Congenital hypopituitarism with monosomy of chromosome 18

Congenital hypopituitarism is a rare disease. It can be caused by isolated inborn defects of the pituitary, gene mutations (PROP1, PIT1), and chromosomal abnormalities.Deletions of chromosome 18 (De Grouchy syndrome types 1 and 2) are a group of rare genetic diseases with a frequency of 1:50,000. Hypopituitarism in these syndromes is detected in from 13 to 56% of cases and depends on the size and location of the deleted segment.We have described a series of clinical cases of patients with congenital hypopituitarism due to deletions in chromosome 18. All children had a characteristic dysmorphic features and delayed mental and speech development. Within first months of life, patients developed muscular hypotension, dysphagia, and respiratory disorders. The patients had various congenital malformations in combination with hypopituitarism (isolated growth hormone deficiency and multiple pituitaryhormone deficiencies). In the neonatal period, there were the presence of hypoglycemia in combination with cholestasis.Hormone replacement therapy led to rapid relief of symptoms.Сhromosomal microarray analysis in 2 patients allowed us to identify exact location of deleted area and deleted genes and optimize further management for them.

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

PurposeCongenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown.MethodsWe studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups.ResultsFirst, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01).ConclusionOur findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.

Hypothyroxinaemia in refractory shock: a clue to diagnose hypopituitarism

The rarity of congenital hypopituitarism (CHP) makes it essential for clinicians to be aware of its varying clinical manifestations. We report a neonate with one such unique presentation. A preterm girl baby was managed for respiratory distress. Diffuse cutis marmorata was present since birth; septic screens were positive with placental histopathology showing chorioamnionitis. Newborn screening showed low free thyroxine and normal TSH. Transient hypothyroxinaemia of prematurity was considered. Her respiratory status worsened on day 9, followed by refractory shock. She was treated for sepsis. Further evaluation for absent heart rate variability in response to vasopressor resistant shock led to the detection of hypocortisolism. Low cortisol along with hypothyroxinaemia made hypopituitarism the working diagnosis. Owing to the variable clinical spectrum of CHP, diagnosis is challenging. We highlight a few clinical and laboratory features, which would help in earlier diagnosis of CHP.

Dysgenesis and dysfunction of pancreas and pituitary due to FOXA2 gene defects

Context Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extra-pituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The Forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut and pancreatic development. Objective To characterize two patients with syndromic hypopituitarism due to FOXA2 gene defects. Results We report a novel heterozygous nonsense c.616C>T (p.Q206X) variant, which leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the GLUT2-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 megabase (Mb) deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. Conclusions Our two cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.

Cholestasis syndrome in a newborn child with congenital hypopituitarism

The purpose of the work is comprehensive examination of a newborn with cholestasis syndrome to determine congenital hypopituitarism. Materials and methods. The child was hospitalized on the 30th day of his life. At admission, complaints were noted about the ictericity of the skin, low body weight gain, convulsive syndrome (history). Differential diagnosis was carried out between diseases such as: impaired liver function, against the background of the course of the infectious-inflammatory process; diseases of the liver and bile ducts of hereditary nature; congenital malformations of the bile tract; metabolic and hormonal disorders. Results. During the survey, the following deviations from the norm were obtained: in the biochemical analysis there was an increase in the level of transaminases, alkaline phosphatase, total and direct bilirubin, hypoglycemia. When evaluating the hormonal profile, an increase in the level of prolactin, thyroid hormone, a decrease in the level of T4 free, insulin, and a complete absence of cortisol were revealed. Magnetic resonance imaging (MRI) of the brain - a picture of subependymal nodes of gray matter heterotopia, ectopia of the neurophysis. Conclusions. Lowering glucose levels, especially when combined with cholestasis syndrome, may be an early but nonspecific sign of congenital hypopituitarism. Hypoglycemia in newborns occurs as a result of intrauterine insufficiency of somatotropic hormone and cortisol related to contrinsular hormones. Cortisol deficiency also contributes to the development of cholestasis syndrome by reducing the expression of tubule transport proteins that regulate bile secretion into bile tubules. In addition to studying the hormonal profile, a brain MRI is performed to verify the diagnosis. Patients with congenital hypopituitarism are characterized by the detection of characteristic signs: the picture of the “empty” or “partially empty” Turkish saddle, as well as the classic triad of symptoms: hypoplasia/pituitary leg aplasia, neurophysis ectopia, adenohypophysis hypoplasia. This clinical case demonstrates that cholestasis syndrome may lie in the debut of a more severe pathology. At the same time, early diagnosis and adequately selected hormone replacement therapy leads to a rapid cessation of life-threatening conditions and an improvement in the quality of life of the child.

