Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form. See 118650 for a possible autosomal dominant form ... Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form. See 118650 for a possible autosomal dominant form of CDP. There are 2 brachytelephalangic forms of CDP: an X-linked recessive form (CDPX1; 302950), caused by mutation in the ARSE gene (300180), and a possible autosomal form (BCDP; 602497). There is also an autosomal dominant tibia-metacarpal type (118651). In addition, CDP can be caused by maternal vitamin K deficiency or warfarin teratogenicity (see 118650).
CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts, and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling, and craniofacial defects (Derry ... CDPX2 patients display skin defects including linear or whorled atrophic and pigmentary lesions, striated hyperkeratosis, coarse lusterless hair and alopecia, cataracts, and skeletal abnormalities including short stature, rhizomelic shortening of the limbs, epiphyseal stippling, and craniofacial defects (Derry et al., 1999). A higher ratio of females to males (36:7) was noted by Spranger et al. (1971) in one type of this disorder, termed type B, and defined as 'moderately affected patients with...asymmetric skeletal changes, occasional cataracts and skin changes.' Because some patients with chondrodysplasia punctata show widespread atrophic and pigmentary lesions of the skin in a linear or whorled pattern, Happle et al. (1977) proposed that these cases may be inherited as an X-linked dominant lethal in hemizygous males. Happle (1979) reviewed 35 cases, all female. The phenotype had mosaic features consistent with lyonization. Bergstrom et al. (1972) described a mother and son with chondrodysplasia punctata. The mother was born with short femora and humeri, the left leg shorter than the right, saddle nose, frontal bossing, flexion contractures at the hips and knees, left talipes equinovarus and hyperkeratosis with erythema of the left side of the body. The son lived only 1 hour. Happle and Kuchle (1983) pictured a sectorial cataract in a woman with X-linked dominant chondrodysplasia punctata and proposed that this reflected lyonization. Manzke et al. (1980) reported 3 affected girls. Two of their mothers showed a mild form of cicatricial alopecia. The pathognomonic dermatologic findings in the children included erythematous skin changes and striated ichthyosiform hyperkeratosis during the first months of life. Later, patterned ichthyosis, follicular atrophoderma, coarse lusterless hair, and cicatricial alopecia become evident. Manzke et al. (1980) estimated that about one-fourth of reported cases are of the X-linked dominant variety. The X-linked dominant form of chondrodysplasia punctata is lethal in the hemizygous male and, in females, shows a pattern of skin defects consistent with functional X-chromosomal mosaicism; the variability in severity and the marked asymmetry of bone and eye changes may have a similar explanation. Cerebral involvement does not seem to occur. The X-linked recessive form is clinically mild but has cerebral involvement. Kalter et al. (1989) described a family first identified through the birth of a scaly, erythrodermic female neonate whose mother and maternal great-grandmother had features that allowed the diagnosis to be made. Only after 5 months did the streaky hyperkeratotic pattern characteristic of the disorder appear. Family members bore other stigmata including patchy cicatricial alopecia, coarse hair, follicular atrophoderma, frontal bossing, cataracts, short stature, and short proximal limbs. Decreased peroxisomal enzyme activity was demonstrated on fibroblast cultures. Sutphen et al. (1995) described a family with Happle syndrome in 3 successive generations. Three of the affected individuals were females: the grandmother, daughter, and granddaughter. The fourth affected individual was a male in the second generation who was found to be severely affected but represented the first known male patient with X-linked dominant chondrodysplasia punctata. His survival was attributable to the presence of a 47,XXY karyotype. This affected