cervical instability is treated with a cervical collar or arthrodesis, and stenosis with decompression [4]. Garnier and colleagues recommend spinal MRI in all infants with CDPX1 and treating the newborn, until spinal cord compression has been safely excluded, as a patient with a suspected craniocervical junction injury [104]. In the severe 2026 case, cervical immobilisation reduced the episodes of reflex asystole, and vertebral fixation was not considered feasible in infancy [15]. Reconstructive surgery for severe maxillary hypoplasia is reserved for older individuals; hearing loss is treated with hearing aids and ventilation tubes, and delays with physiotherapy, occupational therapy, speech and language therapy and an education plan [4]. With cervical instability, extreme neck extension and flexion and contact sports are avoided, and the cervical spine should be imaged before general anaesthesia [4]. The genetic status of at-risk male relatives should be clarified for early assessment of the cervical spine, heart, eyes and hearing [4].

The 2022 French PNDS details the management of CDPX1 [17]. Brachytelephalangy has no functional consequence and requires no treatment. In all infants with the diagnosis, anteroposterior and lateral spinal radiographs and spinal and cervical MRI in the first three months; vertebral involvement is treated conservatively, and surgery is indicated in significant stenosis or instability with clinical manifestations or with spinal cord signal change on MRI, to recover motor function or halt respiratory deterioration. At the craniovertebral junction, the recommended technique is posterior decompression with posterior occipitocervical arthrodesis, under monitoring of motor and sensory evoked potentials and possibly with an external halo, usually removed after 12 weeks of immobilisation and replaced by a cervicothoracic orthosis for a further 3 to 6 months; at the subaxial level, posterior decompression or, in some cases, anterior decompression with arthrodesis is performed. In the surgical series, almost all case reports, ages range from 2 months to 16 years, about one third of patients needed a second operation, the risk of morbidity and mortality is high and surgery stabilises or improves motor function, without guaranteeing respiratory improvement, so follow-up until the end of growth looks for secondary deformities. Congenital contractures are treated with splints, orthoses, physiotherapy and physical and rehabilitation medicine [17].

In the airway, respiratory distress calls for a search for calcifications of the hyoid, the laryngeal cartilages and the tracheobronchial tree with neck and chest radiographs and CT of the airways, which measures laryngeal, tracheal and bronchial calibres, followed by endoscopy under general anaesthesia, diagnostic and sometimes therapeutic [17]. In tracheal stenosis, the PNDS proposes endoscopic dilatation as first line, possibly with non-invasive ventilation during sleep (one dilated case progressed favourably over 9 years); surgical tracheobronchial enlargement and tracheostomy are reserved for failure of these treatments, with considerable morbidity and mortality, and none of the published patients with tracheostomy had been decannulated during follow-up up to 8 years [17]. Severe nasal hypoplasia matters most in the first 2 to 3 months, when breathing is exclusively nasal: nasal saline washes several times a day are recommended, without excess that inflames the mucosa, and nasal corticosteroid if needed, and the nasal aspirator is discouraged; associated choanal atresia is operated on in the first days if bilateral and usually from 1 year if unilateral, and a stent alone is not advised because of the high recurrence rate [17]. Polysomnography is requested if sleep apnoea is suspected. In moderate forms, the Binder phenotype may become more marked with growth and require orthodontic-surgical treatment (early maxillary expansion, orthodontics, maxillary advancement from 16 years) and functional and aesthetic rhinoplasty with cartilage grafts (spreader grafts) [17]. Hearing loss is treated with hearing aids, sometimes from the first months, and speech and language therapy; in conductive hearing loss, from 8 to 12 years and after CT of the petrous bones, surgical exploration with ossiculoplasty may be discussed [17]. Heart disease is followed by paediatric cardiology and the surgical indication discussed at a multidisciplinary meeting; bilateral optic nerve atrophy or hypoplasia requires paediatric ophthalmology and orthoptics, optical correction, amblyopia treatment and, depending on the visual impairment, a specialised setting, and ptosis occluding the visual axis is operated on; gastro-oesophageal reflux may require paediatric gastroenterology and a nasogastric tube, and gastrostomy, rarely described, is discussed case by case [17]. In the presence of motor deficit, pyramidal syndrome or neck pain, craniovertebral junction involvement is sought [17].

7.4. CDPX2

Scoliosis may progress rapidly, and initial surgery has a high rate of failure and revision [7]. In Mason's series, with 20 patients followed for a mean of 7.9 years, dysplastic kyphoscoliosis required a mean of 2.5 procedures, hemiepiphysiodesis had a poor response and the best results were obtained with anterior grafting and posterior arthrodesis; separation of the C2 dentocentral synchondrosis was treated with fusion [107]. In Lykissas's two-centre series (1975–2011), 12 of 13 patients with spinal deformity underwent surgery (1.5 procedures per patient), 80% of those who needed more than one operation were girls with probable CDPX2, and revision occurred in 50% after anteroposterior arthrodesis and in 20% after posterior arthrodesis alone, figures that the abstract itself presents in a way poorly consistent with its conclusion [150]. Scoliosis associated with vertebral hemidysplasia requires anterior structural grafting and posterior arthrodesis [63]. In a systematic review of 44 patients with cervical involvement (CDP and coumarin embryopathy), 21% of those treated conservatively had neurological complications and there were two deaths, one in each group; neurological monitoring is essential [114]. A 7-year-old boy with cervical myelopathy due to kyphosis with os odontoideum underwent fusion from C2 to T2 and, nine months later, because of dysphagia secondary to atlantoaxial subluxation, extension of the fusion to the occiput; the surgical strategy is controversial [151].

The skin is treated with emollients and keratolytics and the alopecia with standard treatment; in ichthyosis, prolonged sun exposure increases the risk of dehydration from overheating, and oily emollients in direct sunlight increase the risk of burns [7]. Cataracts are extracted, and hearing loss and hydronephrosis are followed by the respective specialties [7]. In the first case of severe subglottic stenosis due to laryngotracheal calcifications, in a 2-month-old girl on continuous positive airway pressure, serial endoscopic balloon dilatations restored patency and avoided tracheostomy [108].

The French PNDS orders the orthopaedic management of CDPX2 by problem and age: leg length discrepancy is compensated with an insole, orthopaedic footwear or prosthesis from walking age, or corrected surgically by epiphysiodesis or lengthening, usually from 10 years; clubfoot is treated from birth with casts, physiotherapy and surgery; joint stiffness with splints, orthoses and physiotherapy from birth; postaxial polydactyly with excision at about 1 year; hip and patellar dislocations with surgical stabilisation from 1 year; and cutaneous syndactyly of the toes can be operated on from 1 year; scoliosis, potentially severe, is followed by a paediatrician, orthopaedic surgeon and neurosurgeon in liaison with a rare diseases centre, with monitoring of cardiorespiratory function if it progresses rapidly [17]. In the skin, perinatal ichthyosis may benefit from emollients, but keratolytics are not indicated at that age; cases with functional impact or very inflammatory lesions are referred to a reference centre for dermatological diseases; topical statin, theoretically effective, has not been tested in CDPX2, whose ichthyosis regresses spontaneously; and scarring alopecia can be corrected, at least in part, by surgical techniques [17]. Obstructive cataract is operated on at 6 weeks of life if unilateral and at 8 weeks if bilateral, or as soon as diagnosed if discovered later, with follow-up by paediatric ophthalmology and orthoptics for optical correction and amblyopia treatment; non-surgical cataract with functional impact and optic atrophy follow the same pathway, and glaucoma is treated with drugs or surgery in a specialised setting; hearing loss is managed as in CDPX1 [17]. None of these recommendations includes pharmacological dosing.

For MEND syndrome, the PNDS proposes surgery for cutaneous syndactyly and postaxial polydactyly from 1 year, the usual orthopaedic and rehabilitation treatment of scoliosis, neurosurgery for hydrocephalus, surgery for cleft palate, hypospadias and cryptorchidism, and the same ophthalmological and cardiological management as in CDPX2 [17]. Ichthyosis is treated with emollients up to 2 years; thereafter, if the emollient is not enough, compounded keratolytic preparations may be prescribed, with follow-up at a reference centre for genetic skin diseases [17]. The paediatric neurologist follows the epilepsy (with transfer to the neurologist in adulthood), psychomotor delay and intellectual disability (neuropsychological and adaptive skills assessment); motor delay receives early psychomotor therapy and physiotherapy, language early speech and language therapy and, when the disorders are severe, augmentative and alternative communication (Makaton, PECS, sign language), used at home, at school and at work; behavioural disorders are followed by a psychologist and child psychiatrist, and schooling often takes place in a specialised setting [17].

7.5. CHILD syndrome and CK syndrome

No therapy resolves the lesions in all patients, and trying successive methods is the usual practice [8]. Current therapies target the local cholesterol deficit and the reduction of toxic precursors, and the statin component is necessary, because cholesterol alone did not have a satisfactory effect [8, 64, 65]. All the regimens in Table 7.2 are compounded preparations applied off-label, evaluated in reports or small series, without controlled trials.

Table 7.2. Topical therapy and other interventions in CHILD syndrome

Previous ineffective treatments in Paller's patients included emollients, keratolytics, retinoids, corticosteroids and calcineurin inhibitors [65]. The 2025 classification of disorders of epidermal differentiation presents topical statin in syndromic disorders of cholesterol synthesis as the prototype of pathogenesis-based therapy, combining upstream inhibition with supplementation of the end product, and stresses that systemic therapies may not correct extracutaneous manifestations of embryonic origin [54]. Scoliosis and contractures are treated with orthoses or surgery, and cardiac, pulmonary and renal anomalies by the respective specialties; severe limb defects make the functional prognosis guarded and may require skeletal surgery and prostheses [8, 63, 65]. The French PNDS (French National Diagnosis and Care Protocol) recommends that dermatological care in CHILD syndrome take place, where possible, in a reference centre for genetic skin diseases, and positions topical cholesterol with a statin (simvastatin 2% or lovastatin 2%, as an extemporaneous preparation), described in several case reports with cutaneous improvement, sometimes almost complete, and good tolerability, as a suppressive treatment to be offered when there is functional impact, such as pruritus, or after failure of or contraindication to the conventional treatments of ichthyosis (emollients, keratolytics, topical or systemic retinoids) [17]. The PNDS does not state the cholesterol concentration or the frequency of applications; the reference dosing remains that of the published series (cholesterol 2% with lovastatin 2%, twice daily during the induction phase, reduced to maintenance once or twice weekly, Table 7.2) [17, 65]. It identifies no specific contraindication to topical statin and asks that treatment be started by a dermatologist from a multidisciplinary team at a rare disease centre [17]. Beyond the skin, it recommends compensation of leg-length discrepancy (insole, footwear or prosthesis from the onset of walking; epiphysiodesis or lengthening, as a rule from 10 years of age), splints and physiotherapy for stiffness, excision of polydactyly and surgery for syndactyly at around 1 year, multidisciplinary follow-up of scoliosis, neonatal intensive care for respiratory distress due to pulmonary hypoplasia, paediatric nephrology for renal involvement, paediatric cardiology, paediatric neurology if there is delay, and hearing assessment at birth and during follow-up, with early hearing aid fitting (between 3 and 6 months) or later fitting (at around 1 year) according to the degree and laterality of the hearing loss [17].

