scholarly journals Mutations in LAMB2 Are Associated With Albuminuria and Optic Nerve Hypoplasia With Hypopituitarism

2019 ◽  
Vol 105 (3) ◽  
pp. 595-599
Author(s):  
Mona Tahoun ◽  
Jennifer C Chandler ◽  
Emma Ashton ◽  
Scott Haston ◽  
Athia Hannan ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Optic Nerve ◽  
Basement Membrane ◽  
Anterior Pituitary ◽  
Congenital Nephrotic Syndrome ◽  
Optic Nerve Hypoplasia ◽  
Hormone Deficiency ◽  
Compound Heterozygous ◽  
Macroscopic Hematuria ◽  
Laminin Β2

Abstract Context Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental delay (Pierson syndrome). Case description This report describes a 12-year-old boy with short stature, visual impairment, and developmental delay who presented with macroscopic hematuria and albuminuria. He had isolated growth hormone deficiency, optic nerve hypoplasia, and a small anterior pituitary with corpus callosum dysgenesis on his cranial magnetic resonance imaging, thereby supporting a diagnosis of optic nerve hypoplasia syndrome. Renal histopathology revealed focal segmental glomerulosclerosis. Using next-generation sequencing on a targeted gene panel for steroid-resistant nephrotic syndrome, compound heterozygous missense mutations were identified in LAMB2 (c.737G>A p.Arg246Gln, c.3982G>C p.Gly1328Arg). Immunohistochemical analysis revealed reduced glomerular laminin β2 expression compared to control kidney and a thin basement membrane on electron microscopy. Laminin β2 is expressed during pituitary development and Lamb2–/– mice exhibit stunted growth, abnormal neural retinae, and here we show, abnormal parenchyma of the anterior pituitary gland. Conclusion We propose that patients with genetically undefined optic nerve hypoplasia syndrome should be screened for albuminuria and, if present, screened for mutations in LAMB2.

Spectrum of clinical presentations and endocrinological findings of patients with septo-optic dysplasia: a retrospective study

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Ayse Pinar Cemeroglu ◽  
Tarin Coulas ◽  
Lora Kleis
Keyword(s):  
Optic Nerve ◽  
Corpus Callosum ◽  
Diagnostic Criteria ◽  
Age Of Onset ◽  
Tertiary Care ◽  
Septum Pellucidum ◽  
Optic Nerve Hypoplasia ◽  
Screening Tests ◽  
Hormone Deficiency ◽  
Pituitary Dysfunction

Abstract: Septo-optic dysplasia (SOD) is a rare condition with variable clinical pictures and spectrum of findings.: To analyze the spectrum of findings, frequency and age of onset of hypothalamic-pituitary dysfunctions in children with SOD.A retrospective electronic medical record (EMR) chart review was done for patients with SOD seen in a tertiary care center’s pediatric endocrinology clinic between January 1, 2012, and March 31, 2014. The diagnostic criteria for SOD included presence of ≥2 of the following: (i) optic nerve hypoplasia, (ii) agenesis/hypoplasia of septum pellucidum and/or corpus callosum and (iii) hypothalamic-pituitary dysfunction.Eighty patients fitting the diagnostic criteria of SOD were included in this study. The majority of patients (96%) had optic nerve hypoplasia on magnetic resonance imaging and were diagnosed due to visual issues including nystagmus (36%) or strabismus (13.8%). Hypothalamic-pituitary dysfunction was most common (51%) when optic nerve hypoplasia was present with (36%) or without (15%) dysgenesis of septum pellucidum and/or corpus callosum compared to dysgenesis of septum pellucidum and/or corpus callosum alone (4%). Hypothalamic-pituitary dysfunction was noted in 55% of patients, and most (86%) were diagnosed ≤2 years of age. Central hypothyroidism and growth hormone deficiency were most common followed by secondary/tertiary adrenal insufficiency and diabetes insipidus.: The risk of hypothalamic-pituitary dysfunction in SOD is highest ≤2 years of age and when both optic nerve hypoplasia and dysgenesis of septum pellucidum/corpus callosum are present, suggesting a need for more frequent follow-up and screening tests for hypothalamic-pituitary dysfunction in these patients.

scholarly journals Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia

2019 ◽  
Author(s):  
David Grubich Atac ◽  
Samuel Koller ◽  
James V M Hanson ◽  
Silke Feil ◽  
Amit Tiwari ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Optic Nerve ◽  
Transcriptional Activation ◽  
Functional Characterization ◽  
Optic Nerve Hypoplasia ◽  
Luciferase Reporter ◽  
Bhlh Transcription Factor ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Single Nucleotide Variants

Abstract Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disc anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative, however many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as nonsyndromic congenital retinal nonattachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.

High prevalence of pituitary hormone deficiency in both unilateral and bilateral optic nerve hypoplasia

2019 ◽  
Vol 108 (9) ◽  
pp. 1677-1685 ◽  
Author(s):  
Sara Dahl ◽  
Maria Kristoffersen Wiberg ◽  
Kristina Teär Fahnehjelm ◽  
Lars Sävendahl ◽  
Ronny Wickström
Keyword(s):  
Optic Nerve ◽  
Optic Nerve Hypoplasia ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
High Prevalence

scholarly journals Genetic Variations and Clinical Features of NPHS1-Related Nephrotic Syndrome in Chinese Children: A Multicenter, Retrospective Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Liping Rong ◽  
Lizhi Chen ◽  
Jia Rao ◽  
Qian Shen ◽  
Guomin Li ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Clinical Manifestations ◽  
Congenital Nephrotic Syndrome ◽  
Chinese Children ◽  
Compound Heterozygous ◽  
Childhood Onset ◽  
Effective Response ◽  
Registration System ◽  
Novel Variants ◽  
Compound Heterozygous Variants

Introduction: Few studies have addressed the genetic spectrum of NPHS1 variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of NPHS1 variants in Chinese children with nephrotic syndrome were researched.Method: Genotypical and phenotypical data from 30 children affected by NPHS1 variants were collected from a multicenter registration system in China and analyzed retrospectively.Results: The patients were divided into two groups: congenital nephrotic syndrome (CNS [n = 24]) and non-CNS (early onset nephrotic syndrome [n = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 NPHS1 variants were detected, involving 25 novel variants. The “recurrent variants” included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection.Conclusion: Variants of NPHS1 cause CNS and early childhood-onset nephrotic syndrome. NPHS1 variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.

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