Publications by authors named "Ved Arya"

34 Publications

IgG4-related hypophysitis in adolescence.

J Pediatr Endocrinol Metab 2021 Mar 14;34(3):395-399. Epub 2020 Dec 14.

Department of Paediatric Endocrinology, Variety Children Hospital, King's College Hospital NHS Foundation Trust, London, UK.

Objectives: IgG4-related hypophysitis is a novel clinical disease entity, which is typically seen in the sixth decade of life and is typically complicated by hypopituitarism. We describe an adolescent female with IgG4-related hypophysitis with normal pituitary function and summarize the relevant literature.

Case Presentation: A 11.8-year-old girl presented with headache and left VI cranial nerve palsy. MRI brain identified an enlarged pituitary gland. Endocrine investigations revealed normal pituitary function. She underwent a transsphenoidal biopsy of the pituitary gland, and histological examination confirmed the diagnosis of IgG4-related hypophysitis. Serum IgG4 concentrations were normal and no evidence of other organ involvement was found. Although the patient tested strongly positive for TB on an interferon gamma release assay, pituitary biopsy was negative for granuloma formation and acid-fast bacilli (Ziehl-Neelson staining). IgG4-related hypophysitis was treated with oral prednisolone and mycophenolate-mofetil with a good response.

Conclusions: We describe to the best of our knowledge, the youngest patient in the published literature with IgG4-related hypophysitis presenting without pituitary insufficiency. A literature review identified only five cases of IgG4-related hypophysitis in adolescence. Serum IgG4 concentrations were normal in all, except one of the adolescent patients reported so far, and appear unhelpful in diagnosis in this age group.
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http://dx.doi.org/10.1515/jpem-2020-0535DOI Listing
March 2021

Prolactinoma in childhood and adolescence-Tumour size at presentation predicts management strategy: Single centre series and a systematic review and meta-analysis.

Clin Endocrinol (Oxf) 2021 Mar 26;94(3):413-423. Epub 2020 Dec 26.

Paediatric Endocrinology, Variety Club Children's Hospital, King's College Hospital NHS Foundation Trust, London, UK.

Objective: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis.

Patients And Design: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%).

Conclusions: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.
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http://dx.doi.org/10.1111/cen.14394DOI Listing
March 2021

Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings.

Horm Res Paediatr 2020 25;93(5):335-342. Epub 2020 Nov 25.

Department of Child Health, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Introduction: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate limb shortening. It results from loss-of-function NPR2 mutations affecting the C-type natriuretic peptide receptor. Resistance to growth hormone (GH) action has previously been suggested. We describe outcomes of 2 siblings with AMDM after prolonged high-dose GH treatment.

Patients/methods: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological features of AMDM. Subsequent genetic testing identified a novel homozygous NPR2 mutation. GH provocation testing showed relatively high GH levels. Serum insulin-like growth factor 1 (IGF-1) was ∼2 SD below age/sex-specific mean. High-dose GH (0.075 mg/kg/day) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF-1 towards +3 SDS for age/sex. Annualized height velocities for first 3 years on GH were 7.0, 5.4, and 4.7 cm/year for patient A and 9.4, 8.0, and 5.9 cm/year for patient B. Height gain during puberty was 10.6 (Pt-A) and 5.9 (Pt-B) cm. Final heights after 8.5 years of GH treatment were 130.5 cm (-6.57 SDS, Pt-A) and 134 cm (-4.58 SDS, Pt-B).

Conclusions: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. The final height of our patients was significantly higher than average reported final height (120 cm) of AMDM patients.
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http://dx.doi.org/10.1159/000511874DOI Listing
November 2020

A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome.

J Pediatr Endocrinol Metab 2020 May 22;33(6):809-812. Epub 2020 May 22.

King's College Hospital NHS Foundation Trust, London, UK.

Background Inherited severe insulin resistance syndromes (SIRS) are rare and can be caused by mutations in the insulin receptor gene (INSR). Case presentation A 12-year-old Jamaican girl with a BMI of 24.4 kg/m2 presented with polyuria and polydipsia. A diagnosis of T1DM was made in view of hyperglycaemia (18 mmol/l), and elevated Hba1C (9.9%), and insulin therapy was initiated. Over the next 2 years, she developed hirsutism and acanthosis nigricans, and had minimal insulin requirements with frequent post-prandial hypoglycaemia. In view of this, and her strong family history suggestive of a dominantly inherited type of diabetes, the diagnosis was revisited. Targeted next-generation sequencing (NGS) of the patient's monogenic diabetes genes was performed. What is new? NGS revealed a novel heterozygous missense INSR variant, NM_000208.3:c.3471T>G, p.(His1157Gln), confirming a diagnosis of Type A SIRS. Conclusions Type A SIRS can be difficult to differentially diagnose due to the variable phenotype. Features of insulin resistance may be absent at initial presentation and may develop later during pubertal progress. Awareness of the clinical features and comprehensive genetic testing are essential to identify the condition.
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http://dx.doi.org/10.1515/jpem-2019-0503DOI Listing
May 2020

Haematological chimerism masquerading as disorder of sex development.

