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Novel Genetic causes of Pitutary Hormone Deficiency
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Novel Genetic causes of Pitutary Hormone Deficiency

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 10507

Special Issue Editor

Dr. Mara Giordano

E-Mail Website
Guest Editor
Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy
Interests: genetics of mendelian disorders; molecular diagnostics of neurodevelopmental and growth disorders; pituitary hormone deficiency; kidney genetics diseases; hereditary cancer syndromes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Research over the last 20 years has elucidated the genetic etiologies of Combined Pituitary Hormone Deficiency (CPHD). The pituitary plays a central role in growth regulation, coordinating the multitude of central and peripheral signals to maintain the body's internal balance. Naturally occurring mutations in humans and in mice have demonstrated roles for several factors in the etiology of CPHD. Mutations in transcription factors such as HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2, SOX3, and TBX19 contribute to the understanding of CPHD. Depending upon the expression patterns of these molecules, the phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. More recently, mutations in genes involved in Kallmann syndrome such as PROKR2 were also reported in CPHD, suggesting a potential role for the PROK2 pathway in pituitary development. Although numerous monogenic causes of CPHD have been identified, most patients remain with an unexplained etiology as shown by the relatively low mutation detection rate. The introduction of novel diagnostic approaches and NGS(next-generation sequencing) technology is now leading to the disclosure of novel genetic causes in disorders characterized by pituitary hormone defects.

Prof. Dr. Mara Giordano
Guest Editor

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Published Papers (3 papers)

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Research

12 pages, 1172 KiB  
Article
Case Report: A Detailed Phenotypic Description of Patients and Relatives with Combined Central Hypothyroidism and Growth Hormone Deficiency Carrying IGSF1 Mutations
by Melitza S. M. Elizabeth, Anita Hokken-Koelega, Jenny A. Visser, Sjoerd D. Joustra and Laura C. G. de Graaff
Genes 2022, 13(4), 623; https://doi.org/10.3390/genes13040623 - 30 Mar 2022
Cited by 3 | Viewed by 2122
Abstract
In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional [...] Read more.
In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants. Full article
(This article belongs to the Special Issue Novel Genetic causes of Pitutary Hormone Deficiency)
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12 pages, 2412 KiB  
Article
Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum
by Marilena Nakaguma, Nathalia Garcia Bianchi Pereira Ferreira, Anna Flavia Figueredo Benedetti, Mariana Cotarelli Madi, Juliana Moreira Silva, Jun Z. Li, Qianyi Ma, Ayse Bilge Ozel, Qing Fang, Amanda de Moraes Narcizo, Laís Cavalca Cardoso, Luciana Ribeiro Montenegro, Mariana Ferreira de Assis Funari, Mirian Yumie Nishi, Ivo Jorge Prado Arnhold, Alexander Augusto de Lima Jorge, Berenice Bilharinho de Mendonca, Sally Ann Camper and Luciani R. Carvalho
Genes 2021, 12(8), 1128; https://doi.org/10.3390/genes12081128 - 25 Jul 2021
Viewed by 2367
Abstract
We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone [...] Read more.
We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations. Full article
(This article belongs to the Special Issue Novel Genetic causes of Pitutary Hormone Deficiency)
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25 pages, 5643 KiB  
Article
The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature
by Karlijn Pellikaan, Geeske M. van Woerden, Lotte Kleinendorst, Anna G. W. Rosenberg, Bernhard Horsthemke, Christian Grosser, Laura J. C. M. van Zutven, Elisabeth F. C. van Rossum, Aart J. van der Lely, James L. Resnick, Hennie T. Brüggenwirth, Mieke M. van Haelst and Laura C. G. de Graaff
Genes 2021, 12(6), 875; https://doi.org/10.3390/genes12060875 - 7 Jun 2021
Cited by 5 | Viewed by 5408
Abstract
Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome [...] Read more.
Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS. Full article
(This article belongs to the Special Issue Novel Genetic causes of Pitutary Hormone Deficiency)
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