EARLY ONSET OF MODY5 DUE TO HAPLOINSUFFICIENCY OF HNF1B

Abstract

Objective:

To report 2 patients with haploinsufficiency of hepatic nuclear factor 1 homeobox B (HNF1B) that results in the onset of maturity onset diabetes of the young type 5 (MODY5) before 3 years of age.

Methods:

We present 2 unusual patients with MODY5 that was diagnosed at 33 and 22 months of age, respectively. We describe the presentations, clinical course, and genetic tests of both patients, and lastly, we review the literature on the prevalence and the age of presentation of MODY5 both in children and in adult patients.

Results:

The first patient had severe congenital renal dysplasia, and deoxyribonucleic acid microarray indicated the deletion of 17q12. Hemoglobin A1c (HbA1c) was obtained due to the concern of MODY5, and the initial level (6.6%, 49 mmol/mol) was abnormally elevated. The second patient had mild renal dysplasia and 17q12 deletion encompassing the HNF1B gene. Hyperglycemia was identified during an episode of respiratory illness. HbA1c (6.2%, 44 mmol/mol) level was abnormally elevated. Pancreatic autoantibodies were absent in both patients. Diet modification resulted in an improvement of HbA1c in both patients.

Conclusion:

Our report highlights the importance of considering MODY5 in patients with congenital anomalies of kidney. Identification of children with MODY5 permits early management of hyperglycemia.

INTRODUCTION

Haploinsufficiency or mutation of the hepatic nuclear factor 1 homeobox B (HNF1B) gene causes maturity onset diabetes of the young type 5 (MODY5); a syndrome defined by nonautoimmune diabetes mellitus and structural renal abnormalities. HNF1B is a transcription factor that plays an essential role in embryogenesis of the kidney, pancreas, lung, liver, and intestine (1). Congenital anomalies of the kidney range from renal cysts to severe dysplasia (1). Urinary tract anomalies may also be present. Although up to 58% of patients with an alteration of the HNF1B gene have diabetes mellitus and renal abnormalities (2), less than 1% of affected individuals have diabetes mellitus alone (3). In a cohort from Norway, MODY5 was confirmed in 0.7 percent of children less than 15 years of age with diabetes mellitus. Among patients with confirmed MODY5, 0.8% harbored a mutation of HNF1B (4). By contrast, a cohort from Germany which expanded the criteria to include patients from birth to less than 20 years of age found a prevalence of MODY5 to be 1.2%, and among these patients, 1.7% have MODY5 (5). The median age for the onset of diabetes mellitus in MODY5 is considered to be from 13 years to 25 years depending on the study (3,5,6). The low prevalence of MODY5 among children even though they carry a genetic defect of the HNF1B gene suggests that hyperglycemia may not manifest until later in life, or hyperglycemia may go undetected. Furthermore, the true onset of hyperglycemia in children with congenital anomalies of kidneys due to HNF1B mutation or deletion may have also been overlooked as a screening test for hyperglycemia is not usually performed. In this report, we present 2 cases of MODY5 due to the haploinsufficiency of HNF1B in which the onset of hyperglycemia was detected before 3 years of age.

