Chondrodysplasia Punctata 2, X-Linked

Clinical characteristics.

The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including females with no recognizable physical abnormalities. At least 95% of liveborn individuals with CDPX2 are female. Characteristic features include growth deficiency; distinctive craniofacial appearance; chondrodysplasia punctata (stippling of the epiphyses of the long bones, vertebrae, trachea, and distal ends of the ribs); often asymmetric rhizomelic shortening of limbs; scoliosis; linear or blotchy scaling ichthyosis in the newborn; later appearance of linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; and cataracts.

Diagnosis/testing.

The diagnosis of CDPX2 is established in a female proband with: typical clinical findings, increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts; and/or a heterozygous pathogenic variant in EBP identified by molecular genetic testing.

The diagnosis of CDPX2 is established in a male proband with: typical clinical findings, increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts; and/or a hemizygous pathogenic variant in EBP identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic and individualized. For individuals with typical CDPX2 diagnosed in the newborn period, the following are appropriate: orthopedic management of leg length discrepancy; frequent assessment of kyphoscoliosis; management of respiratory compromise as per pulmonologist; dermatologic management with emollients and keratolytics; sun protection; cataract extraction and correction of vision; standard interventions for hearing loss and hydronephrosis; family support.

Surveillance: Regular orthopedic evaluations to monitor kyphoscoliosis, joint problems, and any leg length discrepancy; follow up with a dermatologist; regular follow up of ophthalmologic abnormalities; audiology evaluations as indicated; monitor hydronephrosis if present.

Agents/circumstances to avoid: Prolonged sun exposure for individuals with ichthyosis, who are at risk of dehydration secondary to overheating. Use of emollients (which are oil based) and direct sun exposure can lead to sunburn.

Genetic counseling.

CDPX2 is inherited in an X-linked manner with early gestational male lethality. Women with an EBP germline pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child: EBP pathogenic variants in sons are usually lethal; daughters will have a range of possible phenotypic expression. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population. If the pathogenic variant cannot be detected in the DNA extracted from the leukocytes of either parent of the proband, three possible explanations are germline mosaicism, somatic mosaicism, or a de novo pathogenic variant in the proband. Prenatal diagnosis for pregnancies at increased risk is possible if the family-specific pathogenic variant is known.

Suggestive Findings

CDPX2 should be suspected in an individual with the following clinical findings:

• Growth deficiency/short stature
• Craniofacial findings
  • Frontal bossing
  • Depressed nasal bridge
  • Sparse eyebrows and lashes, often asymmetric
• Skeletal abnormality
  • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea, and distal ends of the ribs seen on x-ray. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification progresses during childhood (see Figure 1).
  • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric
  • Scoliosis, occasionally congenital
  • Postaxial polydactyly (uncommon)
• Abnormality of skin, hair, and nails
  • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of Blaschko) that usually resolves in the first months of life and may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (see Figure 2) and/or pigmentary abnormalities
  • Coarse scalp hair with scarring alopecia (see Figure 3)
  • Occasional flattened or split nails
  Note: Teeth are normal.
• Ocular anomaly
  • Cataracts often congenital, asymmetric, and/or sectorial
  • Microphthalmia and/or microcornea

Figure 1.

Radiographs from a female infant with CDPX2 demonstrating epiphyseal stippling (also called chondrodysplasia punctata; punctate epiphyseal dysplasia) Radiograph originally published in Herman [2000]; reproduced with permission from Elsevier Ltd.

Figure 2

A. Typical skin findings of CDPX2 at birth, including scaling and an erythematous eruption that follows lines of Blaschko B. Later hyperpigmentation over the back in a two-month-old female

Figure 3.

Scarring, patchy alopecia in a female with CDPX2 Photograph originally published in Herman [2000]; reproduced with permission from Elsevier Ltd.

Establishing the Diagnosis

Female proband. The diagnosis of CDPX2 is established in a female proband with typical clinical findings, characteristic results on biochemical testing (see Table 1), and/or a heterozygous pathogenic variant in EBP identified by molecular genetic testing (see Table 2).

Male proband. The diagnosis of CDPX2 is established in a male proband (with a 46,XY karyotype) with the typical clinical findings, characteristic results on biochemical testing (see Table 1), and/or a mosaic hemizygous pathogenic variant in EBP identified by molecular genetic testing (see Table 2).

Note: Males with non-mosaic hypomorphic EBP pathogenic variants have MEND (male EBP disorder with neurologic defects) syndrome, a clinically distinct phenotype comprising neurologic and structural malformations without chondrodysplasia punctata [Arnold et al 2012].

