FOXA2 gene mutation in a patient with congenital complex pituitary hormone deficiency

Boda, Hiroko; Miyata, Masafumi; Inagaki, Hidehito; Shinkai, Yasuko; Kato, Takema; Yoshikawa, Tetsushi; Kurahashi, Hiroki

doi:10.1016/j.ejmg.2018.11.004

Cited by 10 publications

(7 citation statements)

References 11 publications

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“…Thus, her features further expand the phenotypes associated with proximal 20p11.2 deletions. We also report one unrelated individual with a missense variant (p.R256S) in FOXA2 , whose predominant clinical features were neonatal hypoglycemia, consistent with three previously reported individuals described in the literature (Boda et al, ; Giri et al, ; Vajravelu et al, ). The findings in these two new patients lend additional support for FOXA2 function being critical to midline embryologic development.…”

Section: Introductionsupporting

confidence: 90%

“…Using a luciferase assay, transactivation of critical genes ( ABCC8 , KCNJ11 , HADH , SHH , GLI2 , NKX2‐2 ) for beta cell and pituitary development and function were decreased for this mutant FOXA2 compared to wild‐type FOXA2 , suggesting a LOF as the pathogenic mechanism (Vajravelu et al, ). Finally, Boda et al () described a de novo missense variant (c.664T>G, p.C222G) in a patient with absent anterior and posterior pituitary gland, panhypopituitarism, hypoglycemia without hyperinsulinemia, intestinal malrotation, and anal atresia. Based on protein structural predictions, all three variants are involved with DNA binding ability of FOXA2 (Boda et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, Boda et al () described a de novo missense variant (c.664T>G, p.C222G) in a patient with absent anterior and posterior pituitary gland, panhypopituitarism, hypoglycemia without hyperinsulinemia, intestinal malrotation, and anal atresia. Based on protein structural predictions, all three variants are involved with DNA binding ability of FOXA2 (Boda et al, ). The p.R256S variant in our patient also occurs within the DNA‐binding domain (residues 157–258, [Li et al, ]); however, further functional studies are needed to determine whether the variant seen in this patient causes a dominant‐negative effect or haploinsufficiency.…”

Section: Discussionmentioning

confidence: 99%

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Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

Dines

Liu

Neufeld-Kaiser

et al. 2019

American J of Med Genetics Pt A

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Rare individuals with 20p11.2 proximal deletions have been previously reported, with a variable phenotype that includes heterotaxy, biliary atresia, midline brain defects associated with panhypopituitarism, intellectual disability, scoliosis, and seizures. Deletions have ranged in size from 277 kb to 11.96 Mb. We describe a newborn with a de novo 2.7 Mb deletion of 20p11.22p11.21 that partially overlaps previously reported deletions and encompasses FOXA2. Her clinical findings further expand the 20p11.2 deletion phenotype to include severe midline cranial and intracranial defects such as aqueductal stenosis with hydrocephalus, mesencephalosynapsis with diencephalic‐mesencephalic junction dysplasia, and pyriform aperture stenosis. We also report one individual with a missense variant in FOXA2 who had abnormal glucose homeostasis, panhypopituitarism, and endodermal organ dysfunction. Together, these findings support the critical role of FOXA2 in panhypopituitarism and midline defects.

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Section: Introductionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

Dines

Liu

Neufeld-Kaiser

et al. 2019

American J of Med Genetics Pt A

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“…Our patient shares most of these phenotypes except that our patient does not exhibit hyperinsulinemic hypoglycemia. A recent report identified a de novo heterozygous mutation in the FOXA2 , c.664T> G (p.Cys222Gly), in a patient with intestinal malrotation, anal atresia, and pituitary hormone deficiency (Boda et al, ; Figure ).…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the FOXA2 associated with a complex clinical phenotype

Mohammed

Al‐Khawaga

Bohanna

et al. 2020

Molec Gen & Gen Med

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Background There are few reports describing the proximal deletions of the short arm of chromosome 20, making it difficult to predict the likely consequences of these deletions. Most previously reported cases have described the association of 20p11.2 deletions with Alagille syndrome, while there are others that include phenotypes such as panhypopituitarism, craniofacial dysmorphism, polysplenia, autism, and Hirschsprung disease. Methods Molecular karyotyping, cytogenetics, and DNA sequencing were undertaken in a child to study the genetic basis of a complex phenotype consisting of craniofacial dysmorphism, ocular abnormalities, ectopic inguinal testes, polysplenia, growth hormone deficiency, central hypothyroidism, and gastrointestinal system anomalies. Results We report the smallest described de novo proximal 20p11.2 deletion, which deletes only the FOXA2 leading to the above complex phenotype. Conclusions Haploinsufficiency of the FOXA2 only gene is associated with a multisystem disorder.

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“…Thus, the genetic aetiology of intestinal atresia is likely to be complex and may vary between families and populations, with a simple autosomal recessive mode of inheritance unlikely to explain all cases. It is possible that sporadic cases arise due to development anomalies or de novo mutations, as has been reported for complex congenital defects including intestinal atresia in humans (Boda et al, 2019; Bourque et al, 2019; Magoulas & El‐Hattab, 2012). Additionally, genetic mutations responsible for intestinal atresia may have incomplete penetrance, as has been reported in humans (Fairbanks et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Risk factors for, and genetic association with, intestinal atresia in dairy calves

et al. 2023

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Intestinal atresia is a congenital defect, found in a wide variety of species, that results in complete occlusion of the intestinal lumen (Ducharme et al., 1988). The occlusion can occur in the duodenum, jejunum, ileum, colon, or anus, and prevents the normal movement of gut contents and the passing of faecal material. In calves, common presentations include failure to pass meconium and faeces, inappetence and abdominal distension; affected animals usually die within 7 days of birth or are euthanised (Mee, 2021). Atresia is a well-known congenital defect of the gastrointestinal system in calves and investigations into the aetiology of this condition are warranted.

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FOXA2 gene mutation in a patient with congenital complex pituitary hormone deficiency

Cited by 10 publications

References 11 publications

Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

Expanding phenotype with severe midline brain anomalies and missense variant supports a causal role for FOXA2 in 20p11.2 deletion syndrome

Haploinsufficiency of the FOXA2 associated with a complex clinical phenotype

Risk factors for, and genetic association with, intestinal atresia in dairy calves

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