conventional treatment of diffuse hh with diazoxide is not always effective 
 in controlling hypoglycaemia and can be associated with unpleasant side 
 effects . sirolimus was successfully used to abolish recurrent hypoglycaemia in 
 partially diazoxide - responsive hh , with resolution of unacceptable 
 diazoxide - associated side effects . sirolimus was well tolerated with no clinically significant side 
 effects . shortly after stopping sirolimus hyperinsulinaemic hypoglycaemia ( hh ) from dysregulated insulin secretion of the 
 pancreatic -cells is an important cause of persistent neonatal hypoglycaemia . mutations have been reported in the abcc8 and kcnj11 
 genes on chromosome 11p15.1 , which encode the sulphonylurea receptor 1 ( sur1 ) and the 
 inward rectifying potassium channel ( kir6.1 ) proteins , respectively ( 1 ) . both these proteins constitute the 
 atp - sensitive plasma membrane potassium ( katp ) channel , the regulation of which controls 
 cell membrane polarization , which determines insulin release from the pancreatic 
 -cell . inactivating mutations of the abcc8 and 
 kcnj11 genes result in closure of the katp channels , leading to 
 depolarization of the cell membrane , opening of the voltage - dependent calcium channels 
 and insulin release . diazoxide has been the conventional first - line treatment of diffuse 
 hh as it opens the katp channel and inhibits insulin secretion . however , diazoxide is 
 associated with unpleasant side effects including fluid retention , blood dyscrasias , 
 nausea and hypertrichosis . the use of sirolimus , an inhibitor of mtor ( the mammalian target of rapamycin ) as an 
 immunosuppressant in post - renal transplant patients uncovered its association with 
 hyperglycaemia ( 2 ) . studies of the pancreas in 
 patients with diffuse hh suggest a pathogenic role in overexpression of the mtor pathway 
 ( 3 ) . research has demonstrated that sirolimus 
 can effectively suppress -cell proliferation and reduce the severity of hh . inhibitors of mtor have already been successfully used to treat adults with pancreatic 
 insulin secreting tumours ( 4 ) . in recent reports , sirolimus was efficacious and safe in children with hh who were 
 unresponsive to diazoxide therapy and octreotide , thus obviating the need for near total 
 pancreatectomy ( 5 ) . we report a 3-year 
 3-month - old girl who demonstrated initial partial response to diazoxide , but then 
 developed intermittent , unpredictable hypoglycaemic episodes and severe hypertrichosis 
 with weight gain . sirolimus , which replaced diazoxide , was successfully used in 
 abolishing hypoglycaemia and resolving the diazoxide - associated side effects . shortly 
 after stopping sirolimus , the blood glucose levels remained in the normal range , except 
 during the stress of a viral illness . a chinese girl was born at 36 weeks gestation by normal vaginal delivery , with a birth 
 weight of 3.8  kg ( + 2.1 s.d . ) . she was hypoglycaemic within the first 
 3  h of life , with a capillary blood glucose level of 1.6 she 
 subsequently developed recurrent episodes of non - ketotic hypoglycaemia requiring an 
 intravenous 12.5% dextrose drip with a maximal dextrose concentration of 
 8  mg / kg / min and boluses of intravenous glucagon . investigations performed when she was hypoglycaemic with a serum glucose level 
 of 0.6  mmol / l ( 11  mg / dl ) demonstrated an inappropriately elevated serum 
 insulin concentration of 9.4  u / l , with a normal serum cortisol level of 
 427  nmol / l , a normal growth hormone concentration of 54.6 she was then 
 commenced on oral diazoxide and transferred to our hospital at day 8 of life for 
 continued management . on initial assessment , she was plethoric , well thrived with mild facial hypertrichosis . her tone was normal , with a normal moro reflex . over the next 3 weeks , she required 
 increasing doses of diazoxide , reaching a maximum dose of 20  mg / kg / day , so as to 
 maintain normoglycaemia . hydrochlorothiazide , which has a synergistic effect in 
 suppressing insulin secretion , was added to prevent fluid retention . she did not require 
 further escalation of treatment to octreotide , glucagon or nifedipine . concurrently , the 
 glucose infusion rate was decreased as she was weaned to full feeds providing 106 
 cal / kg / day , with the addition of glucose polymers and cornstarch . her initial response 
 to diazoxide allowed her to be discharged with capillary glucose levels above 
 3.5  mmol / l and a fasting duration of 6  h. she was subsequently followed up at the paediatric endocrine specialist clinic . she 
 experienced no hypoglycaemic episodes and was weaned off glucose polymers and cornstarch 
 with a gradual reduction of diazoxide to a minimum dose of 9 mg / kg / day at 4 months of 
 age . however , the frequency of intermittent borderline hypoglycaemic episodes ( lowest 
 capillary glucose level of 2.5 mmol / l ) increased to an average of twice a week 
 from 6 months of age , necessitating a gradual increase in the diazoxide dose to 
 11.7  mg / kg / day . genomic dna was extracted from peripheral blood leucocytes from the infant and both 
 clinically unaffected parents using standard procedures and sent to the molecular 
 genetics laboratory at the university of exeter medical school for analysis of mutations 
 in the abcc8 and kcnj11 genes . this confirmed that the 
 infant was heterozygous for a novel missense mutation in the abcc8 gene 
 ( c.4154a > t / p.lys1385thr ) . since the lysine residue is highly conserved , this mutation 
 is very likely to be pathogenic . analysis of both parents demonstrated that the mutation 
 arose de novo and originated from the paternal copy of the 