In CK syndrome, aggression and ADHD are treated with behavioural modification and drugs, seizures with standard antiepileptic drugs (none with demonstrated specific efficacy) and spasticity with baclofen, tizanidine, botulinum toxin or antiparkinsonian agents, together with orthopaedics, rehabilitation and ophthalmology; transition to adult care should begin at around 10 years of age [8]. In MSMO1 deficiency, a differential within the same pathway, one report described improvement in growth, weight and arthralgia with oral statin, cholesterol and bile acids, and cutaneous improvement with topical statin and cholesterol [63].

7.6. Phenocopies: prevention of warfarin embryopathy and vitamin K deficiencies

Warfarin embryopathy is the only CDP preventable by a therapeutic decision. The 2025 European Society of Cardiology (ESC) guideline on cardiovascular disease and pregnancy states that VKA cross the placenta and are associated with a risk of embryopathy and fetopathy even at low doses; in most pregnant women they are replaced by LMWH, except in carriers of a mechanical valve and in atrial fibrillation with moderate to severe mitral stenosis [147]. Women on long-term VKA who are planning pregnancy should be counselled, and the switch, as a rule to LMWH, should be made as early as possible after conception [147]. The ESC places the risk of embryopathy in the first trimester between 0.6% and 12%, that of fetopathy in the second and third trimesters (CNS anomalies, intracranial haemorrhage) between 0.7% and 2% and, with low-dose warfarin, between 0.45% and 0.9% according to two systematic reviews; it defines low dose as the dose required for the target INR, equal to or below 5 mg/day of warfarin, 2 mg/day of acenocoumarol or 3 mg/day of phenprocoumon [147]. The 2020 American College of Cardiology and American Heart Association (ACC/AHA) guideline for valvular heart disease states that embryopathy is reduced (<3%), but not eliminated, with warfarin at or below 5 mg/day, and that higher doses in the first trimester are associated with a risk above 30% of fetal loss or embryopathy [148]. The Oxford Desk Reference, based on data from 2001 and 2012, reports a risk of poor outcome of 80% with a mean daily dose above 5 mg and of 3% to 10% with a lower dose [129].

Table 7.3. Anticoagulation of the pregnant woman with a mechanical valve: ESC 2025 and ACC/AHA 2020

Sources: [147, 148]. The classes of recommendation and levels of evidence of the two guidelines are in tables that were not captured in the extracted text and are not reproduced. The ESC further states that neither embryopathy nor fetopathy has been described with LMWH, even at therapeutic dose, and that thromboembolic complications with a mechanical valve were 8.7% with LMWH, 5.8% with UFH and 2.7% with VKA [147]. In the ROPAC III registry, thromboembolic and haemorrhagic complications were more frequent with LMWH-based regimens, valve thrombosis occurred in 6% and was associated with a mitral prosthesis (OR 3.3), and thromboembolism was 10% with anti-Xa monitoring and 21% without it (p = 0.060) [143]. In the original ROPAC, all five first-trimester valve thromboses occurred after the switch to heparin [142]. The conflict between the fetal risk of VKA and the maternal thrombotic risk of heparin explains the difference in emphasis between the two guidelines and calls for preconception counselling by a cardiologist and a maternal-fetal medicine obstetrician, with haematological co-management [129, 147].

The US warfarin label (Jantoven®, revised 8 Jul 2025) contraindicates the drug in pregnancy, except in pregnant women with a mechanical heart valve and high thromboembolic risk [112]. In Portugal, warfarin is authorised and marketed as Varfine® (5 mg tablets; marketing authorisation holder Teofarma, S.r.l.), the only medicinal product with this substance in the Infomed database [154]. In Brazil, the reference medicinal product with active registration is Marevan® (Farmoquímica), with one similar product (Marfarin®) and generic warfarin sodium registered; the registration of Coumadin® is inactive [155]. Following VKA exposure, assessment includes the drugs and doses, the gestational age at exposure, maternal health, the family pedigree and a detailed anomaly scan, and the newborn's coagulation should be monitored if exposure continued until close to delivery [129]. Warfarin pharmacogenetics (VKORC1 -1639G>A and CYP2C9 genotypes) explains part of the variation in maintenance dose and hence in the 5 mg/day threshold [9].

In maternal vitamin K deficiency, prevention consists of recognising pregnant women at risk (hyperemesis gravidarum, Crohn's disease, coeliac disease, short bowel, jejunoileal bypass, bariatric surgery); the sources consulted include no guideline or dose of vitamin K supplementation for these pregnant women [40, 117]. In the hereditary deficiencies (VKCFD1 and VKCFD2), high-dose vitamin K corrects the coagulopathy partially or completely, and prothrombin complex concentrate or fresh frozen plasma are used for bleeding, surgery and delivery, titrated against coagulation tests; the effect on calcifications and non-haemorrhagic symptoms is limited [9, 70]. In Keutel syndrome, treatment is symptomatic [9].

7.7. Regulatory status

Table 7.4. Regulatory status (10 Oct 2026)

The FDA orphan designation database was not consulted, so the absence of orphan designation in the USA is not asserted.

7.8. Clinical trials and studies

Table 7.5. Interventional and natural history studies

There is no randomised efficacy trial in patients with any form of CDP [4, 7–9]. The phase 1 trial of PPI-1011 measured safety and pharmacokinetics in volunteers, and an increase in a serum plasmalogen is not a clinical outcome; it does not allow benefit in patients to be inferred. In a hypomorphic/null Pex7 mouse model, PPI-1040, a synthetic plasmalogen with a vinyl-ether bond, normalised plasma plasmalogens and hyperactivity without increasing those of the brain, lung and kidney, whereas PPI-1011 at an equivalent dose was not effective; the clinical candidate is nevertheless PPI-1011 [158, 162]. The CHILD syndrome case series have no control group, and spontaneous regression of some lesions limits causal attribution [8]. The natural history studies and RhizoQOL are intended to provide the outcomes for future trials [149, 159].

7.9. Developments in the last 12 months

Human trial and press release. The phase 1 of PPI-1011 ended in November 2024 and was published in March 2025; the sponsor announced in a press release of 17 March 2025 that it was preparing a phase 2 study in patients with RCDP and an IND application to the FDA [156, 158]. By 10 October 2026, no phase 2 registration had been found on ClinicalTrials.gov, and the phase 1 record, updated on 9 October 2026, has no posted results; a negative search does not prove that the study does not exist [157].

Preclinical. Brain metabolomics in Pex7 mice and in patients (December 2025) showed that plasma underestimates CNS lipid changes, with implications for the choice of biomarkers in trials [61].

Clinical reports from 2026. Published reports include a case of CDPX1 with reflex asystole due to dynamic cervical compression, the first case of subglottic stenosis in CDPX2 treated by balloon dilatation, a diagnosis of CDPX2 at 12 weeks, cases of atypical CHILD syndrome treated with topical statin and cholesterol, Japanese reports on neonatal atlantoaxial instability (screening ultrasound and neurogenic shock), a clinical image of neonatal CDPX1, an infant with CDP presenting with apnoea and failure to thrive, and a diagnosis of CDPX2 in adulthood [15, 81, 82, 106, 108, 110, 111, 128, 163–165]. Reports from 2025 and 2026 from India and Pakistan describe a novel PEX7 variant and the diagnostic odyssey of RCDP [166, 167]. A Spanish man with mosaic CDPX2 and atypical dermatological manifestations was described in 2025 [168].

Warfarin embryopathy. The ROPAC III registry, the KYBELE paediatric follow-up and a mechanistic review were published in 2026 [69, 143, 144]. The ESC guideline on pregnancy of August 2025, immediately preceding the window, is the current European reference [147].

7.10. Agents to avoid, perioperative care, pregnancy and transition

In CDPX1 and the other CDP with cervical instability, extreme flexion and extension of the neck and contact sports are avoided, and the cervical spine is imaged before any general anaesthesia [4, 114]. In CDPX2, sun protection is necessary and oily emollients should be avoided before direct sun exposure [7]. In Refsum disease due to PEX7, fasting, sudden weight loss, ibuprofen and amiodarone are avoided [9]. The OrphanAnesthesia list of published recommendations did not include, in October 2026, RCDP, CDPX2 or CHILD syndrome [169]; anaesthetic considerations derive from cervical stenosis and instability, laryngotracheal calcifications and nasal hypoplasia, which make the airway potentially difficult [4, 96, 108]. The sources consulted do not describe the management of pregnancy in women with CDPX2 or CHILD syndrome. For surgery in CDPX1, the French PNDS requires an anaesthetic consultation with airway assessment, if necessary with respiratory medicine and otorhinolaryngology: oropharyngeal examination and awake nasofibroscopy down to the glottic plane, which does not assess the subglottis, trachea or bronchi, so preoperative CT of the airways is recommended, supplemented if necessary by endoscopy under general anaesthesia at the first surgical procedure, to choose the tube size; a laryngeal mask is preferred, to avoid secondary laryngotracheal injury and stenosis, a tube smaller than predicted for age and weight is used when there is stenosis, and the patient is positioned with care if there is craniovertebral instability [17]. Transition to adult care is explicitly planned for CK syndrome, from 10 years of age, and survival to adulthood of 35% of patients with RCDP and of almost all patients with the non-classical form requires the same planning [5, 8]. The French PNDS defines the goals of transition: at the end of adolescence, a genetics clinic appointment and a transition clinic to adult services ensure continuity of follow-up and rehabilitation [17].

Rehabilitation, coordinated by physical and rehabilitation medicine and physiotherapy, prevents functional limitations; occupational therapy preserves autonomy with assistive devices, home adaptations, orthoses and fittings suited to short stature; speech and language therapy addresses hearing loss, language delay, early feeding disorders and cleft palate; and psychological support accompanies the patient and family after disclosure of the diagnosis [17]. In France, CDP are not on the list of the 30 long-term conditions (ALD), but full coverage as an off-list ALD may be granted after review of the file; the MDPH assesses orthopaedic, neurodevelopmental, cardiorespiratory or sensory disability; and the individualised reception plan (PAI), agreed between the child, the family, the school and health professionals, defines school adaptations [17]. There is no therapeutic education programme specific to CDP; the PNDS suggests programmes for developmental anomalies or for short stature with or without body asymmetry, such as the «échange de regard» programme of the AnDDI-Rares network, to support family participation and transition [17].

7.11. Divergences between the French PNDS and the other sources

The 2022 French PNDS and GeneReviews agree on the multidisciplinary approach and molecular diagnosis, but diverge in figures, indications and intervals; Table 7.6 gathers the differences and the proposed reading of each [4, 7, 8, 17].

Table 7.6. Divergences between the French PNDS (2022) and the other sources cited

The PNDS contains no doses of systemic drugs; the only concentrations it gives are those of the topical statins [17].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by entity

Table 8.1. Recurrence risks

8.2. RCDP

The parents of a proband are presumed heterozygous and parental testing is recommended; if only one parent has the variant, with confirmed parentage, the explanation may be a de novo variant in the proband or mosaicism in a parent [5]. Apparent homozygosity may correspond to a deletion of one or more exons not detected by sequencing or to uniparental isodisomy, as in the case of RCDP2 due to paternal isodisomy of chromosome 1 [5, 25]. Carriers are asymptomatic and can be detected only molecularly; testing of the partner of a carrier should be considered, especially if of the same ancestry [5]. In the genetically isolated founder population of the Netherlands, preconception carrier screening targeting four recessive diseases, offered since 2012, found 6.1% carriers of RCDP1 among 196 people tested and 33.2% carriers of at least one of the diseases, and proved more effective than cascade testing in that subpopulation [130].

