Chondrodysplasia Punctata 2, X-Linked Dominant

A number sign (#) is used with this entry because X-linked dominant chondrodysplasia punctata-2 (CDPX2) is caused by mutation in the gene encoding delta(8)-delta(7) sterol isomerase emopamil-binding protein (EBP; 300205) on chromosome Xp11.

Hemizygous mutation in the EBP gene can also cause MEND syndrome (300960) in males, which shares some features with CDPX2.

Description

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. CDPX2 arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortness, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia. Affected males are extremely rare and the clinical features in males almost always result from postzygotic mosaicism for an EBP mutation (summary by Aughton et al., 2003 and Arnold et al., 2012).

Genetic Heterogeneity of Chondrodysplasia Punctata

See also CDPX1 (302950), caused by mutation in the ARSE gene (300180).

See 118650, 602497, and 118651 for possible autosomal dominant forms of CDP. In addition, CDP can be caused by maternal vitamin K deficiency or warfarin teratogenicity (see 118650).

Clinical Features

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 (see 'Affected Males' below).

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.

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.

Affected Males

Sutphen et al. (1995) reported a man with CDPX2. 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).

Aughton et al. (2003) reported a 4-year-old boy with mild macrocephaly, scoliosis, rhizomelic shortening of the limbs, epiphyseal and periephiphyseal stippling, butterfly vertebrae, and asymmetry of the femurs. Additional features included coarse, dry hair with spotty scalp alopecia, mild nasal depression, mild midface flattening, and cutaneous linear streaky hypotrophy. He did not have cataracts, and cognition was normal. Laboratory studies showed increased levels of plasma 8-dehydrocholesterol and 8(9)-cholestenol. Genetic analysis showed mosaicism for a missense mutation in the EBP gene (E80K; 300205.0003).

Arnold et al. (2012) reported a 7-year-old boy with a history of transient scaly erythematous lesions on the trunk, extremities, and scalp at birth, which resolved completely leaving linear, hypopigmented, and slightly scaly areas following the lines of Blaschko. He also had patchy alopecia of the scalp and follicular atrophoderma of the knees. No skeletal or ocular abnormalities were noted, and no neurologic abnormalities were reported. Genetic analysis revealed a de novo hemizygous truncating mutation in the EBP gene (Y11X; 300205.0014). Karyotype analysis showed 46,XY, and Arnold et al. (2012) suggested that postzygotic mosaicism had occurred.

Biochemical Features

Kelley et al. (1999) studied 5 patients with variably severe chondrodysplasia punctata, including 2 patients with the diagnosis of CDPX2, for abnormalities in cholesterol biosynthesis. They found abnormal plasma or tissue sterol profiles characterized by increased levels of 8-dehydrocholesterol and 8(9)-cholestenol, suggesting a deficiency of 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase, a principal enzyme of cholesterol biosynthesis. The authors concluded that abnormal cholesterol biosynthesis is a characteristic of some syndromes with rhizomelic shortening and chondrodysplasia punctata.

Herman (2003) reviewed the cholesterol biosynthetic pathway and the 6 disorders involving enzyme defects in post-squalene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), CDPX2, CHILD syndrome (308050), lathosterolosis (607330), and hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM; 215140).

Inheritance

The transmission pattern of CDPX2 in the family reported by Kozlowski et al. (2002) was consistent with X-linked dominant inheritance.

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.

Mapping

The assignment of the EBP gene to Xp11.23-p11.22 and the demonstration of mutations in this gene in patients with CDPX2 clearly demonstrated that the previous assignment to Xq28 was an error (see HISTORY). Traupe et al. (1992) had suggested that Xp11 was excluded as the site of the gene responsible for CDPX2; however, restudy of that family by Derry et al. (1999) using molecular methods permitted revision of the scoring of affected individuals in the family such that Xp11 was no longer excluded.

Molecular Genetics

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.

Nomenclature

Kalter et al. (1989) suggested that the designation Conradi-Hunermann syndrome be reserved for the X-linked dominant form of the disorder. Sheffield (2001) traced the legitimacy of a tripartite eponym for this disorder: Conradi-Hunermann-Happle.

