Terminal osseous dysplasia and pigmentary defects: Clinical characterization of a novel male lethal X-linked syndrome

We describe a new syndrome of distal limb anomalies and pigmentary skin def ects in 10 females of a large, four-generation pedigree. The family was asc ertained through a 4-month-old infant girl with multiple anomalies, includi ng hypertelorism, iris colobomas, low-set ears, midface hypoplasia, punched -out pigmentary abnormalities over the face and scalp, generalized brachyda ctyly, and digital fibromatosis, No affected males were identified in this pedigree, Affected females had a lower than normal male-to-female ratio of liveborn offspring, and some of them also had a history of several miscarri ages. These findings, together with a significant variability in the phenot ype of the affected females, suggest that this condition is inherited in an X-linked dominant fashion, with prenatal male lethality, and that X-inacti vation plays an important role in the phenotypic expression of the disease. The syndrome has been described twice in the literature, but only in spora dic cases; it was therefore not recognized as a mendelian entity. Because t he most consistent findings are anomalies of the distal skeleton of the lim bs and localized pigmentary abnormalities of the skin, we named the syndrom e "terminal osseous dysplasia with pigmentary defects." This condition, tho ugh rare, can be added to the small group of male lethal X-linked dominant disorders in humans. (C) 2000 Wiley-Liss, Inc.