 abcc8 gene . given the genetic finding , in order to exclude a focal 
 lesion , the child subsequently had an f - fluoro - l - dopa positron 
 emission tomography scan , which confirmed that she had the diffuse form of hh . subsequently , the intermittent breakthrough episodes of hypoglycaemia led to an increase 
 in the diazoxide dose to 12.6  mg / kg / day associated with progressive worsening of 
 diffuse hypertrichosis over the whole body including her face , trunk and limbs . her 
 appetite was poor and hence , if hypoglycaemic , required forced feeding , which led to 
 excessive weight gain . since 
 octreotide is administered as a parenteral injection several times a day , with the 
 possibility of tachyphylaxis , the parents were keen to proceed with a trial of oral 
 sirolimus , even though the long - term side effects were not known . at 15 months of age , 
 in view of the intermittent and persistent episodes of hypoglycaemia , she was commenced 
 on oral sirolimus at a dose of 0.1  mg tds ( 0.5  mg / m / day ) , 
 which was titrated to achieve a target level between 5 and 15  ng / ml with regular 
 monitoring of her full blood count , liver and renal function tests . the sirolimus trough 
 level was checked monthly and the dose was titrated upwards to 1.0  mg tds 
 ( 4.4  mg / m / day ) , which eventually maintained the serum sirolimus 
 trough level between 25 and 30  ng / ml , with abolition of hypoglycaemia . the 
 diazoxide dose was concurrently decreased and stopped 3 months after starting 
 sirolimus . she was feeding 
 significantly better and the frequency of feeds was reduced , as her capillary glucose 
 levels were generally above 45  mmol / l . however , she developed oral ulcers with clinically insignificant elevations in the serum 
 ck to a maximum of 694  u / l ( normal range : 20300  u / l ) and alt 
 levels to a maximum of 83  u / l ( 2065 ) . after 15 months of treatment with sirolimus , she was able to maintain her capillary 
 glucose levels > 4  mmol / l for progressive longer periods of time and the 
 borderline hypoglycaemic episodes only occurred when she was unwell with poor feeding 
 and vomiting . as her capillary glucose levels were stable with no hypoglycaemic 
 episodes , she was weaned off sirolimus over the next 6 months . there were no 
 hypoglycaemic episodes when the sirolimus dose was tapered and her capillary glucose 
 levels remained consistently > 4  mmol / l . however , 1 month after stopping 
 sirolimus , she developed a bout of viral gastroenteritis and was hospitalized for 5 days 
 with severe vomiting , watery diarrhoea and poor feeding . mmol / l and she was started on a 10% dextrose drip to maintain 
 normoglycaemia . when she started to feed again mmol / l , the dextrose drip was stopped and she was discharged well . at her 
 most recent outpatient visit , she was 3 years 3 months of age and her developmental 
 milestones were normal . 3.5  mmol / l , even after 10 hours fasting . both the serum ck and alt levels 
 normalized after stopping sirolimus . the management of diffuse hh to prevent recurrent hypoglycaemia and brain damage is very 
 challenging . conventional treatments including the use of diazoxide , octreotide and 
 nifedipine are not always able to prevent hypoglycaemic episodes and are often 
 associated with unpleasant side effects . historically , severe cases of diffuse 
 hyperinsulinism , which did not respond to medical treatment required near total 
 pancreatectomy , result in diabetes mellitus and exocrine pancreatic insufficiency , with 
 possible persistent hypoglycaemia after surgery . recently , the use of sirolimus was 
 introduced as a potential effective alternative medical treatment for congenital 
 hyperinsulinism . this pathway is crucial for -cell function and glycaemic 
 control ( 6 ) the inhibition of the mtor pathway 
 by sirolimus can potentially cause suppression of -cell proliferation and reduce 
 hyperinsulinism . this is the first report of successful treatment with sirolimus in a partially 
 diazoxide - responsive hh child . initial treatment with diazoxide resulted in a 
 significant improvement in the capillary glucose levels and the child could be 
 discharged from hospital on oral feeds . not unexpectedly , there were occasional 
 breakthrough episodes of mild hypoglycaemia not requiring any further admissions or 
 escalation in therapy , which was in keeping with sudden surges of insulin release , as a 
 consequence of the inactivating mutations of the sulphonylurea receptor . however , the 
 diazoxide - associated side effects including poor appetite , excessive weight gain from 
 overfeeding to treat hypoglycaemia and generalized hypertrichosis were very distressing 
 for the family . after conversion to sirolimus , there was significant improvement with complete 
 resolution of hypoglycaemia when the trough sirolimus levels ranged from 25 to 30 this was higher than the original trough sirolimus level of 
 515  ng / ml , as reported by seniappan ( 7 ) , but it was necessary in order to eliminate all the hypoglycaemic episodes 
 while diazoxide was weaned off . the deceleration of weight gain with near complete 
 resolution of the hypertrichosis are other important factors to consider . potential side 
 effects of sirolimus include mucositis , hyperlipidaemia , pneumonitis , severe infections 
 and bone marrow suppression , which have been reported in adult studies and are 
 reversible with dose reduction ( 8) . in our 
 patient , her blood counts remained normal throughout the treatment and there was no 
 increased frequency of infections after starting sirolimus . the side effects noted were 
 transient oral ulcers and clinically insignificant elevations in the serum ck and alt . 
