Developing a Prospective Gestational Lyme Disease Study.

Lyme disease in pregnancy is understudied. The few available reports of Borrelia infection during pregnancy collecting clinical outcomes, with or without confirmed fetal infection both in utero and neonatal, are limited to case reports and small series. Population-based studies are not available. We propose a prospective study of Borrelia infection during pregnancy based in obstetrical practices in both endemic and nonendemic areas, with long term follow-up of pregnancy outcomes and development assessment of offspring infected or exposed to Borrelia in utero using current serological, microscopic, culture, and molecular techniques. In addition to detection of Borrelia burgdorferi sensu stricto, additional Borrelia species and other pathogens known to be transmitted by ticks will be tested. Serial biospecimens including maternal and cord blood, maternal peripheral blood mononuclear cells and urine, and, when clinically indicated, amniotic fluid, chorionic villi, intrauterine cord blood, will be collected with clinical data, imaging, and for infections treatment medications. Offspring will be followed until age 5 years with annual developmental assessments to assess pregnancy outcomes. The study will require parallel development of a biorepository with strategies for management, data security and data sharing. A public-private partnership will be required to support the study.

Acute Rhabdomyolysis in a Child with Multiple Suspicious Gene Variants.

Rhabdomyolysis is diagnosed with creatinine kinase (CK) elevation beyond 1000 U/L or ten times above the normal upper limit. Severe episodes can be fatal from electrolyte imbalance, acute renal failure, and disseminated intravascular coagulation. A 13-month-old child was admitted with a CK of 82,090 U/L in the setting of respiratory tract infection-related hyperthermia of 106.9° farenheit. His medical history was significant for prematurity, dystonia, and recurrent rhabdomyolysis. His home medications clonazepam, clonidine, and baclofen were continued upon admission. He exhibited uncontrolled dystonia despite treatment for dystonia. Therefore, sedative infusions and forced alkaline diuresis were begun to prevent heme pigment-induced renal injury. Despite these interventions, his CK peaked at 145,920 U/L, which is rarely reported in this age group. The patient also developed pulmonary edema despite diuresis and required mechanical ventilation. Sedative infusions were not enough for dystonia management, and he needed the addition of a neuromuscular blocking infusion. He finally responded to these interventions, and the CK normalized after a month. He required a month of mechanical ventilation and two and a half months of hospitalization and extensive rehabilitation. We were able to avert renal replacement therapy despite pulmonary edema and an estimated glomerular filtration rate nadir of 21 mL/min/1.73 m2 based on the bedside Schwartz formula. He made a complete recovery and was discharged home. His growth and development were satisfactory for two years after that event. His extensive diagnostic workup was negative. Unfortunately, he died from septic and cardiogenic shock with mild rhabdomyolysis two years later. Prompt recognition, early institution of appropriate therapies, identification of underlying disease, and triggering events are pivotal in rhabdomyolysis management. Evidence-based guidelines are needed in this context.

Complete uniparental disomy of chromosome 1 in a child with isolated developmental delay.

Complete uniparental disomy of chromosome 1 (UPD1) is an uncommon genetic finding about which a specific phenotype has not yet been established. We present a boy who has complete paternal UPD1 and isolated developmental delay and suggest that there is no clear phenotype of UPD1.

Characteristics of Orofacial Clefting in Hawai'i.

Orofacial clefts are birth defects that require a multi-disciplinary approach for repair and ongoing management as there are often concomitant chronic health issues. Orofacial clefts can occur as an isolated finding, in combination with other anomalies, or as part of a genetic syndrome. When occurring as part of a genetic syndrome, the complexity of management increases and has lifelong implications for these individuals, their families, and their health care providers. Understanding factors related to the occurrence of syndromic orofacial clefting is important for birth defect research and for health care needs assessment and planning. Many research groups have addressed these issues by studying different populations and focusing on different questions. This study was a retrospective chart review of children with orofacial clefts cared for at a pediatric tertiary care center in Hawai'i to evaluate the proportion of isolated and syndromic clefts in the unique population of Hawai'i. The prevalence of syndromic and isolated clefts were then correlated with ethnicity and compared to the prevalence in other studies. Our goal was to increase knowledge about orofacial clefting in the population of Hawai'i. The proportion of isolated orofacial clefting in a population of patients with orofacial clefting cared for at a craniofacial clinic is similar to birth defect registry data for the Hawaiian Islands (59% vs 58%). Pacific Islanders in our study and prior study have a lower proportion of isolated clefts, suggesting that there are more craniofacial patients with syndromic and complex needs in this population. Further study is needed to clarify the etiologic factors.

Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia.

BACKGROUND: Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function. RESULTS: Herein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43. CONCLUSIONS: This study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors.

Further Evidence That the CFTR Variant c.2620-6T>C Is Benign.

The c.2620-6T>C variant in the CFTR gene is a rare variant about which little is known. We present an asymptomatic adult who has this variant as well as the well described delta F508 pathogenic variant in transpresentation. This patient provides additional evidence that this is a benign polymorphism.

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.

Deletion of 7q33-q35 in a Patient with Intellectual Disability and Dysmorphic Features: Further Characterization of 7q Interstitial Deletion Syndrome.

This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome.

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.

Unusual presentation of pelizaeus-merzbacher disease: female patient with deletion of the proteolipid protein 1 gene.

Pelizaeus-Merzbacher disease (PMD) is neurodegenerative leukodystrophy caused by dysfunction of the proteolipid protein 1 (PLP1) gene on Xq22, which codes for an essential myelin protein. As an X-linked condition, PMD primarily affects males; however there have been a small number of affected females reported in the medical literature with a variety of different mutations in this gene. No affected females to date have a deletion like our patient. In addition to this, our patient has skewed X chromosome inactivation which adds to her presentation as her unaffected mother also carries the mutation.

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.

A new model for providing cell-free DNA and risk assessment for chromosome abnormalities in a public hospital setting.

OBJECTIVE: Cell-free DNA (cfDNA) offers highly accurate noninvasive screening for Down syndrome. Incorporating it into routine care is complicated. We present our experience implementing a novel program for cfDNA screening, emphasizing patient education, genetic counseling, and resource management. STUDY DESIGN: Beginning in January 2013, we initiated a new patient care model in which high-risk patients for aneuploidy received genetic counseling at 12 weeks of gestation. Patients were presented with four pathways for aneuploidy risk assessment and diagnosis: (1) cfDNA; (2) integrated screening; (3) direct-to-invasive testing (chorionic villus sampling or amniocentesis); or (4) no first trimester diagnostic testing/screening. Patients underwent follow-up genetic counseling and detailed ultrasound at 18-20 weeks to review first trimester testing and finalize decision for amniocentesis. RESULTS: Counseling and second trimester detailed ultrasound were provided to 163 women. Most selected cfDNA screening (69%) over integrated screening (0.6%), direct-to-invasive testing (14.1%), or no screening (16.6%). Amniocentesis rates decreased following implementation of cfDNA screening (19.0% versus 13.0%, P < 0.05). CONCLUSION: When counseled about screening options, women often chose cfDNA over integrated screening. This program is a model for patient-directed, efficient delivery of a newly available high-level technology in a public health setting. Genetic counseling is an integral part of patient education and determination of plan of care.

Erik Erikson and his problematic identity.

In his psychohistorical biographies of Luther and Gandhi, Erik Erikson proposed that great issues of a particular time and place, as experienced by sensitive and creative individuals who are working to resolve their inner conflicts within these contexts, could find solutions that transcend themselves and yield conceptualizations that transform the world. Although Erikson was able to create a conceptualization of the adolescent task of establishing a coherent identity, one that gave voice to the aspirations and frustrations of the rebellious student movements of the 1960s, he was never able, over his lifetime, to resolve his own identity issues. Was he Dane or German, American or Scandinavian, Jew or Christian or both? His lifelong back-and-forths on this struggle are chronicled.

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.

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.

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.