scholarly journals Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism

2020 ◽  
Vol 105 (6) ◽  
pp. 1748-1758 ◽  
Author(s):  
Johanna Hietamäki ◽  
Louise C Gregory ◽  
Sandy Ayoub ◽  
Anna-Pauliina Iivonen ◽  
Kirsi Vaaralahti ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Cleft Lip ◽  
Fetal Brain ◽  
Underlying Mechanism ◽  
Hormone Deficiency ◽  
Compound Heterozygous ◽  
Pituitary Hormone ◽  
Loss Of Function ◽  
Shh Signaling ◽  
Craniofacial Dysmorphism

Abstract Context Congenital pituitary hormone deficiencies with syndromic phenotypes and/or familial occurrence suggest genetic hypopituitarism; however, in many such patients the underlying molecular basis of the disease remains unknown. Objective To describe patients with syndromic hypopituitarism due to biallelic loss-of-function variants in TBC1D32, a gene implicated in Sonic Hedgehog (Shh) signaling. Setting Referral center. Patients A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. Interventions The patients were investigated by whole genome sequencing. Expression profiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cells followed by mass spectrometry analyses. Main Outcome Measures Genetic and phenotypic features of patients with biallelic loss-of-function mutations in TBC1D32. Results The Finnish patients harboured compound heterozygous loss-of-function variants (c.1165_1166dup p.(Gln390Phefs*32) and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Pakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variant c.1372 + 1G > A p.(Arg411_Gly458del), as did a fetus with a cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed in the developing hypothalamus, Rathke’s pouch, and areas of the hindbrain. TBC1D32 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development. Conclusions Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling.

scholarly journals MON-717 Novel GLI2 Mutations Identified in Pediatric Patients with Combined Pituitary Hormone Deficiency: One Gene, Various Genotypes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sebastian A Vishnopolska ◽  
Debora Braslavsky ◽  
Ana Claudia Keselman ◽  
Ignacio Bergada ◽  
Roxana M Marino ◽  
...  
Keyword(s):  
Cell Line ◽  
Target Genes ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Loss Of Function ◽  
Wild Type ◽  
Gfp Expression ◽  
Shh Signaling ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency

Abstract Combined pituitary hormone deficiency (CPHD) is an important clinical problem caused by mutations in more than 30 different genes. Six genes in the Sonic Hedgehog (SHH) signalling pathway are reported to cause CPHD. SHH signaling is essential to induce pituitary cell identity in cells of Rathke’s pouch by stimulating expression of the transcription factors Lhx3 and Lhx4. In the absence of SHH signaling, a repressive isoform of the transcription factor GLI2 (Gli-Kruppel family member 2) suppresses gene expression. In the presence of SHH signaling, the activating form of GLI2 gains access to the nucleus and induces expression of downstream target genes. Heterozygous GLI2 loss of function mutations are found in patients with holoprosencephaly (HPE), HPE-like phenotypes associated with pituitary anomalies, and combined pituitary hormone deficiency with or without other extra-pituitary findings. We sought to identify the cause of CPHD in 171 unrelated patients diagnosed with or without extra-pituitary manifestations that were recruited from several Argentinean medical centers. We conducted panel sequencing, and identified GLI2 heterozygous variants that were rare and predicted to be deleterious in two unrelated patients, (p.L761P and p.1404Lfs) and a single, heterozygous, rare, likely deleterious GLI2 variant identified by exome sequencing (p.A203T). p.L761P and p.A203T variants were previously reported as candidates for HPE/CPHD, no functional studies were carried out to determine the effect of the variants on the gene function. We performed functional analysis of these variants using a mammalian cell line (NIH/3T3-CG) previously engineered to be a sensor for SHH signaling. It was stably transfected with a reporter gene that expresses GFP in response to GLI2 activation by a SHH agonist. We modified this cell line to assay GLI2 variants. We created a homozygous knock out of both endogenous Gli2 genes using CRISPR-Cas9 editing, and individual cell clones were selected for loss of GFP expression in response to SHH agonist treatment by FACS. We verified that transfecting the knockout cells with wild type Gli2 restored SHH responsive GFP expression. We assayed the ability of three patient GLI2 variants to rescue GFP expression and SHH agonist responsiveness and found that all three failed to fully rescue to wild type levels. This supports the hypothesis that the GLI2 variants in three CPHD patients are likely pathogenic. Thus, we identified three likely pathogenic GLI2 mutations in CPHD patients from Argentina. The variable phenotype of patients with GLI2 mutations worldwide could be caused by variation in other genes, environmental exposures, maternal effects, and/or epigenetic factors.