Clin Endocrinol (Oxf) 2020 05 3;92(5):487-489. Epub 2020 Feb 3.

Department of Paediatric Endocrinology, King's College Hospital, London, UK.

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http://dx.doi.org/10.1111/cen.14160DOI Listing
May 2020

Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.

Horm Res Paediatr 2019 1;92(6):382-389. Epub 2019 Nov 1.

Department of Paediatric Endocrinology, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Background: Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects. We describe the largest case series to date of 5 unrelated patients with SOX3 duplication with a variable clinical phenotype, including the smallest reported SOX3 duplication.

Case Reports: Five male patients who presented with congenital hypopituitarism (CH) were identified to have Xq27.1 duplication encompassing SOX3. The size of the duplication ranged from 323.8 kb to 11 Mb. The duplication was maternally inherited or de novo in 2 patients each (and of unknown inheritance in 1 patient). The age at presentation was variable. Three patients had multiple pituitary hormone deficiencies, whereas 2 patients had isolated growth hormone deficiency. All patients had micropenis and/or small undescended testes. Structural pituitary and/or other midline cranial abnormalities (callosal hypogenesis/absence of the septum pellucidum) were present in all patients. Two patients had a neural tube defect in addition to CH.

Conclusions: This is the largest series reported to date of unrelated patients with CH in association with Xq27.1 duplication encompassing SOX3. The clinical phenotype is variable, which may be due to genetic redundancy or other unknown aetiological factors. We have expanded the phenotypic spectrum through description of the smallest Xq27.1 duplication (323.8 kb) with CH reported to date, as well as a second family with CH and a neural tube defect.
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http://dx.doi.org/10.1159/000503784DOI Listing
July 2020

Hyperinsulinaemic hypoglycaemia in deoxyguanosine kinase deficiency.

Clin Endocrinol (Oxf) 2019 12 11;91(6):900-903. Epub 2019 Sep 11.

Paediatric Endocrinology, King's College Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/cen.14084DOI Listing
December 2019

Exceptional diazoxide sensitivity in hyperinsulinaemic hypoglycaemia due to a novel HNF4A mutation.

Endocrinol Diabetes Metab Case Rep 2019 May 16;2019. Epub 2019 May 16.

Department of Paediatric Endocrinology, Variety Club Children's Hospital, King's College Hospital NHS Foundation Trust, London, UK.

Diazoxide is the first-line treatment for patients with hyperinsulinaemic hypoglycaemia (HH). Approximately 50% of patients with HH are diazoxide resistant. However, marked diazoxide sensitivity resulting in severe hyperglycaemia is extremely uncommon and not reported previously in the context of HH due to HNF4A mutation. We report a novel observation of exceptional diazoxide sensitivity in a patient with HH due to HNF4A mutation. A female infant presented with severe persistent neonatal hypoglycaemia and was diagnosed with HH. Standard doses of diazoxide (5 mg/kg/day) resulted in marked hyperglycaemia (maximum blood glucose 21.6 mmol/L) necessitating discontinuation of diazoxide. Lower dose of diazoxide (1.5 mg/kg/day) successfully controlled HH in the proband, which was subsequently confirmed to be due to a novel HNF4A mutation. At 3 years of age, the patient maintains age appropriate fasting tolerance on low dose diazoxide (1.8 mg/kg/day) and has normal development. Diagnosis in proband's mother and maternal aunt, both of whom carried HNF4A mutation and had been diagnosed with presumed type 1 and type 2 diabetes mellitus, respectively, was revised to maturity-onset diabetes of young (MODY). Proband's 5-year-old maternal cousin, also carrier of HNF4A mutation, had transient neonatal hypoglycaemia. To conclude, patients with HH due to HNF4A mutation may require lower diazoxide than other group of patients with HH. Educating the families about the risk of marked hyperglycaemia with diazoxide is essential. The clinical phenotype of HNF4A mutation can be extremely variable. Learning points: Awareness of risk of severe hyperglycaemia with diazoxide is important and patients/families should be accordingly educated. Some patients with HH due to HNF4A mutations may require lower than standard doses of diazoxide. The clinical phenotype of HNF4A mutation can be extremely variable.
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http://dx.doi.org/10.1530/EDM-19-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528403PMC
May 2019

Idiopathic gonadotropin-independent precocious puberty - is regular surveillance required?

J Pediatr Endocrinol Metab 2019 Apr;32(4):403-407

Consultant Paediatric Endocrinologist, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.

