Browse

You are looking at 1 - 10 of 20 items

Christina Lee Department of Pediatrics, University of Maryland Children’s Hospital, Baltimore, Maryland, USA

Search for other papers by Christina Lee in
Google Scholar
PubMed
Close
,
Leah Hirschman Department of Pediatrics, University of Maryland Children’s Hospital, Baltimore, Maryland, USA

Search for other papers by Leah Hirschman in
Google Scholar
PubMed
Close
,
Teresa York Department of Pediatric Hematology/Oncology, University of Maryland Children’s Hospital, Baltimore, Maryland, USA

Search for other papers by Teresa York in
Google Scholar
PubMed
Close
, and
Paula Newton Department of Pediatric Endocrinology, University of Maryland Children’s Hospital, Baltimore, Maryland, USA

Search for other papers by Paula Newton in
Google Scholar
PubMed
Close

Summary

Neonatal adrenal hemorrhage (NAH) occurs in up to 3% of infants and is the most common adrenal mass in newborns. The most common presentation of NAH is an asymptomatic palpable flank mass which resolves over time without intervention. In rare cases, NAH can present as hemorrhage, shock, or adrenal insufficiency. This case describes a preterm infant born with severe anemia in the setting of bilateral adrenal hemorrhages with resulting adrenal insufficiency. The infant was successfully treated with blood transfusions and steroids. This is a unique presentation of NAH as it was bilateral, presented with severe anemia, and resulted in prolonged adrenal insufficiency.

Learning points

  • Consider adrenal hemorrhage for cases of severe anemia at birth.

  • Adrenal insufficiency is a rare complication of adrenal hemorrhage.

  • Adrenal recovery can take months, if not years.

Open access
Ashwini Maudhoo Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Search for other papers by Ashwini Maudhoo in
Google Scholar
PubMed
Close
,
Avinaash Maharaj Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Search for other papers by Avinaash Maharaj in
Google Scholar
PubMed
Close
,
Federica Buonocore Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

Search for other papers by Federica Buonocore in
Google Scholar
PubMed
Close
,
Gabriel Angel Martos-Moreno Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

Search for other papers by Gabriel Angel Martos-Moreno in
Google Scholar
PubMed
Close
,
Jesús Argente Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
CEI UAM + CSIC, IMDEA Food Institute, Madrid, Spain

Search for other papers by Jesús Argente in
Google Scholar
PubMed
Close
,
John C Achermann Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

Search for other papers by John C Achermann in
Google Scholar
PubMed
Close
,
Li F Chan Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Search for other papers by Li F Chan in
Google Scholar
PubMed
Close
, and
Lou A Metherell Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Search for other papers by Lou A Metherell in
Google Scholar
PubMed
Close

Summary

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8–26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7–48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10−5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient.

Learning points

  • Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases.

  • In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing.

  • Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.

Open access
Katsuo Tao Department of Pediatrics, Fukui Aiiku Hospital, Fukui, Japan

Search for other papers by Katsuo Tao in
Google Scholar
PubMed
Close
,
Midori Awazu Department of Pediatrics, Keio University School of Medicine, shinjyuku, Tokyo, Japan

Search for other papers by Midori Awazu in
Google Scholar
PubMed
Close
,
Misa Honda Department of Pediatrics, Keio University School of Medicine, shinjyuku, Tokyo, Japan

Search for other papers by Misa Honda in
Google Scholar
PubMed
Close
,
Hironori Shibata Department of Pediatrics, Keio University School of Medicine, shinjyuku, Tokyo, Japan

Search for other papers by Hironori Shibata in
Google Scholar
PubMed
Close
,
Takayasu Mori Department of Nephrology, Tokyo Medical and Dental University, Fukui, Japan

Search for other papers by Takayasu Mori in
Google Scholar
PubMed
Close
,
Shinichi Uchida Department of Nephrology, Tokyo Medical and Dental University, Fukui, Japan

Search for other papers by Shinichi Uchida in
Google Scholar
PubMed
Close
,
Tomonobu Hasegawa Department of Pediatrics, Keio University School of Medicine, shinjyuku, Tokyo, Japan

Search for other papers by Tomonobu Hasegawa in
Google Scholar
PubMed
Close
, and
Tomohiro Ishii Department of Pediatrics, Keio University School of Medicine, shinjyuku, Tokyo, Japan