male died at age 31 years due to restricted pulmonary disease secondary to severe kyphoscoliosis. He attained a height of 147.5 cm after orthopedic surgery. Physical findings showed severe skeletal anomalies, including asymmetric skull with hypoplastic right face, short neck, kyphoscoliosis, shortness of the right upper and lower limbs, short right third digit, and dislocation of the head of the right radius. He also had patchy cicatricial alopecia, right cataract, and right esotropia. Intelligence was borderline; his IQ was 83 at age 5 years and 77 at age 11 years. Although Sutphen et al. (1995) suggested that their male with XXY Klinefelter syndrome was the first known case of Happle syndrome in a man, Happle (1995) pointed to reports of 3 unrelated males with this disorder, at least 2 of whom had chromosome studies showing 46,XY karyotype. Contrasting with the XXY male reported by Sutphen et al. (1995), such cases can best be explained either by postzygotic mutation or by a gametic half-chromatid mutation as proposed for other X-linked dominant traits such as incontinentia pigmenti (Lenz, 1975). Bruch et al. (1995) described the case of a 32-year-old woman with ichthyotic skin lesions that developed during early childhood and persisted into adulthood. Psoriasiform skin changes became evident for the first time during adulthood. Both the ichthyotic and psoriasiform skin lesions followed Blaschko lines. Usually in X-linked dominant chondrodysplasia punctata, punctate epiphyseal calcifications and ichthyotic skin lesions are both transient, resolving during early infancy. The coexistence of the 2 forms of skin change in the adult was unusual. Shirahama et al. (2003) noted that anticipation was a striking clinical feature of CDPX2 in the studies of Sutphen et al. (1995) and Traupe et al. (1992) and suggested that skewed methylation may have a role in this phenomenon; see 300205.0012. Kozlowski et al. (2002) presented 2 cases of nonrhizomelic lethal X-linked dominant chondrodysplasia punctata. The mother of 1 of the patients had bone dysplasia consistent with the X-linked dominant form of chondrodysplasia punctata. She had always been smaller than her peers, and spinal curvature, which had been recognized in early childhood, had progressed. By adulthood, she had a gross kyphoscoliosis and was 152 cm in height, with relative truncal shortening. Vertebral wedging was maximal in the lower thoracic spine. The vertebral bodies above and below this region were found to be comparatively normal. The distal end of the left ulna was dysplastic, as was the right femoral head. The left fourth metacarpal was short. A firm diagnosis would not have been possible on the basis of the radiologic findings in the mother alone. In the case of the infant there had been no maternal exposure to embryopathic agents, and, in particular, no warfarin therapy had been given. The infant died at approximately 1 hour of age. Ausavarat et al. (2008) reported 2 unrelated Thai girls with CDPX2 confirmed by genetic analysis. The first girl presented in infancy with asymmetric limb shortening, flat face, saddle nose, and cataracts. She had hyperkeratotic brownish plaques on the lower extremities following the lines of Blaschko and generalized brownish scales sparing the scalp, face, palms, soles, and inguinal area. Radiographs showed generalized punctate calcifications of the epiphyseal regions of long bones, vertebrae, and the pelvic bone. The second girl first presented at age 13 years. She had short stature, asymmetric limb shortening, postaxial polydactyly, pronounced kyphoscoliosis, dry and scaly skin, sparse hair with areas of alopecia, and cataracts. There were atrophic linear skin lesions following the lines of Blaschko mostly on the extremities. Her mother, who also carried the mutation, had sparse hair and atrophic linear skin lesions following the lines of Blaschko. She did not manifest cataracts, polydactyly, scoliosis, or asymmetric limb shortening. Ausavarat et al. (2008) noted that incomplete penetrance has been reported and suggested that the variable expressivity may reflect different patterns of X inactivation.