Context Germ cell tumours (GCTs) secreting β-human chorionic gonadotropin (β-HCG) are a rare cause of gonadotropin-independent precocious puberty (GIPP). Case description A 5.7-year-old boy presented with GIPP. Investigations to elucidate the underlying cause revealed elevated serum β-HCG. Ultrasound of the abdomen and testes, urine steroid profile, bone isotope scan, and sequencing of the luteinizing hormone receptor gene (LHCGR) were normal. Despite paired serum and cerebrospinal fluid β-HCG measurement suggesting local (brain) β-HCG production, repeated magnetic resonance imaging (MRI) of the brain as well as MRI of the mediastinum did not identify a tumour source of persistently elevated serum β-HCG. Treatment with cyproterone acetate and spironolactone was unsuccessful. Increase in testicular volumes prompted the addition of a gonadotropin releasing hormone (GnRH) analogue. Due to progressing virilisation and skeletal maturation, treatment was changed to a combination of anastrozole and bicalutamide at the age of 7 years. One year later, serum β-HCG and testosterone concentrations spontaneously normalised followed by reductions in the height velocity, skeletal maturation and virilisation. The proband achieved his genetic height potential. No medication side effects were observed. The patient subsequently presented with non-secreting pineal GCT at 14 years, 8½ years after his initial presentation with GIPP. Conclusions Our case highlights that GIPP with no definite underlying aetiology at diagnosis should be considered as a prodrome for GCTs, and regular radiological surveillance for earlier tumour identification is warranted. To the best of our knowledge, our case is the first reported case of the use of anastrozole and bicalutamide in the setting of idiopathic GIPP. The good height outcome in our case warrants the trial of anastrozole and bicalutamide in similar cases.
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http://dx.doi.org/10.1515/jpem-2018-0419DOI Listing
April 2019

High-dose biotin in infants mimics biochemical hyperthyroidism with some commercial assays.

Clin Endocrinol (Oxf) 2018 03 26;88(3):507-510. Epub 2018 Jan 26.

Department of Paediatric Endocrinology and Diabetes, Evelina London Children Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/cen.13547DOI Listing
March 2018

Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.

Eur J Endocrinol 2015 Jun 9;172(6):697-705. Epub 2015 Mar 9.

Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK Departments of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKThe Institute of Child HealthUniversity College London, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyChildren State Hospital, 21100 Diyarbakir, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartments of NeonatologyChildren State Hospital, 21100 Diyarbakir, TurkeyDepartment of Medical Biology and GeneticsDicle University, 21100 Diyarbakir, TurkeyFaculty of MedicineUniversity of Southampton, Southampton SO16 6YD, UK

Background: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey.

Design And Methods: NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed.

Results: Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births.

Conclusions: Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.
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http://dx.doi.org/10.1530/EJE-14-0852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411707PMC
June 2015

Postprandial hyperinsulinaemic hypoglycaemia secondary to a congenital portosystemic shunt.

Horm Res Paediatr 2015 21;83(3):217-20. Epub 2015 Jan 21.

Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK.

Background: Portosystemic shunts (PSS) are abnormal vascular connections between the portal vein or its tributaries and the systemic vein that allow mesenteric blood to reach the systemic circulation without first passing through the liver. PSS can be associated with various syndromes and can lead to serious complications. We report a rare case of a child with PSS and recurrent hypoglycaemia.

Case: A 20-month-old girl with Down's syndrome presented with recurrent hypoglycaemic episodes. She had multiple anomalies including a ventricular septal defect, oesophageal atresia and tracheo-esophageal fistula, gastro-oesophageal reflux, and conjugated hyperbilirubinaemia. The initial investigations suggested hyperinsulinaemic hypoglycaemia (HH). She did not respond to diazoxide. An oral glucose tolerance test suggested postprandial HH. Further vascular imaging showed a side-to-side portocaval shunt (Abernethy malformation) with relative hypoperfusion of the liver. Hypoglycaemia resolved following surgical closure of the portocaval shunt.

Conclusion: PSS can rarely be associated with HH, possibly due to lack of insulin degradation in the liver. Surgical closure of the shunt resolves the hypoglycaemia.
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http://dx.doi.org/10.1159/000369014DOI Listing
January 2016

Congenital hyperinsulinism: clinical and molecular characterisation of compound heterozygous ABCC8 mutation responsive to Diazoxide therapy.

Int J Pediatr Endocrinol 2014 15;2014(1):24. Epub 2014 Dec 15.

London centre for Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH and The Institute of Child Health, University College London, London, WC1N 1EH UK.