CASE REPORT

Case 1

A 33-month-old boy with bilateral dysplastic kidney and chronic kidney disease (CKD) stage 5 was referred to our diabetes clinic due to hyperglycemia. He was born at full term (40 weeks) with a normal birth weight (3,175 g). Bilateral dysplastic kidney was diagnosed at birth, and his kidney function deteriorated to CKD stage 5 by 6 months of age. His weight (46th percentile) and height (74th percentile) were within the normal range for his age. His neurologic exam was unremarkable. There was no family history of kidney diseases or diabetes mellitus. Deoxyribonucleic acid (DNA) microarray, which was obtained to investigate a genetic cause for the dysplastic kidneys, revealed a heterozygous microdeletion (1.43 Mb) of chromosome 17q12 region. The deletion encompassed the entire HNF1B gene (Table 1). Genetic testing of other family members was not performed. Hyperglycemia was investigated in light of the deletion of HNF1B. Random blood glucose (204 mg/dL, 11.4 mmol/L) and hemoglobin A1c (HbA1c) (6.6%, 49 mmol/mol) were abnormally elevated. Glutamate decarboxylase 2 (GAD65), islet antigen 2 (IA-2), and insulin autoantibodies were negative. Fasting serum C-peptide (2.37 ng/mL, 0.78 nmol/L) was also normal. Hepatic function tests were normal. The abnormally elevated HbA1c, the presence of kidney anomalies and HNF1B deletion were consistent with MODY5. As hyperglycemia was mild, insulin treatment was not started. Diet modification, including age-appropriate carbohydrate portioning, was implemented. The recommended meal plan was 30 g of carbohydrate per meal and 2 snacks that consisted of 10 g of carbohydrate with avoidance of food and snacks with a high glycemic index. His weight gain and growth were appropriate for his age after the implementation of this meal plan. Premeal blood glucose levels were also monitored at home. The patient’s blood glucose significantly improved after diet modification and his HbA1c was below 6.5% (48 mmol/mol) at every visit. One year after the diagnosis of MODY5, the patient received a kidney transplant and also received several medications, including glucocorticoids, which may have contributed to an increase in HbA1c level (Fig. 1). His postprandial and fasting blood glucose levels were all below 200 mg/dL (11.1 mmol/L), and the caregivers felt that insulin therapy was not obligatory.

Table 1.

Clinical Presentations and Genetic Testing Results of MODY5 Patients in the Report

Age of onset of hyperglycemia	Initial HbA1c and C-peptide	Kidney anomalies	Genetic testing results
2 years and 9 months	6.6% (49 mmol/mol) 2.37 ng/ml (0.78 nmol/L)	Bilateral dysplastic kidneys CKD stage 5	1.43 Mb deletion of 17q12 including HNF1B arr17q12(34,822,500-36,248,918) x1
1 year and 10 months	6.2% (44 mmol/mol) 3.35 ng/ml (1.11 nmol/L)	Mild dysplastic kidneys A subcentimeter cyst in the left kidney	1.5 Mb deletion of 17q12 including HNF1B arr17q12(34,822,465-36,353,953) x1

Abbreviations: CKD = chronic kidney disease; HbA1c = hemoglobin A1c; HNF1B = hepatic nuclear factor 1 homeobox B; MODY5 = maturity onset diabetes of the young type 5.

Fig. 1.

HbA1c of both patients in the case report at the time of diagnosis and after intervention with diet modification. HbA1c = hemoglobin A1c.

Case 2

A 22-month-old boy was referred to our clinic for evaluation of hyperglycemia (blood glucose >200 mg/dL, 11.1 mmol/l) that recurred during an episode of influenza. His weight (45th percentile) and length (8th percentile) were both within the normal range. HbA1c (6.2%, 44 mmol/mol) during the hospitalization was elevated, and repeat analyses indicated a similar mild elevation of HbA1c. Fasting plasma glucose during the hospital stay was 116 mg/dl (6.4 mmol/l). GAD65, IA-2, and insulin antibodies were negative and fasting serum C-peptide (3.35 ng/mL, 1.11 nmol/L) was also normal. As the patient had been placed under foster care since he was 1 year old, the patient’s family history was not available for a review. The patient had global developmental delay and was evaluated by a neurologist who requested a DNA microarray. The result of microarray indicated a heterozygous micro-deletion (1.5 Mb) of chromosome 17q12 encompassing 20 genes: ZNHIT3, MYO19, PIGW, GGNBP2, DHRS11, MRM1, LHX1, AATF, MIR2909, ACACA, C17orf78, TADA2A, DUSP14, SYNRG, DDX52, LOC284100, TBC1D3F, TBC1D3, LOC440434, and HNF1B (Table 1). Renal sonography indicated subtle echogenic changes of renal parenchyma bilaterally consistent with dysplastic kidneys. There was also a subcentimeter (0.4 cm × 0.2 cm × 0.3 cm) cyst in the left kidney. Despite this, renal functions were normal. Even though his HbA1c levels were still below the cutoff for diabetes mellitus, the haploinsufficiency of HNF1B, hyperglycemia, and renal malformations were consistent with MODY5. Nutritional management with carbohydrate portion control, similar to the first patient, resulted in an improvement in glucose control (Fig. 1) and appropriate weight gain and growth for his age.

