Analysis of speech characteristics in children with velocardiofacial syndrome (VCFS) and children with phenotypic overlap without VCFS.

OBJECTIVE: To address two questions of theoretical importance regarding the profile and course of communication impairment associated with velocardiofacial syndrome (VCFS): (1) do speech characteristics of children with VCFS differ from a group of children with some of the phenotypic characteristics of VCFS who do not have the syndrome, and (2) do younger children with VCFS demonstrate speech patterns that differ from older children with VCFS? DESIGN: Prospective, cross-sectional study comparing two groups of children at two age levels. PATIENTS: Thirteen children with VCFS and eight children with some of the phenotypic features of VCFS who did not have the syndrome. Children ranged in age from 3 to 10 years. MAIN OUTCOME MEASURE: (1) Broad phonetic transcription of speech yielding measures of number of consonant types, Percent Consonant Correct, and percentage of glottal stops used; and (2) composite ratings of velopharyngeal function made from perceptual, aerodynamic, and endoscopic evaluations. RESULTS: Younger children with VCFS demonstrated greater speech impairment than older children with VCFS or the children without VCFS, such as smaller consonant inventories, greater number of developmental errors, greater severity of articulation disorder, and higher frequency of glottal stop use. The relationship between ratings of velopharyngeal function and the speech variables analyzed was not straightforward. CONCLUSIONS: Some young children with VCFS demonstrated speech impairment that is qualitatively and quantitatively different from older children with VCFS or children without VCFS. This finding supports the hypothesis that some children with VCFS demonstrate a profile of speech production that is different from normal but also may be specific to the syndrome.

Fluconazole-induced congenital anomalies in three infants.

Fluconazole has been associated with various teratisms in animals, including craniofacial ossification defects, thin, wavy ribs, and renal pelvis defects. We describe three infants born to women who were receiving fluconazole through or beyond the first trimester of pregnancy. All of the infants had congenital anomalies; no other drug was implicated. Only one of the three infants survived. Their anomalies, similar to those observed in animal studies, were largely craniofacial, skeletal (i.e., thin, wavy ribs and ossification defects), and cardiac. One of these infants was previously reported as having Antley-Bixler syndrome; however, given the chronology described herein and the similarity of this infant to the others, we conclude that her deformities also represent the potent teratogenic effect of fluconazole.

Ocular findings associated with a Cys39Arg mutation in the Norrie disease gene.

OBJECTIVE: To diagnose the carriers and noncarriers in a family affected with Norrie disease based on molecular analysis. DESIGN: Family members from three generations, including one affected patient, two obligate carriers, one carrier identified with linkage analysis, one noncarrier identified with linkage analysis, and one female family member with indeterminate carrier status, were examined clinically and electrophysiologically. Linkage analysis had previously failed to determine the carrier status of one female family member in the third generation. Blood samples were screened for mutations in the Norrie disease gene with single-strand conformation polymorphism analysis. The mutation was characterized by dideoxy-termination sequencing. RESULTS: Ophthalmoscopy and electroretinographic examination failed to detect the carrier state. The affected individuals and carriers in this family were found to have a transition from thymidine to cytosine in the first nucleotide of codon 39 of the Norrie disease gene, causing a cysteine-to-arginine mutation. Single-strand conformation polymorphism analysis identified a patient of indeterminate status (by linkage) to be a noncarrier of Norrie disease. CONCLUSION: Ophthalmoscopy and electroretinography could not identify carriers of this Norrie disease mutation. Single-strand conformation polymorphism analysis was more sensitive and specific than linkage analysis in identifying carriers in this family.

Linkage localization of Börjeson-Forssman-Lehmann syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is a form of X-linked mental retardation (XLMR) with characteristic minor physical anomalies. It has no biochemical or cytogenetic markers. Heterozygous females may be entirely normal or may have mild-to-moderate manifestations. We studied 41 individuals from one family with BFLS for linkage on the X chromosome. The highest lod scores were 2.32 with DXS10 and 2.24 with DXS51, both at a theta = 0.0. A single recombinant was found between HPRT and BFLS. These results suggest that the BFLS locus is on the distal portion of Xq. Previously reported linkage studies in families with XLMR have not shown linkage with DXS10. This study suggests that one of the several X chromosome loci whose dysfunction is associated with mental retardation is located on distal Xq.

X-linked progressive cone dystrophy. Clinical characteristics of affected males and female carriers.

