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Androstenedione, testosterone and dihydrotestosterone pre and post hCG stimulation
Source publication
Background
Mutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with 12 reported patients to date. Additional features, previously described, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay, facial dysmorphism, o...
Contexts in source publication
Context 1
... was given daily intramuscular 1500 IU/m2 of hCG for 3 days. Androstenedione, testoster- one and dihydrotestosterone pre and post hCG stimulation were shown in Table 1. According to the laboratory results showed in Table 1, 5-alfa reductase deficiency, partial an- drogen insensitivity, 17-beta-hydroxysteroid dehydrogenase deficiency and congenital adrenal hyperplasia are unlikely to be the cause of genital abnormalities in our patient. ...
Context 2
... testoster- one and dihydrotestosterone pre and post hCG stimulation were shown in Table 1. According to the laboratory results showed in Table 1, 5-alfa reductase deficiency, partial an- drogen insensitivity, 17-beta-hydroxysteroid dehydrogenase deficiency and congenital adrenal hyperplasia are unlikely to be the cause of genital abnormalities in our patient. ...
Citations
... Although, IGF-1/insulin through activation of PI3K has been reported to repress TSH-induced expression of Slc5a5 [74,75], since GLIS3 is required for its transcription, its repression in Glis3-Pax8Cre(LID) and ubiquitous Glis3-KO(LID) thyroids is independent of IGF1/insulin levels [33]. These findings are consistent with reports showing that the regulation of thyroid follicular cell proliferation and TH biosynthesis by TSH involve different mechanisms [7,67,76]. ...
Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 (Nis), become expressed. This, together with observations showing that ubiquitous Glis3KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3KO mice is dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.
... Persistent high TSH has been noted in spite of high doses up to 20-35 µg/kg/day. [11,12] GLIS3 plays a role in the early stages of thyroid development from the pharyngeal endoderm and also in TSH receptor signaling and proliferation of follicles later. [3,13] Hence, NDH patients show varying thyroid anatomy on ultrasonography ranging from aplasia to normal size. ...
... [3,13] Hence, NDH patients show varying thyroid anatomy on ultrasonography ranging from aplasia to normal size. [12,14,15] Facial dysmorphism in our patient was similar to those reported by various authors and included low set ears, prominent eyes, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. [10,11,16] The facial features were more evident with advancing age. ...
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome (OMIM: 610199) caused by GLIS3 gene mutations is a multisystem disorder. To date, only 23 cases of NDH syndrome have been reported worldwide. We report a child diagnosed on day 24 of life with neonatal diabetes, congenital hypothyroidism, congenital glaucoma, and dysmorphic facial features. Genetic analysis revealed a homozygous pathogenic frameshift variant (p.Gln361Profs*193) in the GLIS3 gene, located on chromosome 9p24.2. Our report confirms that infants with neonatal diabetes and congenital hypothyroidism along with facial dysmorphism should be screened for GLIS3 mutations.
... Изучение экспрессии генов у мышей с дефектом GLIS3 и мутациями дикого типа показало, что GLIS3 регулирует экспрессию определенного ряда генов, критичных для биосинтеза тиреоидных гормонов, особенно NIS (SLc5a5) и пендрина (Pds, Slc26a4) [36,37]. ...
... К. Alghamdi и соавт. у пациента с кариотипом 46ХY и новой гомозиготной мутацией (дупликация 2 нуклеотидов в положении с.2313_2314dupTC) в 9 экзоне GLIS3 впервые было описано нарушение строения наружных гениталий (микропенис, двусторонний крипторхизм и мошоночная форма гипоспадии) как еще одно проявление синдрома [36]. ...
Mutations in the GLIS3 gene encoding the GLIS3 transcription factor are cause of a rare syndromic form of neonatal diabetes mellitus (NDM) with congenital hypothyroidism. Additional features include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and other anomalies. This disease in foreign literature is called NDH-syndrome (Neonatal diabetes and Hypothyroidism syndrome).
We present the description of a patient with this syndrome with novel homozygous GLIS3 mutation.
Our patient is a female, who was born with a weight of 1680 gr, length of 44 cm to consanguineous parents. She developed diabetes on 2 day after birth, requiring continuous intravenous insulin. On day 5 of life hypothyroidism was identified. Thyroid anatomy was normal on ultrasound scan. NDH syndrome was suspected.
Genetic analysis revealed a novel homozygous mutation c.1836delT, p.Ser612ArgfsTer33 in exon 5 in GLIS3 gene.
To date, the patient is followed up for 4 years in total. Currently, growth retardation, psychomotor and speech development persist. Carbohydrate metabolism and thyroid profile has been subcompensated against the background of replacement therapy. No other components of the syndrome have been identified.
In this report, we have demonstrated the features of the neonatal diabetes mellitus in a patient with a defect in the GLIS3 gene. Early genetic verification of the diagnosis contributes to the timely starting of personalized therapy, can improve the quality of life of such patients, and, given the nature of inheritance, is necessary for medical genetic counseling of the family.