In 7 unrelated patients with CDPX2, Derry et al. (1999) identified mutations in the EBP gene (e.g., 300205.0001-300205.0002). Braverman et al. (1999) found mutations in the EBP gene in all 7 cases of chondrodysplasia punctata studied (e.g., 300205.0003). ... In 7 unrelated patients with CDPX2, Derry et al. (1999) identified mutations in the EBP gene (e.g., 300205.0001-300205.0002). Braverman et al. (1999) found mutations in the EBP gene in all 7 cases of chondrodysplasia punctata studied (e.g., 300205.0003). None of the mutations were identical to those found by Derry et al. (1999). Braverman et al. (1999) pointed out that the phenotype in CDPX2 females ranges from stillborn to mildly affected individuals identified in adulthood. No correlation between the nature of the mutation and the phenotype was evident. Ikegawa et al. (2000) screened the EBP gene for mutations in 5 individuals with CDPX2 and 3 individuals with chondrodysplasia punctata without extraskeletal (cutaneous and ocular) manifestations of CDPX2. EBP mutations (3 nonsense and 2 missense) were identified in all 5 individuals with CDPX2 but in none of the non-CDPX2 individuals. The authors concluded that EBP mutations that produce truncated proteins result in typical CDPX2, whereas phenotypes resulting from missense mutations are not always typical for CDPX2. Herman et al. (2002) searched for mutations in 26 females with suspected CDPX2. Mutations in the EBP gene were identified in 22 of the 26 females studied, including 20 of the 22 patients who demonstrated an abnormal sterol profile. Thirteen of the mutations were novel. Affected females had typical skin manifestations and all but 1 had skeletal dysplasia. Herman et al. (2002) concluded that plasma sterol analysis was a highly specific and sensitive indicator of the presence of an EBP mutation in females with suspected CDPX2, including a clinically unaffected mother of a sporadic case. No clear genotype/phenotype correlations were ascertained, probably because phenotypic expression is influenced substantially by the pattern of X-inactivation in an affected female.
Specific diagnostic criteria for X-linked chondrodysplasia punctata (CDPX2) have not been published. The clinical diagnosis rests on the presence of a number of the following features. The clinical findings are highly variable, secondary principally to random X-chromosome inactivation, often with more severe presentations in newborns and infants and milder findings, including short stature only, in affected older children and adults....
DiagnosisClinical Diagnosis Specific diagnostic criteria for X-linked chondrodysplasia punctata (CDPX2) have not been published. The clinical diagnosis rests on the presence of a number of the following features. The clinical findings are highly variable, secondary principally to random X-chromosome inactivation, often with more severe presentations in newborns and infants and milder findings, including short stature only, in affected older children and adults.Females. Clinical features of CDPX2 include:Growth deficiency/short statureCraniofacial appearanceFrontal bossingFlat nasal bridgeSparse eyebrows and lashes, often asymmetricSkeletalStippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea and distal ends of the ribs seen on x-ray. This is the main criterion for diagnosis of this disorder in infants. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification occurs during childhood (see Figure 1). Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetricPostaxial polydactyly in up to 5% of individuals. Polydactyly appears to be most common in CDPX2 among the various types of chondrodysplasia punctata.Scoliosis, occasionally congenital Skin, hair, and nailsScaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of X-chromosome inactivation) that usually resolves in the first months of life. This may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (See Figure 2)Coarse hair with scarring alopecia (See Figure 3)Occasional flattened or split nails with normal teethOcularCataracts (in ~2/3; 67%), often congenital, asymmetric and/or sectorial Microphthalmia and/or microcorneaOccasional malformations (<10% of patients)Sensorineural or conductive hearing loss Cleft palateCongenital heart diseaseRenal malformations, including hydronephrosisCNS malformations, including Dandy-Walker variant malformation; uncommon in females but usually present in affected males, especially posterior fossa defects Intelligence. Typically normalFigureFigure 1. Radiographs from a female infant with CDPX2 demonstrating epiphyseal stippling (chondrodysplasia punctata) Radiograph originally published in Herman [2000]; reproduced with permission from Elsevier Ltd. FigureFigure 2. A. Typical skin findings