X‐linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male

Abstract

X-linked dominant chondrodysplasia punctata (CDPX2; Happle syndrome) is recognized almost exclusively in females, who display mosaic and asymmetric features, presumed to arise secondary to random X-inactivation. CDPX2 results from mutation of an X-linked gene coding for sterol-delta(8)-delta(7) isomerase (emopamil binding protein). We describe a boy with clinical features of CDPX2 (including those presumed to arise usually secondary to functional mosaicism in females). Biochemical and molecular studies demonstrate that he is mosaic for a sterol-delta(8)-delta(7) isomerase gene mutation. He is the first reported example of single gene mosaicism giving rise to CDPX2 in a male.

A novel X‐linked multiple congenital anomaly syndrome associated with an EBP mutation

“…His family history was otherwise non-contributory and molecular analysis of EBP in his unaffected mother was normal. Observations gleaned from the cases of Aughton et al [2003] and Sutphen et al [1995] would support that mosaic expression of EBP accounts for the classic Conradi-Hunermann phenotype in females and in the males characterized in their case reports. Milunsky et al [2003] described an attenuated clinical phenotype in a 2 1 / 2 -year-old male with a high-nasal bridge, micrognathia, unilateral cataract, crossed renal ectopia, developmental delays, seizures, but no cardiac or central nervous system malformations were reported.…”

“…One would expect that the characteristic phenotype was likely due to the tissue level mosaicism associated with X-inactivation. Previous survival among 46,XY CDPX2 males has been attributed to hypomorphic EBP mutations with residual sterol isomerase activity and/ or mosaicism [Aughton et al, 2003;Kelley et al, 2005]. Aughton et al [2003] described a cognitively normal 4-year-old male with rhizomelic shortening, scoliosis, vertebral anomalies, epiphysal stippling, limb asymmetry, midfacial flattening, a short, concave nasal root, spotty alopecia, and areas of linear streaky hypotrophy in the skin of all limbs.…”

“…Principal characteristics of this syndrome observed in females include radiographic stippling of the epiphyses (often in an asymmetric distribution), a depressed nasal bridge, scoliosis, short stature, congenital cataracts, and a collection of patchy skin changes, such as ichthyosis, follicular atrophoderma, pigmentary dysplasias, and cicatricial alopecia [Happle, 1979;Manske et al, 1980;Braverman et al, 1999;Has et al, 2000;Ikegawa et al, 2000]. The rare males reported with the X-linked dominant trait of CDPX2 appear to have a range of phenotypes including findings that occur in affected females [Sutphen et al, 1995;Aughton et al, 2003;Milunsky et al, 2003].…”

“…The clinical presentation is variable among affected females, even within the same family and is probably due to random X-inactivation. EBP mutations identified in males are even more uncommon, presumably to due early lethality, but exceptions to the rule have provided for interesting insight into this integral part of sterol biosynthesis and its role in developmental pathways [Aughton et al, 2003;Milunsky et al, 2003;Kelley et al, 2005;Furtado et al, 2007].…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Several males with typical features of CDPX2 have been reported with a 47,XXY karyotype or somatic mosaicism as a mechanism ( 235,(244)(245)(246). However, fi ve males with 46, XY karyotypes, a neurodevelopmental phenotype, and mutations in the ⌬ 8 -⌬…”