Novel Pathogenic Variants in LHX3, LHX4 and GLI2 Identified in Pediatric Patients With Congenital Hypopituitarism: From Variant Calling To Variant Testing

Congenital hypopituitarism (CH), septo-optic dysplasia (SOD), and holoprosencephaly (HPE) constitute an important group of structural birth defects that cause significant morbidity and life-long consequences for quality of life and care. The genetic causes are highly overlapping. As such, these disorders can be considered as a spectrum of related disorders. Improved insight into genetic causes would be valuable for patients, families, and medical geneticists. Very few systematic genetic screens have been carried out for patients with CH. We implemented genetic screening using single-molecule molecular inversion probes sequencing to identify causative mutations in a set of 67 genes previously reported in CH patients and the spectrum encompassing SOD and HPE. We captured genomic DNA from 170 Argentinean pediatric patients with CH, and 54% of the patients in this cohort have craniofacial, ophthalmologic, and/or central nervous system defects. We found candidate pathogenic, likely pathogenic and variants uncertain significance (VUS) in 23% of the cases. In order to evaluate the functional consequences of VUS in LHX3, LHX4, and GLI2, we performed in-vitro functional assays to study the activity of the mutated proteins. To test LHX3/4 variants we co-transfected HEK293T cells with wild type (WT) or mutated LHX3/4 variant plasmids and luciferase reporter genes driven by the ɑGSU promoter or GH1 promoter and assayed for luciferase activity. For GLI2 functional analysis we used the cell line NIH/3T3-CG, stably transfected to express GFP under the presence of GLI2 activated form. Endogenous Gli2 was knocked out by CRISPR-Cas9 and clones were selected for absence of GFP expression upon activation of the sonic hedgehog pathway. We tested the ability of transfected WT or mutated GLI2 expression plasmids to restore GFP fluorescence. We concluded that variants LHX3:p.Pro187Ser LHX4:p.Arg84His, p.Gln100His and p.Trp204Leu and GLI2:p.1404Lfs impair activation of the reporter gene, while the LHX3:p.Leu220Met and GLI2:p.L761P have WT activity on their respective assays. Identification of disease-causing variants in CH is complicated by phenotypic variation, incomplete penetrance, and VUS. Functional testing of potentially pathogenic variants is critical to arrive at a definitive molecular diagnosis. A full catalogue of variant effects in known causative genes would be invaluable for clinicians in order to simplify the interpretation of novel variants and reduce the diagnostic odyssey that families often experience.

Comprehensive identification of pathogenic gene variants in patients with neuroendocrine disorders

Purpose Congenital hypopituitarism (CH) can present in isolation or with other birth defects. Mutations in multiple genes can cause CH, and the use of a genetic screening panel could establish the prevalence of mutations in known and candidate genes for this disorder. It could also increase the proportion of patients that receive a genetic diagnosis. Methods We conducted target panel genetic screening using single-molecule molecular inversion probes sequencing to assess the frequency of mutations in known hypopituitarism genes and new candidates in Argentina. We captured genomic DNA from 170 pediatric patients with CH, either alone or with other abnormalities. We performed promoter activation assays to test the functional effects of patient variants in LHX3 and LHX4. Results We found variants classified as pathogenic, likely pathogenic or with uncertain significance in 15.3% of cases. These variants were identified in known CH causative genes (LHX3, LHX4, GLI2, OTX2 and HESX1), in less frequently reported genes (FOXA2, BMP4, FGFR1, PROKR2, PNPLA6) and in new candidate genes (BMP2, HMGA2, HNF1A, NKX2-1). Conclusion In this work, we report the prevalence of mutations in known CH genes in Argentina and provide evidence for new candidate genes. We show that CH is a genetically heterogeneous disease with high phenotypic variation and incomplete penetrance, and our results support the need for further gene discovery for CH. Identifying population-specific pathogenic variants will improve the capacity of genetic data to predict eventual clinical outcomes.