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      Congenital hyperinsulinism and panhypopituitarism: a rare combination


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          Neonatal hypoglycemia is a serious condition that can have a major impact on the growing neonatal brain. The differential diagnosis of neonatal hypoglycemia is broad and includes hyperinsulinism as well as panhypopituitarism. The FOXA2 gene has been involved in the development of the pancreas as well as the pituitary gland. Six cases have been reported thus far with FOXA2 mutations presenting with variable degrees of hypopituitarism, and only two patients had permanent hyperinsulinism; other cases have been reported with microdeletions in 20p11, the location that encompasses FOXA2, and those patients presented with a wider phenotype. A full-term female infant presented with severe hypoglycemia. Critical sampling showed an insulin of 1 mIU/mL, suppressed beta-hydroxybutyric acids, and suppressed free fatty acids. Blood glucose responded to glucagon administration. Growth hormone (GH) stimulation test later showed undetectable GH in all samples, and cortisol failed to respond appropriately to stimulation. Gonadotropins were undetectable at 1 month of life, and MRI showed ectopic posterior pituitary, interrupted stalk, hypoplastic anterior pituitary, cavum septum pellucidum, and diminutive appearance of optic nerves. Whole-exome sequencing revealed a likely pathogenic de novo c.604 T>C, p.Tyr202His FOXA2 mutation. We expand the known phenotype on FOXA2 mutations and report a likely pathogenic, novel mutation associated with hyperinsulinism and panhypopituitarism.

          Learning points
          • FOXA2 has been shown to play an important role in the neuroectodermal and endodermal development.

          • FOXA2 mutation may lead to the rare combination of hyperinsulinism and panhypopituitarism.

          • Patients reported so far all responded well to diazoxide. Dysmorphology may be subtle, and liver functions should be monitored.

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          Most cited references8

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          Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children.

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            Novel FOXA2 mutation causes Hyperinsulinism, Hypopituitarism with Craniofacial and Endoderm-derived organ abnormalities.

            Congenital hypopituitarism (CH) is characterized by the deficiency of one or more pituitary hormones and can present alone or in association with complex disorders. Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion despite hypoglycaemia that can occur in isolation or as part of a wider syndrome. Molecular diagnosis is unknown in many cases of CH and CHI. The underlying genetic etiology causing the complex phenotype of CH and CHI is unknown. In this study, we identified a de novo heterozygous mutation in the developmental transcription factor, forkhead box A2, FOXA2 (c.505T>C, p.S169P) in a child with CHI and CH with craniofacial dysmorphic features, choroidal coloboma and endoderm-derived organ malformations in liver, lung and gastrointestinal tract by whole exome sequencing. The mutation is at a highly conserved residue within the DNA binding domain. We demonstrated strong expression of Foxa2 mRNA in the developing hypothalamus, pituitary, pancreas, lungs and oesophagus of mouse embryos using in situ hybridization. Expression profiling on human embryos by immunohistochemistry showed strong expression of hFOXA2 in the neural tube, third ventricle, diencephalon and pancreas. Transient transfection of HEK293T cells with Wt (Wild type) hFOXA2 or mutant hFOXA2 showed an impairment in transcriptional reporter activity by the mutant hFOXA2. Further analyses using western blot assays showed that the FOXA2 p.(S169P) variant is pathogenic resulting in lower expression levels when compared with Wt hFOXA2. Our results show, for the first time, the causative role of FOXA2 in a complex congenital syndrome with hypopituitarism, hyperinsulinism and endoderm-derived organ abnormalities.
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              Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia.

              Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                03 May 2023
                01 April 2023
                : 2023
                : 2
                : 22-0355
                [1 ]Department of Pediatrics , Southern Illinois University, Springfield, Illinois, USA
                [2 ]Department of Pediatrics , Division of Neonatology, Southern Illinois University, Springfield, Illinois, USA
                [3 ]Department of Pediatrics , Division of Pediatric Endocrinology and Diabetes, Southern Illinois University, Springfield, Illinois, USA
                Author notes
                Correspondence should be addressed to A Torky; Email: atorky83@ 123456siumed.edu
                Author information
                © the author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                : 17 August 2022
                : 03 May 2023
                United States
                Genetics and Mutation
                Unique/Unexpected Symptoms or Presentations of a Disease
                Unique/Unexpected Symptoms or Presentations of a Disease

                paediatric,female,other,united states,pancreas,pituitary,genetics and mutation,unique/unexpected symptoms or presentations of a disease,may,2023


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