of CDPX2 at birth, including scaling and an erythematous eruption that follows lines of X-chromosome inactivation. B. Later hyperpigmentation over the back in a two-month-old female Photographs originally (more...)FigureFigure 3. Scarring, patchy alopecia in a female with CDPX2 Photograph originally published in Herman [2000]; reproduced with permission from Elsevier Ltd. Males. Classic features of CDPX2 have been reported in:A male with a 47,XXY karyotype [Sutphen et al 1995] Males who have not had molecular characterization [Crovato & Rebora 1985, Hochman & Fee 1987, De Raeve et al 1989, Tronnier et al 1992, Omobono & Goetsch 1993] Several males with somatic mosaicism [Aughton et al 2003, Tan et al 2010] A total of 11 males with non-mosaic EBP mutations and/or diagnostic sterol abnormalities have been reported with a distinct, primarily neurologic phenotype [Milunsky et al 2003, Kelley et al 2005, Furtado et al 2010, Tan et al 2010] that includes:NeurologicHypotoniaModerate to profound developmental delaySeizuresCerebellar (primarily vermis) hypoplasia and/or Dandy Walker variant malformationAgenesis of the corpus callosumFacial dysmorphismsHypertelorismTelecanthusHigh or prominent nasal bridgeLow-set earsMicrognathiaLarge anterior fontanelOther malformations. Cryptorchidism, hypospadias, pelvocalcyeal obstruction, postaxial polydactyly, 2-3 toe syndactyly, VSD, and ASDFeatures of classic CDPX2. Cataracts and ichthyosisTestingBiochemical testing. Sterol analysis of plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts is used for diagnosis. Increased concentrations of 8(9)-cholestenol and 8-dehydrocholesterol are essentially diagnostic of CDPX2 [Kelley et al 1999] (Table 1). Table 1. Concentrations of 8(9)-Cholestenol and 8-Dehydrocholesterol Observed in CDPX2View in own windowAnalyteCDPX2 NormalPlasma 8(9)-cholestenol 0.18—186 μg/mL<0.01 μg/mL (for neonates age 1-2 days)Plasma 8-dehydrocholesterol<0.01—138 μg/mL<0.01 μg/mL (for neonates age 1-2 days)Data from 105 females with presumed CDPX2 [R Kelley, personal communication]Molecular Genetic Testing Gene. EBP, encoding 3β-hydroxysteroid-Δ8, Δ7-isomerase, is the only gene in which mutations are known to cause CDPX2 [Braverman et al 1999, Derry et al 1999].Clinical testing Sequence analysis of the four EBP coding exons and flanking intron sequences identifies a mutation in 85%-95% of females with a clinical diagnosis of CDPX2 and approximately 91% of females with an abnormal sterol profile [Has et al 2000, Herman et al 2002]. Tan et al [2010] identified a mutation in four of four males who had abnormal biochemical results. Sequence analysis does not identify deletions in females with CDPX2; however, to date no deletions have been identified in females with this disorder. Note: The only deletions described are in females with focal dermal hypoplasia and large deletions that include EBP and PORCN. These females do not have features of CDPX2 [Porter & Herman 2011]. Table 2. Summary of Molecular Genetic Testing Used in Chondrodysplasia Punctata 2, X-Linked View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMalesHeterozygous FemalesEBPSequence analysis / mutation scanning 2Sequence variants 3Unknown 4, 590% 6Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 5. Includes the mutation detection frequency using deletion/duplication analysis.6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a probandRadiographs showing stippling of the epiphyses of long bones and vertebrae suggest the diagnosis of CDPX2.Biochemical testing revealing an increased concentration of 8(9)-cholestenol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts is diagnostic. Molecular genetic testing using sequence analysis for EBP mutations confirms the diagnosis, especially when biochemical results are equivocal. Testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Females are heterozygotes for this X-linked male lethal disorder. (2) Identification of the disease-causing mutation in females requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected relative is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Note: Prenatal diagnosis by measurement of 8(9)-cholestenol and 8-dehydrocholesterol is also possible; the risk for a false negative result has not been determined. Genetically Related (Allelic) Disorders As noted above, rare males with a 46, XY karyotype and non-mosaic, presumably hypomorphic, mutation in EBP have been reported with a phenotype distinct from CDPX2. Grange et al [2000] reported an EBP mutation in a female with phenotypic features more suggestive of CHILD syndrome (see NSDHL-Related Disorders), although Happle et al [2000] have argued that the skin findings in this case more accurately represent CDPX2 with extensive asymmetry.
