Robert Wallerstein

Preconception care for women with diabetes and prevention of major congenital malformations.

This article provides an overview of the rationale for diabetes preconception care interventions for women with diabetes and the efficacy in reducing the excess occurrence of major congenital malformations. The problems with broad use of individualized preconception care are considered. In addition, suggestions are made for the implementation of more comprehensive interventions in the community and usual diabetes care settings, to address the multiple ongoing challenges in the prevention of structural anomalies associated with preexisting diabetes. Based on the published evidence, successful preconception care can be considered to include: achievement of individualized target standardized glycosylated hemoglobin levels, adequate nutrition, and minimizing hypoglycemia before and after discontinuing effective contraception and during the transition to early prenatal care.

Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region

Several recent reports of interstitial deletions at the terminal end of the short arm of chromosome 3 have helped to define the critical region whose deletion causes 3p deletion syndrome. We report on an 11‐year‐old girl with intellectual disability, obsessive–compulsive tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial 3p25.3 deletion was characterized using array‐CGH. This deletion overlaps with interstitial 3p25 deletions reported in three recent case reports. These deletions share a 124 kb overlap region including only three RefSeq annotated genes, THUMPD3, SETD5, and LOC440944. The current patient had phenotypic similarities, including intellectual disability, hypotonia, depressed nasal bridge, and long philtrum, with previously reported patients, while she did not have the cardiac defects, seizures ormicrocephaly reported in patients with larger deletions. Therefore, this patient furthers our knowledge of the consequences of 3p deletions, while suggesting genotype–phenotype correlations.

Genetic Variants for Long QT Syndrome among Infants and Children from a Statewide Newborn Hearing Screening Program Cohort

OBJECTIVES Autosomal recessive long QT syndrome (LQTS), or Jervell and Lange-Nielsen syndrome (JLNS), can be associated with sensorineural hearing loss. We aimed to explore newborn hearing screening combined with electrocardiograms (ECGs) for early JLNS detection. STUDY DESIGN In California, we conducted statewide, prospective ECG screening of children ≤ 6 years of age with unilateral or bilateral, severe or profound, sensorineural or mixed hearing loss. Families were identified through newborn hearing screening and interviewed about medical and family histories. Twelve-lead ECGs were obtained. Those with positive histories or heart rate corrected QT (QTc) intervals ≥ 450 ms had repeat ECGs. DNA sequencing of 12 LQTS genes was performed for repeat QTc intervals ≥ 450 ms. RESULTS We screened 707 subjects by ECGs (number screened/number of responses = 91%; number of responses/number of families who were mailed invitations = 54%). Of these, 73 had repeat ECGs, and 19 underwent gene testing. No subject had homozygous or compound heterozygous LQTS mutations, as in JLNS. However, 3 individuals (with QTc intervals of 472, 457, and 456 ms, respectively) were heterozygous for variants that cause truncation or missplicing: 2 in KCNQ1 (c.1343dupC or p.Glu449Argfs*14; c.1590+1G>A or p.Glu530sp) and 1 in SCN5A (c.5872C>T or p.Arg1958*). CONCLUSIONS In contrast to reports of JLNS in up to 4% of children with sensorineural hearing loss, we found no examples of JLNS. Because the 3 variants identified were unrelated to hearing, they likely represent the prevalence of potential LQTS mutations in the general population. Further studies are needed to define consequences of such mutations and assess the overall prevalence.

Chromosome deletion of 14q32.33 detected by array comparative genomic hybridization in a patient with features of dubowitz syndrome.

We report a 4-year-old girl of Mexican origins with a clinical diagnosis of Dubowitz syndrome who carries a de novo terminal deletion at the 14q32.33 locus identified by array comparative genomic hybridization (aCGH). Dubowitz syndrome is a rare condition characterized by a constellation of features including growth retardation, short stature, microcephaly, micrognathia, eczema, telecanthus, blepharophimosis, ptosis, epicanthal folds, broad nasal bridge, round-tipped nose, mild to moderate developmental delay, and high-pitched hoarse voice. This syndrome is thought to be autosomal recessive; however, the etiology has not been determined. This is the first report of this deletion in association with this phenotype; it is possible that this deletion may be causal for a Dubowitz phenocopy.