8.3. CDPX1

The father of an affected boy is neither affected nor a carrier. In families with more than one affected individual, the mother is an obligate heterozygote; if there is more than one affected son and the variant is not detected in maternal leucocytes, germline mosaicism is likely [4]. To date no de novo case has been described: all tested mothers of boys with a detectable variant were carriers [4]. Maternal aunts are at risk of being carriers [4]. As hemizygous men and carrier women may be asymptomatic, the risk of clinically expressed disease in a son of a carrier mother is probably below 50%, and severity cannot be predicted [92, 93]. A prenatal suspicion of CDPX1 should lead to genetic counselling and investigation for spinal cord compression after birth [104]. The French PNDS allows for de novo variants in CDPX1, unlike GeneReviews, which had found none among the mothers tested, and recommends genetic counselling for potentially carrier women in the family [4, 17].

8.4. CDPX2

In a female proband, the variant may be maternal (the mother may be so mildly affected that she is identified only after a more severely affected daughter), paternal (father with somatic or gonadal mosaicism) or de novo, which occurs in about 60% of affected women [7]. Detailed clinical assessment of the parents, including skin, hair, eyes and radiographs, and maternal testing are necessary; sterol profiling identified the clinically unaffected mother of a sporadic case [7, 87]. In the Spanish series, the variant was inherited in three of nine families [88]. Gonadal mosaicism should be considered in apparently sporadic cases, because healthy parents have had two affected daughters [90]. In a male proband, almost always a postzygotic mosaic, the mother is typically not heterozygous, and the risk to siblings is presumed to be low [7]. Mosaic men may transmit the variant to their daughters [7].

8.5. CHILD syndrome and CK syndrome

In a female proband with CHILD syndrome, the variant is maternal or de novo; the mother should be tested, because there may be heterozygotes with minimal lesions or with favourably skewed X-inactivation and a normal phenotype, and a de novo variant is confirmed only by a negative maternal test [8]. Mother-to-daughter transmission is documented, and a woman with an isolated CHILD naevus only may have a daughter with the typical syndrome [8, 51]. Recurrent male fetal losses may reflect maternal transmission of an NSDHL variant [8]. In a mosaic boy, the parents are not carriers [8, 91]. No man with CK syndrome has reproduced [8].

8.6. Prenatal diagnosis, preimplantation diagnosis and reproductive options

With the familial variants identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and PGT are available for all genetic forms [4, 5, 7, 8]. Without a molecular diagnosis, ultrasound of the epiphyses with limb biometry is the available tool in at-risk pregnancies [3]. In CDPX2, the low allele fractions of a mosaic parent should be taken into account when interpreting prenatal diagnosis [7]. The French PNDS describes the pathway in France [17]. The genetics clinic appointment is indispensable, although it need not coincide with disclosure of the diagnosis, and should be prompt if there is an ongoing pregnancy or a pregnancy plan; it includes confirmation of the diagnosis, the mechanism of transmission, the risk to offspring, information for the family, the means of surveillance in pregnancy, the possibility of termination of pregnancy for medical reasons and the principle of preimplantation diagnosis. Requests for prenatal diagnosis are discussed at a multidisciplinary prenatal diagnosis centre (CPDPN), given inter- and intrafamilial variability. In CDPX1 and MEND syndrome, the pregnant carrier may undergo fetal sex determination and, if the fetus is male, molecular diagnosis; in CDPX2 and CHILD syndrome, molecular diagnosis is performed if the fetus is female, and counselling is reassuring for the great majority of male fetuses, because of lethality in utero, with confirmatory ultrasound; in CDPX2 and MEND syndrome, measurement of sterols in amniotic fluid may be combined with molecular analysis. When there is a de novo variant, molecular prenatal diagnosis may be offered at the couple's request, because of the low risk of germline mosaicism; ultrasound surveillance by a reference sonographer is indicated when molecular diagnosis is not performed or when the pregnancy of an affected fetus continues; and PGT may be discussed for carriers [17]. In Greenberg dysplasia, the early appearance of ultrasound signs allows reference ultrasound surveillance without molecular diagnosis to be discussed, and counselling extends to relatives in the case of consanguinity [17].

Disclosure of the diagnosis takes place in a dedicated consultation, preferably jointly with a geneticist when the test was requested by another specialty, and with a psychologist; in prenatal disclosure, the features of the disease, the possible care and follow-up, the possibility of meeting the specialists who will care for the child, transmission and, if indicated after discussion at the CPDPN, termination of pregnancy for medical reasons are explained; in postnatal disclosure, the follow-up plan, the search for complications and social support are added [17]. A second consultation a few weeks later revisits the information and introduces the team, including the social work service; psychological support extends to parents and siblings, and contact with associations and with other families is offered [17].

When the cause remains unknown after investigation and specialist radiological review, the parents should be examined for mild forms (adult radiographs do not show stippling but may show irregular bone growth) and maternal malabsorption or SLE should be investigated; the adult asking about the risk to offspring may be unaware of the history of their own mother's pregnancy [3].

8.7. Anticoagulated women and maternal phenocopies

Preconception counselling of the woman on VKA includes an explanation of the risk of embryopathy according to dose and drug, the plan to switch to LMWH when planning or soon after conception when the indication allows, and, in carriers of a mechanical valve, the shared decision between the regimens in Table 7.3 [147, 148]. After inadvertent exposure limited to the first 8 weeks, the risk of embryopathy is very low, termination of a wanted pregnancy is not recommended by the ENTIS cohort and a level II ultrasound scan is indicated [140]. The Portuguese case of embryopathy with warfarin at 5 mg/day illustrates that a low dose does not eliminate the risk (section 10) [170]. In women with malabsorption, severe hyperemesis or bowel surgery, the risk of fetal vitamin K deficiency should be recognised; in women with SLE, MCTD or scleroderma, fetal ultrasound should look for signs of CDP [40, 41, 117].

8.8. Minors

The sources consulted contain no specific recommendations on carrier testing in minors in the recessive forms. Where the result changes surveillance, the test has immediate clinical utility: in boys at risk of CDPX1, it allows early surveillance of the cervical spine, heart, eyes and hearing [4], and in siblings at risk of Refsum disease due to PEX7 it allows phytanate restriction to be started before symptoms [9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Table 9.1. Epidemiological estimates

The figures in the table are not comparable with one another. The RCDP estimate is a model and not a count of diagnosed cases; that for CDPX1 comes from a single study, and series of patients with brachytelephalangic CDP without an ARSL variant suggest that the form is underdiagnosed or confused with phenocopies [4, 16, 67]. The difference between GeneReviews and Orphanet for CDPX2 is not explained by the sources, and mild forms and mothers with minimal signs are not captured by estimates based on symptomatic cases [7, 11, 106]. In CHILD syndrome, adults are probably underdiagnosed [8]. Citations of 1/100,000 for RCDP and of 1/500,000 for CDPX1 in recent case reports are indirect and add no new data [15, 80].

9.2. Founder effects and ancestry

The PEX7 p.(Leu292Ter) allele accounts for about 50% of mutant alleles in North American series and shares a single haplotype of European origin [71, 72]. In the Dutch cohort, 11 of the 12 patients with heart disease carried c.875T>A, and p.His285Arg has been proposed as a founder variant in Dutch ancestry [5, 100]. In a genetically isolated community in the Netherlands, the carrier frequency of RCDP1 was 6.1% among 196 people tested in a preconception clinic [130]. The bovine model in the Aubrac breed, with an allele frequency of 2.6% for a GNPAT variant, is an animal and not a human founder effect [62]. Reports of RCDP2 and RCDP3 often come from consanguineous families, such as the Saudi family in section 10 and the Turkish families with AGPS [80, 83].

9.3. European, Portuguese and Brazilian data

The largest European series are the Dutch RCDP series (16 patients in the epilepsy cohort, 23 in the heart disease cohort), the Spanish CDPX2 series (13 patients from 9 families), the German, British and Dutch CDPX2 series and the European multicentre ENTIS cohort on VKA in pregnancy, in which the most frequently used drugs were phenprocoumon and acenocoumarol [88–90, 98, 100, 140]. From Portugal, the sources consulted include a case of warfarin embryopathy with warfarin 5 mg/day published by authors from Lisbon and a clinical image of warfarin embryopathy published by Portuguese authors, cited by the 2025 ESC guideline [147, 170, 171]. In France, the 2022 PNDS gives overall estimates (incidence of CDP of 1/110,000 births and of CDPX2 of 1/400,000), without a national cohort or a described method [17]. The sources consulted contain no prevalence data for any form of CDP in Portugal or Brazil.

9.4. Special populations

In males, CDPX2 and CHILD syndrome occur only in mosaic form, with a 47,XXY karyotype or with a hypomorphic variant, and non-mosaic hypomorphic forms manifest as MEND or CK, without stippling [7, 8]. In women, CDPX1 does not manifest, although Bone Dysplasias reports women with a BCDP phenotype, who require phenocopies to be excluded [4, 94]. In adults, stippling is no longer visible and diagnosis depends on early radiographs, sequelae and molecular testing [3]. Pregnant women with a mechanical valve are the population at highest risk of warfarin embryopathy, and pregnant women with autoimmune disease or malabsorption the population at risk of the other phenocopies [40, 41, 147].

9.5. European reference networks and patient associations

ERN BOND brings together the centres for rare bone diseases, including skeletal dysplasias; MetabERN has a subnetwork for peroxisomal and lipid disorders, relevant to RCDP and to disorders of cholesterol synthesis; ERN-Skin covers syndromic ichthyoses, including CDPX2 and CHILD syndrome; ERN ITHACA covers malformation syndromes [19–21, 172]. RhizoKids International (RCDP), the Global Foundation for Peroxisomal Disorders, with a patient registry, and the Foundation for Ichthyosis and Related Skin Types (FIRST; CDPX2 and CHILD syndrome) are international patient associations [173–175]. GeneReviews also lists Little People of America, the MAGIC Foundation, the Human Growth Foundation, the support group for families with CDPX1, the International Skeletal Dysplasia Registry of the University of California, Los Angeles, and the locus-specific variant databases (PEX7 Gene Database, ARSE and NSDHL in LOVD, EBP database) [4, 5, 7, 8]. In the United Kingdom, the Oxford Desk Reference lists Contact a Family [3]. In France, the 2022 PNDS links three rare disease health networks (filières): AnDDI-Rares, with the reference and competence centres for developmental anomalies and malformation syndromes (including the reference centre for the South-East region, at the Hospices Civils de Lyon, coordinator of the PNDS); OSCAR, with the centres for constitutional bone diseases, coordinated by the Hôpital Necker-Enfants Malades, in Paris, and with a competence centre in Lyon; and FIMARAD, with the reference centre for rare genetic diseases of the skin and mucous membranes (MAGEC) of the Assistance Publique–Hôpitaux de Paris [17]. There is no French association specific to CDP; the PNDS refers families to the Association des Personnes de Petite Taille (APPT) and to the association «Un défi de taille» [17].

