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S Chew Sue Mei Wolfson Diabetes and Endocrine Clinic, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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N Pritchard Department of Renal Medicine, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

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H Grayton Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

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I Simonicova Cambridge Genomics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

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S M Park Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

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A I Adler Wolfson Diabetes and Endocrine Clinic, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
University of Oxford Diabetes Trials Unit, Oxford, UK

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Summary

Kabuki syndrome is a genetic disorder characterised by distinctive facial features, developmental delays, and multisystem congenital anomalies. Endocrine complications such as premature thelarche and short stature are common, whereas disorders of glycaemic control are less frequent. We describe a 23-year-old white female referred to the diabetes clinic for hyperglycaemia during haemodialysis. She was subsequently diagnosed with Kabuki syndrome based on characteristic clinical features, confirmed by detecting a heterozygous pathogenic variant in KMT2D. She was known to have had multiple congenital anomalies at birth, including complex congenital heart disease and a single dysplastic ectopic kidney, and received a cadaveric transplanted kidney at the age of 13. She had hyperglycaemia consistent with post-transplant diabetes mellitus (DM) and was started on insulin. Examination at the time revealed truncal obesity. She developed acute graft rejection and graft failure 14 months post-transplant and she was started on haemodialysis. Her blood glucose levels normalised post-graft explant, but she was hyperglycaemic again during haemodialysis at the age of 23. Given her clinical phenotype, negative diabetes antibodies and normal pancreas on ultrasound, she was assumed to have type 2 DM and achieved good glycaemic control with gliclazide.

Learning points

  • Involve clinical genetics early in the investigative pathway of sick neonates born with multiple congenital anomalies to establish a diagnosis to direct medical care.

  • Consider the possibility of Kabuki syndrome (KS) in the differential diagnoses in any neonate with normal karyotyping or microarray analysis and with multiple congenital anomalies (especially cardiac, renal, or skeletal), dysmorphic facial features, transient neonatal hypoglycaemia and failure to thrive.

  • Consider the possibility of diabetes as an endocrine complication in KS patients who are obese or who have autoimmune disorders.

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Umberto Spennato Medical University Clinic, Division of Endocrinology, Diabetes, and Metabolism, Cantonal Hospital Aarau, Switzerland

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Jennifer Siegwart Medical University Clinic, Division of Endocrinology, Diabetes, and Metabolism, Cantonal Hospital Aarau, Switzerland

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Britta Hartmann Institute for Laboratory Medicine, Division Medical Genetics, Cantonal Hospital Aarau, Switzerland

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Elisabeth Julia Fischer Institute for Laboratory Medicine, Division Medical Genetics, Cantonal Hospital Aarau, Switzerland

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Cecilia Bracco Institute for Laboratory Medicine, Division Medical Genetics, Cantonal Hospital Aarau, Switzerland

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Joel Capraro Medical University Clinic, Division of Endocrinology, Diabetes, and Metabolism, Cantonal Hospital Aarau, Switzerland

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Beat Mueller Medical University Clinic, Division of Endocrinology, Diabetes, and Metabolism, Cantonal Hospital Aarau, Switzerland
Medical Faculty of the University of Basel, Switzerland

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Philipp Schuetz Medical University Clinic, Division of Endocrinology, Diabetes, and Metabolism, Cantonal Hospital Aarau, Switzerland
Medical Faculty of the University of Basel, Switzerland

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Andreas Werner Jehle Department of Internal Medicine, Hirslanden Klinik St. Anna, Lucerne, Switzerland
Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland

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Tristan Struja Medical University Clinic, Division of Endocrinology, Diabetes, and Metabolism, Cantonal Hospital Aarau, Switzerland
Medical Faculty of the University of Basel, Switzerland

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Summary

Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient’s clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated ‘H’ cases without ‘D’ and ‘R’, GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications.

Learning points

  • There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents.

  • Unbiased re-evaluation for possible genetic disorders is necessary at every consultation.

  • It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism.

  • The patient’s clinical presentation and family history can be important to establish the correct diagnosis.

  • Physicians should not hesitate to search a patient’s signs and symptoms online.