Background: Mutations in ABCC8 and KCNJ11 are the most common cause of congenital hyperinsulinism (CHI). Recessive as well as dominant acting ABCC8/KCNJ11 mutations have been described. Diazoxide, which is the first line medication for CHI, is usually ineffective in recessive ABCC8 mutations. We describe the clinical and molecular characterisation of a recessive ABCC8 mutation in a CHI patient that is diazoxide response.

Clinical Case: A term macrosomic female infant presented with symptomatic persistent hypoglycaemia confirmed to be secondary to CHI. She exhibited an excellent response to moderate doses of diazoxide (10 mg/kg/day). Molecular genetic analysis of the proband confirmed a biallelic ABCC8 mutation - missense R526C inherited from an unaffected mother and a frameshift c.1879delC mutation (H627Mfs*20) inherited from an unaffected father. Follow-up highlighted persistent requirement for diazoxide to control CHI. Functional analysis of mutants confirmed them to result in diazoxide-responsive CHI, consistent with the clinical phenotype.

Conclusion: Biallelic ABCC8 mutations may result in diazoxide-responsive CHI. Irrespective of the molecular genetic analysis results, accurate assessment of the response to diazoxide should be undertaken before classifying a patient as diazoxide-responsive or unresponsive CHI.
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http://dx.doi.org/10.1186/1687-9856-2014-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290134PMC
January 2015

Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation.

J Pediatr Endocrinol Metab 2015 May;28(5-6):695-9

Introduction: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of severe diazoxide unresponsive HH involves near total pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. mTOR inhibitors are used in cancer patients and recently found to be effective in the treatment of insulinoma and HH patients.

Case: A 36 weeks large for gestational age neonate presented with severe hypoglycaemia on day 1 of life. The hypoglycaemia screen confirmed HH and genetic testing revealed compound heterozygous ABCC8 mutation, confirming diffuse disease. He was unresponsive to the maximal dose of diazoxide (15 mg/kg/day), hence needed treatment with higher concentration of intravenous glucose (25 mg/kg/min), intravenous glucagon and subcutaneous octreotide (30 μg/kg/day) infusions to maintain normoglycaemia. Sirolimus, a mTOR inhibitor, was commenced at 9 weeks of age following which he showed a marked improvement in his glycaemic control. After 4 weeks of sirolimus therapy, he was discharged home on subcutaneous octreotide injection (20 μg/kg/day) and oral sirolimus, thereby avoiding the need for a near total pancreatectomy.

Conclusion: We report the first case of compound heterozygous ABCC8 mutation causing severe diffuse HH that responded to therapy with a mTOR inhibitor.
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http://dx.doi.org/10.1515/jpem-2014-0371DOI Listing
May 2015

Familial isolated growth hormone deficiency due to a novel homozygous missense mutation in the growth hormone releasing hormone receptor gene: clinical presentation with hypoglycemia.

J Clin Endocrinol Metab 2014 Dec;99(12):E2730-4

Developmental Endocrinology Research Group (H.D., S.T., M.S., P.S., V.B.A., K.H.), Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, WC1N 1EH London, United Kingdom; Department of Paediatric Endocrinology (H.D., P.S., V.B.A., K.H.), Great Ormond Street Hospital for Children, NHS Foundation Trust, WC1N 3JH London, United Kingdom; Department of Paediatric Endocrinology (H.D., R.T.B., M.N.O.) and Department of Radiology (N.H., A.B.), Diyarbakir Children's State Hospital, 21100 Diyarbakir, Turkey.

Context: Mutations in the growth hormone releasing hormone receptor (GHRHR) gene are a relatively rare cause of isolated growth hormone deficiency (IGHD).

Objective: This study aimed to understand the biochemical basis of hypoglycemia in the index case and the molecular basis of severe short stature in a large consanguineous family with IGHD.

Patients And Methods: The index case presented with a hypoglycemic convulsion, following which eight members in two related consanguineous Turkish families were identified with IGHD. Homozygosity mapping identified the homozygous regions shared only among the affected individuals. Sanger sequencing of GHRHR, which resided in the shared homozygous region, was performed. In silico analysis of the pathogenic GHRHR variant was performed.

Results: The clinical presentation and hormonal analysis confirmed GH deficiency in all affected individuals. Magnetic resonance imaging scan of the pituitary gland showed anterior pituitary hypoplasia in five affected individuals in which the youngest was only 0.4 years old, but with normal pituitary size in three affected individuals. Homozygosity mapping showed two large homozygous regions on chromosome 7 shared only among affected individuals. Sanger sequencing of GHRHR gene present in one of these shared regions identified a novel homozygous missense mutation (p.C64G) segregating with the disease phenotype. In silico analysis predicted the mutation to be deleterious and disease causing.

