Anisomastia associated with interstitial duplication of chromosome 16, mental retardation, obesity, dysmorphic facies, and digital anomalies: Molecular mapping of a new syndrome by fluorescent in situ hybridization and microsatellites to 16q13 (D16S419-D16S503)

Anisomastia is a common problem among developing adolescent girls. We recen tly evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental re tardation, a stocky body habitus with mild obesity, dysmorphic facies (prom inent, upslanting palpebral fissures, beaked nose, and a prominent philtrum ), webbed neck, low hairline, and severe bilateral clinodactyly of the thir d, fourth, and fifth fingers with acral (but not large joint) flexion contr actures. A peripheral blood high resolution karyotype revealed additional c hromosomal material within the long arm of chromosome 16. Densitometric ana lysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q s uggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS a nalysis showed that the duplication was on the maternally derived chromosom e 16, resulting in two maternal land one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library , labeled, and used for fluorescence in situ hybridization. The BACs contai ning STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13 ) showed two regions of hybridization, indicating that these sites were dup licated, whereas a BAC containing the STS D16S512 (which corresponds to 16q 21-q22) revealed one hybridization signal per 16q, indicating that the corr esponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even tho ugh trisomy 16 is the most common autosomal trisomy in spontaneous abortion s, few patients with unbalanced chromosome 16 abnormalities survive to adul thood; in this report we describe one such patient with an interstitial chr omosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this pat ient and patients with other 16q abnormalities, although the breast finding s were unique. Molecular cytogenetics, including fluorescence in situ hybri dization and densitometric analysis of amplified STSs, provided useful tool s for the precise mapping of the syndrome to 16q13, where the gene(s) respo nsible for this phenotype might be localized.