10. Illustrative Clinical Case

The following cases were summarised from the full text of the articles. The figure links point to the article pages on PubMed Central; the legends were read, but the images were not viewed, because those pages require interactive verification.

10.1. Neonatal RCDP type 2 due to a GNPAT splicing variant

Sayed and colleagues described a newborn from Mecca, Saudi Arabia, the son of healthy first-cousin parents aged 26 and 31 years [80]. The mother had had a first-trimester miscarriage and a delivery at 26 weeks of a daughter who died a few days later from severe respiratory distress and early-onset sepsis; in this pregnancy she had diet-controlled gestational diabetes and had not been exposed to known teratogens. At 35 weeks, ultrasound showed growth below the 5th centile and all long bones below the centiles for gestational age, with a humerus of 38 mm, corresponding to about 23 weeks [80].

The boy was born at 36 weeks weighing 2205 g, with a length of 45 cm and a HC of 31 cm, an upper-to-lower segment ratio of 1.6:1 and proximal shortening of all four limbs, depressed nasal bridge, broad nose, long philtrum, multiple contractures of the hips, knees, shoulders, elbows, wrists and fingers, restrictive lung disease with oxygen dependence and bilateral polar cataracts [80]. Radiographs showed bilateral, symmetrical rhizomelic shortening of the humeri and femora with stippled epiphyses, widened metaphyses and extensive stippled vertebral calcification; hip ultrasound showed stippled echogenic foci and displacement of the femoral epiphyses. The echocardiogram revealed a 2 mm ventricular septal defect and a 2 to 5 mm atrial septal defect, with good function; cervical CT and cranial and abdominal ultrasound were normal [80]. Maternal autoimmunity, warfarin exposure and alcohol were excluded [80].

The exome identified the GNPAT variant NM_014236.4:c.1602+1G>A in the homozygous state, which alters the splice donor site of intron 11, is absent from gnomAD and was classified by the authors as likely pathogenic; Sanger sequencing confirmed heterozygosity in the parents [74, 80]. The article does not report plasmalogen measurement, so the biochemical diagnosis was not documented [80]. The child was discharged with home oxygen, a home care programme and multidisciplinary follow-up, and the family received genetic counselling [80].

Figures in the article: Figure 1, radiographs of the upper limbs with rhizomelic shortening of the humeri, widened metaphyses and stippled calcifications of the proximal and distal epiphyses (PMC10264737, fig. 1); Figure 2, chest and abdominal radiograph with extensive stippled vertebral calcification (fig. 2); Figure 3, ultrasound of the femoral heads with stippling (fig. 3) [80].

The case brings together the elements of the classical form (symmetrical rhizomelia, stippling, cataracts, contractures, septal heart disease and respiratory disease) and illustrates that RCDP2 is clinically indistinguishable from RCDP1 [5, 55]. It departs from recommended practice in that biochemical confirmation was not documented: erythrocyte plasmalogens, with normal VLCFA, are the test that confirms the group and distinguishes the classical from the mild form [5, 55]. The history of losses and of the neonatal death of a sister, with consanguinity, should, in current practice, have prompted the offer of prenatal diagnosis or PGT in subsequent pregnancies, now possible with the variant identified [5].

10.2. Warfarin embryopathy with low-dose warfarin, in Lisbon

Sousa, Barreira and Santos described, at the Centro Hospitalar de Lisboa Ocidental, the son of a 25-year-old primigravida anticoagulated with warfarin since the age of 11 years for mechanical mitral and aortic valve replacement due to rheumatic disease [170]. The mother took warfarin 5 mg/day (INR 2.5–3.5) until week 8, stopped it without medical advice between weeks 8 and 10 without other anticoagulation, resumed it at week 10 with LMWH, stopped the LMWH at week 12 with a therapeutic INR and continued warfarin 5 mg/day until 39 weeks, switching to UFH for the elective caesarean section [170]. The scans at 21 and 30 weeks showed absent nasal bones, small nostrils and malformation of the lumbosacral vertebrae, and fetal echocardiography a small muscular ventricular septal defect [170].

The boy was born at 39 weeks with Apgar scores of 7, 9 and 10, weight 3.65 kg (50th centile), length 49 cm (10th centile) and HC 35 cm, with nasal hypoplasia, depressed nasal pyramid and noisy breathing; the nasal passages admitted only a size 5 catheter, and fibroscopy confirmed stenoses [170]. He required non-invasive ventilation (high flow and continuous positive airway pressure) in the first 36 hours and had tachypnoea, recession, feeding difficulties and moderate axial hypotonia in the first two weeks. Radiographs showed stippling of the lumbosacral vertebrae, the femoral epiphyses, the calcaneus and the tarsal bones. Transfontanellar ultrasound and ophthalmological examination were normal; auditory evoked potentials, absent at birth, normalised at 6 months [170]. He was discharged at one month, without specific treatment, with follow-up in ophthalmology, audiology, paediatric neurology, developmental paediatrics and cardiology; at one year he was asymptomatic with normal development [170].

Figures in the article: Figure 1, facial profile with nasal hypoplasia (PMC5893982, fig. 1); Figure 2, stippling of the lumbosacral vertebrae and femoral epiphyses (fig. 2); Figure 3, bilateral stippling of the calcaneus and tarsal bones (fig. 3) [170].

The case shows that a dose of 5 mg/day, at the low-dose threshold of the ESC and ACC/AHA, does not eliminate the risk of embryopathy, as the guidelines acknowledge [147, 148, 170]. Exposure covered weeks 6 to 8, within the window of highest risk, and the interruption of anticoagulation between weeks 8 and 10, without heparin cover, does not correspond to any of the recommended regimens and exposed the mother to thrombotic risk [147, 148]. The favourable course at one year is consistent with the described natural history, in which most children have normal cognitive development and the nasal malformation persists [33].

10.3. Other recent cases

Rajkumar and colleagues described in 2026, in London, a boy with CDPX1 due to ARSL NM_000047.3:c.1442C>T p.(Thr481Met) inherited from his mother, with tracheal calcification from birth, recurrent lung collapse and pneumothoraces, high cervical cord injury due to atlantoaxial instability and, from 5 months, episodes of asystole triggered by minimal movements or by defecation, reduced with cervical immobilisation; at 9 months vertebral fixation was not feasible and the patient had remained in hospital since birth [15]. The figures in the article show stippling of the humeral epiphyses and vertebrae, linear calcification of the tracheal wall and stenosis of the cervical canal on T2-weighted MRI (PMC13462689, fig. 1; fig. 4) [15]. The case illustrates the severe end of the CDPX1 spectrum and the need for early imaging of the cervical spine and airway [4, 104].

Yang and colleagues described, also in 2026, a fetus of a 19-year-old Chinese primigravida with stippling of almost the entire costal outline and postaxial polydactyly at 12 weeks, a narrow thorax and very short femur and humerus at 16 weeks, and a de novo EBP variant NM_006579.3:c.146T>A p.(Leu49Ter) on trio exome; the pregnancy was terminated and the external post-mortem examination showed a female fetus with a flat profile, hypertelorism, short limbs and polydactyly (PMC13379174, fig. 1) [81]. In the Lefebvre series cited by the authors, the nine female fetuses with an EBP variant had been diagnosed in the second trimester [81].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

RCDP. In the classical form, the White series showed survival of 90% at 1 year and of 50% at 6 years; GeneReviews, for the 35 children over one month of age in that series, gives 55% at 5 years and about 20% at 12 years, and the 2020 review of 66 patients gives 80% at 5 years, 45% at 12 years and 35% to adulthood [5, 101, 102]. Deaths are mainly due to respiratory complications, and an unknown proportion die in the neonatal period [5]. Surviving patients retain severe intellectual disability, spastic tetraplegia, epilepsy and thermal instability [24, 98]. In the non-classical form, 11 of 12 patients reached adulthood, with seizures in 43% and learning difficulties in 87% [5, 86]. These figures describe cohorts that received supportive care but no disease-modifying intervention; the improvement between the older series and those of 2003 and 2020 may reflect respiratory and nutritional care and the selection bias of registries [5, 101].

CDPX1. Life expectancy is usually normal and the skeletal findings improve towards adulthood, but severe morbidity and early mortality occur owing to respiratory compromise and cervical stenosis or instability, which may present in infancy or later [4, 94, 104]. The French PNDS adds that mortality is increased in the severe forms owing to respiratory complications, that about one third of patients operated on at the craniovertebral junction needed a second operation, that surgery stabilises motor function without guaranteeing respiratory improvement and that no published tracheostomised patient had been decannulated by the age of 8 years [17].

CDPX2. The most severe cases die before or soon after birth; after the first weeks, life expectancy and development are as a rule normal, and the prognosis depends on scoliosis, which may compromise cardiorespiratory function, and on cataracts [7, 22, 63]. In non-mosaic hemizygous men, mortality is high [63]. In MEND syndrome, congenital heart disease may determine the vital prognosis [17].

CHILD syndrome and CK syndrome. Lifespan does not appear to be limited, but severe limb defects and cardiac, pulmonary or renal malformations determine the prognosis; early death is mainly due to heart disease or pulmonary hypoplasia [8, 31, 63]. In CK syndrome, men survive to adulthood, with intellectual disability and epilepsy [8, 63].

Warfarin embryopathy. Most children have normal cognitive development, with persistent nasal malformation; stippling is incorporated into the epiphyses with few problems, but cervical instability can cause severe neurological dysfunction [33, 113, 114]. Exposure in the second and third trimesters is associated with CNS anomalies with intellectual disability, and the Dutch cohort of exposed children showed more minor neurological dysfunction and IQ below 80 [33, 115].

11.2. Surveillance

Table 11.1. Recommended surveillance

The RCDP surveillance proposed by GeneReviews originates in the health supervision recommendations of White and colleagues, based on a retrospective review of 35 patients with the classical form [5, 101]. In CDPX1, some patients developed cervical instability later, which justifies continuing radiographic surveillance until the end of growth [4]. The 2025 and 2026 publications on neonatal atlantoaxial instability, neurogenic shock, os odontoideum and laryngotracheal calcifications reinforce surveillance of the craniocervical junction and airway in all CDP, but do not propose formal intervals [108, 128, 151, 163]. As spinal deformity arises mainly in the first year and progresses, radiographic surveillance of the spine should be prolonged in all forms [107]. In children exposed to VKA, surveillance focuses on the nasal airway, cervical spine, hearing, vision and development, as in the Portuguese case [114, 170]. The intervals of the French PNDS result from expert consensus and are more precisely defined than those of GeneReviews; the paediatric schedule in the PNDS tables (monthly to 9 months) does not coincide with the growth schedule in its text (monthly to 6 months), and Table 11.1 keeps both (section 7.11) [17]. The cervical radiograph in flexion and extension every 6 to 12 months in CDPX1, proposed by GeneReviews, is not in the PNDS, which leaves the frequency of orthopaedic follow-up to the findings [4, 17].

