A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism.

Whole genome profiling such as array comparative genomic hybridization has identified novel genomic imbalances. Many of these genomic imbalances have since been shown to associate with developmental delay, intellectual disability and congenital malformation. Here we identified five unrelated individuals who have a recurrent 1.71 Mb deletion/duplication at 2q13 (Human Genome Build 19: 111,392,197-113,102,594). Four of these individuals have developmental issues, four have cranial dysmorphism. Literature review revealed 14 more cases that had similar genomic imbalances at 2q13. Many of them had developmental delay and dysmorphism. Taken together, 93% and 63% of individuals with this genomic imbalance displayed impaired developmental skills and/or abnormal facial features respectively. This copy number variant (CNV) has not been reported in normal control databases. We, therefore, propose that CNV in this region is a risk factor for developmental delay and dysmorphism.

Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders.

BACKGROUND: Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. PATIENTS: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. RESULTS: We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. CONCLUSIONS: The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.

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.

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.

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.

NPHP3 mutations are associated with neonatal onset multiorgan polycystic disease in two siblings.

Two siblings with a severe multiorgan polycystic disease presenting in the neonatal period were identified. Their genetic testing identified compound heterozygous NPHP3 gene mutations, parents being heterozygous carriers. The mutations included a splice-site (c.958-2A>G) and a missense mutation (c.2342G>A; p.G781D), both being extremely rare. NPHP3 encodes for nephrocystin 3 present on the cilia-centrosome complex. We hypothesize that these mutations lead to defective cilia-based signaling, required for normal development of the renal, pancreatic, biliary and portal system. This report outlines a rare neonatal ciliopathy presentation of NPHP3 mutations leading to severe multiorgan failure in two siblings.

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.

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.

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.

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.

Pancreatitis in Kawasaki disease.

Two children with Kawasaki disease presented with vomiting, back and abdominal pain, elevated serum amylase values, and ultrasonographic findings consistent with pancreatitis. In both patients, pancreatitis appeared after approximately two weeks of illness, and both patients underwent extensive evaluations, which yielded negative results, for other disorders associated with pancreatitis. We suggest that in the absence of acute infection, and in the presence of appropriate diagnostic criteria, pancreatitis should be considered in all patients with Kawasaki disease who have severe abdominal pain.

Detection of antisperm antibodies: a cytotoxicity immobilization test.

The sera of 110 couples with unexplained infertility were examined for anti-sperm immobilizing antibodies with the aid of multiple-exposure photography. The sera of 10 females and 3 males had immobilizing activity. Eleven pregnancies occurred in 10 female patients in the group without immobilizing antibodies. None of the 13 females in the couples with immobilizing activity conceived. A negative correlation was found between the occurrence of serum immobilizing antibodies and incidence of pregnancy. No such correlation could be found between the occurrence of autoagglutination in the male's ejaculate and the female partner conceiving. In light of detection of anti-sperm antibodies in a patient with habitual abortions, a possible immune mechanism is suggested.

Endogenous digoxin-like immunoreactivity measured in seminal fluid from a normal male population.

Endogenous digoxin-like immunoreactivity (EDLI) has been detected in different biological fluids and in several pathophysiological conditions. In this study, using radioimmunoassay we reported for the first time the existence of bound and unbound EDLI in normal seminal fluid. The unusual finding was the detection of unbound EDLI in the seminal fluid, while this reactivity was undetected in plasma. Two main hypotheses are presented: (1) local secretion of unbound EDLI and/or (2) passive diffusion from plasma to the seminal fluid of unbound EDLI and subsequent local concentration.

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.