DISCUSSION

MODY5 results from mutation or deletion of HNF1B, a gene belonging to a member of the homeodomain-containing superfamily of transcription factors and plays an important role in the formation of the kidneys and pancreas. The molecular mechanisms of HNF1B in pancreas and kidney morphogenesis were reviewed in detail elsewhere (7,8). In a study by Duval et al (9), pancreatic hypoplasia was found during an autopsy in 75% of fetuses that carried HNF1B gene mutations (9). Hence, some children with HNF1B mutation or deletion may have a subtle form of hyperglycemia related to reduced beta-cell mass that does not result in overt diabetes mellitus until later in life. HNF1B is part of a panel of genes tested in patients with congenital abnormalities of the kidney and urinary tract (10). Approximately 10% of these children have genetic alteration in the HNF1B gene (11). The renal phenotypes due to abnormalities of HNF1B is extremely variable, and genotype-phenotype correlation is lacking (6).

The patients in this report had MODY5 related to microdeletion of chromosome 17q12. The deleted region contains several genes, including HNF1B. This condition resulting from this deletion has been termed 17q12 micro-deletion syndrome (12). Laffargue et al (13) suggested that all cases of HNF1B deletion be classified as 17q12 microdeletion syndrome. Abnormal liver functions and neuropsychiatric symptoms have also been reported in this contiguous gene sequence (13). Haploinsufficiency of HNF1B presents in nearly 50% of MODY5, with heterozygous mutations resulting in frameshift and missense mutations accounting for the other half (9). The presence of renal anomalies and diabetes mellitus are identical in both genetic alterations. However, liver dysfunction and neuropsychiatric symptoms occur in patients with 17q12 deletion syndrome but not in patients with mutation of HNF1B gene (6,14).

The abnormalities of blood glucose in MODY5 usually do not present in early childhood and different reports indicated a different median age of onset ranging from mid-teens to the third decade (3,5,6). To the best of our knowledge, there are only 2 reports of neonatal onset of diabetes mellitus due to HNF1B mutation (15,16). Most patients with MODY5 required insulin therapy at the time of the diagnosis (5). The early onset of hyperglycemia in both patients in this report could be due to the early development of hyperglycemia or because the screening was performed early. The first patient had an HbA1c that fell in the diabetes mellitus range even before the age of 3 years. Currently, there is no consensus regarding the screening for hyperglycemia in a patient with 17q21 deletion. Both cases were successfully managed by diet modification alone, and this suggests that early intervention can alleviate the progression of abnormal glucose homeostasis. The kidney anomalies identified in the second patient were mild despite having a similar 17q12 microdeletion suggesting that other genes play a role in phenotype related to 17q12 deletion.

CONCLUSION

Our report underscores the importance of considering the possibility that children with HNF1B mutation or deletion may also have abnormal glucose control. As a corollary, we recommend that children with congenital anomalies of the kidney and urinary tract or those with a known abnormality of HNF1B be screened for hyperglycemia by determination of HbA1c or postprandial serum glucose as part of the initial evaluation. Early detection of abnormal glucose levels will permit timely intervention to achieve optimal glucose control. Identification of hyperglycemia in children with congenital anomalies of the kidney may suggest an alteration of the HNF1B gene, and consequently, initial genetic testing can be focused specifically on the determination of deletion or mutation of HNF1B.

Abbreviations

HNF1B

hepatic nuclear factor 1 homeobox B

MODY5

Maturity onset diabetes of the young type 5