12. Summary and Final Considerations

The chondrodysplasias punctata share a transient radiological sign, stippled calcification of cartilage, which results from defects in four pathways: peroxisomal plasmalogen synthesis, post-squalene cholesterol synthesis, arylsulfatase L and vitamin K-dependent γ-carboxylation [3, 4]. As stippling disappears in the first years, diagnosis depends on early radiographs and on clues that persist: coronal clefts and symmetrical rhizomelia in RCDP, inverted-triangle distal phalanges in CDPX1 and the phenocopies, follicular atrophoderma, patchy alopecia and sectoral cataracts in CDPX2, and a persistent unilateral lesion with an ipsilateral limb defect in CHILD syndrome [3, 7, 8].

RCDP, generally caused by PEX7 and with a European founder allele, has a classical form with severe intellectual disability, epilepsy, heart disease in about half of patients and survival to adulthood in 35%, and a non-classical form in which almost all reach adulthood; erythrocyte plasmalogens confirm the group and separate the two forms, and phytanic acid guides dietary restriction in the mild form [5, 86, 100]. CDPX1 affects boys and as a rule has a good prognosis, but cervical stenosis and instability and tracheobronchial calcification can be fatal, which justifies early cervical MRI and flexion-extension radiographs until the end of growth [4, 15, 104]. CDPX2 and CHILD syndrome are X-linked dominant disorders of the cholesterol pathway, expressed as mosaics in women; men survive as mosaics or with hypomorphic variants, which give rise to MEND and CK syndromes [7, 8]. In CDPX2, dysplastic kyphoscoliosis is the main cause of morbidity, with high rates of surgical revision [107, 150]. In CHILD syndrome, topical preparations of statin with cholesterol, compounded and off-label, have produced cutaneous improvement in small series without a control group [8, 65].

Phenocopies, in particular warfarin embryopathy, must be excluded in any newborn with CDP, through a maternal history of VKA, malabsorption or autoimmune disease [3, 40, 41]. Embryopathy is the only preventable form: the risk is concentrated between weeks 6 and 12 and is very low when exposure ends by week 8; it is dose-dependent, but does not disappear with warfarin 5 mg/day, and the European and North American guidelines converge on the low-dose threshold and diverge in the emphasis placed on continuing warfarin and in the anti-Xa target for heparin [140, 141, 147, 148, 170].

None of these disorders has an authorised treatment. The 2022 French PNDS, the only published national guidance for CDPX1, CDPX2, MEND syndrome, CHILD syndrome and Greenberg dysplasia, defines by expert consensus early cervical MRI, the stepwise approach to the airway, the surveillance schedule and the place of topical statin as second-line treatment in CHILD syndrome; for RCDP there is no formal guideline. The only synthetic plasmalogen precursor in clinical development has completed phase 1 in healthy volunteers, and the natural history studies and the RhizoQOL instrument are preparing the outcomes for future trials [149, 158, 159]. Follow-up coordinated by the ERN BOND, MetabERN and ERN-Skin networks, together with patient associations, remains the basis of care [19–21, 173].

