Sirolimus Therapy in CongenitalHyperinsulinism: A SuccessfulExperience Beyond InfancyMarta Minute, MDa, Giuseppa Patti, MDa, Gianluca Tornese, MDa,b, Elena Faleschini, MDb, Chiara Zuiani, MDa,Alessandro Ventura, MDa,b

abstractCongenital hyperinsulinism (CHI) due to diffuse involvement of the pancreasis a challenging and severe illness in children. Its treatment is based onchronic therapy with diazoxide and/or octreotide, followed by partialpancreatectomy, which is often not resolutive. Sirolimus, a mammalian targetof 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 CHIdue to a biallelic heterozygous ABCC8 mutation who responded to sirolimuswith a dramatic improvement in his glucose blood level regulation and qualityof life, with no serious adverse events after 6 months of follow-up. To the bestof our knowledge, this is the first report of a successful intervention in anolder child. It provides a promising basis for further studies comparingsirolimus with other treatments, particularly in older children.

Congenital hyperinsulinism (CHI) isa condition characterized by severehypoglycemia related to inappropriateinsulin secretion by pancreatic b cells.Its typical presentation is the presenceof seizures in infants, and it isassociated with the risk of braindamage.1 The most common causes ofCHI are mutations in the ABCC8 andKCNJ11 genes, which encode thesulfonylurea receptor (SUR1) and theinwardly rectifying potassium subunit(Kir6.2) of the pancreatic adenosinetriphosphate–sensitive potassiumchannel (KATP).2 CHI can manifest aseither focal or diffuse: 18F-L-dihydroxyphenylalanine positronemission tomography allows fordifferentiation between the 2 to choosethe correct treatment strategy.3

The management of diffuse, severe CHIis challenging: diazoxide (administeredin doses of 10-15 mg/kg per day) is thedrug of choice,4 followed by octreotide;when medical therapy is ineffective,subtotal pancreatectomy should beconsidered to ensure normoglycemia,

even if there is a high risk ofpostoperative diabetes mellitus orpersistent hyperinsulinemichypoglycemia.5

The successful use of the mammaliantarget of rapamycin (mTOR) inhibitorsirolimus has been recently reported tobe effective and safe for the severe,diffuse form of CHI.6 We report thecase of an 8-year-old white boy withsevere diffuse CHI due to a biallelicheterozygous ABCC8 gene mutationwho was successfully treated withsirolimus.

CASE REPORT

We present the case of an 8-year-oldwhite boy affected by CHI that wasdiagnosed in the first days of life due tosevere and persistent hypoglycemia(35 mg/dL; 1.94 mmol/L) and highinsulin blood levels (25 mU/mL;166.7 pmol/L). The patient was born at36 weeks’ gestational age, aftera pregnancy complicated by insulin-independent maternal diabetes, and

aUniversity of Trieste, Trieste, Italy; and bInstitute forMaternal and Child Health Istituto di Ricerca e Curaa Carattere Scientifico University of Trieste, Department ofPediatrics Burlo Garofolo, Trieste, Italy

Drs Tornese, Faleschini, and Ventura suggested thepatient’s treatment and critically revised andreviewed the manuscript; Drs Minute, Zuiani, andPatti collected the data, drafted the initialmanuscript, and revised the manuscript; and allauthors approved the final manuscript as submittedand agree to be accountable for all aspects of thework.

www.pediatrics.org/cgi/doi/10.1542/peds.2015-1132

DOI: 10.1542/peds.2015-1132

Accepted for publication Jun 24, 2015

Address correspondence to Marta Minute, MD,Clinica Pediatrica, IRCCS Burlo Garofolo, viadell’Istria 65, 34100 Trieste, Italy. E-mail:martaminute@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,1098-4275).

Copyright © 2015 by the American Academy ofPediatrics

FINANCIAL DISCLOSURE: The authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors haveindicated they have no potential conflicts of interestto disclose.

PEDIATRICS Volume 136, number 5, November 2015 CASE REPORT by guest on September 10, 2020www.aappublications.org/newsDownloaded from

weighed 3.680 kg (90–97thpercentile, large for gestational age).

He was diagnosed with a doubleheterozygous ABCC8 biallelicmutation (E1323K/E1506K),encoding for the SUR1 subunit of thepotassium channel; 18F-L-dihydroxyphenylalanine positronemission tomography revealeddiffuse pancreatic involvement, withno sign of focal lesions.

At birth, the patient was treated withboth diazoxide and octreotide, thelatter being discontinued in the firstyears of life due to side effects anda lack of efficacy, which wascomplicated by his parents’ refusal oftreatment by injection. Subtotalpancreatectomy was proposed but wasrefused by the family, because of itssubstantial side effects not associatedwith a significant clinical improvement.