 oral ulcers after administration of sirolimus can be minimized by rinsing the mouth with 
 water or juice . hyperinsulinism often becomes milder over time with slow progressive -cell 
 apoptosis in patients with diffuse hh . animal studies have also demonstrated that 
 rapamycin ( also known as sirolimus ) can cause a 50% reduction in -cell mass by 
 increased apoptosis ( 9 ) . since this 
 patient s capillary glucose levels had been stable for 6 months and the long - term 
 side effects of sirolimus are not known , sirolimus was gradually weaned off over 6 
 months . with this , the oral ulcers stopped appearing . the half - life of sirolimus is 
 approximately 63  h and sirolimus should be eliminated from the body within 5 
 half - lives , or approximately 13.1 days . for this child , the capillary glucose levels 
 were maintained > 4  mmol / l , although she was recently hospitalized for a 
 hypoglycaemic episode associated with severe viral gastroenteritis . close monitoring 
 will be necessary to ascertain if she can maintain long - term normoglycaemia without 
 sirolimus . in conclusion , sirolimus significantly improved this child s blood glucose 
 levels , allowing cessation of diazoxide with resolution of hypertrichosis and prevention 
 of excessive weight gain . this illustrates the utility of sirolimus in treating diffuse 
 hh , which is not fully responsive to diazoxide , while avoiding the untoward side effects 
 of diazoxide . while transient elevations in serum ck and alt levels were noted in our 
 patient , more studies into the long - term efficacy and safety of sirolimus are 
 necessary . the authors declare that there is no conflict of interest that could be perceived as 
 prejudicing the impartiality of the research reported . this research did not receive any specific grant from any funding agency in the public , 
 commercial or not - for - profit sector . written informed consent was obtained from the patient s mother for publication 
 of the submitted article . khalid hussain provided the protocol and guidance with 
 the use of sirolimus in treating congenital hyperinsulinism .
summaryhyperinsulinaemic hypoglycaemia ( hh ) , which causes persistent neonatal hypoglycaemia , 
 can result in neurological damage and it s management is challenging . 
 diazoxide is the first - line treatment , albeit not all patients will fully respond to 
 it , as episodes of hypoglycaemia may persist and it entails unpleasant adverse 
 effects . 
 sirolimus , an mtor inhibitor , has reportedly been successful in treating 
 children with severe diffuse hh , thus obviating the need for pancreatectomy . 
 we 
 report a girl with hh , with a novel heterozygous abcc8 gene missense 
 mutation ( c.4154a > t/ p.lys1385thr ) , who was initially responsive to diazoxide 
 therapy . 
 after 11 months of diazoxide treatment , she developed intermittent , 
 unpredictable breakthrough episodes of hypoglycaemia , in addition to generalized 
 hypertrichosis and weight gain from enforced feeding to avoid hypoglycaemia . 
 sirolimus , which was commenced at 15 months of age , gradually replaced diazoxide , 
 with significant reduction and abolition of hypoglycaemia . 
 the hypertrichosis 
 resolved and there was less weight gain given the reduced need for enforced feeding . 
 sirolimus , which was administered over the next 15 months , was well tolerated with no 
 significant side effects and was gradually weaned off . after stopping sirolimus , 
 apart from hypoglycaemia developing during an episode of severe viral 
 gastroenteritis , the capillary glucose concentrations were maintained 
 > 
 3.5  mmol / l , even after a 10  h fast . 
 sirolimus may have a role in 
 the treatment of partially diazoxide - responsive forms of hh who experience 
 breakthrough hypoglycaemia , but the long - term safety and efficacy of sirolimus are 
 not established.learning points : conventional treatment of diffuse hh with diazoxide is not always effective 
 in controlling hypoglycaemia and can be associated with unpleasant side 
 effects.sirolimus was successfully used to abolish recurrent hypoglycaemia in 
 partially diazoxide - responsive hh , with resolution of unacceptable 
 diazoxide - associated side effects.sirolimus was well tolerated with no clinically significant side 
 effects.shortly after stopping sirolimus , the capillary glucose levels remained 
 normoglycemic .