At least 95% of individuals with X-linked chondrodysplasia punctata 2 (CDPX2) are female. The clinical phenotypes in heterozygous females are highly variable and depend on the pattern of X-chromosome inactivation in relevant tissues (i.e., percentage of wild-type versus mutant active X chromosomes), as well as the exact mutation, and other possible modifying factors. Phenotypes range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including adults with no recognizable physical abnormalities. Severity in females varies greatly within families and among individuals with the same mutation, as would be expected for a pathologic process determined, in part, by the random process of X-chromosome inactivation. ...
Natural History At least 95% of individuals with X-linked chondrodysplasia punctata 2 (CDPX2) are female. The clinical phenotypes in heterozygous females are highly variable and depend on the pattern of X-chromosome inactivation in relevant tissues (i.e., percentage of wild-type versus mutant active X chromosomes), as well as the exact mutation, and other possible modifying factors. Phenotypes range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including adults with no recognizable physical abnormalities. Severity in females varies greatly within families and among individuals with the same mutation, as would be expected for a pathologic process determined, in part, by the random process of X-chromosome inactivation. Although CDPX2 was for many years presumed to be lethal in males, a small number of affected males have been reported [Crovato & Rebora 1985, Hochman & Fee 1987, De Raeve et al 1989, Tronnier et al 1992, Omobono & Goetsch 1993, Sutphen et al 1995, Aughton et al 2003]. Sutphen et al [1995] describe a male with CDPX2 and a 47,XXY karyotype. Aughton et al [2003] describe a male who is mosaic for the mutation c.238G>A (p.Glu80Lys), which has been reported in affected females. Tan et al [2010] describe three males with novel EBP mutations identified in the mosaic state. The clinical characteristics of males with mosaic EBP mutations are well within the marked variability described in affected females.In addition, Milunsky et al [2003] and Furtado et al [2010] reported a neurologic phenotype, distinct from that found in CDPX2, in males with a hemizygous missense EBP mutation. Of the 11 hemizygous or presumed hemizygous males with CDPX2 known to the authors, all have had moderate to severe developmental delay and almost all have clinically important CNS malformations, most notable Dandy-Walker variant, agenesis of the corpus callosum, and major gyral abnormalities. Other unique findings include facial dysmorphisms, skeletal findings (2-3 toe syndactyly, postaxial polydactyly) and urogenital findings (cryptorchidism, hypospadias). Many hemizygous males have chronic ichthyosis, but, as would be predicted, not in patchy distributions. Growth deficiency/short stature. Individuals with CDPX2 have short stature. Reported heights range from the10th-25th percentile to six standard deviations below the mean. Craniofacial appearance. The face and head are often asymmetric. Most individuals with CDPX2 have a flattened nasal bridge and frontal bossing. Other distinctive features include downslanting palpebral fissures, ocular hypertelorism, low-set ears, and high-arched palate [Happle 1979, Herman 2000].Skeletal. Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae and tracheal cartilage and otherwise widespread is seen on x-rays in almost 100% of symptomatic infants; however, this could reflect bias of ascertainment. Approximately 90% of individuals have asymmetric shortening of limbs (occasionally symmetric), involving mostly the femur, humerus, and other tubular bones [Happle 1979]. Moderate to severe kyphoscoliosis is common and can present in infancy or early childhood. Spinal deformities can progress rapidly; in addition, progressive deformity following surgical vertebral fusion is common [Mason et al 2002]. Contractures, other joint