Cytogenetic and array-CGH characterization of a complex de novo rearrangement involving duplication and deletion of 9p and clinical findings in a 4-month-old female.

Approximately 15 patients with partial trisomy 9p involving de novo duplications have been previously described. Here, we present clinical, cytogenetic, FISH and aCGH findings in a patient with a de novo complex rearrangement in the short arm of chromosome 9 involving an inverted duplication at 9p24-->p21.3 and a deletion at 9pter-->p24.2. FISH probes generated from BACs selected from the UCSC genome browser were utilized to verify this rearrangement. It is likely that some previously described duplications of 9p may also be products of complex chromosomal aberrations. This report in which FISH and aCGH were used to more comprehensively characterize the genomic rearrangement in a patient with clinical manifestations of 9p duplication syndrome underscores the importance of further characterizing cytogenetically detected rearrangements.

Molecular studies of segmental aneusomy: FISHing for the atypical cry in del(5)(p15.3).

We report a newborn male with multiple congenital anomalies including growth retardation, hypotonia, dysmorphic facies, widely-spaced nipples, micropenis, cryptorchidism, optic nerve hypoplasia, heart disease, and a striking, high-pitched cry. Chromosome analysis revealed de novo partial trisomy 11q due to a der(5)t(5;11)(p15.3;q22). Fluorescence in situ hybridization (FISH) showed loss of the 5p telomere signal on the der(5) chromosome, indicating the infant has partial monosomy 5p in addition to partial trisomy 11q. Among cases involving trisomy 11q, an unusual cry has only been documented in the presence of a der(5)t(5p;11q). This apparent dependence of the abnormal cry on monosomy 5p suggested the same genetic mechanism that occurs in Cri du chat syndrome (CDCS) may be responsible for the atypical cry in der(5)t(5p;11q) individuals. Neither a commercial CDCS probe (LSI D5S23, D5S721) nor a series of BAC clones encompassing distal regions implicated in the CDCS-associated cat-cry were deleted in our patient. These results suggest a second cry-modifying locus maps telomeric to BAC RP11-94J21 in band 5p15.33. This locus may not only cause the abnormal cry in individuals with a der(5)t(5p;11q) but could also contribute to the phenotypic variability and discordant mapping studies observed for CDCS.

Knowledge of and attitudes about Alzheimer disease genetics: report of a pilot survey and two focus groups.

OBJECTIVES: In preparation for the development of an educational intervention on Alzheimer disease (AD) genetics, we undertook a pilot survey of knowledge in this area and attitudes toward genetic testing for AD among individuals with a family history of AD. METHODS: For the pilot study, we administered a 30-min questionnaire to 57 unaffected individuals from a genetic linkage study. For the focus groups, we interviewed two groups of subjects, ages 44-70 years, with a family history of AD, one of 10 Caucasians and the other of 6 African-Americans. RESULTS: The pilot study showed that there was limited knowledge of genetics overall and AD genetics in particular, considerable concern about personal risk, and little knowledge of or interest in genetic testing for the disease. The focus groups reinforced and fleshed out these impressions and highlighted the importance of caregiving experience in the attitudes toward personal risk for AD. CONCLUSIONS: These results underscore the value of genetics education for this and other complex diseases and suggest specific foci for educational interventions.

Successful long-term treatment of hepatic carnitine palmitoyltransferase I deficiency and a novel mutation.

Individuals with carnitine palmitoyltransferase I (CPT-I) deficiency cannot metabolize long-chain fatty acids and can develop life-threatening hypoglycaemia. We present a boy with CPT-I deficiency maintained on a very low-fat diet with nighttime uncooked cornstarch feedings for 5(1/2) years with good success. He has had normal growth and no episodes of hypoglycaemia or adverse side-effects. We found that he was homozygous for a previously undescribed mutation, T314I, in the CPT1A protein.

Maternal antiepileptic drug use and effects on fetal development.

Many pregnant women take antiepileptic medications, and concern has arisen about the risks this poses to the fetus. It has been debated whether the causative agent is the medication or the underlying maternal disorder. Review of the recent literature indicates that the effects seem to be from the medications themselves. The frequency of malformations is about two to three-fold above the background rate and is dose-related for some of the medications. There seem to be effects on birth weight, length, and head circumference caused by at least some of the medications. The risks are greater when more than one medication is used. Cognitive effects from the medications have been shown, although these effects are of lower magnitude than previously reported. More investigation needs to be done to determine the exact risks of each individual medication, especially the newer ones. Studies on underlying mechanisms indicate potential genetic susceptibility and altered developmental gene expression patterns.

Under-recognition of prenatal alcohol effects in infants of known alcohol abusing women.

Medical records of 124 women and their infants were analyzed for: (1) documentation of maternal alcohol and other substance abuse and (2) evaluation of exposed infants. These results were compared with the study interview and infant examination. More obstetric nurses documented the presence or absence of alcohol and substance abuse than did pediatricians. More women reported using alcohol in the study interview than documented in the medical records. There was slightly better documentation for cocaine use than for alcohol use in the medical records. One of the 19 infants with documentation of maternal alcohol use was noted to have possible alcohol-related features by the pediatrician, in contrast to 7 infants identified by the study examiner. In addition, 2 of these 19 infants were determined by the study examiner to have fetal alcohol syndrome; neither case was diagnosed by the pediatricians. Continued efforts at education regarding the importance of asking about prenatal alcohol exposure and the spectrum of fetal alcohol effects are needed for early diagnosis.

