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Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review.

ABSTRACT: Background:Diabetes mellitus with autosomal dominant inheritance, such as maturity-onset diabetes of the young (MODY), is a genetic form of diabetes mellitus. MODY is a type of monogenic diabetes mellitus in which multiple genetic variants may cause an alteration to the functioning of beta cells. The three most known forms of MODY are caused by modifications to the hnf4a, gck, and hnf1a genes. However, other MODY variants can cause multiple alterations in the embryonic development of the endoderm. This is the case in patients presenting with MODY5, who have a mutation of the hepatic nuclear factor 1B (hnf1b) gene. Case presentation:We present the clinical case of a 15?year-old patient with a family history of diabetes mellitus and a classical MODY type 5 (MODY5) phenotype involving the pancreas and kidney, with a novel, unreported mutation in the hnf1b gene. Conclusions:MODY5 is characterised by a mutation in the hnf1b gene, which plays an important role in the development and function of multiple organs. It should be suspected in patients with unusual diabetes and multisystem involvement unrelated to diabetes. Graphical abstract:

SUBMITTER: Mateus JC

PROVIDER: S-EPMC7448977 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review.

Mateus Juan Camilo JC Rivera Carolina C O'Meara Miguel M Valenzuela Alex A Lizcano Fernando F

Clinical diabetes and endocrinology 20200826

<h4>Background</h4>Diabetes mellitus with autosomal dominant inheritance, such as maturity-onset diabetes of the young (MODY), is a genetic form of diabetes mellitus. MODY is a type of monogenic diabetes mellitus in which multiple genetic variants may cause an alteration to the functioning of beta cells. The three most known forms of MODY are caused by modifications to the <i>hnf4a</i>, <i>gck</i>, and <i>hnf1a</i> genes. However, other MODY variants can cause multiple alterations in the embryon ...[more]

PMID: 32864159

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Project description:BackgroundMaturity-Onset Diabetes of the Young (MODY) is an autosomal dominant condition and represents 1-5% of all cases of diabetes mellitus. MODY is often misdiagnosed as type 1 or type 2 diabetes. The rare subtype 5 (HNF1B-MODY) is due to hepatocyte nuclear factor 1β (HNF1B) molecular alteration and is remarkable for its multisystemic phenotypes characterized by a broad spectrum of pancreatic and extra-pancreatic clinical manifestations.MethodsRetrospective study of patients with HNF1B-MODY diagnosis followed in the Centro Hospitalar Universitário Lisboa Central (Lisbon, Portugal). Demographic data, medical history, clinical and laboratory data, follow-up and treatment procedures were obtained from electronic medical records.ResultsWe found 10 patients with HNF1B variants (7 index cases). The median age at diabetes diagnosis was 28 (IQR 24) years and the median age at HNF1B-MODY diagnosis was 40.5 (IQR 23) years. Six patients were initially misclassified as type 1 and 4 as type 2 diabetes. The average time between diabetes diagnosis and the diagnosis of HNF1B-MODY was 16.5 years. Diabetes was the first manifestation in half of the cases. The other half presented with kidney malformations and chronic kidney disease at pediatric age as the first manifestation. All these patients were submitted to kidney transplantation. Long-term diabetes complications included retinopathy (4/10), peripheral neuropathy (2/10) and ischemic cardiomyopathy (1/10). Other extra-pancreatic manifestations included liver test alterations (4/10) and congenital malformation of the female reproductive tract (1/6). History of a first-degree relative with diabetes and/or nephropathy diagnosed at a young age was present in 5 of the 7 index cases.ConclusionsDespite being a rare disease, HNF1B-MODY is underdiagnosed and often misclassified. It should be suspected in patients with diabetes and CKD, especially when diabetes appears at a young age, a family history is present, and nephropathy appears before/shortly after the diagnosis of diabetes. Presence of unexplained liver disease increases the degree of suspicion for HNF1B-MODY. Early diagnosis is important to minimize complications and to allow familial screening and pre-conception genetic counseling. Trial registration not applicable due to the retrospective nature of the study, non-interventional.

Project description:BackgroundWe aimed to analyze a novel ABCC8 variant of a Chinese patient with suspected maturity-onset diabetes of the young (MODY) and to provide evidence for precise diagnosis and appropriate treatment.MethodA Chinese family with suspected MODY was recruited in this study, which included a 15-year-old female patient with diabetes. Clinical data and blood samples were collected from the proband and other family members. All of the living relatives were given an oral glucose tolerance test. Next-generation sequencing was performed to identify the mutated genes in the proband. Sanger sequencing was utilized to confirm the location of the pathogenic variant in all subjects. Further treatment was referred to targeted family members according to genetic testing.ResultsThe proband was found to have a random blood glucose level of 244.8 mg/dl and an HbA1c level of 9.2%. Before this investigation, her grandparents had been diagnosed with diabetes. The second uncle, two aunts, mother, and cousin of the proband were diagnosed with diabetes by abnormal HbA1C (6.5-12.1%) and fasting blood glucose (FBG, 91.4-189.7 mg/dl). The second aunt of the proband had impaired glucose homeostasis (HbA1C = 6.4% and FBG = 88.0 mg/dl). One novel missense variant c.1432G>A (p.A478T) in exon 9 of the ABCC8 gene was detected in the proband with suspected MODY. The variant was also found in six family members with diabetes or impaired glucose homeostasis, including her second uncle, two aunts, mother, and cousin. After the treatment was switched to glimepiride, the fasting blood glucose was adjusted to 99.54 mg/dl, the 2-h postprandial blood glucose was 153.54 mg/dl, serum fructosamine was 259 μmol/l, and HbA1c was 5.8%. The glycemic control remained optimal, and no hypoglycemic episodes were observed in the living relatives.ConclusionThis study revealed one novel missense variant of the ABCC8 gene in Chinese families. The present findings indicated that the members of this family responded to treatment with sulfonylureas as previously seen in ABCC8 MODY.

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Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review.

Publications

Maturity-onset diabetes of the young type 5 a MULTISYSTEMIC disease: a CASE report of a novel mutation in the HNF1B gene and literature review.

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