Phenotypic variation in Melnick-Needles syndrome is not reflected in X inactivation patterns from blood or buccal smear.

Abstract

Melnick-Needles syndrome is a rare putative X-linked dominant bone dysplasia. The patients have short stature, characteristic facial features, and a normal intelligence. The skeletal dysplasia includes S-shaped curvature of tubular bones and sclerosis of the base of the skull. The phenotype of affected individuals varies, even within families. This could be related to X chromosome inactivation. We report here on a very mildly affected mother and her two severely affected daughters with characteristic features of Melnick-Needles syndrome. In addition, the two daughters had very similar pigmented nevi on their back. X chromosome inactivation analysis of blood DNA revealed a skewed X inactivation pattern in all three affected females, with the normal X chromosome as the predominating active X chromosome. The X inactivation pattern was similar in buccal smear and blood DNA in the mother and one of the daughters, whereas the other daughter had a skewed pattern in blood only. X chromosome inactivation in blood and buccal smear DNA therefore does not explain the phenotypic variation in this family. The skewed X chromosome inactivation is in agreement with X-linked inheritance of Melnick-Needles syndrome and suggests a critical role of the Melnick-Needles gene in hematopoietic cell proliferation. Clinical evidence indicates that Melnick-Needles syndrome is allelic to the otopalatodigital syndromes, which have been assigned to Xq26-28. Haplotype analysis of the X chromosomes in this family was in agreement with the localization of the gene for Melnick-Needles syndrome to Xq25-qtel.