... Associations with GLIS3 (TSH, FT4), PDE8B (TSH), and FOXE1 (FT4) have been identified in a previous GWAS (28), playing an important role in either thyroid development, growth and differentiation (GLIS3, FOXE1), TSH signaling (PDE8B), or TSH-regulated gene expression (FOXE1). The relation with both TSH and FT4 for GLIS3 has been described in literature, which is based on rare mutations leading to congenital hypothyroidism (37,38). Common genetic variants in PDE8B, affecting 3′,5′-cyclic adenosine 5′-monophosphate concentrations in the thyroid, have also shown associations with reciprocal changes in TSH and suggestive associations with FT4 concentrations (39). ...
Objective
While most of the variation in thyroid function is determined by genetic factors, single nucleotide polymorphisms (SNPs) identified via genome-wide association analyses have only explained ~5-9% of this variance so far. Most SNPs were in or nearby genes with no known role in thyroid hormone (TH) regulation. Therefore, we performed a large-scale candidate gene study investigating the effect of common genetic variation in established TH regulating genes on serum TSH and FT4 concentrations.
Methods
SNPs in or within 10kb of 96 TH regulating genes were included (30,031 TSH SNPs, and 29,962 FT4 SNPs). Associations were studied in 54,288 individuals from the ThyroidOmics Consortium. Linkage disequilibrium-based clumping was used to identify independently associated SNPs. SNP-based explained variances were calculated using SumHer software.
Results
We identified 23 novel TSH associated SNPs in predominantly hypothalamic-pituitary-thyroid axis genes and 25 novel FT4 associated SNPs in mainly peripheral metabolism and transport genes. Genome-wide SNP variation explained ~21% (SD 1.7) of the total variation in both TSH and FT4 concentrations, whereas SNPs in the 96 TH regulating genes explained 1.9-2.6% (SD 0.4).
Conclusion
Here we report the largest candidate gene analysis on thyroid function, resulting in a substantial increase in the number of genetic variants determining TSH and FT4 concentrations. Interestingly, these candidate gene SNPs explain only a minor part of the variation in TSH and FT4 concentrations, which substantiates the need for large genetic studies including common and rare variants to unravel novel, yet unknown, pathways in TH regulation.
... Genetic sequencing of these individuals identified various frame shift and point mutations, and deletions in GLIS3 that were likely responsible for the observed phenotypes [27]. Additional studies have since reinforced this linkage [28][29][30][31][32][33], firmly connecting GLIS3 to diabetes, hypothyroidism, polycystic kidney disease, as well as a host of additional phenotypes. GLIS3's connection to diabetes has further been reinforced by genome wide association studies (GWAS), which we have previously reviewed [16,18]. ...
Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3. Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes. As a significant progress has been made in understanding some of GLIS3’s roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors. While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy.
... Other features included intrauterine growth retardation (IUGR), cystic renal disease and hepatic cholestasis or fibrosis. In addition, developmental delay, facial dysmorphism, skeletal abnormalities and exocrine pancreatic dysfunction have been described (4,(17)(18)(19)(20)(21)(22). To date, 14 GLIS3 mutations have been reported (http://www. ...
... hgmd.cf.ac.uk/ac/gene.php) (4,17,(20)(21)(22). ...
... Clinical and molecular findings of previous reported cases with GLIS3 mutations. Since the first description in 2006 of GLIS3 mutations causing a syndromic form of NDM in three siblings of a consanguineous family from Saudi Arabia(17,18), an additional 16 patients have been reported carrying 14 different mutations (Table 2)(17,(19)(20)(21)(22)(23). All patients had NDM presenting between 1 and 31 days of life. ...
Background
Mutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in β-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys.
Cases
We describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development. Sequence analysis of GLIS3 identified a novel homozygous nonsense mutation, c.2392C>T, p.Gln798Ter (p.Q798*), which results in an early stop codon. The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring. Fluctuating blood glucose and intermittent hypoglycemia were observed on follow-up.
Conclusions
This report highlights the importance of early molecular diagnosis for appropriate management of NDM. We describe a novel nonsense mutation of GLIS3 causing NDM, extend the phenotype, and discuss the challenges in clinical management. Our findings provide new areas for further investigation into the roles of GLIS3 in the pathophysiology of diabetes mellitus.
... Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare disorder caused by autosomal recessive mutations in the GLI-similar 3 (GLIS3) gene. Since the first description of two affected siblings in 2003 (1) and the identification of underlying GLIS3 mutations in 2006 (2), almost 20 patients with NDH syndrome have been reported so far (3)(4)(5). GLIS3 is a Krüppel-like zinc-finger transcription factor expressed during early embryogenesis and considered to be important for the proper development of various organs (6,7). ...
... In addition to the two cardinal symptoms neonatal diabetes and congenital hypothyroidism, reported patients frequently suffered from intrauterine growth retardation (IUGR), a typical facial phenotype, cholestasis, liver fibrosis, renal cysts and glaucoma. Further described symptoms include developmental delay, hearing disorder, exocrine pancreatic insufficiency, pancreatic and splenic cysts, osteopenia and cardiac anomalies, as well as single cases with choanal atresia, craniosynostosis and undervirilization of male external genitalia (3)(4)(5)8). Phenotype distribution and severity of organ manifestations varies substantially between individual patients. ...