abnormalities, dislocated patella, and postaxial polydactyly have also been reported [Happle 1979, Herman 2000].Skin, hair, and nails. Scaling ichthyosis, present in newborns in a linear or blotchy pattern, usually resolves in the first weeks or months of life. This erythematous eruption seen at birth often follows the lines of X-chromosome inactivation (i.e., the lines of Blaschko) and has a feather-like edge, but total scaling erythroderma also occurs. As this rash fades, it leaves in a linear or whorled pattern areas of atrophoderma predominantly near hair follicles where scales had been located. Some individuals also have ichthyosis and/or pigmentary abnormalities that persist into childhood. Hair findings include scarring alopecia in patches, sparse eyelashes and eyebrows, and coarse, lusterless hair. Minor nail findings include flattening and splitting of the nail plates [Happle 1979, Herman 2000, Hoang et al 2004]. Ocular. Approximately two thirds of individuals have cataracts at birth or develop them early in life. Cataracts are usually unilateral, asymmetric, and/or sectorial [Happle 1979, Happle 1981, Herman et al 2002]. Other eye findings include microphthalmia and/or microcornea.Neurologic. Intelligence is typically normal in affected individuals unless a CNS malformation is present. Other (rarely seen) neurologic findings can include microcephaly, seizures, and tethered cord [Herman et al 2002].Ear anomalies and hearing. Rarely, dysplastic auricles and sensorineural hearing loss have been reported in affected individuals [Happle 1979, Herman et al 2002].Other findings. Individuals with CDPX2 may also have bilateral or unilateral clubfoot and renal or cardiac malformations [Happle 1979, Herman et al 2002]. Hydronephrosis has been seen in several affected girls.Mortality. Typically life expectancy is normal in individuals with CDPX2 as long as severe scoliosis has not compromised heart and lung function.
There are no confirmed genotype/phenotype correlations. ...
Genotype-Phenotype Correlations There are no confirmed genotype/phenotype correlations. Ikegawa et al [2000] suggested that EBP mutations resulting in truncated proteins cause typical CDPX2 manifestations including skeletal, skin, and ocular findings, while missense mutations may result in a milder phenotype lacking some of these classic findings. However, other studies have shown no such correlation [Braverman et al 1999, Herman et al 2002]. The wide variation in phenotype is most likely due to X-chromosome inactivation patterns [Shirahama et al 2003], making genotype-phenotype correlations difficult to study. Although a genotype-phenotype correlation is more likely to be detected among hemizygous males with a hypomorphic mutation, few EBP-deficient males are known at this time.
Several disorders described below demonstrate features similar to those of chondrodysplasia punctata and/or manifest stippling on radiographs and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The key radiologic finding of chondrodysplasia punctata (CDP) occurs in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogen exposures. ...
Differential DiagnosisSeveral disorders described below demonstrate features similar to those of chondrodysplasia punctata and/or manifest stippling on radiographs and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The key radiologic finding of chondrodysplasia punctata (CDP) occurs in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogen exposures. Rhizomelic chondrodysplasia punctata (RCDP), type 1, 2, or 3. This group of disorders shares with CDPX2 the features of rhizomelic shortening of the limbs, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata), vertebral abnormalities (notching but not commonly CDP), and cataracts that are usually present at birth or appear in the first few months of life. Birth size is often in the lower range of normal, but postnatal growth deficiency is profound, intellectual disability severe, and seizures common. The skeletal findings and