Conclusions: We describe a large consanguineous Turkish kindred with IGHD due to a novel homozygous missense GHRHR mutation. This is the first description of presentation with hypoglycemia and the earliest reported occurrence of anterior pituitary hypoplasia in patients with GHRHR mutation.
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http://dx.doi.org/10.1210/jc.2014-2696DOI Listing
December 2014

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.

Eur J Endocrinol 2014 Dec 8;171(6):685-95. Epub 2014 Sep 8.

Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK

Context: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported.

Objective: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations.

Design: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted.

Results: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology.

Conclusions: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.
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http://dx.doi.org/10.1530/EJE-14-0353DOI Listing
December 2014

Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy.

J Clin Endocrinol Metab 2014 Oct 17;99(10):3660-7. Epub 2014 Jun 17.

Developmental Endocrinology Research Group (H.D., P.S., V.B.A., L.H., K.H.), Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; Department of Paediatric Endocrinology (H.D., P.S., V.B.A., L.H., K.H.), Great Ormond Street Hospital for Children, London WC1N 3JH, United Kingdom; and Institute of Biomedical and Clinical Science (S.E.F., S.E.), University of Exeter Medical School, Exeter EX2 5DW, United Kingdom.

Context: Octreotide, a somatostatin analog, is commonly used in diazoxide unresponsive congenital hyperinsulinism (CHI) patients as a second-line therapy.

Objective: The aims of this study were to evaluate the dose range, side effects, and long-term follow-up of octreotide therapy in a large cohort of CHI patients.

Setting: The study was conducted at an international referral center for the management of CHI.

Patients: Twenty-eight (17 males) diazoxide unresponsive CHI patients (15 biallelic and 10 monoallelic ATP sensitive potassium channel mutation) managed with daily multidose octreotide therapy between 2001 and 2013 participated in the study.

Main Outcome Measures: Regular follow-up of auxology, growth factors (serum IGF-1 and IGF binding protein 3 levels), thyroid functions, liver function tests, and hepatobiliary ultrasonography were measured.

Results: The median age of CHI diagnosis was 1 week (range 1-80 wk). The mean (±SD) dose of octreotide required was 17.8 (±7.5) μg/kg · d (range 7.5-30 μg/kg · d). The mean (±SD) duration of follow-up on octreotide therapy was 52.4 (±33.8) months (range 6 mo to 9.5 y). Elevation of liver enzymes was the most prevalent side effect (n = 13; 46.4%), which resolved spontaneously. Gallbladder pathology was detected in nine patients (32%). Mean (±SD) duration of octreotide therapy before the development of gallbladder pathology was 4.3 (±4.6 mo), whereas 19 patients were free of gallstones after a follow-up of 53.6 ± 32.9 months on octreotide therapy. There was no relationship between the dose or the duration of octreotide therapy and development of gallbladder pathology or liver dysfunction.

Conclusions: Transient elevation of liver enzymes and asymptomatic gallbladder pathology were the most prevalent long-term side effects of octreotide therapy. There was no correlation between the dose or the duration of octreotide therapy and development of liver dysfunction and gallbladder pathology.
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http://dx.doi.org/10.1210/jc.2014-1866DOI Listing
October 2014

Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia.

J Pediatr Endocrinol Metab 2014 Nov;27(11-12):1065-9

Aim: We describe the novel clinical observation of protein induced hyperinsulinaemic hypoglycaemia following remission of transient neonatal diabetes mellitus (TNDM) in a patient with 6q24 methylation defect.

Methods: A male infant of non-consanguineous Caucasian parents, born at 40 weeks of gestation with a birth weight of 3330 g (-0.55 standard deviation score) presented with hyperglycaemia in the first week of life and was diagnosed with 6q24 TNDM. At 22 months of age, he developed recurrent hypoglycaemic episodes. Controlled diagnostic fast, oral glucose tolerance test, protein loading test and mixed meal tolerance test were undertaken. Sequencing of ABCC8, KCNJ11, GLUD1 and HADH were performed.

Results: Investigations suggested a diagnosis of protein sensitive hyperinsulinaemic hypoglycaemia with normal serum ammonia, acylcarnitine profile and urine organic acids. Sequencing of ABCC8, KCNJ11, GLUD1 and HADH did not identify a pathogenic mutation to explain his hyperinsulinaemic hypoglycaemia.

Conclusion: This clinical case demonstrates the novel observation of protein sensitive hyperinsulinaemic hypoglycaemia in a patient with 6q24 TNDM. Long-term follow-up of patients with chromosome 6q24 TNDM is warranted following remission.
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http://dx.doi.org/10.1515/jpem-2014-0031DOI Listing
November 2014

Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

PLoS One 2014 19;9(5):e98054. Epub 2014 May 19.

Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; Institute of Child Health, University College London, London, United Kingdom.

Context: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency.

Setting: International referral centre for the management of CHI.

Patients: Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012.

Intervention: Near-total pancreatectomy.

