TRICHOTHIODYSTROPHY - CLINICAL SPECTRUM, CENTRAL-NERVOUS-SYSTEM IMAGING, AND BIOCHEMICAL-CHARACTERIZATION OF 2 SIBLINGS

Trichothiodystrophy (TTD), an autosomal recessive disorder characteriz ed by sulfur-deficient brittle hair, identifies a group of genetic dis orders with an altered synthesis of high-sulfur matrix proteins and a defect in excision repair of ultraviolet damage in fibroblasts of most TTD patients. In contrast to patients with xeroderma pigmentosum (XP) , TTD patients do not have an increased frequency of skin cancers. TTD patients may be grouped into four categories: 1) those without photos ensitivity and without a defect in excision repair of UV damage; 2) th ose without photosensitivity and with an excision-repair defect in the same gene as in XP-D (complementation group D); 3) those with photose nsitivity and with the XP-D repair defect; 4) those with photosensitiv ity and with a repair defect distinct from that in XP-D. We present a brother and sister in the third category of TTD. Clinically, the patie nts have brittle hair, short stature, ichthyosis, photosensitivity, na il and dental dysplasias, cataracts, mental retardation, and pyramidal tract abnormalities. Diagnosis was made by hair mount, which shows th e characteristic banding pattern with polarizing microscopy, and by ha ir amino acid analysis, which demonstrated decreased high-sulfur matri x proteins. Fibroblasts cultured from skin biopsies had a marked DNA e xcision repair defect similar to the repair defect seen in XP-D. We ha ve documented a unique dysmyelinating disorder on magnetic resonance i maging of the brain that might explain their mental retardation, marke d hyperactivity, and neurologic deficits. Following the discovery that the human excision repair cross complementing rodent ultraviolet grou p 2 (ERCC2) gene is able to correct the ultraviolet sensitivity of XP- I) cell strains, the ERCC2 cDNA from previous TTD patients was sequenc ed and shows frameshifts, deletions and point mutations in the ERCC2 g ene. Molecular analysis of our patients is in progress. Molecular anal ysis of the defects in ERCC2 in clinically distinct patients with XP, XP/Cockayne's syndrome, and TTD may provide insight into the molecular mechanisms of these genetically related but clinically distinct disor ders.