cataracts are more symmetric than in CDPX2. Most children with RCDP do not survive the first decade of life, and a substantial proportion die in the neonatal period. All types of RCDP are inherited in an autosomal recessive manner; type 1 is the most common. (See Rhizomelic Chondrodysplasia Punctata Type 1.) Biochemical diagnosis is based on a deficiency of plasmalogens in erythrocyte membranes and confirmed by demonstration of a mutation in one of three genes: PEX7, encoding the PTS2 peroxisomal protein import system (RCDP type 1); GNPAT, encoding dihydroxyacetonephosphate acyltransferase (RCDP type 2); or AGPS, encoding alkyldihydroacetonephosphate synthase (RCDP type 3). X-linked recessive chondrodysplasia punctata, or brachytelephalangic type (CDPX1) is caused by defects in arylsulfatase E (ARSE), a vitamin K-dependent enzyme. Affected males have hypoplasia of the distal phalanges without limb shortening or cataracts. The diagnosis is confirmed by molecular genetic testing. Contiguous gene deletions involving ARSE and other genes in this region result in more complex phenotypes, including, variously, additional findings of ichthyosis, anosmia, hypogonadism, short stature, and corneal opacities. Chondrodysplasia punctata, tibia-metacarpal and humero-metacarpal types are inherited in an autosomal dominant manner. The gene defect(s) are unknown. Affected individuals have short limbs due primarily to shortening of the metacarpals and tibiae/humeri. No skin or eye changes are present, and prognosis is good.Warfarin embryopathy and other vitamin K deficiencies (including vitamin K epoxide reductase deficiency) are phenotypically similar to CDPX1 with especially severe hypoplasia of the nasal bone (“Binder anomaly”).Maternal systemic lupus erythematosus (SLE) can cause CDP with rhizomelic limb shortening.The following syndrome demonstrates other overlapping features of CDPX2 and may need to be considered. CHILD (congenital hemidysplasia, ichthyosis, and limb defects) syndrome is also X-linked, apparently male-lethal, and associated with skin and limb abnormalities. (See NSDHL-Related Disorders.) The skin lesions typically present at birth and often persist, but can develop at any age, often at a site of skin damage. The skin lesions histologically are ichthyosiform nevi and, more often than not, do not conform to lines of Blaschko [Happle 1981, Herman 2000, Bornholdt et al 2005]. Ipsilateral limb defects, often reduction in type, are found with epiphyseal stippling noted in infancy. Alopecia and internal malformations may occur, and occasional skin lesions on the “unaffected” side or even symmetric lesions have been reported. Cataracts have not been reported. CHILD syndrome is caused by mutations in NSDHL that encodes a cholesterol biosynthetic 4-methylsterol dehydrogenase [König et al 2000]. The enzyme, part of a 4-methylsterol demethylase complex, occurs one step proximal to the EBP sterol isomerase. Both CHILD syndrome and CDPX2 cause pathognomonic abnormalities in plasma or tissue sterol levels. Individuals with CHILD syndrome have increased levels of 4-methyl- and carboxysterols in cultured lymphoblasts, but only occasionally in plasma, whereas those with CDPX2 have increased levels of 8(9)-cholestenol and 8-dehydrocholeterol. In cultured lymphoblasts, both disorders manifest a paradoxical increase in the distal sterol metabolite lathosterol, including hemizygous males with an EBP mutation. The embryologic cause of the CHILD phenotype, common in NSDHL deficiency and rare in EBP deficiency, is unknown. Interestingly, fibroblasts cultured from normal skin from both the hemidysplastic and normal sides of the body can manifest the classic, abnormal sterol profile.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
No published guidelines exist to establish the extent of disease or proper management in an individual with X-linked chondrodysplasia punctata 2 (CDPX2). The following recommendations are based on current literature and the authors’ experience....