Search for other papers by Tomohiro Ishii in
Google Scholar
PubMed
Close

Summary

We report a male infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypercalcemia and hyperphosphatemia since birth. Serum sodium started to increase at 39 days. Although there was no polyuria, urine osmolality was 71 mOsm/kg, when serum osmolality was 296 mOsm/kg with plasma arginine vasopressin 22.5 pg/mL. He was thus diagnosed as NDI. An undetectable level of urine calcium and unsuppressed intact parathyroid hormone suggested hyperparathyroidism including calcium-sensing receptor mutations that could cause hypercalcemia-induced NDI. Polyuria became apparent after the initiation of i.v. infusion for the treatment of hypernatremia. Low calcium and low sodium formula with hypotonic fluid infusion did not correct hypernatremia, hypercalcemia, or hyperphosphatemia. Hydrochlorothiazide and subsequently added celecoxib effectively decreased urine output and corrected electrolytes abnormalities. Normal serum electrolytes were maintained after the discontinuation of low calcium formula. The genetic analysis revealed a large deletion of the arginine vasopressin receptor-2 (AVPR2) gene but no pathogenic variant in the calcium-sensing receptor (CASR) gene. Whether hypercalcemia and hyperphosphatemia were caused by dehydration alone or in combination with other mechanisms remains to be clarified.

Learning points

  • Congenital NDI can present with neonatal hypercalcemia and hyperphosphatemia.

  • Hypercalcemia and hyperphosphatemia can be treated with low calcium and low sodium formula, hydration, hydrochlorothiazide, and celecoxib.

  • Genetic testing is sometimes necessary in the differentiating diagnosis of hypercalcemia associated with NDI.

Open access
Ellada Sotiridou Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by Ellada Sotiridou in
Google Scholar
PubMed
Close
,
Henrike Hoermann Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany

Search for other papers by Henrike Hoermann in
Google Scholar
PubMed
Close
,
Sommayya Aftab Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by Sommayya Aftab in
Google Scholar
PubMed
Close
,
Antonia Dastamani Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by Antonia Dastamani in
Google Scholar
PubMed
Close
,
Eva Thimm Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany

Search for other papers by Eva Thimm in
Google Scholar
PubMed
Close
,
Louise Doodson Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by Louise Doodson in
Google Scholar
PubMed
Close
,
Spyros Batzios Metabolic Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by Spyros Batzios in
Google Scholar
PubMed
Close
,
Sebastian Kummer Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany

Search for other papers by Sebastian Kummer in
Google Scholar
PubMed
Close
, and
Pratik Shah Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
Endocrinology Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK

Search for other papers by Pratik Shah in
Google Scholar
PubMed
Close

Summary

Tyrosinaemia type 1 (TT1) is a rare inherited disorder of amino acid metabolism typically presenting with liver failure and renal tubular dysfunction. We describe three individuals with TT1 and transient hyperinsulinaemic hypoglycaemia (HH). Two siblings with TT1 and acute liver dysfunction were diagnosed with hyperinsulinaemic hypoglycaemia in the neonatal period. Both siblings were successfully treated with diazoxide/chlorthiazide and treatment was gradually weaned and stopped after 8 and 6 months of age respectively. The third patient presented with a neonatal liver failure with mild cholestasis, coagulopathy, fundus haemorrhages, vitamin A and E deficiency and hyperinsulinaemic hypoglycaemia. He maintained euglycaemia on high dose diazoxide (5–12 mg/kg/day) but developed pulmonary hypertension at 12 weeks of age. After discontinuation of diazoxide, he continued maintaining his blood glucose (BG) within the normal range. Although histological abnormalities of the pancreas including beta-cell hyperplasia are well documented, the exact mechanism of excessive insulin secretion in TT1 is not well understood. It may be related to the accumulation of toxic metabolites in the target organs including pancreas. Therefore, in patients with TT1 and persistent hypoglycaemia beyond the recovery of the acute liver failure, it is important to exclude hyperinsulinism which is usually transient and can be successfully treated with diazoxide and chlorothiazide. Further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Learning points:

  • Every child with TT1 should be monitored for signs and symptoms of hypoglycaemia and screened for HH at the time of real hypoglycaemia.

  • If hypoglycaemic episodes persist even after improvement of liver function, hyperinsulinism should be suspected.

  • Treatment with diazoxide is effective, however, children need to be monitored closely for possible side effects.

  • The pathophysiological mechanism of hyperinsulinism in children with TT1 is not elucidated yet and further studies are required to determine which factors contribute to excessive insulin secretion in patients with TT1.

Open access
Daphne Yau Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Daphne Yau in
Google Scholar
PubMed
Close
,
Maria Salomon-Estebanez Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Maria Salomon-Estebanez in
Google Scholar
PubMed
Close
,
Amish Chinoy Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Amish Chinoy in
Google Scholar
PubMed
Close
,
John Grainger Departments of Paediatric Haematology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by John Grainger in
Google Scholar
PubMed
Close
,
Ross J Craigie Departments of Paediatric Surgery, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Ross J Craigie in
Google Scholar
PubMed
Close
,
Raja Padidela Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Raja Padidela in
Google Scholar
PubMed
Close
,
Mars Skae Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Mars Skae in
Google Scholar
PubMed
Close
,
Mark J Dunne Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

Search for other papers by Mark J Dunne in
Google Scholar
PubMed
Close
,
Philip G Murray Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Philip G Murray in
Google Scholar
PubMed
Close
, and
Indraneel Banerjee Departments of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK

Search for other papers by Indraneel Banerjee in
Google Scholar
PubMed
Close

Summary

Congenital hyperinsulinism (CHI) is an important cause of severe hypoglycaemia in infancy. To correct hypoglycaemia, high concentrations of dextrose are often required through a central venous catheter (CVC) with consequent risk of thrombosis. We describe a series of six cases of CHI due to varying aetiologies from our centre requiring CVC for the management of hypoglycaemia, who developed thrombosis in association with CVC. We subsequently analysed the incidence and risk factors for CVC-associated thrombosis, as well as the outcomes of enoxaparin prophylaxis. The six cases occurred over a 3-year period; we identified an additional 27 patients with CHI who required CVC insertion during this period (n = 33 total), and a separate cohort of patients with CHI and CVC who received enoxaparin prophylaxis (n = 7). The incidence of CVC-associated thrombosis was 18% (6/33) over the 3 years, a rate of 4.2 thromboses/1000 CVC days. There was no difference in the frequency of genetic mutations or focal CHI in those that developed thromboses. However, compound heterozygous/homozygous potassium ATP channel mutations correlated with thrombosis (R 2 = 0.40, P = 0.001). No difference was observed in CVC duration, high concentration dextrose or glucagon infused through the CVC. In patients receiving enoxaparin prophylaxis, none developed thrombosis or bleeding complications. The characteristics of these patients did not differ significantly from those with thrombosis not on prophylaxis. We therefore conclude that CVC-associated thrombosis can occur in a significant proportion (18%) of patients with CHI, particularly in severe CHI, for which anticoagulant prophylaxis may be indicated.

Learning points:

  • CVC insertion is one of the most significant risk factors for thrombosis in the paediatric population.

  • Risk factors for CVC-associated thrombosis include increased duration of CVC placement, malpositioning and infusion of blood products.

  • To our knowledge, this is the first study to evaluate CVC-associated thrombosis in patients with congenital hyperinsulinism (CHI).

  • The incidence of CVC-associated thrombosis development is significant (18%) in CHI patients and higher compared to other neonates with CVC. CHI severity may be a risk factor for thrombosis development.

  • Although effective prophylaxis for CVC-associated thrombosis in infancy is yet to be established, our preliminary experience suggests the safety and efficacy of enoxoaparin prophylaxis in this population and requires on-going evaluation.

Open access
Ved Bhushan Arya Department of Paediatric Endocrinology, Variety Club Children’s Hospital, King’s College Hospital NHS Foundation Trust, London, UK

Search for other papers by Ved Bhushan Arya in
Google Scholar
PubMed
Close
,
Jennifer Kalitsi Department of Paediatric Endocrinology, Variety Club Children’s Hospital, King’s College Hospital NHS Foundation Trust, London, UK

Search for other papers by Jennifer Kalitsi in
Google Scholar
PubMed
Close
,
Ann Hickey Department of Neonatology, King’s College Hospital NHS Foundation Trust, London, UK

Search for other papers by Ann Hickey in
Google Scholar
PubMed
Close
,
Sarah E Flanagan Institute of Biomedical and Clinical Science, University of Exeter, Exeter, UK

Search for other papers by Sarah E Flanagan in
Google Scholar
PubMed
Close
, and
Ritika R Kapoor Department of Paediatric Endocrinology, Variety Club Children’s Hospital, King’s College Hospital NHS Foundation Trust, London, UK

Search for other papers by Ritika R Kapoor in
Google Scholar
PubMed
Close

Summary

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.

Open access
Himangshu S Bose Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
Memorial University Medical Center, Savannah, Georgia, USA

Search for other papers by Himangshu S Bose in
Google Scholar
PubMed
Close
,
Alan M Rice Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
Pediatric Endocrinology and Diabetes Center, Kalispell Regional Medical Center, Kalispell, Montana, USA

Search for other papers by Alan M Rice in
Google Scholar
PubMed
Close
,
Brendan Marshall Anatomy and Pathology, Augusta State University, Augusta, Georgia, USA

Search for other papers by Brendan Marshall in
Google Scholar
PubMed
Close
,
Fadi Gebrail Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA
Laboratory of Pathology, Memorial University Medical Center, Savannah, Georgia, USA

Search for other papers by Fadi Gebrail in
Google Scholar
PubMed
Close
,
David Kupshik Laboratory of Biochemistry, Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA

Search for other papers by David Kupshik in
Google Scholar
PubMed
Close
, and
Elizabeth W Perry Anatomy and Pathology, Augusta State University, Augusta, Georgia, USA

Search for other papers by Elizabeth W Perry in
Google Scholar
PubMed
Close

Summary

Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands. The testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells. Electron microscopy showed that the patient’s testicular mitochondrial size was small with little SCC expression within the mitochondria. The mitochondria were not close to the mitochondria-associated ER membrane (MAM), and cells were filled with the microfilaments. Our result revealed that absence of pregnenolone is associated with organelle stress, leading to altered protein organization that likely created steric hindrance in testicular cells.

Learning points:

  • Testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells;

  • Testicular mitochondrial size was small with little SCC expression within the mitochondria;

  • Absence of pregnenolone is associated with organelle stress.

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

Search for other papers by Saurabh Uppal in
Google Scholar
PubMed
Close
,
James Blackburn Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

Search for other papers by James Blackburn in
Google Scholar
PubMed
Close
,
Mohammed Didi Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

Search for other papers by Mohammed Didi in
Google Scholar
PubMed
Close
,
Rajeev Shukla Departments of Pathology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

Search for other papers by Rajeev Shukla in
Google Scholar
PubMed
Close
,
James Hayden Departments of Oncology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

Search for other papers by James Hayden in
Google Scholar
PubMed
Close
, and
Senthil Senniappan Departments of Paediatric Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
Institute of Child Health, University of Liverpool, Liverpool, UK

Search for other papers by Senthil Senniappan in
Google Scholar
PubMed
Close

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

Search for other papers by Sarah Kiff in
Google Scholar
PubMed
Close
,
Carolyn Babb Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK

Search for other papers by Carolyn Babb in
Google Scholar
PubMed
Close
,
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

Search for other papers by Maria Guemes in
Google Scholar
PubMed
Close
,
Antonia Dastamani Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK

Search for other papers by Antonia Dastamani in
Google Scholar
PubMed
Close
,
Clare Gilbert Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK

Search for other papers by Clare Gilbert in
Google Scholar
PubMed
Close
,
Sarah E Flanagan Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

Search for other papers by Sarah E Flanagan in
Google Scholar
PubMed
Close
,
Sian Ellard Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

Search for other papers by Sian Ellard in
Google Scholar
PubMed
Close
,
John Barton Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, UK

Search for other papers by John Barton in
Google Scholar
PubMed
Close
,
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

Search for other papers by M Dattani in
Google Scholar
PubMed
Close
, and
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

Search for other papers by Pratik Shah in
Google Scholar
PubMed
Close

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
Charlotte S Schömig Department of Pediatrics, University of Cologne, Cologne, Germany

Search for other papers by Charlotte S Schömig in
Google Scholar
PubMed
Close
,
Marie-Ève Robinson Division of Endocrinology, Department of Pediatrics, McGill University Health Center, Montreal, Canada

Search for other papers by Marie-Ève Robinson in
Google Scholar
PubMed
Close
, and
Julia E von Oettingen Division of Endocrinology, Department of Pediatrics, McGill University Health Center, Montreal, Canada

Search for other papers by Julia E von Oettingen in
Google Scholar
PubMed
Close

Summary

Congenital hypothyroidism requires prompt treatment to prevent adverse health outcomes. Poor intestinal levothyroxine absorption can complicate management. We present a case of a term female newborn with necrotizing enterocolitis (NEC) requiring subtotal ileum resection. Congenital hypothyroidism was diagnosed by newborn screening. Treatment was complicated by intestinal malabsorption of levothyroxine. Intravenous levothyroxine substitution restored euthyroidism and supraphysiologic PO doses subsequently maintained a euthyroid state. After several months, the required levothyroxine dose was weaned down to typical recommended dosing. In conclusion, small bowel resection secondary to NEC may lead to malabsorption of oral levothyroxine. An intravenous levothyroxine dose of approximately 50% typical PO dosing is effective in providing rapid normalization of free T4 and TSH. High PO doses may be required to maintain euthyroidism. Close thyroid function monitoring and immediate therapy adjustment are essential as the individual absorption may vary widely. Normal absorption levels may be regained due to adaption of the neonatal intestines.

Learning points:

  • In neonates with malabsorption after ileum resection intravenous levothyroxine replacement should be used to provide normalization of free T4 and TSH.

  • Very high doses of up to 500% usual oral levothyroxine may be required to maintain euthyroidism. The estimated degree of malabsorption can be used to determine the initial dose.

  • Close thyroid function monitoring and immediate therapy adjustment are essential as the absorption and intestinal adaption may vary widely.

Open access