Leydig cell hypoplasia type 1 diagnosed in early childhood with inactivating mutation in LHCGR gene

ABSTRACT Leydig cell aplasia/hypoplasia is an autosomal recessive condition. In its complete form, these patients are 46XY but are cryptorchid and phenotypically female. Most cases reported in literature presented with in adolescence with pubertal delay. We reported a case with a predefined mutation in the LHCGR gene, presenting with swelling in the inguinal region and therefore diagnosed in early childhood. We wanted to emphasize the necessity of keeping Leydig cell hypoplasia in mind in the differential diagnosis of sexual development disorders in early childhood.

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Novel compound heterozygous variants in the LHCGR gene identified in a subject with Leydig cell hypoplasia type 1

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2016-0445 ◽

2018 ◽

Vol 31 (2) ◽

pp. 239-245 ◽

Cited By ~ 2

Author(s):

Yufei Xu ◽

Yulin Chen ◽

Niu Li ◽

Xuyun Hu ◽

Guoqiang Li ◽

...

Keyword(s):

Leydig Cell ◽

Splice Site Mutation ◽

Molecular Characteristics ◽

Compound Heterozygous ◽

Site Mutation ◽

Family Pedigree ◽

Correlation Spectrum ◽

Compound Heterozygous Variants ◽

Leydig Cell Hypoplasia

Abstract Background: Leydig cell hypoplasia (LCH) is a rare disease and one of the causes of male disorder of sexual differentiation (DSD). Inactivating mutations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene account for the underlying LCH pathogenicity. This study aimed to analyze the clinical presentation and diagnosis as well as highlight the molecular characteristics of a subject with LCH type 1. Case presentation: Clinical data were collected from the subject and analyzed. Next generation sequencing of the immediate family pedigree using peripheral blood genomic DNA was performed, and the relevant mutations were verified with Sanger sequencing. We describe the case of a 5-year-old patient with DSD, presenting with a lateral inguinal hernia accompanied by abnormal hormone tests. The genetic analysis revealed novel compound heterozygous variants in the LHCGR gene, including a splice site mutation (c.681-1 G>A) and a frameshift variant (c.1582_1585del ATAT, p.Ile528*). Conclusions: We identified novel compound heterozygous variants in the LHCGR gene, and expanded the genotype-phenotype correlation spectrum of LHCGR variants.

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A novel variant in LCHGR gene in 3 siblings with type 1 Leydig cell hypoplasia

Gynecological Endocrinology ◽

10.1080/09513590.2020.1789859 ◽

2020 ◽

Vol 36 (12) ◽

pp. 1136-1139

Author(s):

Amine Aktar Karakaya ◽

Edip Unal ◽

Aslı Beştaş ◽

Funda Taş ◽

Hüseyin Onay ◽

...

Keyword(s):

Leydig Cell ◽

Novel Variant ◽

Leydig Cell Hypoplasia

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Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases

Genes ◽

10.3390/genes10070529 ◽

2019 ◽

Vol 10 (7) ◽

pp. 529

Author(s):

Yassin ◽

D’Arco ◽

Morín ◽

Pagarkar ◽

Harrop-Griffiths ◽

...

Keyword(s):

Inner Ear ◽

Autosomal Recessive ◽

Congenital Deafness ◽

Novel Mutations ◽

Recessive Condition ◽

Autosomal Recessive Condition ◽

New Mutations

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel’s aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

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A novel missense homozygous inactivating mutation in the fourth transmembrane helix of the luteinizing hormone receptor in leydig cell hypoplasia

American Journal of Medical Genetics ◽

10.1002/ajmg.a.20681 ◽

2004 ◽

Vol 130A (2) ◽

pp. 146-153 ◽

Cited By ~ 10

Author(s):

Michael Yiu-Kwong Leung ◽

Osama Al-Muslim ◽

Shao-Ming Wu ◽

Andrew Aziz ◽

Sohail Inam ◽

...

