Faculty Bibliography
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82
Hyponatremic Seizures and Adrenal Hypoplasia Congenita in a Neonate with Congenital Diaphragmatic Hernia [Case Report]
Congenital diaphragmatic hernia (CDH) in neonates may occur as an isolated finding, in association with other anomalies, or as part of a genetic syndrome. We report the first case of an infant with CDH who presented with hyponatremic seizures due to adrenal hypoplasia congenita (AHC). The patient underwent repair of CDH defect. After an uncomplicated postoperative course while on discharge planning, he developed a seizure episode associated with severe hyponatremia and hyperkalemia. Extensive diagnostic workup revealed an NR0B1 gene variant confirming the diagnosis of X-linked AHC. The patient was eventually discharged home on hydrocortisone, fludrocortisone, and salt supplements. There are a few case reports of adrenal insufficiency in neonates with CDH, manifesting with symptoms before and immediately after reparative surgery. Clinical presentation of our patient was unique in manifesting as neonatal seizure secondary to severe hyponatremia after a stable postoperative phase. The patient's electrolytes and hemodynamic status remained stable before, during, and after surgery for CDH. This case underlines the importance of taking detailed family history and continued vigilance for signs and symptoms of adrenal insufficiency in infants with repaired CDH by pediatricians and intensivists.
PMCID:6556792
PMID: 31263616
ISSN: 2090-6803
CID: 3968002
Intellectual disability due to monoallelic variant in GATAD2B and mosaicism in unaffected parent [Case Report]
The GATA zing finger domain-containing protein 2B (GATAD2B) gene encodes the p66beta protein, a subunit of the MeCP1-Mi2/ nucleosome remodeling and deacetylase complex, which is involved in transcription regulation and chromatin remodeling. Pathogenic variants in the GATAD2B gene have recently been associated with a recognizable neurodevelopmental syndrome, characterized by intellectual disability, limited speech, childhood hypotonia, and dysmorphic features. The majority of reported patients resulted from de novo loss of function (LOF) variants. We report a patient identified through whole exome sequencing analysis where a healthy mother was found to be low level mosaic for the pathogenic LOF variant found in her child, who is affected with GATAD2B-associated neurodevelopmental disorder (GAND). This variant was only found with the use of next generation sequencing technology in the mother and confirmed by digital droplet PCR. We summarize additional patients with GATAD2B LOF variants from a literature review and with our patient we contribute to delineate the phenotypic spectrum of GAND. We highlight the importance of detailed genetic testing, testing method, and counseling for cases of somatic mosaicism in an unaffected parent of children with GAND. This inheritance may be underreported and has a direct impact on reproductive planning and prenatal diagnosis.
PMID: 30346093
ISSN: 1552-4833
CID: 3386022
Genotype-phenotype correlations in individuals with pathogenic RERE variants
Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies and sensorineural hearing loss when compared to loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype-phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.
PMCID:5903952
PMID: 29330883
ISSN: 1098-1004
CID: 2906272
Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848
Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
PMCID:5777934
PMID: 29290338
ISSN: 1537-6605
CID: 2899672
Kufor-Rakeb Syndrome Due to a Novel ATP13A2 Mutation in 2 Chinese-American Brothers [Case Report]
PMCID:6336435
PMID: 30746398
ISSN: 2330-1619
CID: 3659352
Loss-of-function variants in NFIA provide further support that NFIA is a critical gene in 1p32-p31 deletion syndrome: A four patient series
The association between 1p32-p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new cases to support this hypothesis. Here, we describe four patients with loss-of-function variants in the NFIA gene identified through WES. The clinical presentation of these patients significantly overlaps with the phenotype described in previously reported cases of 1p32-p31 deletion syndrome, NFIA gene disruptions and intragenic NFIA deletions. Our cohort includes a mother and daughter as well as an unrelated individual who share the same nonsense variant (c.205C>T, p.Arg69Ter; NM_001145512.1). We also report a patient with a frameshift NFIA variant (c.159_160dupCC, p.Gln54ProfsTer49). We have compared published cases of 1p32-p31 microdeletion syndrome, translocations resulting in NFIA gene disruption, intragenic deletions, and loss-of-function mutations (including our four patients) to reveal that abnormalities of the corpus callosum, ventriculomegaly/hydrocephalus, macrocephaly, Chiari I malformation, dysmorphic features, developmental delay, hypotonia, and urinary tract defects are common findings. The consistent overlap in clinical presentation provides further evidence of the critical role of NFIA haploinsufficiency in the development of the 1p32-p31 microdeletion syndrome phenotype.
PMID: 28941020
ISSN: 1552-4833
CID: 2708452
Turner syndrome with 45, X mosaicism and Y/autosome translocation [Meeting Abstract]
Background:Y chromosome material is detected in 6% of Turner syndrome patients by karyotype (1). Y/autosome translocation in Turner syndrome is associated with a) female genitalia or signs of virilization; b) gonadal dysgenesis and a 7-30% future risk of gonadoblastoma (2). We present an atypical phenotype of a Turner syndrome female with 45,X/45,X,dic(Y;5)(p11.3; p15.3). Clinical case: A 9-year and 10-month-old girl presented with short stature (height: 121 cm, -3.2 SD; weight: 37.6 kg, 75%) and Turner syndrome habitus: wide short neck, broad chest, with no signs of virilization, no cardiac defects, no hepatosplenomegaly and with mild learning disability. Lab evaluation: LH 1.14 (<=2.91 U/L); FSH 50.9 (0.72-5.33 U/L); estradiol <2 (
EMBASE:617153110
ISSN: 0163-769x
CID: 2631962
A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3
Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.
PMCID:5223093
PMID: 28017372
ISSN: 1537-6605
CID: 2383432
Clinical Phenotype in a Toddler with a Novel Heterozygous Mutation of the Vitamin D Receptor
We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D).
PMCID:5460444
PMID: 28620554
ISSN: 2090-6501
CID: 2593942
Expansion of phenotype and genotypic data in CRB2-related syndrome
Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.European Journal of Human Genetics advance online publication, 23 March 2016; doi:10.1038/ejhg.2016.24.
PMCID:5027675
PMID: 27004616
ISSN: 1476-5438
CID: 2052072