Biochemical testing. Sterol analysis of plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts can be used for diagnosis. Increased concentrations of 8(9)-cholestenol and 8-dehydrocholesterol are essentially diagnostic of CDPX2 [Kelley et al 1999] (Table 1); however, individuals with molecularly confirmed CDPX2 with normal biochemical profiles have been reported [Whittock et al 2003]. There is no correlation between the levels of plasma 8(9)-cholestenol and 8-dehydrocholesterol and mutational subgroups or specific phenotypic traits [Has et al 2002]. In affected males, biochemical testing will not be of use in differentiating CDPX2 from MEND syndrome (see Genetically Related Disorders).

Histologic examination of skin biopsies of individuals with CDPX2 show dilated ostial hyperkeratosis of the hair follicle with keratin calcium deposits [Leclerc-Mercier et al 2015]. These findings are relatively specific for CDPX2 and have been reported in only a couple of other conditions. Skin biopsy from the affected area may therefore be a useful diagnostic adjunct in individuals with a milder presentation.

Clinical Description

Variability in females. 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 active X chromosomes with the pathogenic variant) and other possible modifying factors. Phenotypes range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, such as adults with only cutaneous features, short stature, or no recognizable physical abnormalities. Severity in females varies greatly within families and among individuals with the same pathogenic variant, as would be expected for a pathogenic process determined, in part, by the random process of X-chromosome inactivation.

Phenotypes in males. Although CDPX2 was for many years presumed to be lethal in males, a small number of affected males have been reported. Sutphen et al [1995] described a male with CDPX2 and a 47,XXY karyotype. Males with mosaic EBP variants have also been reported [Aughton et al 2003, Tan et al 2010, Arnold et al 2012, Pacault et al 2018, Honigman et al 2019, Horinouchi et al 2019] with allele fractions ranging from 20% to 75% detected in blood and skin [Pacault et al 2018, Honigman et al 2019, Horinouchi et al 2019]. The clinical characteristics of males with mosaic EBP pathogenic variants are well within the marked variability described in affected females.

Genotype-Phenotype Correlations

Null EBP variants are associated with a severe CDPX2 phenotype in females and result in intrauterine lethality in males (except in a mosaic state).

Hypomorphic hemizygous EBP variants are associated with a milder MEND phenotype in males (see Genetically Related Disorders) [Barboza-Cerda et al 2014, Barboza-Cerda et al 2019].

Penetrance

A few clinically unaffected females with molecularly confirmed CDPX2 have been reported [Herman et al 2002, Shirahama et al 2003, Hellenbroich et al 2007]. However, these females were ascertained from segregation testing, and phenotyping may not have been as comprehensive as in the proband. Some women have been so mildly affected that they were identified only after having had a child with more severe features in whom CDPX2 was diagnosed. Although these adult women have subtle findings, their findings are sufficient to consider them affected.

Nomenclature

CDPX2 has also been referred to as:

• Conradi-Hünermann syndrome, named after Conradi [1914] and Hünermann [1931], who described the first persons with this disorder;
• Happle syndrome, named after Rudolph Happle [Happle 1979, Happle 1981], who contributed greatly to characterization of the phenotype and delineation of the X-linked mode of inheritance and possible etiologies of the syndrome [Traupe 1999, Sheffield 2001];
• Conradi-Hünermann-Happle syndrome, which recognizes all three individuals who helped to define this disorder.

Prevalence

Prevalence is unknown and incidence is estimated at 1:100,000 to 1:200,000 births.

Genetic Disorders

Chondrodysplasia punctata, tibia-metacarpal (OMIM 118651) and humero-metacarpal types are inherited in an autosomal dominant manner. The associated genes are unknown. Affected individuals have short limbs due primarily to shortening of the tibiae/humeri, metacarpals, and phalanges. Vertebral anomalies are also found. CDP is usually confined to the sacral, carpal, and tarsal areas. No skin or eye changes are present; intellect and life expectancy is normal [Savarirayan et al 2004].

Astley-Kendall dysplasia has been postulated to be an allelic disorder of Greenberg dysplasia [Author, personal communication]. Ossification defects of the cranial vault, spine, and long bones result in shortened and dysplastic long bones and vertebrae in affected individuals.

Teratogen Exposures

Warfarin embryopathy and other vitamin K deficiencies (including vitamin K epoxide reductase deficiency) are phenotypically similar to X-linked chondrodysplasia punctata 1 with especially severe hypoplasia of the nasal bone ("Binder anomaly"), distal phalangeal abnormalities, and punctata of the axial skeleton.

Maternal autoimmune disease (systemic lupus erythematosus [SLE], mixed connective tissue disease and scleroderma) can cause CDP with rhizomelic limb shortening.