Management No published guidelines exist to establish the extent of disease or proper management in an individual with X-linked chondrodysplasia punctata 2 (CDPX2). The following recommendations are based on current literature and the authors’ experience.Evaluations Following Initial Diagnosis Physical examination with attention to growth parameters, skin, hair, and skeleton, as well as possible internal malformations (CNS, cardiac, renal)Full skeletal survey and orthopedic evaluation to assess limb length differences, kyphoscoliosis, and other skeletal abnormalities, including polydactylyPulmonary evaluation, if scoliosis compromises respiratory functionDermatologic evaluation to exclude other causes of the phenotypeOphthalmologic evaluation for congenital cataracts and other eye abnormalitiesDevelopmental assessment (after the newborn period)Echocardiogram for possible congenital heart defect at the time of diagnosisRenal ultrasound examination for possible kidney anomaliesHearing evaluation to detect hearing lossTreatment of ManifestationsTreatment is symptomatic and should be tailored to each patient. For females with typical CDPX2 diagnosed in the newborn period:Orthopedic management of leg length discrepancy; surgical correction of polydactyly; frequent assessment of kyphoscoliosis, which can progress rapidly at any ageCataract extraction and correction of visionDermatologic management of skin lesions Physical, occupational, and speech therapies, if necessaryStandard interventions for congenital heart defects, kidney anomalies, and hearing lossSurveillanceAppropriate surveillance includes:Regular follow-up of ophthalmologic abnormalitiesRegular orthopedic evaluations to monitor kyphoscoliosis or joint problems and assess linear growth and any leg length discrepancyOngoing developmental assessmentsOngoing follow-up with dermatologistRoutine monitoring of any existing cardiac and/or renal abnormalitiesRegular hearing evaluationsEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Chondrodysplasia Punctata 2, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEBPXp11.233-beta-hydroxysteroid-Delta(8),Delta(7)-isomeraseEBP homepage - Mendelian genesEBPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Chondrodysplasia Punctata 2, X-Linked (View All in OMIM) View in own window 300205EMOPAMIL-BINDING PROTEIN; EBP 302960CHONDRODYSPLASIA PUNCTATA 2, X-LINKED DOMINANT; CDPX2Molecular Genetic Pathogenesis X-linked chondrodysplasia punctata 2 (CDPX2) is caused by a deficiency of 3β-hydroxysteroid-Δ8, Δ7-isomerase or “sterol-Δ8-isomerase,” which converts 8(9)-cholestenol to lathosterol during cholesterol biosynthesis. Lathosterol is then converted to 7-dehydrocholesterol, which is a primary precursor for synthesizing both cholesterol and vitamin A [Kelley et al 1999]. Human sterol-Δ8-isomerase is encoded by the EBP (emapomil-binding protein) gene [Braverman et al 1999, Derry et al 1999]. EBP is presumably subjected to X-chromosome inactivation, which is responsible for the variability in phenotypes among females. Normal allelic variants. EBP comprises approximately 7.0 kb of genomic DNA and consists of five exons, of which only four are coding exons. It encodes a 230-aa protein, which is thought to be an integral endoplasmic reticulum membrane protein that contains four potential transmembrane domains and a potential site for cAMP-dependent protein kinase phosphorylation. The synonymous c.15G>T (p.Ala5Ala) rs3048 normal variant in exon 2 is the only non-pathologic sequence change reported with a high frequency in EBP. This variant has a frequency of 39%, 21%, 48%, and 46% in the white, African, Japanese, and Chinese populations, respectively. Pathologic allelic variants. Over 55 EBP mutations have been reported in individuals with CDPX2. Mutations have been found in all of the coding exons of EBP, with a majority of mutations found in exons 2 and 4. Small deletions and insertions, splice site mutations, frameshifts, along with missense and nonsense mutations have been reported. Functional studies have confirmed the pathogenesis of a small number of missense mutations [Braverman et al 1999]. A number of mutations appear to be recurrent, and mutations commonly occur at CpG dinucleotides, representing likely “hot spots” [Herman et al 2002]. Table 3. Selected EBP Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeNormalc.15G>T 1p.Ala5AlaPathologicc.238G>Ap.Glu80LysSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. www.ncbi.nlm.nih.gov/projects/SNPNormal gene product. EBP encodes 3β-hydroxysteroid-Δ8, Δ7-isomerase, an enzyme important in cholesterol biosynthesis. This enzyme converts 8(9)-cholestenol to lathosterol, which is then converted to 7-dehydrocholesterol, a primary precursor for synthesizing cholesterol and vitamin A [Kelley et al 1999].Abnormal gene product. Decreased function of the 3β-hydroxysteroid-Δ8, Δ7-isomerase causes the accumulation of sterol intermediates above the enzymatic block, as well as reduced cellular cholesterol. Plasma cholesterol levels in affected heterozygous females are usually normal. The exact mechanism(s) producing the clinical features seen in females with CDPX2 are not known.