Response to sirolimus in a case of diffuse congenital hyperinsulinaemic hypoglycaemia due to homozygous KCNJ11 mutation

Background

Hyperinsulinism caused by dysregulated insulin release from pancreas as a result of perinatal events or monogenic mutation of insulin synthesis and release pathway or syndromes like Beckwith-Wiedemann is the most common cause of persistent hypoglycaemia in a neonate.1 Among the enlisted causes, congenital hyperinsulinism representing a variety of genetically heterogeneous disorders characterised by dysregulated insulin secretion is the most common with an estimated incidence of 1 in 50 000 live births; the incidence is higher (up to 1 in 2500) in areas of high consanguinity.2 The most common and most severe form of congenital hyperinsulinism is due to recessive inactivating mutations of the beta cell K_ATP channels. This defect interferes with protein expression resulting in absence of channels on the plasma membrane rendering the membrane diazoxide unresponsive.3 The absence of functional K_ATP channels results in uncoupling between plasma glucose and insulin secretion.

Of the two distinct histological forms of K_ATP channels (focal and diffuse), the recessively inherited ABCC8 or KCNJ11 mutations coding for SUR1 and Kir6.2 subunit of channel, respectively, result in diffuse hyperinsulinism where all beta cells of pancreas are affected. Located on chromosome 11p15.1, recessive inactivating mutations in the ABCC8 and KCNJ11 genes are the most common causes of medically unresponsive diffuse congenital hyperinsulinism.4 Treatment options for the diazoxide-unresponsive cases are limited with need of pancreatectomy, within the first few weeks after birth to manage the hypoglycaemia. Medical management in diazoxide-unresponsive hyperinsulinism includes octreotide in combination with continuous or frequent enteral feedings or continuous dextrose through a gastrostomy.5 The utility of sirolimus as a mammalian target of rapamycin (mTOR) inhibitor, which is known to cause hyperglycaemia, has been described in patients with medically unresponsive diffuse congenital hyperinsulinism who were due to undergo pancreatectomy.6 The adverse effects of mTOR inhibitors include stomatitis, increased risk of infections, immunosuppression, abnormalities in renal function, fatigue, transient elevations of aminotransferase concentrations, elevation of triglycerides and pneumonitis.7

Our case highlights the response to sirolimus and its adverse events in a neonate who presented with persistent refractory hypoglycaemia identified to have autosomal recessive pathogenic, homozygous KCNJ11 mutation.

Case presentation

A male neonate was admitted to the neonatal intensive care unit of a tertiary care hospital for refractory and persistent neonatal hypoglycaemia. He was born by vaginal delivery to third degree consanguineous parents at full term (38 weeks) with a birth weight of 3.1 kg (Z-score: −0.52). The pregnancy was uneventful, and the baby cried immediately after birth and did not need any resuscitation. The septic screen was negative (negative C reactive protein and no growth on blood culture). The child had hypoglycaemia from the day of admission. The blood glucose concentrations at the time of admission were 35 mg/dL (<45 mg/dL of blood glucose) with serum insulin of 26.7 µU/mL (5–15 µU/mL) and cortisol of 2.8 µg% (3–23 µg%) in the critical sample (at the time of episode of hypoglycaemia). He was treated with glucose infusion with maximum concentration of 12.5%, diazoxide (20 mg/kg/day), injection octreotide (15 µg/kg/day) and tablet nifedipine. The oral feeding was initiated after achievement of euglycaemia with simultaneous reduction of glucose concentration and glucose infusion rate. He was discharged on injection octreotide (15 µg/kg/day) subcutaneously four times a day, tablet diazoxide (20 mg/kg/day) orally in three divided doses, tablet nifedipine (2 mg/kg/day) orally in three divided doses and tablet hydrochlorothiazide 3.5 mg orally two times per week. He continued to have frequent hypoglycaemic episodes in spite of being on all four medications. His routine screening for hearing was normal, and the anthropometric parameters on discharge at day 29 of life were length of 51 cm (−1.74), weight of 3.570 kg (Z-score: −1.46) and head circumference of 36 cm. The newborn screening test for hypothyroidism, congenital adrenal hyperplasia, galactosaemia and glucose 6-phosphate dehydrogenase (G6PD) deficiency was negative.

