Genetic heterogeneity of syndromic X-linked recessive microphthalmia-anophthalmia: Is Lenz microphthalmia a single disorder?

Nonsyndromic congenital microphthalmia or anophthalmia is a heterogeneous malformation with autosomal dominant, autosomal recessive, and X‐linked modes of inheritance. Lenz microphthalmia syndrome comprises microphthalmia with mental retardation, malformed ears, skeletal anomalies, and is inherited in an X‐linked recessive pattern. Prior studies have shown linkage of both isolated (or nonsyndromic) anophthalmos (ANOP1, [MIM 301590]) and Lenz syndrome [MIM 309800] to Xq27–q28. Nonsyndromic colobomatous microphthalmia [MIM 300345] has been linked to Xp11.4–Xq11.1. We describe a five‐generation African‐American family with microphthalmia or anophthalmia, mental retardation, and urogenital anomalies, in an X‐linked recessive inheritance pattern, consistent with Lenz syndrome. Initial linkage analysis with microsatellite markers excluded the region in Xq27–q28 previously reported as a candidate region for ANOP1 [MIM 301590]. An X‐chromosome scan revealed linkage to a 10‐cM region between markers DXS228 and DXS992 in Xp11.4–p21.2. Multipoint analysis gave a maximum LOD score of 2.46 at marker DXS993. These data show that X‐linked recessive syndromic microphthalmia exhibits genetic heterogeneity. In addition, it suggests that Lenz microphthalmia syndrome, previously thought to be a single disorder, may represent an amalgam of two distinct disorders.