Animal Model

'Tattered' (Td) is an X-linked, semidominant mouse mutation associated with prenatal male lethality. Heterozygous females are small and at 4 to 5 days of age develop patches of hyperkeratotic skin where no hair grows, resulting in a striping of the coat in adults (Uwechue et al., 1996). Craniofacial anomalies and twisted toes have also been observed in some affected females. A potential second allele of Td was described by Seo et al. (1997). The phenotype of Td is similar to that seen in heterozygous females with human X-linked dominant chondrodysplasia punctata as well as another X-linked semidominant mouse mutation, 'bare patches' (Bpa). Derry et al. (1999) identified the defect in Td mice as a single amino acid substitution in the delta(8)-delta(7) sterol isomerase emopamil-binding protein encoded by the Ebp gene in mouse. Liu et al. (1999) isolated the Bpa gene (300275) on Xq28, and found that it encodes a protein with homology to 3-beta-hydroxysteroid dehydrogenases that function in one of the later steps of cholesterol biosynthesis.

History

Happle et al. (1983) suggested that the syndrome of X-linked dominant chondrodysplasia punctata, ichthyosis, and short stature to which his name is sometimes attached was the human homolog of 'bare patches' in the mouse. This presumed homology led to the assumption that CDPX2 mapped to Xq28 Herman and Walton (1990).

The location of the Bpa gene in the mouse suggested that the human counterpart is in the Xq28 region. To test the hypothesis that the CDPX2 locus maps to Xq28, Traupe et al. (1992) performed a linkage study in 3 families comprising a total of 12 informative meioses. Multiple recombinations appeared to exclude the Xq28 region as the site of the gene. Surprisingly, multiple crossovers were also found with 26 other markers distributed over the rest of the X chromosome. Two-point linkage analysis and analysis of recombination chromosomes seemed to exclude the gene from the entire X chromosome. They considered 3 mechanisms that might explain the apparent exclusion of the X-linked gene from the X chromosome by linkage analysis. One was the occurrence of mutations at several different sites on the X chromosome, any one of which could disturb X-inactivation/reactivation. This mechanism has been suggested to explain the phenotype of hypomelanosis of Ito (300337) occurring with X/autosome translocations or ring formation of one X chromosome with breakpoints variously located (Sefiani et al., 1989). A second possibility is that of metabolic interference as proposed by Johnson (1980). This hypothesis would suggest that only females manifest the disorder and that it would segregate in a manner mimicking X-linked dominant transmission. However, males could receive and transmit the abnormal gene but could not exhibit the abnormal phenotype. Such nonpenetrant males would be scored as recombinants. Metabolic interference would predict that all daughters of a nonpenetrant male gene carrier would be affected; transmission of the gene via an unaffected male has not been observed in the families with Happle syndrome. In the 3 kindreds studied, only females were affected in successive generations. Traupe et al. (1992) favored the existence of an unstable premutation that can become silent in males. This explanation would account for the unexpected sex ratio (M:F) of 1.2:1 among surviving sibs. One expects with an X-linked dominant male-lethal gene to find a ratio of 1:2. An unstable premutation would also explain the striking clinical variability of the phenotype, including stepwise increases in disease expression in successive generations.

Traupe (1999) recounted difficulties in mapping the gene for X-linked dominant chondrodysplasia punctata or, as he called it, Happle syndrome. Because of presumed homology to the mouse mutant 'bare patches,' on Xq28, they tested for linkage in that region and excluded it. Indeed, multiple crossovers were found, with 26 other markers spread along the rest of the X chromosome. The linkage of the gene seemed to be excluded for the entire X chromosome by 2-point linkage analysis. On reexamination of the pedigree, they realized that in contrast to their expectation of a gene that is lethal for hemizygous males and thus results in a preponderance of females, they actually observed a close-to-even sex ratio (M:F) of 1.2:1 among surviving sibs after performing a Weinberg proband correction. This result suggested that the assumption that males with a mutant gene for Happle syndrome die in utero could be wrong. Ryan et al. (1997) reported mapping to Xq22 of a mutant gene that is transmitted by unaffected carrier males in an X-linked dominant disorder in which male sparing, rather than male lethality, is responsible for the selective involvement of females. The disorder studied by Ryan et al. (1997) was epilepsy, female restricted, with mental retardation (EFMR; 300088). Craniofrontonasal dysplasia (CFND; 304110) is another X-linked dominant disorder in which females are consistently affected more severely than males, although male carriers show some phenotypic abnormalities (Kapusta et al., 1992).