... Persistently elevated levels of TSH despite normalization of fT4 and use of high levothyroxine doses up to 75 µg/kg/day have been reported in several earlier NDH syndrome case descriptions (2)(3)(4)(5). The reason for this TSH resistance is currently unclear. ...
Background
Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability.
Case presentation
We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis.
Conclusions
Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.
... 2.11.1 Genetic alteration and clinical phenotype Homozygous inactivating mutations in the GLI similar 3 (GLIS3) gene, coding for the transcription factor GLIS3, cause permanent neonatal diabetes mellitus, that may be accompanied by exocrine pancreas dysfunction and a large variety of non-pancreatic manifestations such as intrauterine growth retardation, congenital hypothyroidism, congenital glaucoma, polycystic kidneys, liver disease, skeletal deformity and bilateral sensorineural deafness (Alghamdi et al., 2017;Dimitri et al., 2011Dimitri et al., , 2015Kim et al., 2003b;Senee et al., 2006;Taha et al., 2003). The presence and nature of these extrapancreatic manifestations are dependent on the type and localization of the GLIS3 mutation (Dimitri et al., 2011(Dimitri et al., , 2015. ...
Monogenetic forms of diabetes represent 1%–5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.
... The neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome (OMIM: 610199), characterized by intrauterine growth retardation, early onset of nonimmune diabetes mellitus and congenital hypothyroidism, also shows partial phenotypic overlap with the pleiotropic disorder reported here. Biallelic pathogenic variants in the GLIS3 gene have been reported in 13 patients with NDH syndrome (Senee et al., 2006;Dimitri et al., 2011Dimitri et al., , 2015Alghamdi et al., 2017). Besides the cardinal features, additional manifestations comprise facial dysmorphism, developmental delay and learning difficulties, sensorineural hearing loss, renal parenchymal disease, hepatic disease, exocrine pancreatic dysfunction, and skeletal and genital abnormalities (Dimitri et al., 2015;Alghamdi et al., 2017). ...
... Biallelic pathogenic variants in the GLIS3 gene have been reported in 13 patients with NDH syndrome (Senee et al., 2006;Dimitri et al., 2011Dimitri et al., , 2015Alghamdi et al., 2017). Besides the cardinal features, additional manifestations comprise facial dysmorphism, developmental delay and learning difficulties, sensorineural hearing loss, renal parenchymal disease, hepatic disease, exocrine pancreatic dysfunction, and skeletal and genital abnormalities (Dimitri et al., 2015;Alghamdi et al., 2017). GLIS3 belongs to a subfamily of Krü ppel-like zinc finger proteins, functions as activator or repressor of gene transcription, and plays a critical role in the regulation of multiple biological processes (Jetten, 2018). ...
In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
... The majority of these genes have been associated with isolated CH, and there have only been a few reports of genes associated with CH and extra-thyroidal congenital malformations (ECMs) [4][5][6]. For example, SLC26A4 mutations can lead to CH with deafness [7] and GLIS3 mutations can lead to a multi-system phenotype including CH and neonatal diabetes [8][9][10][11]. ...
Background: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder. Although most patients present with isolated CH, some patients present with CH and extra-thyroidal congenital malformations (ECMs), for which less is known about the underlying genetics. The aim of this study was to investigate the genetic mechanisms in patients with CH and ECMs using chromosomal microarray (CMA) and whole exome sequencing (WES). Methods: Peripheral venous blood samples were collected from 16 patients with CH and ECMs. Genomic DNA was extracted from peripheral blood leukocytes. CMA and WES were performed to detect copy number and single nucleotide variants. Results: CMA identified clinically significant copy number variants in 7 patients consistent with their phenotypes. For 6 of them, the genotype and phenotype suggested a syndromic diagnosis, and the remaining patient carried a pathogenic microdeletion and microduplication including GLIS3. WES analysis identified 9 different variants in 7 additional patients. The variants included 2 known mutations (c.1096C>T (p.Arg366Trp) in KCNQ1 and c.848C>A (p.Pro283Gln) in NKX2-5) and 7 novel variants: one nonsense mutation (c.4330C>T (p.Arg1444*) in ASXL3), one frameshift mutation (c.1253_1259delACTCTGG (p.Asp418fs) in TG), three missense variants (c.1472C>T (p.Thr491Ile) in TG, c.4604A>G (p.Asp1535Gly) in TG, and c.2139G>T (p.Glu713Asp) in DUOX2, and two splice site variants (c.944-1G>C and c.3693 + 1G>T) in DUOX2. Conclusions: We report the first genetic study of CH patients with ECMs using CMA and WES. Overall, our detection rate for pathogenic and possibly pathogenic variants was 87.5% (14/16). We report 7 novel variants, expanding the mutational spectrum of TG, DUOX2, and ASXL3.
