Facial dysgenesis: a novel facial syndrome with chromosome 7 deletion p15.1-21.1.

We describe a female neonate with a unique constellation of features including anophthalmia and cryptophthalmos, temporal remnant "eye tags," bilateral cleft lip, unilateral cleft palate, a proboscis with absent nasal septum, choanal atresia, micrognathia, square stoma, and bilateral external auditory canal atresia. Gross brain structure, pituitary function, limbs, trunk, and genitalia were normal. Skeletal survey, echocardiogram and abdominal viscera were unremarkable except for a split central sinus of the right kidney. BAER exam indicated she could hear and temporal CT confirmed the presence of cochlea and possible ossicles. Cytogenetic evaluation revealed an interstitial deletion at chromosome 7p15.1-21.1. TWIST, a gene encoding a transcription factor involved in craniofacial development, is deleted by FISH analysis. The absence of a mutation on the non-deleted allele of TWIST as determined by sequencing virtually eliminates complete loss of the TWIST gene as the cause of this patient's severe phenotype. The HOXA gene cluster also encodes transcription factors that are crucial for directing cephalad to caudad somatic fetal development. HOXA1, the most telomeric of the 13 members of the HOXA gene cluster, is located at the centromeric boundary of the patient's chromosome 7 deletion. By FISH analysis, neither allele of HOXA1 is deleted and sequencing reveals no mutations. Haploinsufficiency or complete loss of the HOXA1 gene also does not appear to cause this patient's severe phenotype. Previous reports of chromosome 7p15-21 deletions do not have phenotypes similar to this patient.

Delayed membranous ossification of the cranium associated with familial translocation (2;3)(p15;q12).

The relationship of delayed membranous cranial ossification to cranium bifidum and parietal foramina syndromes is unclear. We report on a family with delayed cranial membranous ossification (OMIM 155980) that segregates with an apparently balanced reciprocal translocation between chromosomes 2 and 3. The propositus had apparently low-set ears, proptosis, and a soft skull at birth. A radiographic survey of the skeleton showed markedly decreased ossification of the cranial bones and no other skeletal abnormalities. The mother and maternal grandmother of the propositus have brachycephaly, hypertelorism, and a history of a soft skull at birth. Chromosome analysis of peripheral blood from the propositus showed 46,XY,t(2;3)(p15;q12). The propositus, mother, and grandmother carry the same reciprocal translocation, whereas the mother's two phenotypically normal sibs have a normal karyotype. We used an STS-linked BAC resource to define the translocation breakpoint by identifying flanking BAC clones from both chromosomes 2, 1006D24 (D2S2279) and 1060A5 (D2S2231), and chromosome 3, 3D17 (WI8558) and 3D18 [CITB Human BAC Library, J.R.K.]. This represents the second report of a family with delayed membranous ossification of the cranium and the first report of the phenotype segregating with a chromosome rearrangement.

Molecular cytogenetic analysis and clinical findings in a newborn with prenatally diagnosed rec(7)dup(7q)inv(7)(p22q31.3)pat.

We report prenatal and early postnatal findings in a newborn with a partial trisomy of chromosome 7 (7q31.3-qter), arising from meiotic recombination of a paternal pericentric inversion, inv(7)(p22q31.3). The inversion breakpoints were localized and the regions of duplication and deletion were defined by fluorescence in situ hybridization (FISH) analysis using a series of locus-specific and subtelomeric probes. To our knowledge, only three cases involving a recombinant 7 with duplication of 7q have been reported, two of these being first cousins. The clinical findings in our patient included skeletal abnormalities, facial dysmorphism, dilated cerebral ventricles, microretrognathia and short neck. These findings and some aspects of the neonatal course were consistent with the phenotype previously reported for duplication of distal 7q, without associated monosomy for sequences from another chromosome.

PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma.

The two most common types of genetic alterations yet identified in uterine endometrioid carcinoma (UEC) are PTEN mutations and microsatellite instability (MI). Furthermore, MI-positive UECs (defined as tumors with detectable alterations at two or more different microsatellite loci) are significantly more likely to contain PTEN mutations than are MI-negative UECs. To determine whether PTEN inactivation is a relatively early event in endometrial tumorigenesis, we evaluated complex atypical hyperplasia (CAH), the direct precursor to UEC, for the presence of PTEN mutations. Mutations were present in 3 of 11 (27%) CAHs with synchronous UEC and in 4 of 18 (22%) CAHs that were not associated with invasive carcinoma. One case with synchronous CAH and UEC contained a germ-line PTEN mutation. In addition, we evaluated the same series of CAHs for MI. We identified four MI-positive CAHs with synchronous UEC but did not detect the MI phenotype in any CAHs without associated invasive carcinoma. A PTEN-mutant (germ-line mutation) MI-negative CAH was synchronous with a PTEN-mutant MI-positive UEC. These results suggest that mutation of PTEN can be an early event in the pathogenesis of UEC and may precede the development of the MI phenotype in a subset of cases.

Chromosome microdissection identifies cryptic sites of DNA sequence amplification in human ovarian carcinoma.

DNA sequence amplification contributes to the multistep process of carcinogenesis, and overexpression of amplified genes has been shown to contribute to the malignant phenotype. Cytogenetic analyses of human tumor cells, including ovarian malignancies, frequently show cytological evidence of DNA amplification in the form of double minutes and homogeneously staining regions. In this report, we have combined the techniques of chromosome microdissection and fluorescence in situ hybridization (P. S. Meltzer et al., Nat. Genet., 1: 24-28, 1992) to identify the composition and chromosomal origin of seven homogeneously staining regions from seven cases of ovarian cancer. Twelve specific chromosome band regions were identified as amplified including 11q, 12p, 16p, 19p, and 19q. These results provide important insights into the organization of amplified sequences within ovarian malignancies and add further to our recognition of regions likely to harbor genes important to the development or progression of ovarian cancer.

Nonrandom inactivation of the Y-bearing X chromosome in a 46,XX individual: evidence for the etiology of 46,XX true hermaphroditism.

We previously reported a subject with 46,XX true hermaphroditism who had a 46,X,del(X) karyotype and Y-chromosomal sequences in genomic DNA. We hypothesized that the Y-chromosomal sequences were translocated to the deleted X chromosome and that the incomplete testis determination of this individual was the result of inactivation of the translocated X chromosome. In situ hybridization studies demonstrated that the Y-chromosomal sequences were located on the distal portion of the short arm of the deleted X chromosome. Investigation of the replication of the X chromosome, using a modified R-banding technique and localization of Y-chromosomal sequences by in situ hybridization, showed that the translocated X chromosome was late replicating in all 100 EBV-transformed lymphoblasts that were examined. By contrast, when cells from a subject with 46,XX maleness were studied, the translocated X chromosome was late replicating in only 21 of 47 cells. As the late-replicating X chromosome is presumed to be the inactive X chromosome, selection of cells in which the Y-bearing X chromosome has been inactivated may play a role in the incomplete testis determination in subjects with "Y-positive" 46,XX true hermaphroditism.

The Barr body is a looped X chromosome formed by telomere association.

We examined Barr bodies formed by isodicentric human X chromosomes in cultured human cells and in mouse-human hybrids using confocal microscopy and DNA probes for centromere and subtelomere regions. At interphase, the two ends of these chromosomes are only a micron apart, indicating that these inactive X chromosomes are in a nonlinear configuration. Additional studies of normal X chromosomes reveal the same telomere association for the inactive X but not for the active X chromosome. This nonlinear configuration is maintained during mitosis and in a murine environment.