Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions.

TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1's role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.

Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1.

Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders.

BACKGROUND: Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia. METHODS AND RESULTS: Based on routine diagnostic testing of approximately 8200 samples using array comparative genomic hybridisation, we identified 20 individuals (14 children and six parents in 12 families) with microdeletions of 15q13.3. Phenotypes in the children included developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems. Both parents were available in seven families, and the deletion was de novo in one, inherited from an apparently normal parent in four, and inherited from a parent with learning disability and bipolar disorder in two families. Of the 14 children, six in five families were adopted, and DNA was available for only one of these 10 biological parents; the deletion was very likely inherited for one of these families with two affected children. Among the unavailable parents, two mothers were described as having mental retardation, another mother as having "mental illness", and one father as having schizophrenia. We hypothesise that some of the unavailable parents have the deletion. CONCLUSIONS: The occurrence of increased adoption, frequent autism, bipolar disorder, and lack of penetrance are noteworthy findings in individuals with deletion 15q13.3. A high rate of adoption may be related to the presence of the deletion in biological parents. Unconfirmed histories of antisocial behaviours in unavailable biological parents raise the concern that future research may show that deletion 15q13.3 is associated with such behaviours.

The impact of group fissions on genetic structure in Native South America and implications for human evolution.

In a series of publications beginning in the 1960s, Neel and colleagues suggested that genetically nonrandom, or "lineal", population fissions contributed to genetic structure in ancient human groups. The authors reached this conclusion by studying the genetic consequences of village fissions among the Yanomamo, a Native South American group thought to have been relatively unaffected by European contact and, therefore, representative of the human past. On the basis of ethnographic accounts and pedigree data, they further concluded that patrilineal relationships were particularly important in shaping the genetic structure of villages following fissions. This study reexamines the genetic consequences of village fissions using autosomal STRs, Y-chromosome STRs, and mitochondrial DNA sequences collected from large samples of individuals from multiple Yanomamo villages. Our analyses of the autosomal STRs replicate the previous finding that village fissions have produced substantial genetic structure among the Yanomamo. However, our analyses of Y-chromosome STRs and mtDNA d-loop polymorphisms suggest that other population processes, including village movements, inter-village migration, and polygynous marriage, affect genetic structure in ways not predicted by a simple model of patrilineal fissions. We discuss the broader implications of population fissions for human evolution and the suitability of using the Yanomamo as a model for the human past.

The forgotten female: Pediatric and adolescent gynecological concerns and their reproductive consequences.

Future reproductive performance is not often addressed in pediatric and adolescent gynecological conditions. This overview reviews conditions that present in childhood and adolescence and discusses what is known about the future fertility in these women. The following topics are selected: STD exposure, dysfunctional uterine bleeding, eating disorders, adolescent athletics, polycystic ovarian syndrome, premature ovarian failure, childhood cancer survivors, Mullerian duct anomalies, congenital adrenal hyperplasia, cystic fibrosis, and epilepsy.

Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X-linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function.

Novel ring chromosome composed of X- and Y-derived material in a girl with manifestations of Ullrich-Turner syndrome.

We present a female infant who has a novel genetic variant of Ullrich-Turner syndrome. Chromosome analysis on amniotic fluid cells obtained because of ultrasound observation of nuchal thickening showed 45,X in all cells. The infant was born with a low posterior hairline and moderate edema over hands and feet. Postnatal chromosome analysis demonstrated two cell lines-47% of the metaphases were 45,X, but 53% had a ring chromosome in addition to the normal X. FISH studies using alpha satellite probes, an X-whole-chromosome-paint (WCP) probe, and a Y-cocktail probe determined that the ring was composed of both X and Y sequences. FISH studies also determined that the KAL locus was present on the ring, but that XIST was absent. PCR-based analysis of lymphocyte DNA documented that the ring contained sequences from both the short and the long arm of the Y chromosome. X-chromosome analysis using a panel of highly polymorphic markers indicated that the ring contained material derived only from Xp22.1 to Xp21.3. No Xq material was identified on the ring, and androgen receptor-based X-inactivation studies suggested that the intact X chromosome was not subject to random X inactivation.

Two distal mutations in the gene encoding emerin have profoundly different effects on emerin protein expression.

Emerin, the product of the gene responsible for X-linked Emery-Dreifuss muscular dystrophy (EDMD), has a ubiquitous tissue distribution and is localised to the nuclear envelope. We present here the relationship between emerin protein expression, nuclear localization and clinical phenotype for two distal mutations identified in unrelated EDMD patients. The first mutation predicts the replacement of the last eight amino acids of emerin with the addition of 101 amino acids, but no emerin expression is detected. The second mutation, 35 bp upstream from the first mutation, deletes six amino acids from the transmembrane region, but in this case emerin expression is seen. Emerin from this second patient is expressed at reduced levels, mistargeted and has altered biochemical properties compared to wild type emerin. In both cases the clinical phenotype was similar to patients with typical null mutations. We discuss these data in comparison with previous reports of other C-terminal mutations in the emerin gene and suggest that the efficiency of emerin's nuclear membrane localization is affected by the hydrophobicity (and possibly length) of its transmembrane region, and a longer C-terminal tail prevents nuclear localization.