13. References

1. Orphanet. Chondrodysplasia punctata (ORPHA:93442) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/93442
2. 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.
3. Firth HV, Hurst JA. Chondrodysplasia punctata. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 98–100.
4. Braverman NE, Bober MB, Brunetti-Pierri N, Suchy SF. Chondrodysplasia Punctata 1, X-Linked. 2008 Apr 22 [updated 2020 Oct 15]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1544/
5. Braverman NE, Carroll R, Muss C, Fallatah W, Jain M. PEX7-Related Rhizomelic Chondrodysplasia Punctata. 2001 Nov 16 [updated 2025 Aug 7]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1270/
6. Waterham HR, Wanders RJA, Leroy BP. Adult Refsum Disease. 2006 Mar 20 [updated 2021 Sep 30]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1353/
7. Kumble S, Savarirayan R. EBP-Related X-Linked Chondrodysplasia Punctata. 2011 May 31 [updated 2026 Jun 4]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK55062/
8. Kurban M, El Feghaly J, Hamie L. NSDHL-Related Disorders. 2011 Feb 1 [updated 2024 Sep 5]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK51754/
9. GeneGuidance — gene curation database (records PEX7, GNPAT, AGPS, PEX5, FAR1, EBP, NSDHL, VKORC1, GGCX, LBR, MGP). Version of 2026-09-26.
10. Orphanet. Rhizomelic chondrodysplasia punctata (ORPHA:177) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/177
11. Orphanet. X-linked dominant chondrodysplasia punctata (ORPHA:35173) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/35173
12. Orphanet. Brachytelephalangic chondrodysplasia punctata (ORPHA:79345) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/79345
13. Orphanet. CHILD syndrome (ORPHA:139) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/139
14. Orphanet. Vitamin K antagonist embryofetopathy (ORPHA:1914) [Internet]. Paris: INSERM; [cited 2026 Oct 10]. Available from: https://www.orpha.net/en/disease/detail/1914
15. Rajkumar J, Okoye AG, Belani P, Haque S, Greenough A. X-linked ARSL chondrodysplasia punctata: expanding the spectrum with a severe multisystem phenotype. Case Rep Perinat Med. 2026;15(1):20250031. doi:10.1515/crpm-2025-0031. PMID: 42591988. PMC13462689.
16. Luisman T, Smith T, Ritchie S, Malone KE. Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis. 2021;16(1):300. doi:10.1186/s13023-021-01889-z. PMID: 34229749. PMC8258949.
17. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Chondrodysplasies ponctuées : déficit de la biosynthèse du cholestérol et déficit en arylsulfatase E. Centre de compétences Maladies osseuses constitutionnelles et Centre de référence Anomalies du développement et syndromes malformatifs Sud-Est, Hospices Civils de Lyon [Internet]. Saint-Denis La Plaine: HAS; 2022 Dec 12 [cited 2026 Nov 6]. Available from: https://www.has-sante.fr/jcms/p_3392235
18. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160(2):191-196. doi:10.1001/archinte.160.2.191. PMID: 10647757.
19. ERN BOND — European Reference Network on Rare Bone Diseases. Available from: https://ernbond.eu (accessed 10 Oct 2026).
20. MetabERN — European Reference Network for Hereditary Metabolic Disorders (subnetwork Peroxisomal and lipid-related disorders). Available from: https://metab.ern-net.eu (accessed 10 Oct 2026).
21. ERN-Skin — European Reference Network for rare and complex diseases of the skin. Available from: https://ern-skin.eu (accessed 10 Oct 2026).
22. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Chondrodysplasia punctata, Conradi-Hünermann type (MIM 302960). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 353–6.
23. Jones KL, Jones MC, del Campo M. Chondrodysplasia punctata, X-linked dominant type (Conradi-Hünermann syndrome). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 530–3.
24. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Chondrodysplasia punctata, rhizomelic type (MIM 215100, 222765, 600121). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 360–2.
25. Jones KL, Jones MC, del Campo M. Autosomal recessive chondrodysplasia punctata (chondrodysplasia punctata, rhizomelic type). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 534–5.
26. Sheffield LJ, Danks DM, Mayne V, Hutchinson AL. Chondrodysplasia punctata-23 cases of a mild and relatively common variety. J Pediatr. 1976;89(6):916-923. doi:10.1016/s0022-3476(76)80596-3. PMID: 993917.
27. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Chondrodysplasia punctata, autosomal dominant type (MIM 118650). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 368–70.
28. Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet. 1979;53(1):65-73. doi:10.1007/bf00289453. PMID: 535904.
29. Happle R, Koch H, Lenz W. The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr. 1980;134(1):27-33. doi:10.1007/bf00442399. PMID: 7408908.
30. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome (MIM 308050). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 357–9.
31. Jones KL, Jones MC, del Campo M. CHILD syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 436–7.
32. Maroteaux P. Brachytelephalangic chondrodysplasia punctata: a possible X-linked recessive form. Hum Genet. 1989;82(2):167-170. doi:10.1007/bf00284052. PMID: 2722194.
33. Jones KL, Jones MC, del Campo M. Fetal warfarin syndrome (warfarin embryopathy, fetal coumarin syndrome). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 796–7.
34. Shaul WL, Emery H, Hall JG. Chondrodysplasia punctata and maternal warfarin use during pregnancy. Am J Dis Child. 1975;129(3):360-362. doi:10.1001/archpedi.1975.02120400060014. PMID: 1121966.
35. Pauli RM, Madden JD, Kranzler KJ, Culpepper W, Port R. Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata. J Pediatr. 1976;88(3):506-508. doi:10.1016/s0022-3476(76)80281-8. PMID: 1245966.
36. Warkany J. A warfarin embryopathy?. Am J Dis Child. 1975;129(3):287-288. doi:10.1001/archpedi.1975.02120400005001. PMID: 1121959.
37. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980;68(1):122-140. doi:10.1016/0002-9343(80)90181-3. PMID: 6985765.
38. van Driel D, Wesseling J, Sauer PJ, Touwen BC, van der Veer E, Heymans HS. Teratogen update: fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology. 2002;66(3):127-140. doi:10.1002/tera.10054. PMID: 12210474.
39. Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet. 1987;41(4):566-583. PMID: 3499071. PMC1684308.
40. Menger H, Lin AE, Toriello HV, Bernert G, Spranger JW. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Am J Med Genet. 1997;72(2):129-134. doi:10.1002/(sici)1096-8628(19971017)72:2<129::aid-ajmg2>3.0.co;2-q. PMID: 9382132.
41. Chitayat D, Keating S, Zand DJ, Costa T, Zackai EH, Silverman E, et al. Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases. Am J Med Genet A. 2008;146A(23):3038-3053. doi:10.1002/ajmg.a.32554. PMID: 19006208.
42. Heymans HS, Oorthuys JW, Nelck G, Wanders RJ, Schutgens RB. Rhizomelic chondrodysplasia punctata: another peroxisomal disorder. N Engl J Med. 1985;313(3):187-188. doi:10.1056/nejm198507183130322. PMID: 4010717.
43. Braverman N, Steel G, Obie C, Moser A, Moser H, Gould SJ, et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet. 1997;15(4):369-376. doi:10.1038/ng0497-369. PMID: 9090381.
44. Motley AM, Hettema EH, Hogenhout EM, Brites P, ten Asbroek AL, Wijburg FA, et al. Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor. Nat Genet. 1997;15(4):377-380. doi:10.1038/ng0497-377. PMID: 9090382.
45. Purdue PE, Zhang JW, Skoneczny M, Lazarow PB. Rhizomelic chondrodysplasia punctata is caused by deficiency of human PEX7, a homologue of the yeast PTS2 receptor. Nat Genet. 1997;15(4):381-384. doi:10.1038/ng0497-381. PMID: 9090383.
46. Ofman R, Hettema EH, Hogenhout EM, Caruso U, Muijsers AO, Wanders RJ. Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2. Hum Mol Genet. 1998;7(5):847-853. doi:10.1093/hmg/7.5.847. PMID: 9536089.
47. Barøy T, Koster J, Strømme P, Ebberink MS, Misceo D, Ferdinandusse S, et al. A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Hum Mol Genet. 2015;24(20):5845-5854. doi:10.1093/hmg/ddv305. PMID: 26220973.
48. Braverman N, Lin P, Moebius FF, Obie C, Moser A, Glossmann H, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nat Genet. 1999;22(3):291-294. doi:10.1038/10357. PMID: 10391219.
49. Derry JM, Gormally E, Means GD, Zhao W, Meindl A, Kelley RI, et al. Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com. Nat Genet. 1999;22(3):286-290. doi:10.1038/10350. PMID: 10391218.
50. Kelley RI, Wilcox WG, Smith M, Kratz LE, Moser A, Rimoin DS. Abnormal sterol metabolism in patients with Conradi-Hünermann-Happle syndrome and sporadic lethal chondrodysplasia punctata. Am J Med Genet. 1999;83(3):213-219. doi:10.1002/(sici)1096-8628(19990319)83:3<213::aid-ajmg15>3.0.co;2-c. PMID: 10096601.
51. König A, Happle R, Bornholdt D, Engel H, Grzeschik KH. Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet. 2000;90(4):339-346. doi:10.1002/(sici)1096-8628(20000214)90:4<339::aid-ajmg15>3.0.co;2-5. PMID: 10710235.
52. Grange DK, Kratz LE, Braverman NE, Kelley RI. CHILD syndrome caused by deficiency of 3beta-hydroxysteroid-delta8, delta7-isomerase. Am J Med Genet. 2000;90(4):328-335. doi:10.1002/(sici)1096-8628(20000214)90:4<328::aid-ajmg13>3.0.co;2-f. PMID: 10710233.
53. Franco B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, et al. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell. 1995;81(1):15-25. doi:10.1016/0092-8674(95)90367-4. PMID: 7720070.
54. Paller AS, Teng J, Mazereeuw-Hautier J, Hernández-Martín Á, Granier Tournier C, Hovnanian A, et al. Syndromic epidermal differentiation disorders: a new classification toward pathogenesis-based therapy. Br J Dermatol. 2025;193(4):592-618. doi:10.1093/bjd/ljaf123. PMID: 40184496.
55. Wanders RJA, Engelen M, Vaz FM. Inborn errors of non-mitochondrial fatty acid metabolism including peroxisomal disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 42, sections 42.1 (42.1.1–42.1.5) and 42.3. https://doi.org/10.1007/978-3-662-63123-2_42
56. Itzkovitz B, Jiralerspong S, Nimmo G, Loscalzo M, Horovitz DD, Snowden A, et al. Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3. Hum Mutat. 2012;33(1):189-197. doi:10.1002/humu.21623. PMID: 21990100.
57. Duker AL, Niiler T, Eldridge G, Brereton NH, Braverman NE, Bober MB. Growth charts for individuals with rhizomelic chondrodysplasia punctata. Am J Med Genet A. 2017;173(1):108-113. doi:10.1002/ajmg.a.37961. PMID: 27616591.
58. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Neonatal adrenoleukodystrophy/disorders of peroxisomal biogenesis. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 481–90.
59. Bams-Mengerink AM, Majoie CB, Duran M, Wanders RJ, Van Hove J, Scheurer CD, et al. MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata. Neurology. 2006;66(6):798-803; discussion 789. doi:10.1212/01.wnl.0000205594.34647.d0. PMID: 16567694.
60. Fallatah W, Cui W, Di Pietro E, Carter GT, Pounder B, Dorninger F, et al. A Pex7 Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1. Front Cell Dev Biol. 2022;10:886316. doi:10.3389/fcell.2022.886316. PMID: 35898397. PMC9310236.
61. Sankhe R, Williams MI, Fallatah W, Mackay L, Brown ML, Bhagwat P, et al. Metabolomic Profiling Reveals Brain Lipid Alterations in PEX7-Deficient Models of Rhizomelic Chondrodysplasia Punctata. Biomolecules. 2025;16(1):6. doi:10.3390/biom16010006. PMID: 41594547. PMC12839017.
62. Boulling A, Corbeau J, Grohs C, Barbat A, Mortier J, Taussat S, et al. A bovine model of rhizomelic chondrodysplasia punctata caused by a deep intronic splicing variant in the GNPAT gene. Genet Sel Evol. 2025;57(1):23. doi:10.1186/s12711-025-00969-z. PMID: 40394457. PMC12090490.
63. Waterham HR, Clayton PT. Disorders of isoprenoid/cholesterol synthesis. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 37, sections 37.7 and 37.8. https://doi.org/10.1007/978-3-662-63123-2_37
64. Seeger MA, Paller AS. The role of abnormalities in the distal pathway of cholesterol synthesis in the Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects (CHILD) syndrome. Biochim Biophys Acta. 2014;1841(3):345-352. doi:10.1016/j.bbalip.2013.09.006. PMID: 24060582.
65. Paller AS, van Steensel MA, Rodriguez-Martín M, Sorrell J, Heath C, Crumrine D, et al. Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Invest Dermatol. 2011;131(11):2242-2248. doi:10.1038/jid.2011.189. PMID: 21753784. PMC3193573.
66. Daniele A, Parenti G, d'Addio M, Andria G, Ballabio A, Meroni G. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata. Am J Hum Genet. 1998;62(3):562-572. doi:10.1086/301746. PMID: 9497243. PMC1376941.