The boy was subsequently treatedwith diazoxide only (up to 12.5 mg/kgper day) combined with a dietaryregimen consisting of cornstarchsupplementation and theadministration of complexcarbohydrates every 3 hours.However, he showed poor glycemiccontrol characterized by frequentsevere hypoglycemia (an average of 8episodes per month at ,40 mg/dL[2.2 mmol/L]) requiring treatmentwith intramuscular glucagon at least2 times per month. Hemoglobin A1cwas 4.8% to 5.2% (29–33 mmol/mol).The patient’s neurologic developmentwas impaired, with emotionallability and attention deficit, withthe need for dedicated learningsupport.

At the age of 7 years, he experienced3 episodes of hypoglycemic seizures

in the course of the same month whileat school, which resulted in theadoption of a continuous glucose-monitoring system (CGMS) as an off-label method to steadily check hisglucose levels.7 CGMS helped both inearly recognition of hypoglycemicevents and in identifyinghypoglycemia patterns, leading toimprovements in the timing ofinterventions, dosing of diazoxide, andfeeding schedule. Nevertheless, hisquality of life was still severelyimpaired by the frequent episodes ofhypoglycemia and anxiety related totheir occurrence. In addition, CGMSindicated an extremely high variabilityin his glucose levels (mean: 135 673 mg/dL [7.56 4.1 mmol/L]) (Fig 1).

According to the conclusions ofSeniappan et al,6 we decided to treathim with sirolimus. After obtaining

FIGURE 1Daily and weekly blood glucose levels (mg/dL) measured by CGMS before therapy with sirolimus was initiated.

e1374 MINUTE et al by guest on September 10, 2020www.aappublications.org/newsDownloaded from

parental consent and ethical committeeapproval, we started with a low dose of0.5 mg/day, which was then slowly

increased by 0.5 to 1 mg every 2 weeks,aiming to achieve a blood level ofsirolimus between 5 and 15 ng/mL.

Soon after sirolimus treatment began,steady state was achieved, glucoseblood level control improved, anddiazoxide dosage was gradually tapered.

After 6 months of treatment the boy iscurrently receiving 7 mg of sirolimus(with a blood level of 12.1 ng/mL)(Fig 2), supplemented with a reduceddose of diazoxide (4 mg/kg per day).His glucose blood level has beenstabilized (mean: 118 6 21 mg/dL[6.6 6 1.2 mmol/L]) (Fig 3), obviatingthe need for rescue treatment withglucagon since the therapy wasstarted. Teachers have reporteda dramatic improvement in attentionand school performance. The qualityof life of both the boy and his familyalso improved considerably.

We compared CGMS data before andafter treatment was initiated. Values inthe optimal range of glycemia increasedfrom 30% to 72% after treatment; lowvalues (blood glucose level,80 mg/mL

FIGURE 2Drug dosages and sirolimus levels during therapy.

FIGURE 3Daily and weekly blood glucose levels (mg/dL) measured by CGMS after 6 months of sirolimus therapy.

PEDIATRICS Volume 136, number 5, November 2015 e1375 by guest on September 10, 2020www.aappublications.org/newsDownloaded from

[4.4 mmol/L]) decreased from 24%to 5% (x2, P , .001).

Our patient experienced some of themuco-cutaneous side effects ofsirolimus, such as mild acne and oralaftosis. An isolated episode ofhematemesis occurred after 2 monthsof treatment and was managed witha brief course of treatment withproton pump inhibitors. We did notobserve elevations in creatinine,serum aminotransferase, or lipids ora reduction in leukocyte count.

DISCUSSION

The management of diffuse severe CHIunresponsive to diazoxide andoctreotide is a challenging medicalproblem. It is known that monoallelicABCC8/KCNJ11 mutations can causeboth diazoxide-responsive as well asdiazoxide-unresponsive CHI. Nearly allbiallelic ABCC8/KCNNJ11 mutationsresult in unresponsive CHI.8,9 Theproposed subtotal pancreatectomy isassociated with severe adverse effectsand poor efficacy.5

Seniappan et al8 showed that 4 infantswith severe CHI had a clear glycemicresponse to sirolimus therapy, withoutmajor adverse effects during the firstyear of follow-up. Three patientsweaned off all other therapies; 1patient with a double homozygousABCC8 biallelic mutation weaned offintravenous glucose but requireda small dose of octreotide to maintainnormoglycemia. More recently, thesame group described the efficacy ofsirolimus in an infant with severehyperinsulinemic hypoglycemia due toa compound heterozygous ABCC8 genemutation.10 The authors alsoinvestigated the mechanism of actionof sirolimus by studying theexpression of mTOR in diffuse CHI.They observed that the mTORpathway is involved in thetransdifferentiation of acinar cells;with the use of morphoproteomicanalysis they also showed that themTOR pathway is overexpressed inthe acinar cells of patients with severeCHI.11

Our patient has severe, diffuse CHIdue to a biallelic heterozygous ABCC8gene mutation. He experienceda marked improvement in his glucoseblood level regulation and quality oflife in response to treatment withsirolimus. The child suffered some ofthe known muco-cutaneous sideeffects of sirolimus, such as mild acneand oral aftosis. Because sirolimuscan induce immunosuppression,abnormalities in renal function, andincreased serum aminotransferase orlipid levels,12 we strictly monitoredthese parameters by measuringcreatinine, aminotransferase, andlipid levels and leukocyte counts. Nolaboratory abnormalities have beennoticed to date.