The authors evaluated nine affected males and six female carriers from a four-generation family with X-linked cone dystrophy. As the affected males grew older, visual acuity deteriorated, central scotomas deepened, and macular changes became more prominent. There was granularity of the macula in younger individuals and bull's eye lesions and central geographic atrophy of the retinal pigment epithelium (RPE) in the older subjects. The retinas of some affected males had a bronze-green tapetal-like sheen. Color vision was impaired in all affected males and resembled an acquired type II defect (Verriest classification). One younger subject had paradoxical pupillary constriction to darkness. Visual-evoked potential (VEP) latencies were prolonged in some affected males, suggesting that photoreceptor degeneration caused transsynaptic degeneration of ganglion cells. All female carriers had visual acuities of 20/30 or better, but some showed mild ophthalmoscopic changes and abnormalities of color vision, electroretinograms (ERGs), and VEPs.

Microcephaly in familial holoprosencephaly.

The holoprosencephaly sequence (HS) is characterized by abnormalities in forebrain cleavage and midface development. Familial holoprosencephaly has been reported in several families and there appears to be variable expression of the disorder in those who inherit the gene. Previous investigators have suggested hypotelorism and/or missing central incisors as mild manifestations of autosomal dominant HS. We evaluated a large kindred with three individuals with severe brain anomalies and 12 individuals with minor manifestations of the disorder. The most consistent sign in those mildly affected was microcephaly. We suggest that head circumference is an important part of the evaluation of the relatives of a patient with holoprosencephaly.

Localisation of Xp21 meiotic exchange points in Duchenne muscular dystrophy families.

The inheritance of Duchenne muscular dystrophy in 25 families was studied with 13 X chromosome specific cloned DNA fragments from 10 loci in and surrounding Xp21. When multiple probes were informative, the meiotic exchange points for each meiosis were located in individual families. Neither genetic nor physical evidence indicates an unusually high recombination rate across Xp21 in these 25 families.

Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal insufficiency associated with Xp21 interstitial deletion.

We report an interstitial deletion in the short arm of the X chromosome in a 6-year-old boy with Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal insufficiency, intermittent hypoglycemia, spasticity, psychomotor retardation, and growth delay. His mother also has this deletion in an X chromosome. From our findings, we propose that the human glycerol kinase locus and the human X-linked adrenal hypoplasia locus are in the Xp21 band.

Glycerol kinase deficiency inhibits glycerol utilization in phosphoglyceride and triacylglycerol biosynthesis.

Glycerol 3-phosphate is an initial metabolite in the biosynthesis of phosphoglycerides and triacylglycerols. Both glycerol and glucose are precursors of glycerol 3-phosphate. Cultured skin fibroblasts from patients with glycerol kinase deficiency utilized glucose, but not glycerol in the biosynthesis of phosphoglycerides and triacylglycerols. Phosphoglyceride and triacylglycerol biosynthesis in glycerol kinase deficiency fibroblasts is not diminished by the inability to use glycerol as a precursor of glycerol 3-phosphate.

Orbital hypotelorism. An isolated autosomal dominant trait.

Four patients from three consecutive generations of a family with ocular hypotelorism are described. Radiographs document a subnormal distance between the medial orbital walls. To our knowledge, this is the first report of heritable isolated orbital hypotelorism. The pedigree is consistent with an autosomal dominant disorder.

Abnormality of chromosome 11 in patients with features of Beckwith-Wiedemann syndrome.

Two unrelated children with features of Beckwith-Wiedemann syndrome have been found to have partial duplication of chromosome 11p. A review of six other reported cases of partial duplication of 11 p revealed features of this syndrome not previously recognized. We suggest that karyotype studies with banding techniques should be done in children with features of Beckwith-Wiedemann syndrome and developmental delay or retardation.

Deletions of different segments of the long arm of chromosome 4.

We report the clinical and chromosomal findings in 8 patients with deletions of the long arm of chromosome 4. Four of these patients appear to have terminal deletions beginning in band 4q31, and therefore, lack the digital 1/3 of the long arm of chromosome 4. We confirm that deletion of 4q31 leads to qter causes a recognizable syndrome, and we further define the phenotype of that syndrome. A 5th patient has a horter terminal deletion, ie, 4q33 leads to qter. This deletion causes a milder phenotypic expression than that seen in the severe 4q terminal-deletion syndrome. The remaining 3 patients have interstitial deletions of the long arm of the 4th chromosome, including segments 4q21.1 leads to q25, 4q21.3 leads to q26, and 4q27 leads to q31.3. The phenotypic expression noted in these patients is variable in differs from the 4q terminal-deletion syndrome.

Prenatal diagnosis of dysplastic kidney disease.

Sonolucent areas in the region of the kidneys were demonstrated by ultrasound in a 23-week-old fetus. These sonolucent areas persisted and enlarged during the pregnancy and the infant had the Potter phenotype and Potter type 2A dysplastic kidneys at birth. The use of prenatal sonographic evaluation of the fetal kidneys is discussed.