Prenatal diagnosis of fatal infantile olivopontocerebellar hypoplasia syndrome.

We report the first case of prenatal diagnosis of fatal infantile olivopontocerebellar hypoplasia syndrome, OMIM 225753. Ultrasound findings noted at 28 weeks' gestation included polyhydramnios, a small stomach bubble, a small but morphologically normal cerebellum, dilatation of the fourth ventricle, and long periods of normal fetal movement punctuated by sudden bursts of violent seizure-like activity of the fetal extremities. At birth, the child was noted to be hypertonic, myoclonic, hyper-reflexic, demonstrated poor gastrointestinal motility, and had severe apneic episodes. Magnetic resonance imaging (MRI) demonstrated marked hypoplasia or atrophy of the cerebellum, pons and medulla, mild atrophy of the cerebral cortex, and mild ex vacuo venticulomegaly of the fourth, third and lateral ventricles. This child died from respiratory insufficiency at 14 days of age. The parents of this child had previously lost a child with similar clinical and anatomical findings. Prenatal sonographers should be aware of the existence of this rare syndrome and should look carefully at the size of the cerebellum in cases of polyhydramnios or when in utero 'seizure-like' activity is seen. The importance of establishing this diagnosis lies in the fact that it appears to have a very poor postnatal prognosis and is likely to be inherited as an autosomal recessive disease.

Vaginal and uterine anomalies in the pediatric and adolescent patient.

Congenital malformations of the vagina, cervix, and uterus, although rare, may have profound implications for the young gynecological patient. These anomalies are often detected in the adolescent period. For proper management, the physician requires a thorough understanding of normal embryology and sexual differentiation. Although clinical experience helps the gynecologist appreciate the disturbed anatomic configurations, each and every individual who presents with a defect must be thoroughly evaluated because genital tract aberrations do not necessarily follow any defined and consistent pattern. Other anomalies often coexist, particularly related to the renal tract, so a thorough assessment is warranted. Genital malformations can be particularly disturbing to the patient and her family because they not only have reproductive implications but also significant psychological and sexual overtones that need to be addressed and dealt with in a sensitive and reassuring manner. This report is meant to provide an overview of the various abnormalities encountered and guide the clinician by providing an approach to management. A more indepth discussion is best found in the classic textbooks (Rock JA: Surgery for anomalies of the müllerian ducts. In: Te Linde's Operative Gynecology (8th ed). Edited by J Rock, J. Thompson. Philadelphia, Lippincott-Raven, 1997; Edmonds DK: Sexual development anomalies and their reconstruction: upper and lower tracts. In: Pediatric and Adolescent Gynecology. Edited by J Sanfilippo, D Muram, P Lee, J Dewhurst. Philadelphia, W.B. Saunders, 1994; Jones HW Jr: Reconstruction of congenital uterovaginal anomalies. In: Female Reproductive Surgery. Edited by J Rock, A Murphy, HW Jones Jr. Baltimore, Williams & Wilkins, 1992).

Anovulation and monophasic cycles.

Normal pubertal development is often considered complete when the adolescent experiences her first menstrual period. However, sexual maturity is not attained until the onset of regular ovulatory cycles, which may take a number of months to years to accomplish. This maturation process is orchestrated by a neuroendocrine cascade and modified by autocrine and paracrine events in the ovary. The control of these complex relationships takes time and could not be expected to be fully functional with menarche. During the first menstrual months, the hypothalamic-pituitary-ovarian axis is immature, resulting in the secretion of only estrogens from the developing follicles; positive feedback to trigger ovulation develops later. Consequently, estrogen secretion is variable and unopposed by progesterone, which would normally be produced in ovulatory cycles. Estrogen-only primed endometrium often leads to irregular menstrual cycles with variable flow. Surprisingly, most adolescents do well and have few complaints in spite of these anovulatory cycles. If an abnormality is experienced with the menstrual cycle, once understood physiologically, it can be managed simply, by watchful expectancy or intermittent progestin therapy. Occasionally, sever menstrual bleeding is encountered, and in a proportion of these patients a thorough assessment will delineate an underlying medical problem that needs to be addressed. The management of these patients requires ingenuity from the pediatric reproductive endocrinologist and aggressive hormonal manipulation. Most patients do well, but some require long-term continuing care.

Quantitative research on therapeutic touch. An integrative review of the literature 1985-1995.

