Maturity‐onset diabetes of the young type 5, presenting as diabetic ketoacidosis with alkalemia: A report of a case

Abstract A 34‐year‐old man visited our Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, because of dry mouth and weight loss. His plasma glucose level was 32.8 mmol/L and serum levels of ketone bodies were increased, but with metabolic alkalemia. He was also suffering from renal tubular hypomagnesemia and hypokalemia. Abdominal computed tomography showed bilateral renal cysts. These findings were suggestive of maturity‐onset diabetes of the young type 5. Genetic testing showed heterozygous hepatocyte nuclear factor 1 beta gene deletion. In the present case, it seemed reasonable to view hepatocyte nuclear factor 1 beta gene deletion as the common cause of maturity‐onset diabetes of the young type 5‐associated diabetic ketoacidosis and tubular malfunction‐induced hypokalemic alkalosis. This case exemplifies the importance of hepatocyte nuclear factor 1 beta gene abnormality as a potential cause of diabetic ketoacidosis with alkalemia.


INTRODUCTION
Maturity-onset diabetes of the young (MODY) is a group of monogenic forms of diabetes that are inherited in an autosomal dominant manner. Although the prevalence of MODY syndromes is estimated to be between 0.6 and 2% of all diabetes 1 , hepatocyte nuclear factor 1 beta (HNF1B)-MODY type 5 (MODY5) is exceedingly rare, comprising less than 5% of all MODY subtypes 2 . More importantly, MODY5 is uniquely associated with a broad clinical spectrum from renal phenotypes to pancreatic b-cell dysfunction 3 . Clinical symptoms, such as polyuria and/or weight loss, are present in 47% of patients, but ketoacidosis is rare at the time of diabetes diagnosis in patients with MODY5 4 .
Here, we report a patient newly diagnosed as MODY5, who presented with diabetic ketoacidosis with renal tubular alkalemia, and later was diagnosed genetically as HNF1B syndrome.

CASE REPORT
A 34-year-old man visited Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, because of dry mouth and weight loss of 10 kg within 1 year. He had no medical history, except for hyperglycemia identified in a health examination 1 year before that was left untreated. He had no family history of diabetes or kidney disease. His height was 170 cm and bodyweight was 47.0 kg. Laboratory examination showed that the casual plasma glucose level was 32.8 mmol/L, with the hemoglobin A1c level was 189 mmol/mol (Table 1). Although serum levels of ketone bodies were increased, blood gas analysis showed a pH of 7.48 and HCO 3 of 36.7 mmol/L, suggesting an existence of metabolic alkalosis. Therefore, he was diagnosed with diabetic ketoacidosis with alkalemia and treated with linagliptin as a tentative pharmacotherapy. He was admitted to our hospital 1 week later for further examination and treatment.
After admission, linagliptin was stopped and multiple daily injections of insulin were initiated. Urinalysis showed a rather low level of urinary C-peptide secretion (9.8 nmol/day), suggesting a certain level of b-cell dysfunction. Anti-islet antibodies in the serum were negative. The patient's hyperglycemia improved a few days later. During the course, however, he developed profound hypomagnesemia and hypokalemia. Additional urine electrolyte analysis showed an inappropriately high fractional excretion of magnesium (FeMg: 22.7%) and increased urinary potassium excretion (38 mmol/day), suggesting renal magnesium and potassium wasting. A challenge with hydrochlorothiazide showed a blunted response. We then initially suspected that along with diabetes, the patient was complicated with Gitelman syndrome.
Abdominal computed tomography showed bilateral multiple renal cysts and pyelectasis ( Figure 1). Based on these clinical observations, MODY5 was suspected. Furthermore, the HNF1B score, a pivotal tool for rational genetic testing 5 , was 19, confirming a high level of clinical suspicion for HNF1B-related disease. We carried out multiplex ligation probe amplification using patient-derived lymphocyte, and identified heterozygous entire deletion of the HNF1B gene ( Figure 2).
After the diagnosis, we continued multiple daily injections of insulin, taking into consideration a decline of insulin secretion in the future. We also started supplementation of potassium and magnesium with high confidence in the prevention of muscle weakness, convulsion or arrhythmia.

DISCUSSION
We herein report a case of MODY5 presenting diabetic ketoacidosis with alkalemia as an initial manifestation, possibly due to the coexistence of HNF1B-associated renal tubular dysfunction.
Genetic mutations of HNF1B, located on chromosome 17q12, cause multiple organ disorders, collectively known as the HNF1B syndrome. Among 33 Japanese patients with HNF1B-related disorders, including the present case, whole-gene deletion and heterozygous variants account for up to 14 and 19 cases, respectively 6 . Although the genotype-phenotype relationship has not yet been conclusive, a report suggests that patients with HNF1B deletion less often show endstage chronic kidney disease than those with point mutations 4 , consistent with an absence of kidney dysfunction in the present case.
It is well known that manifestations of HNF1B syndrome vary among patients 3 . For example, diabetes or renal morphological abnormalities, such as renal cystic disease, was present in 38.7 and 77.4% of patients, respectively 6 . The co-existence of renal cysts in diabetes-complicating cases is known as renal cysts and diabetes syndrome, as found in the current case. Clinical features observed in the present case are summarized in Figure 3.
It has been reported that HNF1B mutations can also affect Na-Cl cotransporter function in the distal convoluted tube, leading to hypokalemia, hypomagnesemia and metabolic alkalosis 7,8 . In the present case, hypokalemic alkalosis potentially caused by Na-Cl cotransporter dysfunction seems to predominate over a mild diabetic ketoacidosis caused by insulin deficiency in MODY5 (Figure 3).
Diabetic ketosis typically manifests with acidemia due to an accumulation of acidic ketone bodies. However, it can present as alkalemia under certain, but limited, conditions, including vomiting and the use of diuretics, for which it was not relevant in the present case.
The absence of clinical manifestation in the patient's parents shows that the deletion of the gene might be a spontaneous de novo mutation, although we could not obtain agreement from his parents for their genetic analysis. De novo mutations reportedly occur relatively frequently, as seen in 50-60% of patients with HNF1B gene abnormality 9 . This is believed to be the case, because chromosome 17q12 contains a sequence with high homogeny, and meiotic cross-over might sometimes lead to mistakes during gene replication 10 .
Collectively, when a young diabetes patient presents with diabetic ketoacidosis with alkalemia or electrolyte abnormalities, genetic testing for MODY5 is recommended. Conversely, when a patient is genetically diagnosed as MODY5, clinical screening tests for HNF1B mutation-related multi-organ complications need to be carried out.

COMPLIANCE WITH ETHICAL STANDARDS
Genetic testing was carried out in accordance with the ethical standards of Nagoya City University and Kobe University,