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Nele Van Roy Department of Diabetes and Endocrinology, Vitaz, Sint-Niklaas, Belgium

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Sylvester Heerwegh Department of Diabetes and Endocrinology, Vitaz, Sint-Niklaas, Belgium

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Dashty Husein Department of Diabetes and Endocrinology, Vitaz, Sint-Niklaas, Belgium

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Joke Ruys Department of Ophthalmology, Vitaz, Sint-Niklaas, Belgium

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Peter Coremans Department of Diabetes and Endocrinology, Vitaz, Sint-Niklaas, Belgium

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Summary

Bardet–Biedl syndrome (BBS) is a rare, autosomal recessive, multisystem non-motile ciliopathy of progressive onset. It is primarily characterised by rod–cone dystrophy, early-onset obesity and related complications, postaxial polydactyly, renal and genitourinary abnormalities, learning disabilities, and hypogonadism. The diagnosis is based on Beales’ modified diagnostic criteria. We present a case of two monozygotic female twins, 17 years of age at presentation, referred for obesity since childhood. The initial hormonal work-up was negative and no dysmorphic features were noted. They were diagnosed with exogenous obesity. However, after ophthalmologic problems became apparent, rod–cone dystrophy was observed and genetic testing was performed. A mutation in the BBS2 gene led to the diagnosis of BBS, although the full diagnostic criteria were not met. This case not only highlights the need to raise awareness for BBS but also exposes two limitations of the current diagnostic standard. The first limitation is the low sensitivity of the clinical diagnostic model, due to the progressive onset and the high variability of the syndrome. The second limitation is the unclear role of genetic testing. As genetic testing becomes more widely available, genetic diagnosis preceding clinical diagnosis will become more common, leading to a diagnostic conundrum. We propose an update of the diagnostic model. A less strict application in the presence of confirmed genetic mutations should be applied, as this could facilitate earlier diagnosis and intervention. This is important because therapeutic agents are being developed that could have a significant impact on quality of life and prognosis.

Learning points

  • Due to the low prevalence, the significant inter-and intrafamilial variation, and the slowly evolving phenotype, monogenic forms of obesity such as Bardet–Biedl syndrome are difficult to diagnose. Despite advances in the understanding of the presentation, pathophysiology and access to accurate genetic characterisation, a substantial number of diagnoses are still made by ophthalmology, as recognition of BBS in other departments of medicine, remains limited.

  • Clinical diagnosis of BBS is based on Beales’ modified diagnostic criteria which require the presence of four primary features or three primary features plus two secondary features. This model has its limitations. Due to the progressive onset of clinical symptoms, patients generally do not meet the diagnostic criteria early in life, leading to a delay in diagnosis. In addition, the role of genetic testing remains controversial. However, as it becomes more widely available, genetic diagnosis may precede a full clinical diagnosis.

  • BBS has an impact on the quality of life and prognosis of both the patient and the family. Obesity management strategies are an important part of the multidisciplinary approach, as there is no cure available. Setmelanotide has shown promising results in a phase 3 trial, but its effect in clinical practice remains unproven.

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Natalie Below Diabetes Centre, Gartnavel General Hospital, Glasgow, UK
University of Glasgow, Glasgow, UK

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Deborah Morrison Diabetes Centre, Gartnavel General Hospital, Glasgow, UK

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Ruth McGowan West of Scotland Centre for Genomic Medicine, Glasgow, UK

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Gregory C Jones Diabetes Centre, Gartnavel General Hospital, Glasgow, UK

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Summary

A 20-year-old South Asian male presented with polyuria, polydipsia, HbA1c 81 mmol/mol, BMI 28.8 and family history of both type 1 and type 2 diabetes mellitus. As autoantibody testing was negative and c-peptide level demonstrated significant endogenous insulin secretion, type 1 diabetes was excluded. Given his age and family history, the differential diagnosis included maturity-onset diabetes of the young (MODY), a rare form of diabetes caused by a single-gene variant. A high probability of MODY was calculated and he was subsequently referred for genetic testing. Although a useful tool, the pre-test probability calculator for MODY is only validated in White Europeans. A heterogenous variant of unknown clinical significance of the NEUROD1 gene was detected, leading to gliclazide use with poor response. The patient responded well to metformin. Type 2 diabetes was considered the most likely diagnosis. This case highlights the diagnostic challenges in young patients of Asian ethnicity and the importance of interpreting genetic results of unknown significance within the clinical context. Ethnicity-specific BMI thresholds should be used when classifying patients as overweight or obese.

Learning points

  • Variants of unknown significance detected by genetic sequencing should be interpreted within the context of the patient’s other clinical parameters.

  • It is important to use ethnicity-specific BMI thresholds for obesity.

  • Diagnosis of type 2 diabetes mellitus at younger ages is becoming increasingly common.

  • The pre-test probability calculator for MODY is only validated in White Europeans; although a useful guide, results should be interpreted with caution in patients of other ethnicities.