Mosaic paternal genome-wide uniparental isodisomy with down syndrome

We report on a 6‐month‐old girl with two apparent cell lines; one with trisomy 21, and the other with paternal genome‐wide uniparental isodisomy (GWUPiD), identified using single nucleotide polymorphism (SNP) based microarray and microsatellite analysis of polymorphic loci. The patient has Beckwith‐Wiedemann syndrome (BWS) due to paternal uniparental disomy (UPD) at chromosome location 11p15 (UPD 11p15), which was confirmed through methylation analysis. Hyperinsulinemic hypoglycemia is present, which is associated with paternal UPD 11p15.5; and she likely has medullary nephrocalcinosis, which is associated with paternal UPD 20, although this was not biochemically confirmed. Angelman syndrome (AS) analysis was negative but this testing is not completely informative; she has no specific features of AS. Clinical features of this patient include: dysmorphic features consistent with trisomy 21, tetralogy of Fallot, hemihypertrophy, swirled skin hyperpigmentation, hepatoblastoma, and Wilms tumor. Her karyotype is 47,XX,+21[19]/46,XX[4], and microarray results suggest that the cell line with trisomy 21 is biparentally inherited and represents 40‐50% of the genomic material in the tested specimen. The difference in the level of cytogenetically detected mosaicism versus the level of mosaicism observed via microarray analysis is likely caused by differences in the test methodologies. While a handful of cases of mosaic paternal GWUPiD have been reported, this patient is the only reported case that also involves trisomy 21. Other GWUPiD patients have presented with features associated with multiple imprinted regions, as does our patient.

Current knowledge of prenatal diagnosis of mosaic autosomal trisomy in amniocytes: karyotype/phenotype correlations

Genetic counseling for prenatal diagnosis of autosomal trisomy is complex because of the uncertainty of outcome, which is important for management decisions. Compilation of cases of prenatally diagnosed autosomal trisomies in amniocytes has been done previously in an attempt to elucidate the clinical phenotype of these pregnancies. It has been greater than a decade since these studies were completed. To update this work, we reviewed cases reported in the literature since that time. These cases are correlated with the prior reports to increase knowledge about outcomes and to hopefully improve the data available for genetic counseling. The risk of abnormal outcome can be summarized as: very high risk (>60%) for 47,+2/46; 47,+9/46; 47,+16/46; 47,+20/46; and 47,+22/46; high risk (40–59%) for 47,+5/46; 47,+14/46; and 47,+15/46; moderately high risk (20–39%) for 47,+7/46 47,+12/46; and 47,+17/46; moderate risk (up to 19%) for 47,+6/46 and 47,+8/46, and none were low risk. 47,+6/46 was originally indeterminate, 47,+7/46 was originally moderate risk, 47,+9/46 was originally high risk, and 47,+17/46 was originally low risk.

Familial congenital bilateral vocal fold paralysis: A novel gene translocation

OBJECTIVES True vocal fold (TVF) paralysis is a common cause of neonatal stridor and airway obstruction, though bilateral TVF paralysis is seen less frequently. Rare cases of familial congenital TVF paralysis have been described with implied genetic origin, but few genetic abnormalities have been discovered to date. The purpose of this study is to describe a novel chromosomal translocation responsible for congenital bilateral TVF immobility. METHODS The charts of three patients were retrospectively reviewed: a 35 year-old woman and her two children. The mother had bilateral TVF paralysis at birth requiring tracheotomy. Her oldest child had a similar presentation at birth and also required tracheotomy, while the younger child had laryngomalacia without TVF paralysis. Standard karyotype analysis was done using samples from all three patients and the parents of the mother, to assess whether a chromosomal abnormality was responsible. RESULTS Karyotype analysis revealed the same balanced translocation between chromosomes 5 and 14, t(5;14) (p15.3, q11.2) in the mother and her two daughters. No other genetic abnormalities were identified. Neither maternal grandparent had the translocation, which appeared to be a spontaneous mutation in the mother with autosomal dominant inheritance and variable penetrance. CONCLUSIONS A novel chromosomal translocation was identified that appears to be responsible for familial congenital bilateral TVF paralysis. While there are other reports of genetic abnormalities responsible for this condition, we believe this is the first describing this particular translocation.

