Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.
- CGMS —
- continuous glucose-monitoring system
- CHI —
- congenital hyperinsulinism
- mTOR —
- mammalian target of rapamycin
Congenital hyperinsulinism (CHI) is a condition characterized by severe hypoglycemia related to inappropriate insulin secretion by pancreatic β cells. Its typical presentation is the presence of seizures in infants, and it is associated with the risk of brain damage.1 The most common causes of CHI are mutations in the ABCC8 and KCNJ11 genes, which encode the sulfonylurea receptor (SUR1) and the inwardly rectifying potassium subunit (Kir6.2) of the pancreatic adenosine triphosphate–sensitive potassium channel (KATP).2 CHI can manifest as either focal or diffuse: 18F-l-dihydroxyphenylalanine positron emission tomography allows for differentiation between the 2 to choose the correct treatment strategy.3
The management of diffuse, severe CHI is challenging: diazoxide (administered in doses of 10-15 mg/kg per day) is the drug of choice,4 followed by octreotide; when medical therapy is ineffective, subtotal pancreatectomy should be considered to ensure normoglycemia, even if there is a high risk of postoperative diabetes mellitus or persistent hyperinsulinemic hypoglycemia.5
The successful use of the mammalian target of rapamycin (mTOR) inhibitor sirolimus has been recently reported to be effective and safe for the severe, diffuse form of CHI.6 We report the case of an 8-year-old white boy with severe diffuse CHI due to a biallelic heterozygous ABCC8 gene mutation who was successfully treated with sirolimus.
We present the case of an 8-year-old white boy affected by CHI that was diagnosed in the first days of life due to severe and persistent hypoglycemia (35 mg/dL; 1.94 mmol/L) and high insulin blood levels (25 μU/mL; 166.7 pmol/L). The patient was born at 36 weeks’ gestational age, after a pregnancy complicated by insulin-independent maternal diabetes, and weighed 3.680 kg (90–97th percentile, large for gestational age).
He was diagnosed with a double heterozygous ABCC8 biallelic mutation (E1323K/E1506K), encoding for the SUR1 subunit of the potassium channel; 18F-l-dihydroxyphenylalanine positron emission tomography revealed diffuse pancreatic involvement, with no sign of focal lesions.
At birth, the patient was treated with both diazoxide and octreotide, the latter being discontinued in the first years of life due to side effects and a lack of efficacy, which was complicated by his parents’ refusal of treatment by injection. Subtotal pancreatectomy was proposed but was refused by the family, because of its substantial side effects not associated with a significant clinical improvement.
The boy was subsequently treated with diazoxide only (up to 12.5 mg/kg per day) combined with a dietary regimen consisting of cornstarch supplementation and the administration of complex carbohydrates every 3 hours. However, he showed poor glycemic control characterized by frequent severe hypoglycemia (an average of 8 episodes per month at <40 mg/dL [2.2 mmol/L]) requiring treatment with intramuscular glucagon at least 2 times per month. Hemoglobin A1c was 4.8% to 5.2% (29–33 mmol/mol). The patient’s neurologic development was impaired, with emotional lability and attention deficit, with the need for dedicated learning support.
At the age of 7 years, he experienced 3 episodes of hypoglycemic seizures in the course of the same month while at school, which resulted in the adoption of a continuous glucose-monitoring system (CGMS) as an off-label method to steadily check his glucose levels.7 CGMS helped both in early recognition of hypoglycemic events and in identifying hypoglycemia patterns, leading to improvements in the timing of interventions, dosing of diazoxide, and feeding schedule. Nevertheless, his quality of life was still severely impaired by the frequent episodes of hypoglycemia and anxiety related to their occurrence. In addition, CGMS indicated an extremely high variability in his glucose levels (mean: 135 ± 73 mg/dL [7.5 ± 4.1 mmol/L]) (Fig 1).
According to the conclusions of Seniappan et al,6 we decided to treat him with sirolimus. After obtaining parental consent and ethical committee approval, we started with a low dose of 0.5 mg/day, which was then slowly increased by 0.5 to 1 mg every 2 weeks, aiming to achieve a blood level of sirolimus between 5 and 15 ng/mL. Soon after sirolimus treatment began, steady state was achieved, glucose blood level control improved, and diazoxide dosage was gradually tapered.