Open access
Hiroaki Iwasaki Division of Endocrinology and Metabolism, Department of Internal Medicine, Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan
Division of Endocrinology and Metabolism, Department of Internal Medicine, Minamiyamato Hospital, Yamato, Kanagawa, Japan

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Summary

A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around the left shoulder and the right hip joint. The patient could not fully extend her fingers because of skin sclerosis in both hands. Laboratory studies showed hyperphosphataemia and a high ratio of renal tubular maximum reabsorption of phosphate to glomerular filtration rate. There were no abnormalities in serum calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone levels, whereas serum fibroblast growth factor 23 was low. Hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome (HFTC/HHS) was diagnosed using whole genome sequencing that revealed a novel frameshift beyond the 584th threonine located in the lectin domain of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 associated with a duplication of the 1748th thymine in the coding region of the corresponding gene. Furthermore, anti-nuclear, anti-centromere, and anti-cardiolipin antibodies were positive, implying that comorbid limited type scleroderma might play a role in tumoural calcinosis (TC) development. A low phosphate diet was prescribed with phosphate-lowering medications, including aluminium hydroxide, acetazolamide, and sevelamer hydrochloride. The patient displayed a decrease in serum phosphate levels from 6.5 to 5.5 mg/dL 10 months after the initiation of treatment, but her TC had not improved during treatment for more than 1 year. This case was interesting because the patient with HFTC/HHS exhibited TC despite being over her 60s, and subsequent scleroderma might contribute to the specific clinical course. When HFTC/HHS presents with elderly-onset TC, the involvement of comorbidities in exacerbating TC should be considered.

Learning points

  • HFTC/HHS occurs on an autosomal recessive basis, but its clinical course and manifestations differ significantly throughout the cases.

  • HFTC/HHS may be undiagnosed until later in life because of its rarity, unfamiliarity, and phenotype diversity; therefore, HFTC/HHS should be included in the differential diagnosis of elderly patients with unexplained hyperphosphataemia or ectopic calcinosis.

  • Comorbidities, including rheumatologic disorders, may contribute to developing HFTC/HHS-associated calcinosis.

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Andreia Amado Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Elisabete Teixeira i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

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Sule Canberk i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

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Sofia Macedo i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal

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Bárbara Castro Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Hugo Pereira Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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João Varanda Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Susana Graça Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Amélia Tavares Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

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Carlos Soares Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Maria João Oliveira Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Manuel Oliveira Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal

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Paula Soares i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

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Manuel Sobrinho Simões i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
Centro Hospitalar Universitário São João, Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

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Antónia Afonso Póvoa Centro Hospitalar Vila Nova de Gaia/Espinho, Portugal, R. Conceição Fernandes S/N, 4434-502 Vila Nova de Gaia, Portugal
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, R. Alfredo Allen 208, 4200-135 Porto, Portugal
IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal

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Summary

We report a 61-year-old male patient without personal history of thyroid carcinoma or radiation exposure. In 2011, he presented with a cervical mass whose biopsy diagnosed a papillary thyroid carcinoma (PTC) in a lymph node metastasis (LNM). Total thyroidectomy with lymphadenectomy of central and ipsilateral compartment was performed. Histopathology identified a 2 mm follicular variant of PTC and LNM in 25/25 lymph nodes. The patient was treated with 150 mCi of radioactive iodine (RAI), followed by levothyroxine suppressive therapy. In 2016, a retrotracheal mass was diagnosed, suggesting local recurrence; patient was submitted to surgical excision and RAI therapy (120 mCi). Due to seizures, in 2019, a brain CT was performed that diagnosed brain metastases. The patient underwent debulking of the main lesion. Histopathology analysis confirmed a metastatic lesion with variated morphology: classical PTC and follicular pattern and hobnail and tall cell features. Molecular analysis revealed BRAFV600E in LNM at presentation and BRAFV600E and TERT promoter (TERTp) mutations in the recurrent LNM and brain metastasis. Based upon this experience we review the reported cases of subcentimetric PTC with brain metastases and discuss the molecular progression of the present case.

Learning points

  • Papillary microcarcinoma (PMCs) usually have very good prognosis with low impact on patient survival.

  • PMCs presenting in elderly patients with LNM at diagnosis may carry a guarded outcome.

  • Brain metastasis although rare indicate aggressive phenotypic features.

  • Patient risk stratification of PMCs based on histopathological analysis and genetic testing may have a significant impact on prognosis providing therapeutic markers, that may predict disease progression and overall outcome.

