Heterozygous recurrent HNF4A variant p.Arg85Trp causes Fanconi renotubular syndrome 4 with maturity onset diabetes of the young, an autosomal dominant phenocopy of Fanconi Bickel syndrome with colobomas.

Heterozygous pathogenic variants in HNF4A cause hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent missense pathogenic variant c.253C>T (p.Arg85Trp) has been associated with a syndromic form of hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with the autosomal recessive Fanconi Bickel Syndrome, and her affected son. The son's presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of hyperinsulinism and maturity onset of the diabetes of the young changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the premolecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.