scholarly journals Paediatric Langerhans Cell Histiocytosis Disease: Long-Term Sequelae in the Hypothalamic Endocrine System

2021 ◽  
pp. 1-9
Author(s):  
Elisa Vaiani ◽  
Guido Felizzia ◽  
Fabiana Lubieniecki ◽  
Jorge Braier ◽  
Alicia Belgorosky
Keyword(s):  
Anterior Pituitary ◽  
Langerhans Cell Histiocytosis ◽  
Endocrine System ◽  
Langerhans Cell ◽  
Hormone Deficiency ◽  
Bone Lesions ◽  
Pituitary Hormone ◽  
Multisystem Disease ◽  
Anterior Pituitary Hormone

Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.

Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia

Development ◽  
2002 ◽  
Vol 129 (18) ◽  
pp. 4229-4239 ◽  
Author(s):  
Lori T. Raetzman ◽  
Robert Ward ◽  
Sally A. Camper
Keyword(s):  
Cell Survival ◽  
Anterior Pituitary ◽  
Molecular Genetic ◽  
Cell Types ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Cells ◽  
Temporal Shift ◽  
Pituitary Development ◽  
Show Evidence

Deficiencies in the homeobox transcription factors LHX4 and PROP1 cause pituitary hormone deficiency in both humans and mice. Lhx4 and Prop1 mutants exhibit severe anterior pituitary hypoplasia resulting from limited differentiation and expansion of most specialized cell types. Little is known about the mechanism through which these genes promote pituitary development. In this study we determined that the hypoplasia in Lhx4 mutants results from increased cell death and that the reduced differentiation is attributable to a temporal shift in Lhx3 activation. In contrast, Prop1 mutants exhibit normal cell proliferation and cell survival but show evidence of defective dorsal-ventral patterning. Molecular genetic analyses reveal that Lhx4 and Prop1 have overlapping functions in early pituitary development. Double mutants exhibit delayed corticotrope specification and complete failure of all other anterior pituitary cell types to differentiate. Thus, Lhx4 and Prop1 have critical, but mechanistically different roles in specification and expansion of specialized anterior pituitary cells.

Multiple Anterior Pituitary Hormone Deficiency

2009 ◽  
pp. 1363-1364
Author(s):  
Mark Oette ◽  
Marvin J. Stone ◽  
Hendrik P. N. Scholl ◽  
Peter Charbel Issa ◽  
Monika Fleckenstein ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Anterior Pituitary Hormone

scholarly journals Evaluation of pituitary imaging in patients with PROP-1 gene mutation

Medicina ◽  
2009 ◽  
Vol 45 (9) ◽  
pp. 693 ◽  
Author(s):  
Natalija Tkačenko ◽  
Danutė Lašienė ◽  
Silvija Jakštienė ◽  
Algidas Basevičius ◽  
Rasa Verkauskienė
Keyword(s):  
Transcription Factor ◽  
Pituitary Gland ◽  
Gene Mutation ◽  
Anterior Pituitary ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Imaging Studies ◽  
Pituitary Hyperplasia ◽  
Pituitary Hypoplasia ◽  
Genetically Determined