Open access
Foram Patel Department of Pediatrics, Southern Illinois University, Springfield, Illinois, USA

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Ginger Darling Department of Pediatrics, Division of Neonatology, Southern Illinois University, Springfield, Illinois, USA

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Ahmed Torky Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Southern Illinois University, Springfield, Illinois, USA

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Summary

Neonatal hypoglycemia is a serious condition that can have a major impact on the growing neonatal brain. The differential diagnosis of neonatal hypoglycemia is broad and includes hyperinsulinism as well as panhypopituitarism. The FOXA2 gene has been involved in the development of the pancreas as well as the pituitary gland. Six cases have been reported thus far with FOXA2 mutations presenting with variable degrees of hypopituitarism, and only two patients had permanent hyperinsulinism; other cases have been reported with microdeletions in 20p11, the location that encompasses FOXA2, and those patients presented with a wider phenotype. A full-term female infant presented with severe hypoglycemia. Critical sampling showed an insulin of 1 mIU/mL, suppressed beta-hydroxybutyric acids, and suppressed free fatty acids. Blood glucose responded to glucagon administration. Growth hormone (GH) stimulation test later showed undetectable GH in all samples, and cortisol failed to respond appropriately to stimulation. Gonadotropins were undetectable at 1 month of life, and MRI showed ectopic posterior pituitary, interrupted stalk, hypoplastic anterior pituitary, cavum septum pellucidum, and diminutive appearance of optic nerves. Whole-exome sequencing revealed a likely pathogenic de novo c.604 T>C, p.Tyr202His FOXA2 mutation. We expand the known phenotype on FOXA2 mutations and report a likely pathogenic, novel mutation associated with hyperinsulinism and panhypopituitarism.

Learning points

  • FOXA2 has been shown to play an important role in the neuroectodermal and endodermal development.

  • FOXA2 mutation may lead to the rare combination of hyperinsulinism and panhypopituitarism.

  • Patients reported so far all responded well to diazoxide. Dysmorphology may be subtle, and liver functions should be monitored.

Open access
Valerie Lai Department of Medicine, University of Alberta, Edmonton, AB, Canada

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Mariam Shahidi Department of Medicine, University of Alberta, Edmonton, AB, Canada
Division of Endocrinology and Metabolism, University of Alberta, Edmonton, AB, Canada

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Alicia Chan Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada

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Shailly Jain-Ghai Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada

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Summary

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase deficiency is an inborn error of metabolism resulting in a lack of ketogenesis and leucine catabolism. Hallmarks of decompensation include hypoglycemia without ketosis (or hypoketosis), metabolic acidosis, and hyperammonemia. Management includes avoiding fasting and restricting dietary protein and fat. Conversely, type 2 diabetes mellitus (T2DM) requires carbohydrate restriction and/or anti-hyperglycemic agents; thus, managing these co-existing disorders is challenging. A 36-year-old male with HMG-CoA lyase deficiency and T2DM (Hemoglobin A1c (HbA1c): 7.9%) presented with confusion and shock. Blood work revealed metabolic acidosis, hyperammonemia, hyperglycemia, and hypoketosis. The patient was diagnosed with hyperosmolar non-ketotic hyperglycemia and hyperammonemia secondary to HMG-CoA lyase metabolic decompensation requiring intensive care unit admission. Hyperammonemia management was challenging because alternative calories with i.v. dextrose (due to hyperglycemia) and i.v. lipids (due to HMG-CoA lyase deficiency) could not be provided as usual. The patient was started on hemodialysis and i.v. insulin with marked improvement. Once stabilized, metformin and insulin were initiated. T2DM impaired cellular glucose uptake and produced a state similar to hypoglycemia, despite the patient being profoundly hyperglycemic, which led to metabolic decompensation of HMG-CoA lyase deficiency. Managing T2DM and HMG-CoA lyase deficiency warrants special considerations due to the potential for metabolic decompensation with both hyperglycemia and hypoglycemia.

Learning points

  • In a patient with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase deficiency and type 2 diabetes mellitus (T2DM), management principles include avoiding hypoglycemia to prevent metabolic decompensation, providing insulin for proper glucose utilization, and moderation of carbohydrate intake to prevent consequences of chronic hyperglycemia.

  • The development of insulin resistance in the form of T2DM in HMG-CoA lyase deficiency likely triggered a state similar to hypoglycemia, leading to cellular energy deficiency and subsequently metabolic decompensation.

  • It is important to avoid hypoglycemia in patients with HMG-CoA lyase deficiency and T2DM, as the risk of metabolic decompensation is increased due to the lack of ketogenesis in HMG-CoA lyase deficiency.

  • Selection of antidiabetic agents in this patient population requires careful consideration, and agents that have a higher risk of hypoglycemia should be avoided.

