FOXE1 – Bamforth-Lazarus syndrome

Bamforth-Lazarus syndrome is an autosomal recessive disorder caused by biallelic variants in FOXE1, encoding thyroid transcription factor 2 (TTF-2). Clinically it presents with congenital hypothyroidism due to thyroid agenesis or hypoplasia, cleft palate, spiky hair, choanal atresia, and bifid epiglottis. Affected individuals may also exhibit facial dysmorphism and, rarely, porencephaly as first described in a neonatal case (PMID:24341142).

Genetic evidence includes two siblings homozygous for a forkhead‐domain missense variant p.Ser57Asn with impaired DNA binding and transcriptional activity (PMID:12165566), a consanguineous patient with homozygous p.Arg73Ser demonstrating gain‐of‐function promoter activation (PMID:24219130), and a novel homozygous frameshift variant c.141dupC (p.Leu49ProfsTer75) in an unrelated patient expanding the phenotypic spectrum (PMID:35963604).

The core phenotype—cleft palate (HP:0000175), facial abnormality (HP:0000271), porencephalic cyst (HP:0002132), and congenital hypothyroidism (HP:0000851)—is highly consistent across AR-inherited cases. Parental heterozygotes are unaffected, confirming recessive segregation.

Mechanistically, FOXE1 loss-of-function underlies thyroid dysgenesis and palate defects; in vitro assays show defective DNA binding and reduced transactivation of thyroid gene promoters (PMID:12165566; PMID:16882747). In mouse Foxe1⁻/⁻ embryos, downstream targets Msx1 and Tgfβ3 are nearly absent in palatal shelves, recapitulating clefting (PMID:21177256).

There is no substantial conflicting evidence; gain-of-function R73S further broadens mechanistic insight without disputing causality. Additional zebrafish models mirror hypothyroid and craniofacial phenotypes, supporting cross-species concordance.

Collectively, genetic and experimental data support a Moderate ClinGen gene–disease validity. Further studies may reach higher classification.

Key Take-home: Biallelic FOXE1 loss-of-function variants reliably cause Bamforth-Lazarus syndrome and should be included in genetic diagnostic panels for syndromic congenital hypothyroidism with cleft palate.

References

• Genetic Counseling (Geneva, Switzerland) • 2013 • Bamforth syndrome: is porencephaly a new finding? PMID:24341142
• Human Molecular Genetics • 2002 • A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. PMID:12165566
• Thyroid • 2014 • A novel FOXE1 mutation (R73S) in Bamforth-Lazarus syndrome causing increased thyroidal gene expression. PMID:24219130
• European Journal of Medical Genetics • 2022 • A new FOXE1 homozygous frameshift variant expands the genotypic and phenotypic spectrum of Bamforth-Lazarus syndrome. PMID:35963604
• Human Molecular Genetics • 2011 • MSX1 and TGF-beta3 are novel target genes functionally regulated by FOXE1. PMID:21177256

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