Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21.

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.

Transient elevation of sweat chloride concentration in a malnourished girl with the Mauriac syndrome.

Elevated sweat chloride concentration in a patient with Mauriac syndrome has been reported only once. The authors of that report regarded their patient's underlying malnutrition, and not Mauriac syndrome per se, as the cause of the elevated sweat chloride concentration. We describe a second example of transient elevation of sweat chloride concentration, which confirms that the malnutrition intrinsic to Mauriac syndrome, rather than the syndrome itself, was the probable cause of elevated sweat chloride values.

Marked female predilection in some syndromes associated with facial hemangiomas.

Analysis of the literature yielded 42 examples of the combination of sternal non-union and supraumbilical raphé without evidence of sex predilection. However, among an additional 31 cases in which the triad included facial hemangioma, there was almost exclusive female occurrence. Another condition involves extensive unilateral hemangioma of the face, absence of ipsilateral carotid and vertebral vessels, mental retardation, and Dandy-Walker malformation. Still another disorder has been proposed which includes facial hemangioma and dilatation of the carotid syphon. Both of these conditions exhibit marked female predilection. Examples of overlap of all three "disorders" cause the authors to question the independence of these disorders, hypothesizing instead that they represent a spectrum.

Prenatal diagnosis of Smith-Lemli-Opitz syndrome, type II.

Smith-Lemli-Opitz syndrome, type II (SLOS-II) is a severe autosomal recessive disorder characterized by a distinctive face, unusual cleft palate, postaxial polydactyly, congenital heart defects, renal anomalies, and male pseudohermaphroditism. We present the first report of prenatal diagnosis of SLOS-II, as well as an additional report of prenatal detection of multiple anomalies, in which a positive diagnosis of SLOS II was made postnatally. In neither case was the pregnancy known prospectively to be at risk for SLOS-II. In the former case, targeted sonographic examination at 31 weeks of gestation showed intrauterine growth retardation, atrioventricular septal defect, mesomelic shortening of the arms, small kidneys, overlapping fingers, and female external genitalia; a 46,XY chromosome constitution had been ascertained previously. A provisional diagnosis of SLOS-II was made prenatally. In the latter case, targeted sonographic examination at 18 weeks of gestation showed severe oligohydramnios, atrioventricular septal defect, and Dandy-Walker malformation. The kidneys and bladder were not visualized. The chromosome constitution was 46,XX. The diagnosis of SLOS-II was made postnatally. In both cases, additional findings compatible with SLOS-II were noted postnatally. Prenatal detection of congenital heart defects and renal abnormalities, in combination with certain additional findings (most notably, female external genitalia in the presence of a 46,XY karyotype, polydactyly, disproportionately short limbs, or intrauterine growth retardation) and a normal karyotype, suggests the diagnosis of SLOS-II, and warrants further investigation.

Familial medial telangiectatic nevus: variant of nevus flammeus--port-wine stain.

Six families in which a few members, in three generations, were affected with medial telangiectatic nevus (salmon patch, stork bite, angel's kiss) on the forehead, glabella, upper eyelids, upper lip, nose, and nuchal and occipital areas are presented. This is a mild variant of lateral telangiectatic nevus (nevus flammeus, port-wine stain) that disappears in about 50 percent of patients during the first years of life. In one family, lateral telangiectatic nevus (nevus flammeus, port-wine stain) and superficial (strawberry) hemangioma coexisted with medial telangiectatic nevus. This paper discusses the familial incidence of medial telangiectatic nevus and a new modality of treatment. Moreover, the paper presents a classification of vascular malformations and proposes a new terminology.

Dir dup(X) (q13-->qter) in a girl with growth retardation, microcephaly, developmental delay, seizures, and minor anomalies.

In males, duplication of a portion of Xq is associated with multiple congenital anomalies and developmental delay. Most females recognized as having dup(Xq) are phenotypically apparently normal relatives of phenotypically abnormal males; phenotypic normalcy has been attributed to selective inactivation of the duplicated X chromosome. Heretofore, apparently only 5 distinctly phenotypically abnormal females with dup(Xq) have been reported. We report on a 3-year-old girl with developmental delay, growth retardation, microcephaly, minor anomalies, and a seizure disorder who had a nonmosaic, de novo direct duplication of the terminal portion of one X chromosome. In each of 50 lymphocytes examined, the duplicated X chromosome was found to be late-replicating. This case shows that selective inactivation (as reflected by late replication) of the duplicated X chromosome does not inevitably confer phenotypic normalcy on females with dup(Xq), and suggests that other mechanisms must account for the phenotypic differences observed among females with dup(Xq), such as expression of recessive genes on the active X chromosome, incomplete inactivation of some portion of the duplicated chromosomal segment, an imprinting effect, or some combination of these.