The most common genetically determined cause of multiple pituitary hormone deficiency is PROP-1 gene mutation. PROP-1 is a transcription factor involved in the development of pituitary gland and affects hormonal synthesis of anterior pituitary. The aim of our study was to evaluate radiological aspects of the pituitary region in patients with PROP-1 gene mutation. Pituitary imaging studies were performed in 12 patients with a confirmed PROP-1 gene mutation. Pituitary hyperplasia was found in 5 (42%) and pituitary hypoplasia in 4 (33%) patients. Changes in pituitary size were not associated with the type of PROP-1 gene mutation.

scholarly journals Otx2b mutant zebrafish have pituitary, eye and mandible defects that model mammalian disease

2020 ◽  
Vol 29 (10) ◽  
pp. 1648-1657 ◽  
Author(s):  
Hironori Bando ◽  
Peter Gergics ◽  
Brenda L Bohnsack ◽  
Kevin P Toolan ◽  
Catherine E Richter ◽  
...  
Keyword(s):  
Human Genetics ◽  
Clinical Symptoms ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Functional Evaluation ◽  
Loss Of Function ◽  
Sodium Influx ◽  
Large Numbers ◽  
Vertebrate Model ◽  
Rare Genetic Variants

Abstract Combined pituitary hormone deficiency (CPHD) is a genetically heterogeneous disorder caused by mutations in over 30 genes. The loss-of-function mutations in many of these genes, including orthodenticle homeobox 2 (OTX2), can present with a broad range of clinical symptoms, which provides a challenge for predicting phenotype from genotype. Another challenge in human genetics is functional evaluation of rare genetic variants that are predicted to be deleterious. Zebrafish are an excellent vertebrate model for evaluating gene function and disease pathogenesis, especially because large numbers of progeny can be obtained, overcoming the challenge of individual variation. To clarify the utility of zebrafish for the analysis of CPHD-related genes, we analyzed the effect of OTX2 loss of function in zebrafish. The otx2b gene is expressed in the developing hypothalamus, and otx2bhu3625/hu3625 fish exhibit multiple defects in the development of head structures and are not viable past 10 days post fertilization (dpf). Otx2bhu3625/hu3625 fish have a small hypothalamus and low expression of pituitary growth hormone and prolactin (prl). The gills of otx2bhu3625/hu3625 fish have weak sodium influx, consistent with the role of prolactin in osmoregulation. The otx2bhu3625/hu3625 eyes are microphthalmic with colobomas, which may underlie the inability of the mutant fish to find food. The small pituitary and eyes are associated with reduced cell proliferation and increased apoptosis evident at 3 and 5 dpf, respectively. These observations establish the zebrafish as a useful tool for the analysis of CPHD genes with variable and complex phenotypes.

The pituitary and hypopituitarism

2020 ◽  
pp. 83-120
Author(s):  
Gary Butler ◽  
Jeremy Kirk
Keyword(s):  
Anterior Pituitary ◽  
Pituitary Hormones ◽  
Thyroid Stimulating Hormone ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Sexual Characteristics ◽  
Biochemical Assessment ◽  
Cranial Diabetes Insipidus ◽  
Clinical Problems ◽  
Stimulating Hormone