67. Matos-Miranda C, Nimmo G, Williams B, Tysoe C, Owens M, Bale S, et al. A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies. Genet Med. 2013;15(8):650-657. doi:10.1038/gim.2013.13. PMID: 23470839.
68. Wainwright H, Beighton P. Warfarin embryopathy: fetal manifestations. Virchows Arch. 2010;457(6):735-739. doi:10.1007/s00428-010-0982-9. PMID: 20922410.
69. Magee E, Kuhnel G, Geetha-Loganathan P. Warfarin-Induced Developmental Toxicity: Insights into Embryogenesis, Teratogenicity, and Molecular Pathways. J Dev Biol. 2026;14(3):34. doi:10.3390/jdb14030034. PMID: 42647228. PMC13511227.
70. Jin DY, Chen X, Wang M, Qi X, Stafford DW, Lewis S, et al. Molecular insights into the comorbidity of vitamin K-dependent clotting factor deficiency and chondrodysplasia punctata. J Thromb Haemost. 2025;23(12):3832-3844. doi:10.1016/j.jtha.2025.08.011. PMID: 40876756. PMC13455504.
71. Braverman N, Steel G, Lin P, Moser A, Moser H, Valle D. PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter. Genomics. 2000;63(2):181-192. doi:10.1006/geno.1999.6080. PMID: 10673331.
72. Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, et al. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat. 2002;20(4):284-297. doi:10.1002/humu.10124. PMID: 12325024.
73. Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, et al. Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet. 2002;70(3):612-624. doi:10.1086/338998. PMID: 11781871. PMC384941.
74. 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. PMC5765404.
75. Brunetti-Pierri N, Andreucci MV, Tuzzi R, Vega GR, Gray G, McKeown C, et al. X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am J Med Genet A. 2003;117A(2):164-168. doi:10.1002/ajmg.a.10950. PMID: 12567415.
76. ClinVar. VCV000021032 — NM_000047.3(ARSL):c.1442C>T (p.Thr481Met). Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/21032/ (accessed 10 Oct 2026).
77. ClinVar. VCV000007780 — NM_000288.4(PEX7):c.875T>A (p.Leu292Ter). Bethesda (MD): National Center for Biotechnology Information. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/7780/ (accessed 10 Oct 2026).
78. ClinVar. VCV000007785 — NM_000288.4(PEX7):c.903+1G>C. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/7785/ (accessed 10 Oct 2026).
79. ClinVar. VCV000190410 — NM_001351132.2(PEX5):c.677dup (p.Val227fs). Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/190410/ (accessed 10 Oct 2026).
80. Sayed J, Gamal A, Theyab A, Algahtani M, Aldaadi BB. Neonatal rhizomelic chondrodysplasia punctata type 2 caused by a novel homozygous variant in the GNPAT gene. Clin Case Rep. 2023;11(6):e7504. doi:10.1002/ccr3.7504. PMID: 37323250. PMC10264737.
81. Yang YD, Dai WS, Zhang YL, Li DZ. Prenatal Diagnosis of X-Linked Chondrodysplasia Punctata 2 Presented with Calcific Stippling in Ribs and Postaxial Polydactyly Identified in the First Trimester: A Case Report. J Med Ultrasound. 2026;34(2):255-257. doi:10.4103/jmu.jmu-d-25-00017. PMID: 42491987. PMC13379174.
82. Zeyrek M, Balan K, Ersoy-Evans S. Bilateral Involvement in CHILD Syndrome Successfully Treated With Cholesterol-Lovastatin Combination. Pediatr Dermatol. 2026;43(5):1220-1223. doi:10.1111/pde.70247. PMID: 42083494.
83. İli EG, Gezdirici A, Di Pietro E, Yergeau C, Braverman N. Expanding the genotypic and phenotypic landscapes of rhizomelic chondrodysplasia punctata type 3 (RCDP3) with two novel families, and a review of the literature. Am J Med Genet A. 2022;188(11):3229-3235. doi:10.1002/ajmg.a.62959. PMID: 35986576.
84. Arnold AW, Bruckner-Tuderman L, Has C, Happle R. Conradi-Hünermann-Happle syndrome in males vs. MEND syndrome (male EBP disorder with neurological defects). Br J Dermatol. 2012;166(6):1309-1313. doi:10.1111/j.1365-2133.2012.10808.x. PMID: 22229330.
85. McLarren KW, Severson TM, du Souich C, Stockton DW, Kratz LE, Cunningham D, et al. Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. Am J Hum Genet. 2010;87(6):905-914. doi:10.1016/j.ajhg.2010.11.004. PMID: 21129721. PMC2997364.
86. Fallatah W, Schouten M, Yergeau C, Di Pietro E, Engelen M, Waterham HR, et al. Clinical, biochemical, and molecular characterization of mild (nonclassic) rhizomelic chondrodysplasia punctata. J Inherit Metab Dis. 2021;44(4):1021-1038. doi:10.1002/jimd.12349. PMID: 33337545.
87. Herman GE, Kelley RI, Pureza V, Smith D, Kopacz K, Pitt J, et al. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med. 2002;4(6):434-438. doi:10.1097/00125817-200211000-00006. PMID: 12509714.
88. Cañueto J, Girós M, Ciria S, Pi-Castán G, Artigas M, García-Dorado J, et al. Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hünermann-Happle syndrome: new insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature. Br J Dermatol. 2012;166(4):830-838. doi:10.1111/j.1365-2133.2011.10756.x. PMID: 22121851.
89. Steijlen PM, van Geel M, Vreeburg M, Marcus-Soekarman D, Spaapen LJ, Castelijns FC, et al. Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome. Br J Dermatol. 2007;157(6):1225-1229. doi:10.1111/j.1365-2133.2007.08254.x. PMID: 17949453.
90. Has C, Bruckner-Tuderman L, Müller D, Floeth M, Folkers E, Donnai D, et al. The Conradi-Hünermann-Happle syndrome (CDPX2) and emopamil binding protein: novel mutations, and somatic and gonadal mosaicism. Hum Mol Genet. 2000;9(13):1951-1955. doi:10.1093/hmg/9.13.1951. PMID: 10942423.
91. Happle R, Effendy I, Megahed M, Orlow SJ, Küster W. CHILD syndrome in a boy. Am J Med Genet. 1996;62(2):192-194. doi:10.1002/(sici)1096-8628(19960315)62:2<192::aid-ajmg14>3.0.co;2-j. PMID: 8882402.
92. Casarin A, Rusalen F, Doimo M, Trevisson E, Carraro S, Clementi M, et al. X-linked brachytelephalangic chondrodysplasia punctata: a simple trait that is not so simple. Am J Med Genet A. 2009;149A(11):2464-2468. doi:10.1002/ajmg.a.33039. PMID: 19839041.
93. Sheffield LJ, Osborn AH, Hutchison WM, Sillence DO, Forrest SM, White SJ, et al. Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata. J Med Genet. 1998;35(12):1004-1008. doi:10.1136/jmg.35.12.1004. PMID: 9863597. PMC1051512.
94. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Chondrodysplasia punctata, brachytelephalangic type (MIM 302950, 602497). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 363–7.
95. Wardinsky TD, Pagon RA, Powell BR, McGillivray B, Stephan M, Zonana J, et al. Rhizomelic chondrodysplasia punctata and survival beyond one year: a review of the literature and five case reports. Clin Genet. 1990;38(2):84-93. doi:10.1111/j.1399-0004.1990.tb03554.x. PMID: 2208770.
96. Abousamra O, Kandula V, Duker AL, Rogers KJ, Bober MB, Mackenzie WG. Cervical Spine Deformities in Children With Rhizomelic Chondrodysplasia Punctata. J Pediatr Orthop. 2019;39(9):e680-e686. doi:10.1097/bpo.0000000000001014. PMID: 31503224.
97. Khanna AJ, Braverman NE, Valle D, Sponseller PD. Cervical stenosis secondary to rhizomelic chondrodysplasia punctata. Am J Med Genet. 2001;99(1):63-66. doi:10.1002/1096-8628(20010215)99:1<63::aid-ajmg1117>3.0.co;2-9. PMID: 11170096.
98. Bams-Mengerink AM, Koelman JH, Waterham H, Barth PG, Poll-The BT. The neurology of rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis. 2013;8:174. doi:10.1186/1750-1172-8-174. PMID: 24172221. PMC4228450.
99. Duker AL, Eldridge G, Braverman NE, Bober MB. Congenital heart defects common in rhizomelic chondrodysplasia punctata. Am J Med Genet A. 2016;170A(1):270-272. doi:10.1002/ajmg.a.37404. PMID: 26408048.
100. Huffnagel IC, Clur SA, Bams-Mengerink AM, Blom NA, Wanders RJ, Waterham HR, et al. Rhizomelic chondrodysplasia punctata and cardiac pathology. J Med Genet. 2013;50(7):419-424. doi:10.1136/jmedgenet-2013-101536. PMID: 23572185.
101. White AL, Modaff P, Holland-Morris F, Pauli RM. Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet A. 2003;118A(4):332-342. doi:10.1002/ajmg.a.20009. PMID: 12687664.
102. Duker AL, Niiler T, Kinderman D, Schouten M, Poll-The BT, Braverman N, et al. Rhizomelic chondrodysplasia punctata morbidity and mortality, an update. Am J Med Genet A. 2020;182(3):579-583. doi:10.1002/ajmg.a.61413. PMID: 31769196.
103. Wolpoe ME, Braverman N, Lin SY. Severe tracheobronchial stenosis in the X-linked recessive form of chondrodysplasia punctata. Arch Otolaryngol Head Neck Surg. 2004;130(12):1423-1426. doi:10.1001/archotol.130.12.1423. PMID: 15611404.
104. Garnier A, Dauger S, Eurin D, Parisi I, Parenti G, Garel C, et al. Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases. Eur J Pediatr. 2007;166(4):327-331. doi:10.1007/s00431-006-0239-4. PMID: 16937129.
105. Broeren E, Stover S, Bennett K, Giordano J, Galloway S, Lauzon J, et al. Prenatal Ultrasonographic Features Associated With ARSL and X-Linked Chondrodysplasia Punctata 1 (CDPX1): Literature Review and Case Series. Prenat Diagn. 2024;44(13):1663-1670. doi:10.1002/pd.6649. PMID: 39313411.
106. Kramer N, Glatzel V, Sander A, Kuna AC, Flaig MJ, Giehl K. [Initial diagnosis of Conradi-Hünermann-Happle syndrome (chondrodysplasia punctata type 2) in adulthood]. Dermatologie (Heidelb). 2026;77(Suppl 1):34-37. doi:10.1007/s00105-026-05695-1. PMID: 42811217.
107. Mason DE, Sanders JO, MacKenzie WG, Nakata Y, Winter R. Spinal deformity in chondrodysplasia punctata. Spine (Phila Pa 1976). 2002;27(18):1995-2002. doi:10.1097/00007632-200209150-00007. PMID: 12634559.
108. Villarreal EG, Chiang J, Propst EJ, Wolter NE. Airway Involvement in Conradi-Hünermann-Happle Syndrome: A Novel Clinical Manifestation. Laryngoscope. 2026;136(7):3240-3245. doi:10.1002/lary.70463. PMID: 41735768. PMC13253157.
109. Chen K, Hu B, Chen Q, Su F, Chen LQ. CHILD syndrome combined linear porokeratosis in a patient with a good response to the topical lovastatin/cholesterol ointment. J Dermatolog Treat. 2025;36(1):2478217. doi:10.1080/09546634.2025.2478217. PMID: 40464756.
110. Wyer J, Moss C, Poudel P, Ibbs S. CHILD syndrome without limb defects in a 1-year-old child: revised nomenclature and successful treatment with topical simvastatin 2%-cholesterol 2%. Clin Exp Dermatol. 2026;51(9):1758-1760. doi:10.1093/ced/llag193. PMID: 42082353.
111. Zhang X, Zhong Z, Wang H, Xue R, Lin Z. A patient with CHILD syndrome mimicking Hailey-Hailey disease: A diagnostic challenge. J Am Acad Dermatol. 2026. Online ahead of print (S0190-9622(26)03292-5). doi:10.1016/j.jaad.2026.08.020. PMID: 42575321.
112. Jantoven (warfarin sodium) tablets [prescribing information]. ANDA040416. Revised 2025 Jul 8. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=19a69a72-ac5d-45d5-a94d-a5aaecbe4730
113. Agarwal M, Phadke SR. Atlantoaxial dislocation in a child affected by warfarin embryopathy: a case report. Clin Dysmorphol. 2013;22(3):124-126. doi:10.1097/mcd.0b013e3283630275. PMID: 23722702.
114. Vogel TW, Menezes AH. Natural history and management of cervical spine disease in chondrodysplasia punctata and coumarin embryopathy. Childs Nerv Syst. 2012;28(4):609-619. doi:10.1007/s00381-012-1694-z. PMID: 22274407.
115. Wesseling J, Van Driel D, Heymans HS, Rosendaal FR, Geven-Boere LM, Smrkovsky M, et al. Coumarins during pregnancy: long-term effects on growth and development of school-age children. Thromb Haemost. 2001;85(4):609-613. doi:10.1055/s-0037-1615641. PMID: 11341493.
116. Hetzel PG, Glanzmann R, Hasler PW, Ladewick A, Bührer C. Coumarin embryopathy in an extremely low birth weight infant associated with neonatal hepatitis and ocular malformations. Eur J Pediatr. 2006;165(6):358-360. doi:10.1007/s00431-005-0064-1. PMID: 16411088.
117. Toriello HV, Erick M, Alessandri JL, Bailey D, Brunetti-Pierri N, Cox H, et al. Maternal vitamin K deficient embryopathy: association with hyperemesis gravidarum and Crohn disease. Am J Med Genet A. 2013;161A(3):417-429. doi:10.1002/ajmg.a.35765. PMID: 23404932.
118. Eash DD, Weaver DD, Brunetti-Pierri N. Cervical spine stenosis and possible vitamin K deficiency embryopathy in an unusual case of chondrodysplasia punctata and an updated classification system. Am J Med Genet A. 2003;122A(1):70-75. doi:10.1002/ajmg.a.20242. PMID: 12949976.
119. Alessandri JD, Ramful D, Cuillier F. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency. Clin Dysmorphol. 2010;19(2):85-87. doi:10.1097/mcd.0b013e328335c14a. PMID: 20177377.
120. Brunetti-Pierri N, Hunter JV, Boerkoel CF. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency?. Am J Med Genet A. 2007;143A(2):200-204. doi:10.1002/ajmg.a.31573. PMID: 17163521.
121. Shanske AL, Bernstein L, Herzog R. Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature. Pediatrics. 2007;120(2):e436-41. doi:10.1542/peds.2006-2997. PMID: 17671048.
