FOXP3 mutations causing early‐onset insulin‐requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome

Abstract

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.

Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency

“…The site of mutations does not seem to affect the phenotype, course, or outcome of the disease. 53 The disease is difficult to diagnose because it can present as isolated early-onset diabetes 54 or enteropathy 55 or manifest later in childhood. 56 In addition to the predominant triad of symptoms and failure to thrive caused by enteropathy and chronic illness, other autoimmune manifestations have been observed, including nephropathy, hepatitis, autoimmune thyroiditis, autoimmune hemolytic anemia, thrombocytopenia, neutropenia, lymphadenopathy, arthritis, alopecia, food allergies, and, rarely, neurologic manifestations.…”

Unusual and early onset IPEX syndrome: a case report

“…As new cases proven by genetic analysis were added over the world, considerable clinical heterogeneity was reported. [13][14][15] On the other hand, similar genotypes did not always give rise to similar phenotypes in terms of disease manifestation and severity of IPEX. 16 Patients who have mutations which delete the expression of the functional FOXP3 protein (such as patients who have mutations at the polyadenylation area like frameshift or premature stop kodone) have the tendency to have a serious clinical chart.…”

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

“…Patients with the classically described syndrome have a severe clinical course, resulting in death within the first few years of life without stem cell transplant; however, ongoing reports demonstrate the phenotypic spectrum of cases who may only have diabetes in isolation [31, 32]. …”

“…Mutations in the X-linked gene FOXP3 are a rare cause of infancy-onset monogenic autoimmune diabetes, along with numerous other features including enteropathy causing severe diarrhea and malnutrition, severe eczema, and autoimmune thyroid disease [1]. Patients with the classically described syndrome have a severe clinical course, resulting in death within the first few years of life without stem cell transplant; however, ongoing reports demonstrate the phenotypic spectrum of cases who may only have diabetes in isolation [31, 32].…”