Large duplication in MTM1 associated with myotubular myopathy.

Myotubular myopathy is a subtype of centronuclear myopathy with X-linked inheritance and distinctive clinical and pathologic features. Most boys with myotubular myopathy have MTM1 mutations. In remaining individuals, it is not clear if disease is due to an undetected alteration in MTM1 or mutation of another gene. We describe a boy with myotubular myopathy but without mutation in MTM1 by conventional sequencing. Array-CGH analysis of MTM1 uncovered a large MTM1 duplication. This finding suggests that at least some unresolved cases of myotubular myopathy are due to duplications in MTM1, and that array-CGH should be considered when MTM1 sequencing is unrevealing.

Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations.

We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.

Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics.

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

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.