Quantitative research on Therapeutic Touch (TT), published in referred nursing journals from 1985 to 1995, is reviewed. Therapeutic Touch is defined by Dolores Krieger, the founder of this nursing intervention. The authors of this Integrative Review examine what is known and not known to date in order to facilitate appropriate application of this modality in practice, and to offer recommendations for future research. Critical characteristics of eleven quantitative studies are identified and analyzed. These characteristics include: author/year/journal/title; study purpose (hypotheses); background/literature review/conceptual citations; sample selection method; study design/random assignment; independent variable/length of treatment/control and confounders; dependent variables/measurements; outcomes; study limitations; and implications for future research. After reviewing the studies, it is concluded that there is evidence to support the practice of Therapeutic Touch for the reduction of pain or anxiety. There is clearly a lack of congruity between the research statement, conceptual framework, operational definition of TT and the findings. This incongruity is discussed and incorporated in the recommendations for future research including outcome, theory-generating and theory-testing research.

A randomized clinical trial of oxidized regenerated cellulose adhesion barrier (Interceed, TC7) alone or in combination with heparin.

OBJECTIVE: To compare the efficacy of heparin-saturated oxidized regenerated cellulose absorbable adhesion barrier, Interceed (TC7; Johnson and Johnson Medical Inc., New Brunswick, NJ) to oxidized regenerated cellulose alone for the prevention of postoperative adhesions. DESIGN: Clinical trial. By random assignment, one ovary was wrapped in oxidized regenerated cellulose, and the contralateral ovary was wrapped in oxidized regenerated cellulose saturated with a heparin solution (1,000 U/mL). PATIENT(S): Forty women with defects on both ovaries due to adhesiolysis and/or ovarian cystectomy. MAIN OUTCOME MEASURE: Adhesion formation and raw ovarian surface area were assessed at second-look laparoscopy 10 days to 16 weeks later. RESULT(S): At the second-look laparascopy-adhesions were present on 52.5% (21/40) of the ovaries treated with oxidized regenerated cellulose plus heparin and in 65% (26/40) of the contralateral ovaries treated with oxidized regenerated cellulose alone. For ovaries treated with oxidized regenerated cellulose plus heparin, the raw surface area was reduced from 9.41 +/- 1.27 cm2 (mean +/- SE) at laparotomy to 1.33 +/- 0.52 cm2 at second-look laparoscopy. The corresponding figures for ovaries treated with oxidized regenerated cellulose alone were from 10.24 +/- 1.08 to 1.92 +/- 0.54 cm2, respectively. The mean difference between the reductions in raw surface area (85.9% for oxidized regenerated cellulose plus heparin; 81.3% for oxidized regenerated cellulose alone) was not significantly different from zero (difference = - 0.24 cm2; 95% confidence interval = -2.56 to 3.04). CONCLUSION(S): Adding heparin did not enhance significantly the adhesion-reducing capacity of oxidized regenerated cellulose adhesion barrier when applied to ovarian surfaces after cystectomy and/or ovariolysis at laparotomy. This conclusion is subject to the possibility of a type II error.

Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation syndrome despite mini-dose heparin prophylaxis.

Thromboembolic events are serious but rare complications following ovarian stimulation for in-vitro fertilization (IVF). We report a case of severe ovarian hyperstimulation syndrome (OHSS), presenting in a second IVF cycle with a late complication of right internal jugular vein thrombosis despite mini-dose heparin prophylaxis. Thrombosis and thromboembolism as late complications of OHSS have been reported by others but not after prophylactic heparinization. The patient was successfully treated with heparin and the twin pregnancy is ongoing. In pregnant patients with severe OHSS consideration should be given to treatment with low dose heparin throughout the first trimester to prevent the serious complications of thrombosis and thromboembolism.

Intravenous albumin does not prevent the development of severe ovarian hyperstimulation syndrome in an in-vitro fertilization programme.

A cohort study was undertaken to compare the effect at the time of oocyte retrieval of the i.v. administration of either 1000 ml of lactated Ringer's solution or 1000 ml of a 5% solution of human albumin on in-vitro fertilization patients at risk for severe ovarian hyperstimulation syndrome (OHSS). A total of 207 patients with an oestradiol concentration > 10,000 pmol/l and/or > 15 follicles (> 10 mm diameter) on the day of human chorionic gonadotrophin (HCG) injection were reviewed. Of these, 158 women received 500 ml of lactated Ringer's solution both before and after egg retrieval, and 49 women received two infusions of 500 ml of 5% human albumin in normal saline at the time of egg retrieval. Severe OHSS developed in two patients who received human albumin and in 10 women who did not receive the albumin. This difference was not statistically significant. There were no differences between the two groups in terms of age, number of follicles punctured at transvaginal oocyte retrieval or oestradiol concentration at the time of HCG injection. The administration of a 5% human albumin solution does not prevent the development of severe OHSS in at risk patients. It does appear to blunt the severity of the condition.