Main Outcome Measures: Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency.

Results: Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g). Clinical exocrine insufficiency was observed in 22 (49%) patients. No statistically significant difference in weight and height standard deviation score (SDS) was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients.

Conclusions: The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098054PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026387PMC
January 2015

Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning.

Clin Endocrinol (Oxf) 2014 Dec 19;81(6):847-54. Epub 2014 May 19.

Institut für experimentelle pädiatrische Endokrinologie, Charité Universitätsmedizin, Berlin, Germany.

Context: Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI.

Objective: The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI.

Design: A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK.

Results: In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery.

Conclusions: Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.
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http://dx.doi.org/10.1111/cen.12473DOI Listing
December 2014

Clinical characteristics and phenotype-genotype analysis in Turkish patients with congenital hyperinsulinism; predominance of recessive KATP channel mutations.

Eur J Endocrinol 2014 Jun 31;170(6):885-92. Epub 2014 Mar 31.

Departments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, TurkeyDepartments of NeonatologyPaediatric EndocrinologyGreat Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UKDevelopmental Endocrinology Research GroupMolecular Genetics Unit, The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKDepartments of Paediatric EndocrinologyAnkara Children's Hematology and Oncology Training Hospital, Ankara, TurkeyDepartments of Paediatric EndocrinologyChildren State Hospital, Diyarbakır, TurkeyDepartments of Paediatric EndocrinologyInönü University, Malatya, TurkeyDepartments of Paediatric EndocrinologyYüzüncü Yıl University, Van, TurkeyInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UKDepartment of Medical Biology and GeneticsDicle University, Diyarbakır, Turkey

Objective: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype-phenotype correlations and describe the treatment outcome of Turkish CHI patients.

Design And Methods: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected.

Results: Diazoxide unresponsiveness was observed in nearly half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype-phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001).Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate-rich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients.

Conclusions: This is the largest study to report genotype-phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.
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http://dx.doi.org/10.1530/EJE-14-0045DOI Listing
June 2014

Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia.

N Engl J Med 2014 Mar;370(12):1131-7

From the Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, University College London (S.S., P.S., V.A., K.H.), and the Departments of Paediatric Endocrinology (S.S., P.S., V.A., K.H.) and Histopathology (D.P., M.A.), Great Ormond Street Hospital for Children, London, and the Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter (S.F., S.E.) - all in the United Kingdom; the Department of Pathology, University of California, San Francisco, San Francisco (S.A.); and the Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston (N.T., R.E.B.).

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 μg per kilogram per day). All the patients had a clear glycemic response to sirolimus, although one patient required a small dose of octreotide to maintain normoglycemia. There were no major adverse events during 1 year of follow-up.
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http://dx.doi.org/10.1056/NEJMoa1310967DOI Listing
March 2014

Insulinoma in childhood: clinical, radiological, molecular and histological aspects of nine patients.

Eur J Endocrinol 2014 May 10;170(5):741-7. Epub 2014 Apr 10.

Pediatric Endocrinology, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.

Background: Insulinomas are a rare cause of hyperinsulinaemic hypoglycaemia (HH) in children. The clinical features, investigations, management and histology of these rare pancreatic tumours in children have not been described in a large cohort of patients.

Methods: We conducted a retrospective review of cases diagnosed between 2000 and 2012, presenting to two referral centres in the United Kingdom. Clinical, biochemical, imaging (magnetic resonance imaging (MRI) and 6-L-¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-DOPA) PET/CT scanning) and histological data were collected.

Results: Nine children (age range 2-14.5 years) were diagnosed during the study period at Great Ormond Street Hospital (n=5) and Royal Manchester Children's Hospital (n=4). The combination of abdominal MRI scan (7/8) and ¹⁸F-DOPA PET/CT scan (2/4) correctly localised the anatomical location of all insulinomas. Before surgery, diazoxide therapy was used to treat hypoglycaemia, but only four patients responded. After surgical resection of the insulinoma, hypoglycaemia resolved in all patients. The anatomical localisation of the insulinoma in each patient was head (n=4), uncinate process (n=4) and tail (n=2, one second lesion) of the pancreas. Histology confirmed the diagnosis of insulinoma with the presence of sheets and trabeculae of epithelioid and spindle cells staining strongly for insulin and proinsulin, but not for glucagon or somatostatin. Two children were positive for MEN1, one of whom had two separate insulinoma lesions within the pancreas.

Conclusions: We describe a cohort of paediatric insulinoma patients. Although rare, insulinomas should be included in the differential diagnosis of HH, even in very young children. In the absence of a single imaging modality in the preoperative period, localisation of the tumour is achieved by combining imaging techniques, both conventional and functional.
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http://dx.doi.org/10.1530/EJE-13-1008DOI Listing
May 2014

Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia.

