Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

Abstract

X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.

Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome)

“…15,16 Finally, a single male with microcephaly and significant neurologic impairment, a unilateral cataract, patchy hypopigmentation, renal anomalies, but no epiphyseal stippling or skeletal dysplasia was found to have a novel hemizygous EBP missense mutation, L18P. 17 Only one of our cases was known to be familial (Patient 10). Clinical features in three generations of affected individuals in this family, including an affected male with a 47,XXY karyotype, have been reported.…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…The facies, where reported, were dysmorphic with hypertelorism, prominent nasal bridge, and micrognathia. All of the males had the typical abnormal sterol profi les found in females with CDPX2 (see below), although molecular analysis with an EBP mutation was reported in a single case ( 231 ). In this patient, hypotonia, seizures, ptosis, and patchy hypopigmentation were also noted.…”

“…-sterol isomerase gene have been reported ( 230,231 ). Although there is some phenotypic overlap with features seen in females with CDPX2, all three surviving males had moderate to severe mental retardation.…”

“…2 ) ( 228, 229 ). Recently, several males with hypomorphic EBP mutations and a phenotype distinct from that of CDPX2 have been described ( 230,231 ).…”

A novel X‐linked phenotype caused by hypomorphic EBP mutations

“…This paper referred to Milunsky et al [2003a] who had described a boy with ''a severe atypical phenotype for X-linked dominant Conradi-H€ unermannHapple syndrome and a mutation in EBP.'' I proposed to categorize this mutation as a hypomorphic EBP allele giving rise to a nonlethal phenotype quite different from CDPX2.…”