After 6 months of treatment the boy is currently receiving 7 mg of sirolimus (with a blood level of 12.1 ng/mL) (Fig 2), supplemented with a reduced dose of diazoxide (4 mg/kg per day). His glucose blood level has been stabilized (mean: 118 ± 21 mg/dL [6.6 ± 1.2 mmol/L]) (Fig 3), obviating the need for rescue treatment with glucagon since the therapy was started. Teachers have reported a dramatic improvement in attention and school performance. The quality of life of both the boy and his family also improved considerably.
We compared CGMS data before and after treatment was initiated. Values in the optimal range of glycemia increased from 30% to 72% after treatment; low values (blood glucose level <80 mg/mL [4.4 mmol/L]) decreased from 24% to 5% (χ2, P < .001).
Our patient experienced some of the muco-cutaneous side effects of sirolimus, such as mild acne and oral aftosis. An isolated episode of hematemesis occurred after 2 months of treatment and was managed with a brief course of treatment with proton pump inhibitors. We did not observe elevations in creatinine, serum aminotransferase, or lipids or a reduction in leukocyte count.
The management of diffuse severe CHI unresponsive to diazoxide and octreotide is a challenging medical problem. It is known that monoallelic ABCC8/KCNJ11 mutations can cause both diazoxide-responsive as well as diazoxide-unresponsive CHI. Nearly all biallelic ABCC8/KCNNJ11 mutations result in unresponsive CHI.8,9 The proposed subtotal pancreatectomy is associated with severe adverse effects and poor efficacy.5
Seniappan et al8 showed that 4 infants with severe CHI had a clear glycemic response to sirolimus therapy, without major adverse effects during the first year of follow-up. Three patients weaned off all other therapies; 1 patient with a double homozygous ABCC8 biallelic mutation weaned off intravenous glucose but required a small dose of octreotide to maintain normoglycemia. More recently, the same group described the efficacy of sirolimus in an infant with severe hyperinsulinemic hypoglycemia due to a compound heterozygous ABCC8 gene mutation.10 The authors also investigated the mechanism of action of sirolimus by studying the expression of mTOR in diffuse CHI. They observed that the mTOR pathway is involved in the transdifferentiation of acinar cells; with the use of morphoproteomic analysis they also showed that the mTOR pathway is overexpressed in the acinar cells of patients with severe CHI.11
Our patient has severe, diffuse CHI due to a biallelic heterozygous ABCC8 gene mutation. He experienced a marked improvement in his glucose blood level regulation and quality of life in response to treatment with sirolimus. The child suffered some of the known muco-cutaneous side effects of sirolimus, such as mild acne and oral aftosis. Because sirolimus can induce immunosuppression, abnormalities in renal function, and increased serum aminotransferase or lipid levels,12 we strictly monitored these parameters by measuring creatinine, aminotransferase, and lipid levels and leukocyte counts. No laboratory abnormalities have been noticed to date.
Monitoring of pulmonary function is recommended in patients with underlying lung disease who are receiving sirolimus treatment.12 We closely monitored the child for respiratory symptoms, and no adverse effect on respiratory function has been observed.
In summary, we report the first case of diffuse CHI out of the infancy period who responded to therapy with an mTOR inhibitor. Even if further studies are needed, primarily to identify long-term sequelae and side effects, sirolimus appears to be a promising therapeutic option to treat children with biallelic ABCC8 mutations unresponsive to diazoxide.
- Accepted June 24, 2015.
- Address correspondence to Marta Minute, MD, Clinica Pediatrica, IRCCS Burlo Garofolo, via dell’Istria 65, 34100 Trieste, Italy. E-mail:
Drs Tornese, Faleschini, and Ventura suggested the patient’s treatment and critically revised and reviewed the manuscript; Drs Minute, Zuiani, and Patti collected the data, drafted the initial manuscript, and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Beltrand J,
- Caquard M,
- Arnoux J-B,
- et al
- ↵Senniappan S, Tatevian N, Shah P, et al. The role of mTORC1/RagGTPase and IGF1R/mTORC2/Akt pathways and the response of diffuse congenital hyperinsulinism to sirolimus. 2014. Available at: http://espe2014abstracts.eurospe.org/hrp/0082/hrp0082p1-d1-175.htm. Accessed March 9, 2015
- Copyright © 2015 by the American Academy of Pediatrics