mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success.
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to obviate the need for pancreatectomy, but experience is limited.



We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI.



This was an observational review of 10 severe CHI patients treated with mTOR inhibitors, in France and the United Kingdom, with the intention of achieving glycemic control without pancreatectomy. Safety information was recorded.



We examined whether mTOR inhibitors achieved glycemic control, fasting tolerance, and weaning of supportive medical therapy.



mTOR inhibition achieved euglycemia, fasting tolerance, and reduced medical therapy in only three patients (30%). Triglyceride levels were elevated in five patients (50%). One child required a blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the CHI pancreas.



mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Marie
M
Szymanowski
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Maria Salomon
MS
Estebanez
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Raja
R
Padidela
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Bing
B
Han
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Karolina
K
Mosinska
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Adam
A
Stevens
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Lena
L
Damaj
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Florence
F
Pihan-Le Bars
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Emilie
E
Lascouts
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Rachel
R
Reynaud
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Catherine
C
Ferreira
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Claire
C
Bansept
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Pascale
P
de Lonlay
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Cécile
C
Saint-Martin
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Mark J
MJ
Dunne
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Indraneel
I
Banerjee
Department of Pediatrics (M.S.), Centre Hospitalier Universitaire Estaing, 63003 Clermont-Ferrand Cedex 1, France; Department of Pediatric Endocrinology (M.S.E., R.P., I.B.), Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Faculty of Life Science (B.H., K.M., A.S., M.J.D.), University of Manchester, Manchester M13 9PL, United Kingdom; Department of Pediatrics (L.D., F.P.-L.B., E.L.), Sud Hospital, 35203 Rennes, France; Department of Pediatrics (R.R., C.F.), Timone Hospital, 13385 Marseille Cedex 5, France; Metabolism Unit (C.B., P.d.L., J.-B.A.), Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris Cedex 15, France; Imagine-Genetic Disease Institute (P.d.L.), 75015 Paris, France; Paris Descartes University (P.d.L.), 75270 Paris, France; and Department of Genetics (C.S.-M.), Assistance Publique-Hôpitaux de Paris Groupe Hospitalier Pitié-Salpêtrière, Pierre et Marie Curie University, 75013 Paris Cedex 13, France.
Jean-Baptiste
JB
Arnoux
D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000188:drug therapy* / Q000235:genetics; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007223:Infant; D008297:Male; D017063:Outcome Assessment, Health Care; D012720:Severity of Illness Index; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus