Clinical Overview > Topic > Paediatric endocrinology

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Yang Timothy Du Endocrine and Metabolic Unit, Royal Adelaide Hospital

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Lynette Moore School of Medicine, University of Adelaide
SA Pathology, Women’s and Children’s Hospital

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Nicola K Poplawski Adult Genetics Unit, Royal Adelaide Hospital

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Sunita M C De Sousa Endocrine and Metabolic Unit, Royal Adelaide Hospital
School of Medicine, University of Adelaide
Adult Genetics Unit, Royal Adelaide Hospital
Center for Cancer Biology, SA Pathology and University of South Australia Alliance, Adelaide, South Australia, Australia

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Summary

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology.

Learning points:

  • Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history.

  • Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management.

  • Identification of a genetic disorder may have important implications for family planning.

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Suguru Watanabe Department of Pediatrics, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan
Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

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Jun Kido Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

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Mika Ogata Department of Pediatrics, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan

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Kimitoshi Nakamura Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

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Tomoyuki Mizukami Department of Pediatrics, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan

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Summary

Hyperglycemic hyperosmolar state (HHS) and diabetic ketoacidosis (DKA) are the most severe acute complications of diabetes mellitus (DM). HHS is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis. A 14-year-old Japanese boy presented at the emergency room with lethargy, polyuria and polydipsia. He belonged to a baseball club team and habitually drank sugar-rich beverages daily. Three weeks earlier, he suffered from lassitude and developed polyuria and polydipsia 1 week later. He had been drinking more sugar-rich isotonic sports drinks (approximately 1000–1500 mL/day) than usual (approximately 500 mL/day). He presented with HHS (hyperglycemia (1010 mg/dL, HbA1c 12.3%) and mild hyperosmolality (313 mOsm/kg)) without acidosis (pH 7.360), severe ketosis (589 μmol/L) and ketonuria. He presented HHS in type 1 diabetes mellitus (T1DM) with elevated glutamate decarboxylase antibody and islet antigen 2 antibody. Consuming beverages with high sugar concentrations caused hyperglycemia and further exacerbates thirst, resulting in further beverage consumption. Although he recovered from HHS following intensive transfusion and insulin treatment, he was significantly sensitive to insulin therapy. Even the appropriate amount of insulin may result in dramatically decreasing blood sugar levels in patients with T1DM. We should therefore suspect T1DM in patients with HHS but not those with obesity. Moreover, age, clinical history and body type are helpful for identifying T1DM and HHS. Specifically, drinking an excess of beverages rich in sugars represents a risk of HHS in juvenile/adolescent T1DM patients.

Learning points:

  • Hyperglycemic hyperosmolar state (HHS) is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis.

  • The discrimination between HHS of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in initial presentation is difficult.

  • Pediatrician should suspect T1DM in patients with HHS but not obesity.

  • Age, clinical history and body type are helpful for identifying T1DM and HHS.

  • Children with T1DM are very sensitive to insulin treatment, and even appropriate amount of insulin may result in dramatically decreasing blood sugar levels.

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Saurabh Uppal Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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James Blackburn Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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Mohammed Didi Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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Rajeev Shukla Departments of Pathology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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James Hayden Departments of Oncology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

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Senthil Senniappan Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
Institute of Child Health, University of Liverpool, Liverpool, UK

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Summary

Beckwith–Wiedemann syndrome (BWS) can be associated with embryonal tumours and congenital hyperinsulinism (CHI). We present an infant with BWS who developed congenital hepatoblastoma and Wilms’ tumour during infancy. The infant presented with recurrent hypoglycaemia requiring high intravenous glucose infusion and was biochemically confirmed to have CHI. He was resistant to diazoxide but responded well to octreotide and was switched to Lanreotide at 1 year of age. Genetic analysis for mutations of ABCC8 and KCNJ11 were negative. He had clinical features suggestive of BWS. Methylation-sensitive multiplex ligation-dependent probe amplification revealed hypomethylation at KCNQ1OT1:TSS-DMR and hypermethylation at H19 /IGF2:IG-DMR consistent with mosaic UPD(11p15). Hepatoblastoma was detected on day 4 of life, which was resistant to chemotherapy, requiring surgical resection. He developed Wilms’ tumour at 3 months of age, which also showed poor response to induction chemotherapy with vincristine and actinomycin D. Surgical resection of Wilms’ tumour was followed by post-operative chemotherapy intensified with cycles containing cyclophosphamide, doxorubicin, carboplatin and etoposide, in addition to receiving flank radiotherapy. We report, for the first time, an uncommon association of hepatoblastoma and Wilms’ tumour in BWS in early infancy. Early onset tumours may show resistance to chemotherapy. UPD(11p15) is likely associated with persistent CHI in BWS.

Learning points:

  • Long-acting somatostatin analogues are effective in managing persistent CHI in BWS.

  • UPD(11)pat genotype may be a pointer to persistent and severe CHI.

  • Hepatoblastoma and Wilms’ tumour may have an onset within early infancy and early tumour surveillance is essential.

  • Tumours associated with earlier onset may be resistant to recognised first-line chemotherapy.

Open access
Sarah Kiff Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Department of Endocrinology, Royal Hospital for Sick Children, Edinburgh, UK

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

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Maria Guemes Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, Great Institute of Child Health, University College London, London, UK

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

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

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Sarah E Flanagan Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

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Sian Ellard Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

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John Barton Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, UK

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M Dattani Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, Great Institute of Child Health, University College London, London, UK

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Pratik Shah Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK
Genetics and Genomic Medicine Programme, Great Institute of Child Health, University College London, London, UK

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Summary

We report a case of partial diazoxide responsiveness in a child with severe congenital hyperinsulinaemic hypoglycaemia (CHI) due to a homozygous ABCC8 mutation. A term baby, with birth weight 3.8 kg, born to consanguineous parents presented on day 1 of life with hypoglycaemia. Hypoglycaemia screen confirmed CHI. Diazoxide was commenced on day 7 due to ongoing elevated glucose requirements (15 mg/kg/min), but despite escalation to a maximum dose (15 mg/kg/day), intravenous (i.v.) glucose requirement remained high (13 mg/kg/min). Genetic testing demonstrated a homozygous ABCC8 splicing mutation (c.2041-1G>C), consistent with a diffuse form of CHI. Diazoxide treatment was therefore stopped and subcutaneous (s.c.) octreotide infusion commenced. Despite this, s.c. glucagon and i.v. glucose were required to prevent hypoglycaemia. A trial of sirolimus and near-total pancreatectomy were considered, however due to the significant morbidity potentially associated with these, a further trial of diazoxide was commenced at 1.5 months of age. At a dose of 10 mg/kg/day of diazoxide and 40 µg/kg/day of octreotide, both i.v. glucose and s.c. glucagon were stopped as normoglycaemia was achieved. CHI due to homozygous ABCC8 mutation poses management difficulties if the somatostatin analogue octreotide is insufficient to prevent hypoglycaemia. Diazoxide unresponsiveness is often thought to be a hallmark of recessively inherited ABCC8 mutations. This patient was initially thought to be non-responsive, but this case highlights that a further trial of diazoxide is warranted, where other available treatments are associated with significant risk of morbidity.

Learning points:

  • Homozygous ABCC8 mutations are commonly thought to cause diazoxide non-responsive hyperinsulinaemic hypoglycaemia.

  • This case highlights that partial diazoxide responsiveness in homozygous ABCC8 mutations may be present.

  • Trial of diazoxide treatment in combination with octreotide is warranted prior to considering alternative treatments, such as sirolimus or near-total pancreatectomy, which are associated with more significant side effects.

Open access
N Chelaghma Department of Endocrinology, Peterborough City Hospital, Peterborough, UK

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J Rajkanna Department of Endocrinology, Peterborough City Hospital, Peterborough, UK

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J Trotman East Midlands and East of England NHS Genomic Laboratory Hub, Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

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G Fuller East Midlands and East of England NHS Genomic Laboratory Hub, Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

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T Elsey East Midlands and East of England NHS Genomic Laboratory Hub, Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

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SM Park Department of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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SO Oyibo Department of Endocrinology, Peterborough City Hospital, Peterborough, UK

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Summary

Hypogonadotrophic hypogonadism is due to impaired or reduced gonadotrophin secretion from the pituitary gland. In the absence of any anatomical or functional lesions of the pituitary or hypothalamic gland, the hypogonadotrophic hypogonadism is referred to as idiopathic hypogonadotrophic hypogonadism (IHH). We present a case of a young lady born to consanguineous parents who was found to have IHH due to a rare gene mutation.

Learning points:

  • The genetic basis of a majority of cases of IHH remains unknown.

  • IHH can have different clinical endocrine manifestations.

  • Patients can present late to the healthcare service because of unawareness and stigmata associated with the clinical features.

  • Family members of affected individuals can be affected to varying degrees.