J Clin Endocrinol Metab 2014 Feb 27;99(2):391-4. Epub 2013 Nov 27.

London Centre for Paediatric Endocrinology (V.B.A., K.H.), Great Ormond Street Hospital for Children National Health Service Foundation Trust, London WC1N 3JH, United Kingdom; The Institute of Child Health (V.B.A., K.H.), University College London, London WC1N 1EH, United Kingdom; Institute of Biomedical and Clinical Science (S.E.F., S.E.), University of Exeter Medical School, Exeter EX2 5DW, United Kingdom; and Department of Pediatrics (E.S., B.R.-M.), Medical University of Vienna, 1090 Vienna, Austria.

Background: Hyperinsulinemic hypoglycemia (HH), characterized by unregulated insulin secretion, is an important cause of persistent and severe hypoglycemia. The biochemical picture of HH is hypoketotic hypo-fatty-acidemic hypoglycemia along with elevated serum insulin. Not infrequently, serum insulin might be undetectable in HH despite the presence of evidence of insulin action (suppressed ketogenesis and lipolysis). However, autonomous activity of the downstream insulin signaling pathway without the presence of the ligand (insulin) will give rise to the same clinical and biochemical picture, apart from undetectable serum insulin/C-peptide. AKT2, a serine/threonine protein kinase, is involved downstream to the insulin receptor in mediating the physiological effects of insulin.

Aim: We describe the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypoglycemia.

Patients And Methods: The proband presented with hemihypertrophy and symptomatic hypoglycemia. Investigations confirmed evidence of insulin action, despite absence of detectable serum insulin on multiple occasions. Molecular genetic testing for common causes of HH (ABCC8, KCNJ11, and GLUD1) was negative. Sequencing of AKT2 identified a de novo mosaic c.49G→A (p.E17K) mutation, consistent with the clinical and biochemical phenotype.

Conclusions: This is the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypo-fatty-acidemic hypoglycemia. In patients presenting a clinical and biochemical picture of HH with undetectable serum insulin, consideration of autonomous activation of the downstream insulin signaling pathway should be made.
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http://dx.doi.org/10.1210/jc.2013-3228DOI Listing
February 2014

Neonatal hypoglycemia.

Indian J Pediatr 2014 Jan 1;81(1):58-65. Epub 2013 Aug 1.

Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London Centre for Pediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK.

Glucose is essential for cerebral metabolism. Unsurprisingly therefore, hypoglycemia may result in encephalopathy. Knowledge of the homeostatic mechanisms that maintain blood glucose concentrations within a tight range is the key for diagnosis and appropriate management of hypoglycemia. Neonatal hypoglycemia can be transient and is commonly observed in at-risk infants. A wide range of rare endocrine and metabolic disorders can present with neonatal hypoglycemia, of which congenital hyperinsulinism is responsible for the most severe form of hypoglycemia. Collection of appropriate blood samples for hormones and intermediary metabolites during an episode of hypoglycemia is critical for diagnosis and appropriate management. Prompt diagnosis with aggressive early intervention remains the mainstay of treatment to avert irreversible brain damage.
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http://dx.doi.org/10.1007/s12098-013-1135-3DOI Listing
January 2014

The molecular mechanisms, diagnosis and management of congenital hyperinsulinism.

Indian J Endocrinol Metab 2013 Jan;17(1):19-30

Department of Pediatric Endocrinology, Great Ormond Street Hospital for Children NHS Trust WC1N 3JH and Institute of Child Health, University College London, WC1N 1EH, United Kingdom.

Congenital hyperinsulinism (CHI) is the result of unregulated insulin secretion from the pancreatic β-cells leading to severe hypoglycaemia. In these patients it is important to make an accurate diagnosis and initiate the appropriate management so as to avoid hypoglycemic episodes and prevent the potentially associated complications like epilepsy, neurological impairment and cerebral palsy. At a genetic level abnormalities in eight different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) have been reported with CHI. Loss of function mutations in ABCC8/KCNJ11 lead to the most severe forms of CHI which are usually medically unresponsive. At a histological level there are two major subgroups, diffuse and focal, each with a different genetic etiology. The focal form is sporadic in inheritance and is localized to a small region of the pancreas whereas the diffuse form is inherited in an autosomal recessive (or dominant) manner. Imaging using a specialized positron emission tomography scan with the isotope fluroine-18 L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET-CT) is used to accurately locate the focal lesion pre-operatively and if removed can cure the patient from hypoglycemia. Understanding the molecular mechanisms, the histological basis, improvements in imaging modalities and surgical techniques have all improved the management of patients with CHI.
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http://dx.doi.org/10.4103/2230-8210.107822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659902PMC
January 2013

Prematurity, macrosomia, hyperinsulinaemic hypoglycaemia and a dominant ABCC8 gene mutation.

