Somatic/gonadal mosaicism in a syndromic form of ectrodactyly, including eye abnormalities, documented through array-based comparative genomic hybridization.

Split hand/foot malformation (SHFM) is characterized by underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. SHFM is a heterogeneous condition caused by abnormalities at one of multiple loci, including SHFM1 (SHFM1 at 7q21-q22), SHFM2 (Xq26), SHFM3 (FBXW4/DACTYLIN at 10q24), SHFM4 (TP63 at 3q27), and SHFM5 (DLX1 and DLX 2 at 2q31). SHFM3 is unique in that it is caused by submicroscopic tandem chromosome duplications of FBXW4/DACTYLIN. In order to show that array-based comparative genomic hybridization should be considered an essential aspect of the genetic analysis of patients with SHFM, we report on a family with two brothers who have ectrodactyly. Interestingly, both also have ocular abnormalities. Their sister and both parents are healthy. DNA of all five family members was analyzed using oligonucleotide-based DNA microarray and quantitative PCR. The two affected brothers were found to have a small duplication of approximately 539 kb at 10q24.32. The patients' sister and father do not have the microduplication, but qPCR showed that mother's DNA carries the duplication in 20% of blood lymphocytes. In this family, two children were affected with ectrodactyly having a duplication over the SHFM3 locus. The mother, who shows no clinical features of ectrodacytyly, is a mosaic for the same duplication. Therefore, we demonstrate that somatic/gonadal mosaicism is a mechanism that gives rise to SHFM. We also suggest that ocular abnormalities may be part of the clinical description of SHFM3.

Clinical and behavioral features of patients with Borjeson-Forssman-Lehmann syndrome with mutations in PHF6.

OBJECTIVE: To describe clinical and behavioral features of 10 men from 2 families with Borjeson-Forssman-Lehmann syndrome (BFLS) and missense mutations in the PHF6 zinc-finger transcription factor gene. STUDY DESIGN: BFLS behavioral features were compared with other age-matched men with other syndromes and similar intellectual functioning through the use of standardized questionnaires: the Child Behavior Checklist, the Vineland Adaptive Behavior Scales, and the Reiss Personality Profile. Participants included 10 with BFLS, 10 with Prader-Willi syndrome, and 23 with Klinefelter syndrome variants (13 with 48,XXYY, 4 with 48,XXXY, and 6 with 49,XXXXY). RESULTS: Contrary to initial reports, our men with BFLS had no microcephaly, seizures, or short stature. They manifested deep-set eyes with large ears, coarse facial features, small external genitalia, gynecomastia, and obesity. Family A had mild to moderate mental retardation, whereas family B was more severely affected. On Vineland Adaptive Behavior Scales, men with BFLS had higher daily living and social skills than communicative skills. Men with BFLS also had lower internalizing and externalizing symptoms and appeared more social and helpful than men with Prader-Willi syndrome or Klinefelter syndrome variant. CONCLUSIONS: Men with BFLS from 2 families with mutations in the PHF6 gene manifested distinctive clinical features and a low risk for maladaptive behaviors.

Stocco dos Santos X-linked mental retardation syndrome: clinical elucidation and localization to Xp11.3-Xq21.3.

Mental retardation (MR) affects an estimated 2-3% of the population. A considerable fraction of mental retardation is due to X-linked genes. Of these genes, about 136 are responsible for syndromic X-linked MR (XLMR). One such XLMR syndrome, Stocco dos Santos, was first described in 1991. This family was re-visited, which allowed further delineation of the clinical phenotype. Additionally, linkage analysis was conducted, which resulted in the localization of this XLMR syndrome to the pericentric region, Xp11.3 to Xq21.1, with a maximum LOD score of 3.14 at loci AR and DXS983.

Shashi XLMR syndrome: report of a second family.

This report describes a family with mental retardation in two brothers. The pedigree is consistent with either X-linked mental retardation or autosomal recessive inheritance. The clinical features consist of coarse face, prominent lower lip, large testes, and obesity. This same constellation of findings was observed in a family with X-linked mental retardation (XLMR) reported by Shashi et al. [2000: Am J Hum Genet 66:469-479]. Furthermore, haplotype analysis was consistent with localization of the Shashi XLMR syndrome in Xq26-q27. Thus, the family likely represents a second occurrence of the Shashi XLMR syndrome.