Genetic studies in the focal dermal hypoplasia of Goltz syndrome

Abstract

The focal dermal hypoplasia of Goltz (FDH) syndrome is an X-linked disorder with skin, skeletal, and ocular defects. The FDH phenotype shares features with the microphthalmia with linear skin defects (MLS) syndrome, which is associated with deletions of Xp22. Familial cases of FDH are rare; no genetic studies were performed previously. We studied linkage to twelve polymorphic markers between DXS43 and OAI in an FDH family, including an affected mother (FDH7), her husband, affected daughter (FDH8), and unaffected son. Phenotypically, the mother's findings were limited mostly to the skin. Her karyotype was normal, 46, XX. She had patterned telangiectanc streaks, atrophic areas, scalp aplasia cutis congenita, perianal papillomas, and subepidermal lipomatosis. Her ocular exam was normal; there was no evidence of osteopathia striata on knee radiographs. Dentition was normal except for multiple caries and some grooving at the edges of her molars Breasts were symmetric; nails were relatively normal. Her 12 year old daughter has normal growth and development, similar cutaneous lesions, including scalp aplasia cuds congenita, an atrophic erythematous area of the face, hyper-and hypopigmented areas, multiple dystrophic nails, grooved surfaces of her teeth, high palate, mild scoliosis, 3-4 finger syndactyly, and 2-3-4 toe syndactyly. X-inactivation/methylauon analysis of FDH7 and FDH8, and six other FDH patients was performed in DNA from peripheral blood. FDH7 showed a skewed methylation pattern at the AR locus. FDH8 also showed skewed methylation at the AR and MAOA loci, but had a random pattern at the DXS16 locus, which lies closer to the MLS critical regioa Methylation patterns along the X-chromosome were also not homogenous in the other patients with FDH and did not correlate with phenotype severity. FDH7 was heterozygous at DXS43, DXS1053, DXS1224, DXS7104, DXS7109, DXS1043, KAL, and OAI. At each locus, her children inherited different maternal alleles. Thus, although limited, our linkage analysis is consistent with mapping of Ihe FDH syndrome to the MLS critical region in Xp22.