Fanconi Renotubular Syndrome 4 With Maturity-Onset Diabetes Of The Young

A number sign (#) is used with this entry because Fanconi renotubular syndrome-4 with maturity-onset diabetes of the young (FRTS4) is caused by heterozygous mutation in the HNF4A gene (600281) on chromosome 20q13.

Heterozygous mutation in the HNF4A gene can also cause isolated MODY1 (125850).

For a general phenotypic description and a discussion of genetic heterogeneity of Fanconi renotubular syndrome, see FRTS1 (134600).

Clinical Features

Stanescu et al. (2012) reported a female infant who presented with macrosomia and severe hypoglycemia associated with hyperinsulinism in the first hours of life. Over the following years, she required lower doses to maintain normoglycemia, and treatment was discontinued at age 4 years. By age 1 year, she had also developed radiologic evidence of rickets, increased plasma alkaline phosphatase, decreased phosphorus, glycosuria, proteinuria, and metabolic acidosis. These features were reminiscent of the Fanconi-Bickel syndrome (227810). The child also had hepatomegaly with elevated transaminases; liver biopsy showed abundant cytoplasmic glycogen with mild portal inflammation and fibrosis.

Hamilton et al. (2014) reported 2 sisters with neonatal hypoglycemia associated with hyperinsulinism and macrosomia. Both were diagnosed with Fanconi renotubular syndrome and nephrocalcinosis resulting in short stature and rickets. One sister had a similarly affected son. The renal phenotype was manifest as low molecular weight proteinuria, aminoaciduria, glycosuria, phosphaturia, calciuria, and low serum urate. Three additional unrelated patients with a similar disorder were subsequently identified; 2 of these patients developed diabetes mellitus at ages 20 and 12 years, respectively.

Inheritance

The transmission pattern of FRTS4 in the families with MODY reported by Hamilton et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a girl with Fanconi renotubular syndrome with MODY, Stanescu et al. (2012) identified a de novo heterozygous missense mutation in the HNF4A gene (R76W; 600281.0008).

Hamilton et al. (2014) identified a heterozygous R76W mutation in 3 members of a family with FRTS4 and a pancreatic beta-cell phenotype manifest as macrosomia and neonatal hypoglycemia associated with hyperinsulinemia. Three additional unrelated carriers of the heterozygous R76W mutation were subsequently identified from a cohort of 147 probands with HNF4A mutations; all had the Fanconi renal phenotype with nephrocalcinosis. The R76W mutation, which occurs in the DNA-binding domain, was hypothesized to cause defective interaction with major regulatory genes; however, functional studies were not performed. Analysis of urine and serum samples from 20 diabetic patients with other HNF4A mutations showed no evidence of a Fanconi renal phenotype. Hamilton et al. (2014) concluded that this specific mutation is associated with a unique phenotype comprising both MODY and FRTS.