Malformations reported in chorionic villus sampling exposed children: a review and analytic synthesis of the literature.

PURPOSE: To determine whether the frequency of vascular disruption defects, other than limb defects, is increased in reports of chorionic villus sampling (CVS) exposed children compared with an unexposed population. METHODS: Only studies that reported the total number of CVS-exposed pregnancies and details of pregnancy outcome, including all the malformations, were included. Twenty-five articles met these criteria. RESULTS: The frequencies of gastroschisis, intestinal atresias, and clubfoot were significantly increased among the CVS-exposed infants as compared with the baseline unexposed population. The frequencies of other vascular disruption defects, including Poland sequence, amniotic band sequence, and cleft lip/cleft palate, were not increased. CONCLUSION: CVS-exposed children have an increased frequency of intestinal atresia, gastroschisis, and clubfoot compared with the nonexposed population. The fact that an increased frequency of other defects attributed to vascular disruption was not found may be due to under-ascertainment, misclassification, or "lumping" of the defects identified in previous studies.

The prenatal detection of significant alcohol exposure with maternal blood markers.

OBJECTIVE: To examine the efficacy of a combination of 4 blood markers of alcohol use in detecting alcohol-abusing pregnant women. STUDY DESIGN: Two new markers of alcohol use, whole blood-associated acetaldehyde and carbohydrate-deficient transferrin, and 2 traditional markers of alcohol use, gamma-glutamyl transpeptidase and mean red blood cell volume, were measured in the blood of pregnant women. Each woman was interviewed about alcohol and drug use, medical and obstetric histories, and nutrition. Each infant was examined by a clinician who was blinded to exposure status. RESULTS: All of the women who reported drinking an average of 1 or more ounces of absolute alcohol per day had at least 1 positive blood marker. The infants of mothers with 2 or more positive markers had significantly smaller birth weights, lengths, and head circumferences than the infants with negative maternal screens. The presence of 2 or more positive markers was more predictive of infant outcome than any self-reporting measure. CONCLUSIONS: These markers, which detect more at-risk pregnant women than self-reporting methods, could lead to better efforts at detection and prevention of alcohol-induced fetal damage.

Marked heterogeneity in Niemann-Pick disease, type C. Clinical and ultrastructural findings.

Niemann-Pick disease type C (NP-C) is an autosomal recessive lysosomal lipid storage disorder of unknown etiology. Diagnosis of NP-C is based on characteristic clinical findings and reduced fibroblast esterification of LDL-derived cholesterol. We describe three patients who demonstrate the NP-C spectrum of clinical heterogeneity in age of onset, presenting signs, pattern of organ system involvement, and natural history. In addition, electron microscopic analysis of skin biopsy specimens from these patients revealed marked variability in the extent and cellular distribution of intralysosomal storage and was suggestive of the correct diagnosis in only one case. These cases demonstrate both the limitations of electron microscopy for diagnosis of NP-C and the marked clinical variability in patients with this disorder. Practical clinical guidelines for appropriate suspicion of NP-C are presented.

Genital abnormalities in females with Bardet-Biedl syndrome.

The major manifestations of the Bardet-Biedl syndrome are digital anomalies, tapetoretinal degeneration, obesity, renal abnormalities, and hypogenitalism (described mainly in males). We report on 2 girls with Bardet-Biedl syndrome who also had vaginal atresia. A similar association in females with Bardet-Biedl syndrome was suggested in published reports of 11 affected individuals who had structural genital abnormalities, (some of which were missed in childhood), including persistent urogenital sinus, ectopic urethra, hypoplasia of the uterus, ovaries and fallopian tubes, uterus duplex, and septate vagina. The association of atresia of the vagina and other malformations of female genital structures in individuals with Bardet-Biedl syndrome has often been missed in childhood and should be looked for more systematically.

A case of a closed partial cloacal septation defect with a patent urachus.

A boy with a closed partial cloacal septation defect with a patent urachus is reported. He had an intact abdominal wall, a patent urachus, a colovesical fistula, intact genitalia and urethra, imperforate anus, and a lipomyelocystocoele. Patients with similar constellation of findings have been reported as cloacal exstrophy variants. What distinguishes this case from the other reported variants is the intact abdominal wall with the patent urachus, the small and normally formed phallus and urethra, and the presence of a lipomyelocystocoele. We discuss the possible embryologic mechanism responsible for this boy's findings and possible relationship with the cloacal exstrophy spectrum. We also discuss new terminology for the epispadias-exstrophy spectrum. Furthermore this case reminds us that there is considerable variability within the epispadias-exstrophy spectrum.

A case of agnathia, situs inversus, and a normal central nervous system.

We report here a premature female infant with agnathia, low-set but normally formed ears, a downward eye slant, choanal atresia and a cleft palate. She had severe respiratory distress and died despite maximum intervention at 5 days of age. Autopsy revealed situs inversus totalis; crossed fused renal ectopia; agnathia; normal thyroid, larynx, trachea, and bronchi; incomplete lobation of the lungs; immature pulmonary development with early hyaline membranes; and a normal central nervous system. This lack of significant central nervous system abnormalities distinguishes this infant from the majority of previously reported infants with agnathia and situs inversus.