The Role of Pediatricians in Families with a History of Familial Adenomatous Polyposis

Colon cancer is not an entity that pediatricians routinely confront; however, a family history of colon cancer can have pediatric implications when it is part of familial adenomatous polyposis syndrome. Colonic (multiple intestinal polyps) and extracolonic manifestations (such as hepatoblastoma or brain tumors) can be the presenting features in children. The authors present 2 patients from different families with familial adenomatous polyposis who presented with the extracolonic manifestation of this syndrome and a family history of colon cancer. Identification of these families and education of their primary care givers can lead to improved screening and management of these high-risk individuals.

Antenatal detection of maternal unipartental disomy of chromosome 2 in a fetus with non‐chromosomal, non‐syndromic alobar holoprosencephaly

Holoprosencephaly (HPE) refers to a group of disorders caused by incomplete division of the forebrain with awide range of associated phenotypes [Solomon et al., 2010]. It is themost common forebrain anomaly with a prevalence of 1:250 in embryos and 1:10,000 in liveborn infants [Bous et al., 2012]. Fetal development of HPE may be caused by genetic and teratogenic phenomena [Cohen and Shiota, 2002; Solomon et al., 2010], by aneuploidy (e.g., trisomy 13), or by other genetic syndromes with autosomal recessive, autosomal dominant, or X-linked mutations [Solomon et al., 2000; Cohen and Shiota, 2002]. Diabetes mellitus is a teratogenic risk factor for HPE [Solomon et al., 2000; Cohen and Shiota, 2002]. Mutations in 12 genes are known to cause apparently non-syndromic HPE [Solomon et al., 2010; Bous et al., 2012]. Mutations of four genes, SHH, ZIC2, SIX3, and TGIF, account for most non-chromosomal, non-syndromic HPE [Solomon et al., 2010]. This 24-year-old primigravidwomanpresented for prenatal care in her first trimester. Anatomic screening, performed at 18 6/7 weeks, showed the fetus to have hydrocephalus, alobar holoprosencephaly (HPE), mid-face hypoplasia with bilateral cleft lip and palate, a proboscis, a cervical meningocele, and post-axial polydactyly in the fetal feet (Fig. 1). The family history was unremarkable, and no known environmental or teratogenic exposures were identified. Her hemoglobin A1C was 4.8, suggesting a low likelihood of diabetes mellitus. An amniocentesis was performed and amniotic fluid was tested for karyotype, alpha fetoprotein, and single nucleotide polymorphism (SNP) chromosomal microarray (CMA). The karyotype was 46,XY. CMA showed evidence of isodisomy of chromosome 2 (UPD2) as (arr 2p25.3q37.3 (12, 771–243, 783, 384) 2 hmz). No deletions, mosaicism, or supernumerary chromosomes were noted. Ultrasonography was performed again at 21 4/7 weeks at the patient’s request and the above findings were confirmed. The patient was counseled about her options for continuation and termination of the pregnancy and she opted for termination by dilation and evacuation (D&E), which was performed at 22 weeks gestation. Counseling included that a D&E would preclude the

Pregnancy outcome in a woman with prune belly syndrome

Prune belly syndrome is a rare congenital syndrome that primarily affects male fetuses. Affected men are universally infertile; however, there is a paucity of information published on the reproductive potential of affected women. Pregnancy outcomes in affected women have not been described in the literature. We describe the case of pregnancy in an affected woman. Her pregnancy progressed without complication. Her fetus had no stigmata of the syndrome. Her labour and delivery were, however, complicated by a prolonged second stage of labour and need for vacuum-assisted vaginal delivery.