ESPE Abstracts (2018) 89 FC3.5

Genotype and Phenotype Correlation in Syndromic Forms of Hyperinsulinaemic Hypoglycaemia - a 10-year follow-up Study in a Tertiary Centre

Antonia Dastamania, Eirini Kostopouloub, Emma Clementsc, Silvana Caiuloa, Prateek Shanmuganandaa, Kate Morgana, Clare Gilberta, Mehul Dattania,d, Sarah Flanaganc, Sian Ellardc, Jane Hurste & Pratik Shaha

aEndocrinology Department, Great Ormond Street Hospital for Children, London, UK; bResearch Laboratory of the Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, School of Medicine, University of Patras, Patras, Greece; cGenetics Laboratory, Royal Devon & Exeter NHS Foundation Trust University of Exeter Medical School, Exeter, UK; dGenetics and Epigenetics in Health and Disease Section, Genetics and Genomics Medicine Program, UCL GOS Institute of Child Health, London, UK; eGenetics Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Introduction: Hyperinsulinaemic Hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in infancy. It is characterised by hypoketotic, hypofattyacidaemic and hyperinsulinaemic hypoglycaemia. The molecular basis of HH includes defects in pathways that regulate insulin release; to date, 12 genes have been associated with monogenic forms of HH (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1, PMM2). However, no genetic aetiology has been identified in 50% of patients. Recently, various syndromic genetic forms of CHI have been documented including Beckwith-Wiedemann (BWS), Kabuki (KS), Turner (TS), Sotos, Simpson-Golabi-Behmel, Costello, Trisomy 13, Timothy and Usher syndrome.

Objective: We aimed to characterise the different syndromic forms of HH, their response to treatment, and their long-term outlook.

Method: We performed a retrospective study of patients diagnosed with syndromic forms of HH in a specialist tertiary centre.

Results: We recruited 60 children with syndromes or syndromic features presenting with hypoglycaemic episodes were recruited. Investigations confirmed HH in 52 cases. The following syndromes were identified: BWS (n=19), KS (n=7), TS (n=6), Rubenstein Taybi Syndrome (RTS; n=1), chromosome 16p11.2 deletion (n=2), Prader-Willi (n=1), CHARGE (n=1), Trisomy 21 (n=1), Di George (n=1), Sotos (n=1), Costello (n=1), Allagile (n=1), Usher (n=1) and 9 cases with syndromic features (no specific syndrome identified). Forty-four were responsive to diazoxide, with one TS developing pulmonary hypertension, while five were unresponsive (5 BWS, 1 RTS). Octreotide was effective in six cases (4 BWS, 1 TS; 1 BWS partially responsive). Lanreotide monthly injections were successfully administered in one BWS case. Sirolimus was used in three cases (2 BWS, 1 RSS) and proved partially effective. Pancreatectomy was required in six cases: 3 BWS, 1 KS, 1 Costello and one with an undefined syndrome. Thirty-eight patients discontinued medication at ages ranging from 1 month to 4.5 years, while four stopped medication post-pancreatectomy and 14 children continue to require medication (10 Diazoxide, 3 Octreotide, 1 Lanreotide).

Conclusion: Our study highlights the association of HH with various syndromes. The early diagnosis of HH is fundamentally important for preventing hypoglycaemic brain injury. Hence, children with features suggestive of syndromes associated with HH must be closely monitored for hypoglycaemia and, when detected, be screened for possible HH. Our data indicate that most cases (70%) of syndromic forms of HH are Diazoxide-responsive and resolve over time. Further studies, including prospective, long-term follow-up data, are required to clarify underlying mechanisms and monitor disease progression into adulthood.