BMJ Case Rep 2013 Apr 5;2013. Epub 2013 Apr 5.

Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Congenital hyperinsulinism (CHI) is a rare cause of hyperinsulinaemic hypoglycaemia (HH) and is due to an inappropriate secretion of insulin by the pancreatic β-cells. Genetic defects in key genes lead to dysregulated insulin secretion and consequent hypoglycaemia. Mutations in the genes ABCC8/KCNJ11, encoding SUR1/Kir6.2 components of the K(ATP) channels, respectively, are the commonest cause of CHI. A 33(+6) week gestation male infant weighing 3.38 kg (above 90th centile) presented with severe neonatal symptomatic hypoglycaemia. He required a glucose infusion rate of 20 mg/kg/min to maintain normoglycaemia (blood glucose levels at >3.5 mmol/l). Investigations established the diagnosis of HH (blood glucose 2.2 mmol/l with simultaneous insulin of 97.4 mU/l). Subsequent molecular genetic studies identified a heterozygous pathogenic ABCC8 missense mutation, p.R1353H (c.4058G>A), inherited from an unaffected mother. His HH was diazoxide responsive and resolved within 3 months of life.
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http://dx.doi.org/10.1136/bcr-2013-008767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645779PMC
April 2013

Clinical and molecular characterisation of hyperinsulinaemic hypoglycaemia in infants born small-for-gestational age.

Arch Dis Child Fetal Neonatal Ed 2013 Jul 29;98(4):F356-8. Epub 2013 Jan 29.

Developmental Endocrinology Research Group, Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London, UK.

Objective: To characterise the phenotype and genotype of neonates born small-for-gestational age (SGA; birth weight <10th centile) who developed hyperinsulinaemic hypoglycaemia (HH).

Methods: Clinical information was prospectively collected on 27 SGA neonates with HH, followed by sequencing of KCNJ11 and ABCC8.

Results: There was no correlation between the maximum glucose requirement and serum insulin levels. Serum insulin level was undetectable in five infants (19%) during hypoglycaemia. Six infants (22%) required diazoxide treatment >6 months. Normoglycaemia on diazoxide <5 mg/kg/day was a safe predictor of resolved HH. Sequencing of KCNJ11/ABCC8 did not identify any mutations.

Conclusions: Serum insulin levels during hypoglycaemia taken in isolation can miss the diagnosis of HH. SGA infants may continue to have hypofattyacidaemic hypoketotic HH beyond the first few weeks of life. Recognition and treatment of this group of patients are important and may have important implications for neurodevelopmental outcome of these patients.
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http://dx.doi.org/10.1136/archdischild-2012-302880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686249PMC
July 2013

Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.

Eur J Endocrinol 2013 Apr 15;168(4):557-64. Epub 2013 Mar 15.

London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, The Institute of Child Health, University College London, London, UK.

Background: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI.

Aim: To characterise the clinical and molecular aspects of a large cohort of patients with CHI.

Methodology: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A).

Results: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3).

Conclusions: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.
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http://dx.doi.org/10.1530/EJE-12-0673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599069PMC
April 2013

Hyperinsulinaemic hypoglycaemia:genetic mechanisms, diagnosis and management.

J Clin Res Pediatr Endocrinol 2012 Dec 2;4(4):169-81. Epub 2012 Oct 2.

University College London, Institue of Child Health, Developmental Endocrinology Research Clinical, Molecular Genetics Unit, London, United Kingdom.

Hyperinsulinaemic hypoglycaemia (HH) is characterized by unregulated insulin secretion from pancreatic β-cells. Untreated hypoglycaemia in infants can lead to seizures, developmental delay, and subsequent permanent brain injury. Early identification and meticulous managementof these patients is vital to prevent neurological insult. Mutations in eight different genes (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1, HNF4A and UCP2) have been identified to date in patients with congenital forms of hyperinsulinism (CHI). The most severe forms of CHI are due to mutations in ABCC8 and KCJN11, which encode the two components of pancreatic β-cell ATP-sensitive potassium channel. Recent advancement in understanding the genetic aetiology, histological characterisation into focal and diffuse variety combined with improved imaging (such as fluorine 18 L-3, 4-dihydroxyphenylalanine positron emission tomography 18F-DOPA-PET scanning) and laparoscopic surgical techniques have greatly improved management. In adults, HH can be due to an insulinoma, pancreatogenous hypoglycaemic syndrome, post gastric-bypass surgery for morbid obesity as well as to mutations in insulin receptor gene. This review provides an overview of the molecular basis of CHI and outlines the clinical presentation, diagnostic criteria, and management of these patients.
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http://dx.doi.org/10.4274/jcrpe.821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537282PMC
December 2012