Keyword(s):

Luteinizing Hormone ◽

Leydig Cell ◽

Hormone Receptor ◽

Transmembrane Helix ◽

Luteinizing Hormone Receptor ◽

Inactivating Mutation ◽

Leydig Cell Hypoplasia

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A novel inactivating mutation of the LH/chorionic gonadotrophin receptor with impaired membrane trafficking leading to Leydig cell hypoplasia type 1

Acta Endocrinologica ◽

10.1530/eje-14-1095 ◽

2015 ◽

Vol 172 (6) ◽

pp. K27-K36 ◽

Cited By ~ 13

Author(s):

Adolfo Rivero-Müller ◽

Iulia Potorac ◽

Axelle Pintiaux ◽

Adrian F Daly ◽

Albert Thiry ◽

...

Keyword(s):

Leydig Cell ◽

Membrane Trafficking ◽

Novel Mutation ◽

Chorionic Gonadotrophin ◽

Molecular Characteristics ◽

Structural Domain ◽

Cell Trafficking ◽

The Impact ◽

Leydig Cell Hypoplasia

ObjectiveThe LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in theLHCGRgene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familialLHCGRmutation.MethodsFive affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed.ResultsThe five affected patients were all homozygous for a novel mutation in theLHCGRgene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain.In vitrostudies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin.ConclusionsThis novelLHCGRmutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.

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A Novel Intronic Pathogenic Variant in STAR With a Dominant Negative Mechanism Causes Attenuated Lipoid Congenital Adrenal Hyperplasia

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211014685 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110146

Author(s):

Erin Finn ◽

Kimberly Kripps ◽

Christina Chambers ◽

Michele Rapp ◽

Naomi J. L. Meeks ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Autosomal Recessive ◽

De Novo ◽

Dominant Negative ◽

Adrenal Hyperplasia ◽

Primary Adrenal Insufficiency ◽

Heterozygous Variant ◽

Novel Variant ◽

Autosomal Recessive Condition ◽

Clinically Significant

Lipoid congenital adrenal hyperplasia (LCAH) is typically inherited as an autosomal recessive condition. There are 3 reports of individuals with a dominantly acting heterozygous variant leading to a clinically significant phenotype. We report a 46,XY child with a novel heterozygous intronic variant in STAR resulting in LCAH with an attenuated genital phenotype. The patient presented with neonatal hypoglycemia and had descended testes with a fused scrotum and small phallus. Evaluation revealed primary adrenal insufficiency with deficiencies of cortisol, aldosterone, and androgens. He was found to have a de novo heterozygous novel variant in STAR: c.65-2A>C. We report a case of a novel variant and review of other dominant mutations at the same position in the literature. Clinicians should be aware of the possibility of attenuated genital phenotypes of LCAH and the contribution of de novo variants in STAR at c.65-2 to the pathogenesis of that phenotype.

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Disorders of the Epithelial Na+ Channel in Liddle’s Syndrome and Autosomal Recessive Pseudohypoaldosteronism Type 1

Nephron Experimental Nephrology ◽

10.1159/000020685 ◽

2000 ◽

Vol 8 (6) ◽

pp. 320-325 ◽

Cited By ~ 22

Author(s):

Young S. Oh ◽

David G. Warnock

Keyword(s):

Autosomal Recessive ◽

Liddle’S Syndrome ◽

Liddle's Syndrome ◽

Pseudohypoaldosteronism Type

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Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants

Neuropediatrics ◽

10.1055/s-0040-1715631 ◽

2020 ◽

Author(s):

Matthias Eckenweiler ◽

Johannes A. Mayr ◽

Sarah Grünert ◽

Angela Abicht ◽

Rudolf Korinthenberg

Keyword(s):

Early Childhood ◽

Early Diagnosis ◽

Metabolic Disorder ◽

Autosomal Recessive ◽

Psychomotor Development ◽

Compound Heterozygosity ◽

Pathogenic Variants ◽

Clinical Stabilization ◽

Biotin Supplementation ◽

Thiamine Treatment

AbstractEpisodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

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