A Novel Homozygous Mutation in the KCNJ11 Gene of a Neonate with Congenital Hyperinsulinism and Successful Management with Sirolimus

Abstract

Congenital hyperinsulinism (CHI) is the most common cause of neonatal persistent hypoglycemia caused by mutations in nine known genes. Early diagnosis and treatment are important to prevent brain injury. The clinical presentation and response to pharmacological therapy may vary depending on the underlying pathology. Genetic analysis is important in the diagnosis, treatment, patient follow-up, and prediction of recurrence risk within families. Our patient had severe hypoglycemia and seizure following birth. His diagnostic evaluations including genetic testing confirmed CHI. He was treated with a high-glucose infusion, high-dose diazoxide, nifedipine, and glucagon infusion. A novel homozygous mutation (p.F315I) in the KCNJ11 gene, leading to diazoxide-unresponsive CHI, was identified. Both parents were heterozygous for this mutation. Our patient’s clinical course was complicated by severe refractory hypoglycemia; he was successfully managed with sirolimus and surgical intervention was not required. Diazoxide, nifedipine, and glucagon were discontinued gradually following sirolimus therapy. The patient was discharged at 2 months of age on low-dose octreotide and sirolimus. His outpatient clinical follow-up continues with no episodes of hypoglycemia. We present a novel homozygous p.F315I mutation in the KCNJ11 gene leading to diazoxide-unresponsive CHI in a neonate. This case illustrates the challenges associated with the diagnosis and management of CHI, as well as the successful therapy with sirolimus.

Oral Sirolimus: An Option in the Management of Neonates with Life-Threatening Upper Airway Lymphatic Malformations

“…In fact, most authors of case reports of sirolimus in neonates start with a dose of 0.5 mg/m 2 /12 h, and sometimes it is reduced to even 0.2-0.3 mg/m 2 /12 h, while maintaining levels between 5 and 15 ng/mL. 10 Recent studies are stabilizing sirolimus doses for neonates and infants to achieve target concentration range between 5-10 and 10-15 ng/mL. In fact, in our Vascular Anomalies Unit, we now use the suggested doses by Adams et al and start with 0.4 mg/m 2 /12 h before 1 month of age, increasing every month to achieve target levels between 10 and 15 ng/mL.…”

Congenital Hyperinsulinism: Diagnosis and Treatment Update

“…Sirolimus has been reported to be an effective and safe drug for severe, diazoxide unresponsive, diffuse CHI with no major side effects ( 147 ). Following the first report, significant numbers of cases have been reported ( 148 , 149 , 150 , 151 , 152 , 153 , 154 ). As sirolimus has potentially adverse effects (perhaps related to dose) arising from its immunosuppressive effects, measurement of the blood levels is vitally important for reaching an optimal therapeutic level.…”

Preventive treatment with oral sirolimus and aspirin in a newborn with severe Sturge‐Weber syndrome

“…Sirolimus dosage for vascular anomalies is commonly started at 0.8 mg/m 2 /12 h. The therapeutic range in vascular anomalies is typically lower than for kidney transplants, with a range between 5 and 15 ng/mL often considered adequate . In addition, lower dose regimens are suggested for neonates and younger children receiving treatment with sirolimus for vascular anomalies, with most authors starting at a dose of 0.5 mg/m 2 /12 h with subsequent reduction of the dose to 0.2‐0.3 mg/m 2 /12 h to maintain serum levels between 5 and 15 ng/mL …”