Technical report: fallopian tube recanalization--a simplified technique.

A simplified technique of fallopian tube catheterization is described in which the tube is recanalized with a guidewire alone. The technique has been used to treat 13 infertile women, age range 27-39 years (mean 32 years), with a diagnosis of proximal tubal obstruction. One tube was perforated; all other tubes were successfully recanalized. Three women conceived within 10 months of the procedure. The technique has results similar to the standard coaxial catheter method but is simple and quick.

Human serum biotinidase. cDNA cloning, sequence, and characterization.

Biotinidase (EC 3.5.1.12) catalyzes the hydrolysis of biocytin, the product of biotin-dependent carboxylase degradation, to biotin and lysine. Biotinidase deficiency is an inherited metabolic disorder of biotin recycling that is characterized by neurological and cutaneous abnormalities, and can be successfully treated with biotin supplementation. Sequences of tryptic peptides of the purified human serum enzyme were used to design oligonucleotide primers for polymerase chain reaction amplification from human hepatic total RNA to generate putative biotinidase cDNA fragments. Sequence analysis of a cDNA isolated from a human liver library by plaque hybridization with the largest cDNA probe revealed an open reading frame of 1629 bases encoding a protein of 543 amino acid residues, including 41 amino acids of a potential signal peptide. Comparison of the open reading frame with the known biotinidase tryptic peptides and recognition of the expressed protein encoded by this cDNA by monoclonal antibodies prepared against purified biotinidase demonstrated the identity of this cDNA. Southern analyses suggested that biotinidase is a single copy gene and revealed that human cDNA probes hybridized to genomic DNA from mammals, but not from chicken or yeast. Northern analysis indicated the presence of biotinidase mRNA in human heart, brain, placenta, liver, lung, skeletal muscle, kidney, and pancreas.

Tetrasomy 9p: tissue-limited idic(9p) in a child with mild manifestations and a normal CVS result. Report and review.

Supernumerary isochromosomes resulting in autosomal tetrasomy are rare and have been described only for 12p, 18p, and 9p. Nineteen previous cases of tetrasomy 9p have been reported, and in 6 cases, tissue-specific mosaicism was implied with the i(9p) cell line present exclusively or predominantly in blood. We report on an infant who had apparently normal chromosomes (46,XY) on CVS. He was referred for genetic evaluation because of mild developmental delay and minor anomalies. In 75% of blood cells he had an extra isodicentric 9p chromosome (pter-->q12-->pter). The interpretation of tetrasomy 9p was confirmed by elevated GALT activity. No tetrasomy 9p cells were seen in 100 skin fibroblasts. This case demonstrates the tissue specific mosaicism in tetrasomy 9p which rendered the anomaly undetectable by CVS. It also demonstrates the mild end of the clinical spectrum associated with tetrasomy 9p.

Natural cycle in vitro fertilization-embryo transfer at the University of Ottawa: an inefficient therapy for tubal infertility.

OBJECTIVE: To describe our experience with natural cycle IVF making clinical and endocrine comparisons with our standard stimulated cycle IVF program. DESIGN: We attempted 75 natural IVF-ET cycles with hCG given to preempt the LH surge and compared these with 450 attempts at standard superovulation IVF-ET done in our unit during the same time period. PATIENTS: Natural cycle patients are normally ovulating women < age 38. Superovulation IVF-ET patients are all < 41 years old. Patients in both groups had partners with normal semen parameters and tubal factor infertility. MAIN OUTCOME MEASURES: Cancellation rates, pregnancy rates per egg retrieval, per ET procedure, and luteal phase E2:P ratios of the treatment cycles are compared. RESULTS: There were 35 of 75 (47%) natural cycle and 112 of 450 (25%) superovulation cycle cancellations. An egg was retrieved in only 24 of 40 (60%) natural cycles and 336 of 338 (99%) superovulation egg retrieval procedures. Pregnancy rates per ovum pick-up procedure were significantly higher: 65 of 338 (19%) in the superovulation versus 2 of 40 (5%) in the natural cycle groups. Pregnancy rates per ET were not significantly different between natural IVF-ET, 2 of 18 (11%) and superovulation IVF-ET, 65 of 298 (22%). The E2:P ratios 5 days after ET were similar in both groups at 18 +/- 4 after natural IVF-ET and 21 +/- 18 after superovulation IVF-ET. CONCLUSIONS: [1] Cancellation rates for natural cycle IVF are very high. [2] Midluteal E2:P ratios are the same in both groups. [3] Pregnancy rates per egg retrieval are significantly lower for natural versus superovulation IVF-ET. [4] In our experience, natural cycle IVF-ET is an inefficient therapy for tubal infertility compared with superovulation IVF-ET.