Cholesterol metabolism defect associated with Conradi-Hunerman-Happle syndrome

We present a 6-week-old black girl with Conradi-Hunerman-Happle syndrome (C HS). The mother had no past medical history of illness, and the pregnancy p rogressed normally to a spontaneous vaginal delivery at 36 weeks. There was no known significant family history. A diagnosis of chondrodysplasia punct ata was made at birth from physical examination and X-ray findings. On phys ical examination at 6 weeks, a koala face, a saddle nose, and a right-sided cataract were noted (Figs 1a,b). There was unilateral left-sided ichthyosi s well demarcated at the midline, with whorled brown fine scale following B lashko's lines on the patient's right side. Orthopedic complications were b ilateral but were more pronounced on the left side. There was bilateral sho rtening of the humerus, with polydactyly of the right hand, arachnodactyly of the left fingers, bilateral clubbing, and mild contractures of the feet. X-Rays showed multiple calcifications along the spine, proximal and distal femoral epiphysis, and proximal humeral epiphysis (Fig. 2). The patient was treated with emollients (aquaphor) twice daily with continu ing improvement in ichthyosis. The clubbed feet were treated with splinting and the polydactyly was corrected by surgery. Ophthalmology was to follow the patient for her right-sided cataract. At the patient's 4-month follow-u p, the ichthyosis showed a marked improvement with some residual hypopigmen ted atrophoderma noted. The distribution remained unchanged. Biopsies taken of ichthyotic lesions showed compact hyperkeratosis and foll icular plugging. Vesicles within the stratum corneum contained amorphous ma terial (Figs 3a,b). The granular cell layer was thickened with retained ova l nuclei. The epidermal and adnexal epithelium were disorganized. Increased apoptotic/dyskeratotic keratinocytes were seen within the epidermis, but w ere most evident within the follicular epithelium. Ultrastructural studies showed saccular dilations of the acellular space wi thin the stratum corneum. These acellular spaces were filled with unprocess ed lamellated pleated sheets and vesicle complexes and processed lamellae. Dyskeratotic cells were seen within the stratum spinosum. Red blood cell (RBC) plasmalogen levels and polyunsaturated fatty acids (PU FA), including decosahexaenoic acid (DHA), were within normal limits. Plasm a very long chain fatty acids (VLCFA), including C26 : 0/C22 : 0 ratios, ph ytanic and pristanic acids, plasmalogen, and phytanic/pristanic ratios, tri hydroxycholestanic acid (THCA) and dihydroxycholestanoic acid (DHCA) includ ing their ratios, THCA/cholic acid and DHCA/chenodeoxycholic acid, and PUFA s including DHA were within normal limits. Urine organic acids and piecolic acid were within normal limits. Despite these normal values, there was an increase in cholest-8(9)-en-3 beta -ol of 6.8 mug/mL (normal, 0.01-0.10 mug /mL) and an increase in 8-dehydrocholesterol (5.1 mug/mL) (normal, <0.10 <m u>g/mL).