Monitoring of pulmonary function isrecommended in patients withunderlying lung disease who arereceiving sirolimus treatment.12 Weclosely monitored the child forrespiratory symptoms, and noadverse effect on respiratory functionhas been observed.

In summary, we report the first caseof diffuse CHI out of the infancyperiod who responded to therapywith an mTOR inhibitor. Even iffurther studies are needed, primarilyto identify long-term sequelae andside effects, sirolimus appears to bea promising therapeutic option totreat children with biallelic ABCC8mutations unresponsive to diazoxide.

ABBREVIATIONS

CGMS: continuous glucose-monitoring system

CHI: congenital hyperinsulinismmTOR: mammalian target of

rapamycin

REFERENCES

1. de Lonlay-Debeney P, Poggi-Travert F,Fournet JC, et al. Clinical features of 52neonates with hyperinsulinism. N Engl JMed. 1999;340(15):1169–1175

2. Arya VB, Aziz Q, Nessa A, Tinker A,Hussain K. Congenital hyperinsulinism:

clinical and molecular characterisationof compound heterozygous ABCC8mutation responsive to diazoxidetherapy. Int J Pediatr Endocrinol. 2014;2014(1):24–28

3. Petraitien _e I, Barauskas G, Gulbinas A,et al. Congenital hyperinsulinism.Medicina (Kaunas). 2014;50(3):190–195

4. Hussain K. Diagnosis and managementof hyperinsulinaemic hypoglycaemia ofinfancy. Horm Res. 2008;69(1):2–13

5. Beltrand J, Caquard M, Arnoux J-B, et al.Glucose metabolism in 105 children andadolescents after pancreatectomy forcongenital hyperinsulinism. DiabetesCare. 2012;35(2):198–203

6. Senniappan S, Alexandrescu S, TatevianN, et al. Sirolimus therapy in infants withsevere hyperinsulinemic hypoglycemia.N Engl J Med. 2014;370(12):1131–1137

7. Saif M, Kapoor A, Kochar IPS, Jindal R.Continuous glucose monitoring systemfor congenital hyperinsulinemia. IndianPediatr. 2013;50(4):421–422. Available at:www.ncbi.nlm.nih.gov/pubmed/23665604. Accessed March 9, 2015

8. Kapoor RR, Flanagan SE, James CT, et al.Hyperinsulinaemic hypoglycaemia anddiabetes mellitus due to dominantABCC8/KCNJ11 mutations. Diabetologia.2011;54(10):2575–2583

9. Saint-Martin C, Zhou Q, Martin GM, et al.Monoallelic ABCC8 mutations area common cause of diazoxide-unresponsive diffuse form of congenitalhyperinsulinism. Clin Genet. 2015;87(5):448–454

10. Shah P, Arya VB, Flanagan SE, et al.Sirolimus therapy in a patient withsevere hyperinsulinaemic hypoglycaemiadue to a compound heterozygous ABCC8gene mutation. J Pediatr EndocrinolMetab. 2015;28(5–6):695–699

11. Senniappan S, Tatevian N, Shah P, et al.The role of mTORC1/RagGTPase andIGF1R/mTORC2/Akt pathways and theresponse of diffuse congenitalhyperinsulinism to sirolimus. 2014.Available at: http://espe2014abstracts.eurospe.org/hrp/0082/hrp0082p1-d1-175.htm. Accessed March 9, 2015

12. Sankhala K, Mita A, Kelly K, MahalingamD, Giles F, Mita M. The emerging safetyprofile of mTOR inhibitors, a novel classof anticancer agents. Target Oncol. 2009;4(2):135–142

e1376 MINUTE et al by guest on September 10, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2015-1132 originally published online October 26, 2015; 2015;136;e1373Pediatrics 

Alessandro VenturaMarta Minute, Giuseppa Patti, Gianluca Tornese, Elena Faleschini, Chiara Zuiani and

Beyond InfancySirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/136/5/e1373including high resolution figures, can be found at:

Referenceshttp://pediatrics.aappublications.org/content/136/5/e1373#BIBLThis article cites 11 articles, 1 of which you can access for free at:

Subspecialty Collections

http://www.aappublications.org/cgi/collection/therapeutics_subTherapeuticshttp://www.aappublications.org/cgi/collection/pharmacology_subPharmacologyhttp://www.aappublications.org/cgi/collection/endocrinology_subEndocrinologyfollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

by guest on September 10, 2020www.aappublications.org/newsDownloaded from

DOI: 10.1542/peds.2015-1132 originally published online October 26, 2015; 2015;136;e1373Pediatrics 

Alessandro VenturaMarta Minute, Giuseppa Patti, Gianluca Tornese, Elena Faleschini, Chiara Zuiani and

Beyond InfancySirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience

http://pediatrics.aappublications.org/content/136/5/e1373located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397. the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2015has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on September 10, 2020www.aappublications.org/newsDownloaded from