Open access
Jananie Suntharesan Department of Endocrinology, Alder Hey Children’s Hospital, Eaton Road, Liverpool, UK

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Louise Apperley Department of Endocrinology, Alder Hey Children’s Hospital, Eaton Road, Liverpool, UK

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Senthil Senniappan Department of Endocrinology, Alder Hey Children’s Hospital, Eaton Road, Liverpool, UK

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Summary

A male phenotype accompanied by a 45,X karyotype is rare. It may occur due to Y chromosomal translocation or insertion to X/autosome. Clinical presentation may vary depending on the presence of the Y chromosomal locus and the degree of loss of autosome material. 45,X males can present with short stature and Turner syndrome phenotype due to haploinsufficiency of genes which are normally expressed in both X and Y chromosomes. The presence of the sex-determining region Y (SRY) gene leads to the differentiation of bipotential gonads to testis. Most individuals go through puberty normally, but some may need pubertal induction for delayed puberty. Rarely some can have a pubertal arrest. The risk of gonadoblastoma is minimal in these individuals due to functioning testicular tissue. The azoospermia factor (AZF) region is found on the long arm of the Yq chromosome and is needed for spermatogenesis. In a 45,X male with unbalanced translocation of Y chromosome, spermatogenesis can be affected due to the lack of AZF leading to Sertoli cell-only syndrome. This will have an implication on fertility in adult life. We present a 14-year-old boy with developmental delay, learning difficulties and subtle dysmorphic features who was diagnosed with 45,X,der(2)t(Y:2)(?:p25). Fluorescence in situ hybridisation analysis revealed translocation of SRY (Yp11.3) to the terminal part of the short arm of chromosome 2 resulting in the deletion of most of the Y chromosome (Yp11.2-q12) and part of chromosome 2(2p25.3). This is the first case where SRY translocation to chromosome 2 presents with the above clinical presentation.

Learning points

  • 45,X karyotype is rare in male.

  • It may occur due to SRY translocation or an insertion to X/autosome.

  • SRY gene translocation to chromosome 2 has been not reported in the literature.

  • Clinical presentation can be varied due to degree of loss of chromosomal material.

  • Due to loss of AZF region found on the long arm of the Yq, spermatogenesis can be affected. Loss of 2p25 leads to learning difficulty and obesity.

Open access
Maha Khalil Abass Pediatric Endocrinology Division, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates

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Aisha Al Shamsi Clinical Genetics Department, Tawam Hospital, Al Ain, United Arab Emirates

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Iftikhar Jan Paediatric Surgery Division, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates

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Mohammed Suhail Yasin Masalawala Clinical Trial Unit, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates

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Asma Deeb Pediatric Endocrinology Division, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
College of Medicine and Health Sciences, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates

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Summary

The most frequent causes of pancreatitis classically have been known to be gallstones or alcohol. However, genetics can also play a key role in predisposing patients to both chronic and acute pancreatitis. The serine protease inhibitor Kazal type 1 (SPINK 1) gene is known to be strongly associated with pancreatitis. Patients with these underlying genetic mutations can have severe diseases with a high morbidity rate and frequent hospitalization. We report an Arab girl who presented with acute pancreatitis at the age of 7 years progressing to recurrent chronic pancreatitis over a few years. She had severe obesity from the age of 4 years and developed type 2 diabetes at the age of 12. She had a normal biliary system anatomy. Genetic analysis showed that she had combined heterozygous mutations in the SPINK1 gene (SPINK1, c.101A>G p.(Asn34Ser) and SPINK1, c.56-37T>C). Her parents were first-degree cousins, but neither had obesity. Mother was detected to have the same mutations. She had type 2 diabetes but never presented with pancreatitis. This case is the first to be reported from the Arab region with these combined mutations leading to recurrent chronic pancreatitis. It illustrates the importance of diagnosing the underlying genetic mutation in the absence of other known causes of pancreatitis. Considering the absence of pancreatitis history in the mother who did not have obesity but harboured the same mutations, we point out that severe obesity might be a triggering factor of pancreatitis in the presence of the mutations in SPINK1 gene in this child. While this is not an assumption from a single patient, we show that not all carriers of this mutation develop the disease even within the same family. Triggering factors like severe obesity might have a role in developing the disease.

Learning points

  • Acute recurrent pancreatitis and chronic pancreatitis are uncommon in children but might be underdiagnosed.

  • Biliary tract anomalies and dyslipidaemias are known causative factors for pancreatitis, but pancreatitis can be seen in children with intact biliary system.

  • Genetic diagnosis should be sought in children with pancreatitis in the absence of known underlying predisposing factors.

  • SPINK1 mutations can predispose to an early-onset severe recurrent pancreatitis and acute pancreatitis.

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