Open access
Avinash Suryawanshi Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, New South Wales, 2139, Australia
Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia

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Timothy Middleton Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, New South Wales, 2139, Australia
Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia

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Kirtan Ganda Department of Endocrinology and Metabolism, Concord Repatriation General Hospital, Concord, New South Wales, 2139, Australia
Concord Clinical School, The University of Sydney, Sydney, New South Wales, 2139, Australia

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Summary

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic condition caused by mutations in the ABCD1 gene that result in accumulation of very long chain fatty acids (VLCFAs) in various tissues. This leads to demyelination in the CNS and impaired steroidogenesis in the adrenal cortex and testes. A 57-year-old gentleman was referred for the assessment of bilateral gynaecomastia of 6 months duration. He had skin hyperpigmentation since 4 years of age and spastic paraparesis for the past 15 years. Physical examination findings included generalised hyperpigmentation (including skin, buccal mucosa and palmar creases), blood pressure of 90/60 mmHg, non-tender gynaecomastia and bilateral hypoplastic testes. Lower limb findings were those of a profoundly ataxic gait associated with significant paraparesis and sensory loss. Primary adrenal insufficiency was confirmed and investigations for gynaecomastia revealed normal testosterone with mildly elevated luteinising hormone level and normal prolactin. The combination of primary adrenal insufficiency (likely childhood onset), partial testicular failure (leading to gynaecomastia) and spastic paraparesis suggested X-ALD as a unifying diagnosis. A serum VLCFA panel was consistent with X-ALD. Subsequent genetic testing confirmed the diagnosis. Treatment with replacement doses of corticosteroid resulted in improvement in blood pressure and increased energy levels. We have reported the case of a 57-year-old man with a very late diagnosis of X-ALD manifested by childhood onset of primary adrenal insufficiency followed by paraparesis and primary hypogonadism in adulthood. Thus, X-ALD should be considered as a possibility in a patient with non-autoimmune primary adrenal insufficiency and neurological abnormalities.

Learning points

  • Adult patients with X-ALD may be misdiagnosed as having multiple sclerosis or idiopathic spastic paraparesis for many years before the correct diagnosis is identified.

  • Screening for X-ALD with a VLCFA panel should be strongly considered in male children with primary adrenal insufficiency and in male adults presenting with non-autoimmune primary adrenal insufficiency.

  • Confirmation of a genetic diagnosis of X-ALD can be very useful for a patient's family as genetic testing enables detection of pre-symptomatic female heterozygotes who can then be offered pre-natal testing to avoid transmission of the disease to male offsprings.

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Maura Bucciarelli Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA

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Ya-Yu Lee Division of Endocrinology, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA

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Vasudev Magaji Division of Endocrinology, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, 18103, USA

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Summary

Ectopic ACTH secretion from breast cancer is extremely rare. We report a case of a 30-year-old woman with a history of breast cancer, who presented with psychosis and paranoid behaviour. CT of the head showed white matter disease consistent with posterior reversible encephalopathy syndrome (PRES). Despite using mifepristone with multiple antihypertensives including lisinopril, spironolactone and metoprolol, she was hypertensive. Transaminitis did not allow mifepristone dose escalation and ketoconazole utilization. Etomidate infusion at a non-sedating dose in the intensive care unit controlled her hypertension and cortisol levels. She was transitioned to metyrapone and spironolactone. She was discharged from the hospital on metyrapone with spironolactone and underwent chemotherapy. She died 9 months later after she rapidly redeveloped Cushing's syndrome and had progressive metastatic breast cancer involving multiple bones, liver and lungs causing respiratory failure.

Learning points

  • Cushing's syndrome from ectopic ACTH secreting breast cancer is extremely rare.

  • Cushing's syndrome causing psychosis could be multifactorial including hypercortisolism and PRES.

  • Etomidate at non-sedating doses in intensive care setting can be effective to reduce cortisol production followed by transition to oral metyrapone.

Open access
Suresh Chandran Departments of Neonatology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Fabian Yap Kok Peng Paediatric Endocrinology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Victor Samuel Rajadurai Departments of Neonatology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Yap Te Lu Paediatric Surgery, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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Kenneth T E Chang Children's Pathology, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

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S E Flanagan Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK

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S Ellard Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK

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Khalid Hussain Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK

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Summary

background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia.

Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation.

Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease.

Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.

Learning points

  • HH is a cause of severe hypoglycaemia in the newborn period.

  • Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease.

  • 18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions.

  • Gallium-68 tetra-aza-cyclododecane-N NNN-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions.

  • The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear.

  • Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.

Open access