X-linked dominant chondrodysplasia punctata type 2

X-linked dominant chondrodysplasia punctata type 2 (CDPX2).

Chondrodysplasia punctata is a defect of endochondral bone formation characterized by abnormal foci of calcification in cartilaginous elements.

In x-rays, chondrodysplasia punctata appears as epiphyseal stippling. X-linked dominant chondroplasia punctata type 2 (CDPX2, also known as Conradi-Hünermann-Happle syndrome or Happle syndrome; MIM.302960) was first delineated by Happle in 1979.

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.

This X-linked dominant disorder is typically lethal in hemizygous males. Heterozygous females present at birth with generalized congenital ichthyosiform erythroderma, a scaly hyperkeratotic rash in linear and blotchy patterns following the lines of Blaschko, consistent with the effects of X-inactivation. Older patients suffer from ichthyosis, atrophoderma, layered splitting of the nails, trichorrhexis nodosa, and patchy alopecia.

Skeletal abnormalities include chondrodysplasia punctata, asymmetrical rhizomelic limb shortening, scoliosis, and hexadactyly.

Craniofacial anomalies include an asymmetrical head shape, due to unilateral hypoplasia, and a flat nasal bridge. Asymmetrical and sectorial cataracts are found in CDPX2.

Like the distribution of the dermatological findings, the asymmetrical nature of the craniofacial malformations and the cataracts is likely due to differential X-inactivation.

Synopsis

 rhizomesoacromelic limb shortening of the upper and lower extremities
 craniofacial dysmorphism
 chondrodysplasia punctata

Laboratory

 elevated cholest-8(9)-ene-3beta-ol in serum and tissues.

Etiology

 germline mutation in the gene encoding delta(8)-delta(7) sterol isomerase emopamil-binding protein (EBP) (MIM.300205)

Physiopathology

Because chondrodysplasia punctata has been described in SLOS, Kelley et al. investigated the possibility that abnormal sterol synthesis could cause other genetic disorders with chondrodysplasia punctata.

This group identified five CDPX2 patients with increased tissue 8-dehydrocholesterol and cholesta-8(9)-en-3β-ol, consistent with a deficiency of 3β-hydroxysterol Δ8,Δ7-isomerase activity.

This enzyme was first identified as a high-affinity emopamil-binding protein (EBP), a putative four–transmembrane domain integral membrane protein of 230 amino acids.

Mutations of the EBP gene in CDPX2 patients, first reported by Derry et al. and Braverman et al., include a preponderance of presumed null alleles, suggesting that mild missense alleles either are less penetrant or yield a different phenotypic presentation.

In the tattered mouse, a missense mutation (G107R) of Ebp confers an X-linked male-lethality trait.

Heterozygous females are growth-retarded and have a “tattered” appearance due to hyperkeratotic patches of alopecia.

The hemizygous male phenotype includes intrauterine growth retardation, micrognathia, short limbs, retarded ossification, and intestinal agenesis.

References

 Rakheja D, Read CP, Hull D, Boriack RL, Timmons CF. A severely affected female infant with x-linked dominant chondrodysplasia punctata: a case report and a brief review of the literature. Pediatr Dev Pathol. 2007 Mar-Apr;10(2):142-8. PMID: 17378690