The clinical exome sequencing revealed likely pathogenic homozygous c.101G>A (p.Arg34His) variant on exon 1 for KCNJ11 gene confirming the diagnosis of autosomal recessively inherited familial hyperinsulinaemic hypoglycaemia. The child underwent neuroimaging by multiplanar, multisequence MRI without contrast in which no significant abnormality was detected. The patient was referred to our paediatric endocrine unit at 3 months of age for persistent episodes of hypoglycaemia even on medications at home. The weight and length at the time were 5.8 kg (Z-score: −1.09) and 56 cm (Z-score: −3.05), respectively. His gallium-68 dotatate scan (GA-68 DOTA) showed somatostatin receptor expression in the mid and distal body of pancreas suggestive of diffuse nesidioblastosis (figure 1 and figure 2). Long-acting octreotide therapy was offered to the patient but was not available at that time. The parents were also given option of surgical therapy but they refused invasive form of management for the child. The child was treated with tablet sirolimus after explaining the parents its possible side effects in dose of 0.5 mg/m²/day and gradually tapered off all other medications. The child was euglycaemic within 2 weeks with no episodes of symptomatic hypoglycaemia on oral tablet sirolimus 0.5 mg/m²/day with achievement of developmental milestones as per age of 4 months. The parents were advised to follow-up with us on two times per week basis to monitor sugar values, developmental assessment and to monitor side effects of sirolimus; however, they were lost to follow-up for 1.5 months.

Figure 1

Linear uptake in distal pancreas/superior pole of left kidney is seen on gallium-68 dotatate scan.

Figure 2

Uptake in body of pancreas is seen on gallium-68 dotatate scan.

At the age of 5.5 months, he was admitted to our paediatric intensive care unit with complaint of fever for 4 days and difficulty in breathing for 1 day which was progressive and associated with abdominal distension, lethargy, poor feeding and reduced urine output. He had tachycardia (pulse—192 beats per minute) and tachypnoea (respiratory rate—70 breaths per minute) with chest retractions and reduced air entry on left side. The haemogram showed elevated total counts (23.5 x 10⁹ cells per litre) with neutrophilic predominance (73.7%) and reduced platelet count (46 000 cells per mm³) with positive C reactive protein (320 mg/dL). The chest X-ray revealed homogeneous opacity noted in left lung field suggestive of massive pleural effusion with underlying collapse. The ultrasound confirmed moderate left-sided pleural effusion with fatty liver and minimal ascites. He was given a fluid bolus and was put on high frequency nasal cannula at 12 L/min with 50% Fio₂. Antibiotics ceftriaxone (100 mg/kg/day) and vancomycin (60 mg/kg/day) were initiated. With no improvement in the respiratory distress, he was shifted to non-invasive pressure ventilation and later intubated and put on pressure synchronized intermittent mandatory ventilation (SIMV) mode of ventilation. The antibiotic was upgraded to meropenem (60 mg/kg/day) and antiviral oseltamivir was started. The patient developed hypotension and required inotropic support with epinephrine, norepinephrine and vasopressin for refractory shock. The troponin T, creatine kinase-myoglobin binding (CK-MB), lactate dehydrogenase (LDH) and ferritin were elevated (44.89 ng/L, 366.6 IU/L, 4704 IU/L and 8479 µg/L, respectively). The serum alanine aminotransferase, serum aspartate aminotransferase and serum triglyceride concentrations were also elevated to 184.5 units/L, 2064.5 units/L and 258.7 mg/dL, respectively. The 2D echo was suggestive of ejection fraction of 50% with no other significant structural anomaly. Bilateral intercostal drainage tube was inserted in view of left-sided pleural effusion and right-sided pneumothorax. The child developed anuria with raised serum creatinine (1.52 mg/dL) with sodium within reference range (138 mEq/L) and low potassium (2.73 mEq/L) for which peritoneal dialysis was started. Fresh frozen plasma was administered for altered coagulation profile (prothrombin time 31.4 vs control of 13.2, international normalized ratio (INR) of 2.4 and activated partial thromboplastin time of 36.78 vs control of 27.3).

Outcome and follow-up

The child could not survive despite high-frequency oscillatory ventilation (HFOV), antibiotics, inotropes, peritoneal dialysis and blood transfusion. The cause of death was recorded as refractory septic shock with acute respiratory distress syndrome due to pneumonia with multiple organ dysfunction syndrome and haemophagocytic lymphohistiocytosis.