• The pituitary is formed of two anatomically and embryologically distinct lobes: ◦ anterior pituitary: which secretes growth hormone (GH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin ◦ posterior pituitary: which secretes vasopressin and oxytocin. • Hypopituitarism is deficiency of one or more pituitary hormones. Some hormones, e.g. GH (LH/FSH), are more likely to present with isolated deficiencies, while others, e.g. TSH, ACTH, are more often found as part of multiple pituitary hormone deficiency (MPHD). • Deficiencies may be congenital (including genetic) or acquired; secondary to tumour, trauma, infiltration, infection, or irradiation. • GH deficiency: ◦ diagnosed using a combination of clinical, radiological, and biochemical assessment (including GH stimulation testing) ◦ treatment is with GH (including if necessary into adulthood). • LH/FSH deficiency: ◦ If acquired, often one of the first anterior pituitary hormones to be lost. ◦ Congenital forms: ■ present with cryptorchidism and/or micropenis in males ■ may occur in isolation, or in association with anosmia (Kallmann and CHARGE syndromes). ◦ Treatment: sex steroid therapy to induce secondary sexual characteristics, and recombinant FSH/LH to induce fertility potential. • ACTH deficiency: ◦ Unlike primary adrenal problems, hyperpigmentation does not occur. ◦ Although mineralocorticoid production is preserved, hyponatraemia may still occur. ◦ Treatment is with hydrocortisone. • TSH deficiency: ◦ TSH may be low, normal, or raised (but inappropriate for free thyroxine level). ◦ Treatment is with thyroxine. • Vasopressin deficiency: ◦ produces cranial diabetes insipidus ◦ treatment is with DDAVP (orally or nasally). • Prolactin and oxytocin deficiency rarely produce clinical problems.

Hypopituitarism: replacement of adrenal, thyroid, and gonadal axes

2011 ◽  
pp. 145-152 ◽  
Author(s):  
Trevor A. Howlett
Keyword(s):  
Anterior Pituitary ◽  
Patient Management ◽  
Hormone Replacement ◽  
Thyroid Stimulating Hormone ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Best Management ◽  
Anterior Pituitary Hormone ◽  
The Subject ◽  
Based Medicine

Hormone replacement of anterior pituitary hormone deficiency is one of the most frequent clinical interventions in pituitary disease, yet is an area which has rarely been the subject of rigorous scientific evaluation. Even in an era of ‘evidence-based’ medicine, recommendations for patient management are frequently based predominantly on clinical experience, consensus guidelines and occasional retrospective reviews rather than on controlled, prospective clinical trials. Within these limitations, this chapter will attempt to give a balanced view on current best management of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) and gonadotropin deficiency.

scholarly journals OTX2 Loss of Function Mutation Causes Anophthalmia and Combined Pituitary Hormone Deficiency with a Small Anterior and Ectopic Posterior Pituitary

2009 ◽  
Vol 94 (1) ◽  
pp. 314-319 ◽  
Author(s):  
Toshihiro Tajima ◽  
Akira Ohtake ◽  
Masaya Hoshino ◽  
Shin Amemiya ◽  
Nozomu Sasaki ◽  
...  
Keyword(s):  
Brain Magnetic Resonance Imaging ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Dominant Negative Effect ◽  
Pituitary Hormone ◽  
Posterior Lobe ◽  
Loss Of Function ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Negative Effect

Abstract Context: Orthodenticle homeobox 2 (OTX2) is a transcription factor necessary for ocular and forebrain development. In humans, heterozygous mutations of OTX2 cause severe ocular malformations. However, whether mutations of OTX2 cause pituitary structural abnormalities or combined pituitary hormone deficiency (CPHD) has not been clarified. Objectives: We surveyed the functional consequences of a novel OTX2 mutation that was detected in a patient with anophthalmia and CPHD. Patient: We examined a Japanese patient with growth disturbance, anophthalamia, and severe developmental delay. He showed deficiencies in GH, TSH, LH, FSH, and ACTH. Brain magnetic resonance imaging revealed a small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and Chiari malformation. Results: Sequence analysis of OTX2 demonstrated a heterozygous two bases insertion [S136fsX178 (c.576-577insCT)] in exon 3. The mutant Otx2 protein localized to the nucleus, but did not activate the promoter of the HESX1 and POU1F1 gene, indicating a loss of function mutation. No dominant negative effect in the presence of wild-type Otx2 was observed. Conclusion: This case indicates that the OTX2 mutation is a cause of CPHD. Further study of more patients with OTX2 defects is necessary to clarify the clinical phenotypes and endocrine defects caused by OTX2 mutations.

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