122. Jacob A, Raman A, Jinkala SR, Vellathussery Chakkalakkoombil S, Gowda M. Brachytelephalangic Chondrodysplasia Punctata Phenotype in Prenatally Diagnosed VKCFD1: A Novel GGCX Variant. Prenat Diagn. 2025 Oct. Epub ahead of print. doi:10.1002/pd.6903. PMID: 41030118.
123. Deng Q, Wang W, Wang M, Wu Y, Jin Y, Zhou X, et al. Fetal chondrodysplasia punctata: a clinical study of five cases. Am J Transl Res. 2026;18(4):3182-3189. doi:10.62347/xmjv3287. PMID: 42170480. PMC13186731.
124. Andrietti S, Maccarrone A, Gullo G, Billone V, De Paola L, Gaggero C, et al. Prenatal Ultrasound Diagnosis of Binder Phenotype: Case Series of Seven Patients and Literature Review. Reports (MDPI). 2025;8(3):188. doi:10.3390/reports8030188. PMID: 41003474. PMC12473893.
125. Firth HV, Hurst JA. Cataract. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 88–91.
126. Firth HV, Hurst JA. Nasal anomalies. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 242–5.
127. Saudubray JM, García-Cazorla Á. Clinical approach to inborn errors of metabolism in paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, sections 1.1 (Table 1.1) and 1.6.12 (Table 1.43). https://doi.org/10.1007/978-3-662-63123-2_1
128. Sakuraba S, Adachi H, Kato A, Arai H. Neurogenic Shock Secondary to Atlantoaxial Subluxation in an Infant With Chondrodysplasia Punctata. Pediatr Int. 2026;68(1):e70547. doi:10.1111/ped.70547. PMID: 42706949. PMC13551249.
129. Firth HV, Hurst JA. Drugs in pregnancy. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 718–21.
130. Mathijssen IB, Henneman L, van Eeten-Nijman JM, Lakeman P, Ottenheim CP, Redeker EJ, et al. Targeted carrier screening for four recessive disorders: high detection rate within a founder population. Eur J Med Genet. 2015;58(3):123-128. doi:10.1016/j.ejmg.2015.01.004. PMID: 25641760.
131. De Biase I, Yuzyuk T, Cui W, Zuromski LM, Moser AB, Braverman NE. Quantitative analysis of ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry for diagnosing peroxisome biogenesis disorders. Clin Chim Acta. 2023;542:117295. doi:10.1016/j.cca.2023.117295. PMID: 36914043.
132. O'Connor C, Bussmann N, Mhaolcatha SN, Heffron C, O'Shea S. Early Skin Biopsy in Conradi-Hünermann-Happle Syndrome (X-Linked Dominant Chondrodysplasia Punctata). J Cutan Pathol. 2025;52(10):597-600. doi:10.1111/cup.14837. PMID: 40889793. PMC12401640.
133. Nino M, Matos-Miranda C, Maeda M, Chen L, Allanson J, Armour C, et al. Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet A. 2008;146A(8):997-1008. doi:10.1002/ajmg.a.32159. PMID: 18348268.
134. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Greenberg dysplasia (MIM 215140). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 351–2.
135. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Chondrodysplasia punctata, tibia-metacarpal type (MIM 118651). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 371–4.
136. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Keutel syndrome (MIM 245150). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 375.
137. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Spondylometaepiphyseal dysplasia, short limb–abnormal calcification type (MIM 271665). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 183–8.
138. Weaver KN, El Hallek M, Hopkin RJ, Sund KL, Henrickson M, Del Gaudio D, et al. Keutel syndrome: report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis. Am J Med Genet A. 2014;164A(4):1062-1068. doi:10.1002/ajmg.a.36390. PMID: 24458983.
139. Sareli P, England MJ, Berk MR, Marcus RH, Epstein M, Driscoll J, et al. Maternal and fetal sequelae of anticoagulation during pregnancy in patients with mechanical heart valve prostheses. Am J Cardiol. 1989;63(20):1462-1465. doi:10.1016/0002-9149(89)90008-8. PMID: 2729133.
140. Schaefer C, Hannemann D, Meister R, Eléfant E, Paulus W, Vial T, et al. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb Haemost. 2006;95(6):949-957. doi:10.1160/th06-02-0108. PMID: 16732373.
141. D'Souza R, Ostro J, Shah PS, Silversides CK, Malinowski A, Murphy KE, et al. Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis. Eur Heart J. 2017;38(19):1509-1516. doi:10.1093/eurheartj/ehx032. PMID: 28329059. PMC5429939.
142. van Hagen IM, Roos-Hesselink JW, Ruys TP, Merz WM, Goland S, Gabriel H, et al. Pregnancy in Women With a Mechanical Heart Valve: Data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation. 2015;132(2):132-142. doi:10.1161/circulationaha.115.015242. PMID: 26100109.
143. van der Zande JA, Ramlakhan KP, Sliwa K, Gnanaraj JP, Al Farhan H, Malhamé I, et al. Pregnancy with a prosthetic heart valve, thrombosis, and bleeding: the ESC EORP Registry of Pregnancy and Cardiac disease III. Eur Heart J. 2026;47(11):1318-1335. doi:10.1093/eurheartj/ehaf265. PMID: 40237423. PMC13016632.
144. Arici S, Yildirim AI, Keskin GY, Genc FA, Tas E, Corbacioglu S, et al. Long-term pediatric outcomes after first-trimester exposure to low-dose warfarin plus enoxaparin versus enoxaparin alone in pregnancies with mechanical heart valves: the KYBELE children study. BMC Cardiovasc Disord. 2026;26(1):429. doi:10.1186/s12872-026-05837-2. PMID: 41957566. PMC13202826.
145. Rallapalli A, Kulandaisami M, Goraya J, Sankhyan N. Chondrodysplasia Punctata: A Diagnostic Clue for Zellweger Spectrum Disorder. Indian J Pediatr. 2025;92(11):1222-1223. doi:10.1007/s12098-025-05803-4. PMID: 41114783.
146. European Medicines Agency. Orphan designations — medicines data. Amsterdam: EMA. Available from: https://www.ema.europa.eu/en/documents/report/medicines-output-orphan_designations-json-report_en.json (accessed 10 Oct 2026).
147. De Backer J, Haugaa KH, Hasselberg NE, de Hosson M, Brida M, Castelletti S, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J. 2025;46(43):4462-4568. doi:10.1093/eurheartj/ehaf193. PMID: 40878294.
148. Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP, Gentile F, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e72-e227. doi:10.1161/cir.0000000000000923. PMID: 33332150.
149. Bose M, Anglade TC, Donlon CI, Kerrihard AL, Berger HF, Berkowitz AS, et al. Development and evaluation of RhizoQOL, a quality-of-life caregiver-reported survey for rhizomelic chondrodysplasia punctata, a rare peroxisomal disorder. Orphanet J Rare Dis. 2025;20(1):147. doi:10.1186/s13023-025-03660-0. PMID: 40165314. PMC11956500.
150. Lykissas MG, Sturm PF, McClung A, Sucato DJ, Riordan M, Hammerberg KW. Challenges of spine surgery in patients with chondrodysplasia punctata. J Pediatr Orthop. 2013;33(7):685-693. doi:10.1097/bpo.0b013e31829e86a9. PMID: 23836071.
151. Otsuka K, Watanabe K, Suzuki S, Ozaki M, Ozaki M, Nagoshi N, et al. Severe Kyphosis with Os Odontoideum in Chondrodysplasia Punctata and the Case for Occipitocervical Fusion: A Case Report. JBJS Case Connect. 2025;15(1):. doi:10.2106/jbjs.cc.24.00580. PMID: 40112088.
152. Bergqvist C, Abdallah B, Hasbani DJ, Abbas O, Kibbi AG, Hamie L, et al. CHILD syndrome: A modified pathogenesis-targeted therapeutic approach. Am J Med Genet A. 2018;176(3):733-738. doi:10.1002/ajmg.a.38619. PMID: 29392821.
153. Kallis P, Bisbee E, Garganta C, Schoch JJ. Rapid improvement of skin lesions in CHILD syndrome with topical 5% simvastatin ointment. Pediatr Dermatol. 2022;39(1):151-152. doi:10.1111/pde.14865. PMID: 34787337.
154. INFARMED – Autoridade Nacional do Medicamento e Produtos de Saúde. Infomed: database of medicinal products for human use. Varfine (warfarin), tablet, 5 mg; marketing authorisation holder Teofarma, S.r.l.; marketing authorisation status: authorised; marketed. Available from: https://extranet.infarmed.pt/INFOMED-fo/pesquisa-avancada.xhtml (search by active substance «varfarina»). Accessed 2026 Oct 10.
155. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos: medicamentos registrados no Brasil (DADOS_ABERTOS_MEDICAMENTOS.csv), warfarin sodium registrations — Marevan (Farmoquímica S/A, registration 103900147, active), Marfarin (Laboratório Teuto Brasileiro, active), generics (Teuto; União Química, active), Coumadin (Bristol-Myers Squibb, inactive). Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv. Accessed 2026 Oct 10.
156. Med-Life Discoveries. MLD announces positive first-in-human Phase I results of its synthetic plasmalogen precursor drug PPI-1011 [press release]. Saskatoon (SK): Med-Life Discoveries; 2025 Mar 17. Available from: https://www.biospace.com/press-releases/mld-announces-positive-first-in-human-phase-i-results-of-its-synthetic-plasmalogen-precursor-drug-ppi-1011
157. Med-Life Discoveries LP. A Phase 1, Randomized, Double-blind, Placebo-controlled, Combined Single and Multiple Ascending Dose Study of PPI-1011 in Subjects to Assess Safety, Tolerability, and Pharmacokinetics. ClinicalTrials.gov identifier: NCT05969977. Available from: https://clinicaltrials.gov/study/NCT05969977 (accessed 10 Oct 2026).
158. Smith T, Knudsen KJ, Ritchie SA. First-In-Human Safety, Tolerability, and Pharmacokinetics of PPI-1011, a Synthetic Plasmalogen Precursor. Clin Transl Sci. 2025;18(3):e70195. doi:10.1111/cts.70195. PMID: 40083139. PMC11906485.
159. Med-Life Discoveries LP. A Prospective Natural History Study of Patients With Rhizomelic Chondrodysplasia Punctata (RCDP). ClinicalTrials.gov identifier: NCT04031287. Available from: https://clinicaltrials.gov/study/NCT04031287 (accessed 10 Oct 2026).
160. Nemours Children's Clinic. Rhizomelic Chondrodysplasia Punctata Registry at Nemours Children's Health. ClinicalTrials.gov identifier: NCT04569162. Available from: https://clinicaltrials.gov/study/NCT04569162 (accessed 10 Oct 2026).
161. McGill University Health Centre. Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD). ClinicalTrials.gov identifier: NCT01668186. Available from: https://clinicaltrials.gov/study/NCT01668186 (accessed 10 Oct 2026).
162. Fallatah W, Smith T, Cui W, Jayasinghe D, Di Pietro E, Ritchie SA, et al. Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata. Dis Model Mech. 2020;13(1):dmm042499. doi:10.1242/dmm.042499. PMID: 31862688. PMC6994958.
163. Morishima N, Takeuchi S, Nakamura Y, Nagafuji M, Hitaka D, Kanai Y, et al. Ultrasound for evaluation of atlantoaxial instability in neonates with chondrodysplasia punctata. Pediatr Neonatol. 2026;67(4):449-451. doi:10.1016/j.pedneo.2026.04.003. PMID: 42203567.
164. Bhanudeep S, Reddy R. Neonatal X-linked recessive chondrodysplasia punctata. QJM. 2026;119(6):505-506. doi:10.1093/qjmed/hcaf268. PMID: 41172261.
165. Matsuda R, Nakamura T, Fukuda K, Enokizono M, Tsujioka Y, Kono M, et al. A Male Infant With Chondrodysplasia Punctata Presenting With Apnea and Growth Faltering: A Case Report. J Paediatr Child Health. 2026;62(7):1283-1287. doi:10.1111/jpc.70418. PMID: 42104561. PMC13378315.
166. A R, Vellingiri B, Peer S, Wander A. Novel PEX7 gene variant-associated rhizomelic chondrodysplasia punctata type 1: a clinico-radio-biochemical diagnosis. BMJ Case Rep. 2026;19(5):e270700. doi:10.1136/bcr-2025-270700. PMID: 42173544.
167. Qurat Ul Ain, Halim A, Shabbir A, Marriam A. A diagnostic and management odyssey of a rare case of rhizomelic chondrodysplasia punctata. J Pak Med Assoc. 2025;75(8):1287-1289. doi:10.47391/jpma.21660. PMID: 40851144.
168. Corbella-Bagot L, Ivars M, Montenegro L, Casas-Alba D, Morón JA, Olival J, et al. X-linked dominant chondrodysplasia punctata (CDPX2): A rare case of male mosaicism with atypical dermatological manifestations. J Dtsch Dermatol Ges. 2025;23(9):1161-1163. doi:10.1111/ddg.15772. PMID: 40583375.
169. OrphanAnesthesia. Published guidelines [Internet]. Available from: https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines.html (accessed 10 Oct 2026).
170. R Sousa A, Barreira R, Santos E. Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome. BMJ Case Rep. 2018;2018:bcr-2017-223159. doi:10.1136/bcr-2017-223159. PMID: 29627779. PMC5893982.
171. Ferreira S, Costa R, Malveiro D, Vieira F, Tuna M. Warfarin embryopathy: Balancing maternal and fetal risks with anticoagulation therapy. Pediatr Neonatol. 2018;59(5):534-535. doi:10.1016/j.pedneo.2018.02.005. PMID: 29501347.
172. ERN ITHACA — European Reference Network [Internet]. Available from: https://www.ern-ithaca.eu (accessed 10 Oct 2026).
173. RhizoKids International. Available from: https://www.rhizokids.org (accessed 10 Oct 2026).
174. Global Foundation for Peroxisomal Disorders. Available from: https://www.thegfpd.org (accessed 10 Oct 2026).
175. Foundation for Ichthyosis & Related Skin Types (FIRST). Available from: https://www.firstskinfoundation.org (accessed 10 Oct 2026).