Case Report
The proband is an 11-year-old boy, the first child of a healthy African-Brazilian distantly related parents. He was born at term with a birth weight of 2230 g, length of 45 cm (both below the third percentile). At the age of 6 months, he was diagnosed with diabetic ketoacidosis (blood glucose: 600 mg/dl, ketonuria: ++ and Bicarbonate 8 meq-L) when treatment with insulin was initiated. At the age of 1-year and 8-months, the patient was referred to our University Diabetes Center. Physical examination revealed a paucity of adipose tissue, severe acanthosis nigricans in axillae and neck, macrogenitossomy, hypertrichosis, acrochordons and premature dentition. He also had coarse facial features with flat nasal root, large and prominent ears and prognathism. His developmental milestones were delayed and growth retardation was observed. Biochemical analysis showed fasting plasma glucose: 79 mg/dl, HbA1C: 6.9%, Fasting C-peptide: 5.3ng/ml, anti-glutamic-acid decarboxylase antibody negative and normal lipid profile. Based on medical history and clinical findings, Rabson-Mendenhall Syndrome was hypothesized. Sequencing the INSRidentified two variants: a missense mutation in exon 19 (NM_000208.3: 3845C>T, p.Ala1162Val) and an intronic variant located in the canonical splice acceptor site of intron 3 (c.975-2A>T). The former variant was already described in a Brazilian patient with RMS (2) and the latter variant was not previously reported and, the in silico bioinformatic tool Mutation Taster predicted that the variant is disease causing. Given the patient’s clinical characteristics, compound heterozygosity was considered. He was maintained on insulin therapy until the age of 2.5 y (Determir 3 U/day), when due to several episodes of hypoglycemia, this medication was stopped (HbA1c: 6.2%, fasting C-peptide: 13.2 ng/ml). However, one year later persistent hyperglycemia returned, and insulin was reintroduced. Insulin doses has been titrated up over the years to 5.7 UI/kg/day. Metformin and pioglitazone were included in the therapy. Despite this, a progressive worsening of hyperglycemia occurred, with levels of glycated hemoglobin reaching 10.5% and fasting C-peptide decreasing to 1.7 ng/ml. Given that the SGLT2 inhibitors promote a reduction in blood glucose by enhancing urinary glucose excretion in a mechanism independent of insulin action and that some previous reports show the efficacy of this class of drugs in genetically induced severe insulin resistance, treatment with empafliflozin was considered. Recombinant IGF-1 and metreleptin, a recombinant human methionyl leptin, also have been used in patients with severe insulin resistance but due to their unavailability in our country and high cost, we could not consider them as an option. The parents were informed about the off-label use of empaglifozin and possible adverse events and agreed with its prescription. Empaglifozin was started at a low dose (2.5 mg/day) in addition to insulin and metformin, rising two months later to the current dose of 5 mg/day, with a strict monitoring of adverse effects mainly ketonemia. After 7 months of empaglifozin, HbA1c decreased to 7.7% (reduction of 2.8% from basal) and insulin dose could be reduced in 30% (table 1). The patient underwent series of blood β-hydroxybutyrate test, which results were in the range of 0.1-0.5 mmol/l.