Balanced reciprocal translocation mosaicism associated with an abnormal phenotype.

Balanced reciprocal translocation mosaicism is rarely reported in humans. Only two previous cases have been associated with an abnormal phenotype. We report on a third case of apparently balanced reciprocal translocation mosaicism associated with an abnormal phenotype, largely different from those reported previously. Since low levels of mosaicism may not be detected in routine cytogenetic analyses, balanced reciprocal translocation mosaicism may be associated with an abnormal phenotype more often than has been recognized to date.

Müllerian duct abnormalities and galactosaemia heterozygosity: report of a family.

Familial aggregates of Müllerian fusion anomalies (MFAs) and of Müllerian aplasia (MA) are rare. I report the case of a girl with MA and 'streak-like' ovaries, whose mother had a MFA. No similar mother-daughter pair appears to have been reported previously. The girl, mother, and maternal grandmother each have low galactose-1-phosphate uridyl transferase activities and are each heterozygous for the 'classic' galactosaemia allele. These findings support previous suggestions that MA may sometimes be related to abnormal galactose metabolism, and further suggest that, in some cases, MFAs may also be related to disordered galactose metabolism.

Cholelithiasis in infants with Down syndrome. Three cases and literature review.

Only four cases of cholelithiasis have been reported in patients with Down syndrome and none in Down syndrome infants. The cases of three Down syndrome infants (all males) with cholelithiasis are reported. Each exhibited different fetal complications, and in each, Down syndrome was diagnosed at birth. Gallstones apparently were congenital (a rarity) in one infant, since they were detected on the first day of life. Cholelithiasis was an incidental finding in another of the infants when, at 12 weeks old, he had renal ultrasonography because of a urinary tract infection. The third infant was 4 months old when sonographic studies revealed a gallstone. Despite the confirmation of cholelithiasis in all three infants, none has since had any signs or symptoms that suggest the need for intervention. Cholelithiasis is probably more common in Down syndrome infants than has been supposed, but whether Down syndrome infants with gastrointestinal (GI) malformations are more likely to have gallstones than are children with similar GI malformations but with normal karyotypes is unknown.

Chromosome 7p--syndrome: craniosynostosis with preservation of region 7p2.

Deletion of a portion of the short arm of chromosome 7 is associated with a recognizable phenotype which often includes craniosynostosis. Recent reports have suggested that craniosynostosis occurs only if there is a deletion involving band 7p21 or the segment distal to that band. We report on a boy who had an interstitial deletion of 7p, not involving band 7p21 or the segment distal to that band, who nevertheless had craniosynostosis. Thus, it appears that the determination of craniosynostosis in this syndrome is more complicated than has been suggested previously.

Single maxillary central incisor in a girl with del(18p) syndrome.

We present a girl with del(18p) syndrome and a single maxillary central incisor; she is only the second patient in whom this association has been reported.

Dizygotic twins concordant for truncus arteriosus.

Persistent truncus arteriosus (TA) is an uncommon congenital cardiovascular malformation, which comprises between 0.4% and 4% of all congenital heart defects. Occurrence of TA in siblings has been reported infrequently. Twins concordant for isolated TA appear to have been reported only once previously. In this paper, we describe dizygotic twin females who were concordant for isolated TA.

Nasopharyngeal teratoma ('hairy polyp'), Dandy-Walker malformation, diaphragmatic hernia, and other anomalies in a female infant.

Nasopharyngeal teratomas are rare and are infrequently associated with extra-oral malformations. The case of a premature female infant with multiple congenital anomalies, including nasopharyngeal teratoma, Dandy-Walker malformation, diaphragmatic hernia, and congenital heart defect, is presented. This constellation of malformations does not appear to have been reported previously.

Physical features of Prader-Willi syndrome in neonates.

A retrospective study of 16 patients was undertaken to identify physical features that may typify neonates with Prader-Willi syndrome. Several features known to be typical of Prader-Willi syndrome in early infancy were confirmed, including hypotonia and genital hypoplasia. A number of features that have not previously been emphasized as characterizing Prader-Willi syndrome were also identified, most notably abnormal cry and, in males, signs of genital hypoplasia but with an apparently normal phallus. Other features included disproportionately large head circumference, disproportionately large anterior fontanelle, mild micrognathia, mild anomalies of the gingivae or alveolar ridges, and changes in the appearance of the skin. Appreciation of these features may assist the pediatrician in recognizing the child with Prader-Willi syndrome during the neonatal period, before the appearance of better-known findings of later onset, such as obesity and acromicria.