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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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Presoon Kuruvilla Department of Internal Medicine, Caritas Hospital, Kerala, India

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Angel John Department of Internal Medicine, Caritas Hospital, Kerala, India

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Ashith Murali Department of Internal Medicine, Caritas Hospital, Kerala, India

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Summary

Insulin autoantibody syndrome (IAS) or Hirata’s disease is a rare condition characterized by recurrent fasting hypoglycaemic and postprandial hyperglycaemic episodes. Insulin autoantibodies are diagnostic for the condition. Hirata’s disease has been seen to be associated with other autoimmune conditions. Vitiligo is a common depigmentation disorder whose exact cause is unknown but thought to have an autoimmune aetiology. Although autoimmunity plays a role in the pathogenesis of both the diseases, association between the two has not been reported till date. In our case, a 72-year-old Indian woman with vitiligo for the past 30 years presented with recurrent episodes of fasting hypoglycaemia. She was found to have very high levels of fasting insulin, C-peptide, and insulin antibody and was diagnosed with IAS. Thus, we conclude that the clinical spectrum of Hirata’s disease has to be taken as more heterogenous than previously assumed.

Learning points

  • Insulin autoantibody syndrome (IAS) or Hirata’s disease is a rare condition characterized by recurrent fasting hypoglycaemic and postprandial hyperglycaemic episodes in which insulin plays a major role.

  • Insulin autoantibodies are diagnostic for IAS. The endocrine insulin and its autoantibodies play a major role in the pathogenesis of the disease.

  • Vitiligo is a common depigmentation disorder whose exact cause is unknown but thought to have an autoimmune aetiology.

  • IAS and vitiligo are two diseases with autoimmune aetiology which has been seen to be associated with each other (the first case to be reported).

  • The clinical spectrum of Hirata’s disease has to be taken as more heterogenous than previously assumed.

  • On dealing with autoimmune diseases, we should also keep in mind about other diseases with autoimmune pathogenesis.

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Omayma Elshafie Department of Endocrinology, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman

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Anjali Jain Department of Nuclear Medicine, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman

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Summit Bichpuria Department of Radiology, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman

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Yamina Rassou Department of Pathology, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman

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Syed Furqan Hashmi Department of Radiation Oncology, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman

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Abir Bou Khalil Department of Endocrinology, Sultan Qaboos Comprehensive Cancer Care and Research Centre, Muscat, Oman

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Summary

A 60-year-old woman presented to our clinic with an acute onset 3 months history of right ankle pain. The patient had a history of poorly differentiated thyroid cancer, which was treated with total thyroidectomy, left lateral neck dissection levels II–V and central neck dissection levels VI–VII followed by postoperative I-131 radioactive iodine (131I) ablation therapy 3.7 GBq 6 months ago. The post-131I WBS showed residual iodine-avid thyroid tissue with no other iodine-avid disease or metastasis. SPECT/CT of the neck and chest showed nonavid bilateral pulmonary nodules, discrete nodal masses in mediastinum and nonavid bone lesions. FDG-PET CT scan showed FDG-avid mediastinal lymph nodes (LN), innumerable non-FDG-avid subcentimetric pulmonary nodules and few FDG-avid lytic lesions in the skeleton. X-ray and MRI of the right ankle showed a well-marginated lytic lesion in the posterior body of calcaneus and 5 × 6 cm soft tissue mass lesion, respectively. The histopathology of the calcaneus mass confirmed a positive immunostaining for thyroid origin which includes thyroglobulin and TTF-1 with PAX-8. Endobronchial mediastinal and bronchial LN biopsy confirmed thyroid cancer metastasis. Gene mutation showed HRAS and GNA13 with a high tumor mutational burden. We describe a rare case of poorly differentiated thyroid cancer in a patient who presented with right ankle pain; we confirmed the cause to be a calcaneus metastasis from the thyroid cancer, with calcaneus being an extremely rare site for bone metastases. Gene mutations points toward treatment with immune checkpoint inhibitors.

Learning points

  • Poorly differentiated thyroid carcinoma (PDTC) usually metastasizes to lung and bone but can rarely occur in the calcaneus.

  • Patients with distant metastases have significantly worse long-term prognosis.

  • Radiotherapy is effective in reducing the metastatic pains as well as reducing the size of the metastasis.

  • PAX-8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas.

  • The importance of searching for gene mutations to decide the treatment of PDTC.

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Dave Duggan Waikato Regional Diabetes Service, Te Whatu Ora Health New Zealand, Hamilton, New Zealand

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Cinthia Minatel Riguetto Waikato Regional Diabetes Service, Te Whatu Ora Health New Zealand, Hamilton, New Zealand

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Summary

There is a scarcity of literature relating to post-bariatric hypoglycaemia (PBH) in pregnancy. Recurrent hyperglycaemia and hypoglycaemia can have significant consequences for both the mother and the developing fetus. We describe a case of a young pregnant woman who was diagnosed with symptomatic PBH in the second trimester of pregnancy using continuous glucose monitoring (CGM) 3 years after Roux-en-Y gastric bypass (RYGB) surgery. Instigating a low glycaemic index and complex carbohydrate diet significantly improved the patient’s glycaemic excursions. Given that this condition is likely underdiagnosed as a complication of RYGB surgery, a greater awareness of this complication is needed. Patients should be adequately consented pre-operatively for this relatively frequent late surgical complication to enable patients to identify symptoms of this condition at an early stage and seek medical treatment.

Learning points

  • PBH is an important diagnosis in patients post-RYGB surgery, particularly in women of childbearing age when consequences of both hyperglycaemia and hypoglycaemia during pregnancy can adversely affect both mother and the fetus.

  • Adverse outcomes of recurrent hypoglycaemia to the fetus can include small for gestational age, intrauterine growth restriction and possible impairment of beta cell function.

  • Providing adequate carbohydrate intake to allow growth of the fetus during pregnancy while also attempting to resolve both hyperglycaemia and hypoglycaemia associated with PBH by reducing the intake of simple carbohydrates and high glycaemic index foods can prove challenging.

  • Patients should be adequately consented for late complications of RYGB surgery such as PBH in order to allow early recognition of symptoms and enable prompt treatment.

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Ishara Ranathunga Department of Diabetes and Endocrinology, North Cumbria Integrated Care NHS Foundation Trust, Whitehaven, UK

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Chandima Idampitiya Department of Diabetes and Endocrinology, North Cumbria Integrated Care NHS Foundation Trust, Whitehaven, UK

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Summary

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by the destruction of the pancreatic beta cells, which produce insulin. Individuals with T1DM usually require at least 3-5 years to develop microvascular complications in comparison to people with type 2 diabetes (T2DM), who may develop complications even before the diagnosis of diabetes. We discuss a patient who presented with proliferative diabetic retinopathy subsequently diagnosed with T1DM and diabetic neuropathy following investigations. Diabetic retinopathy or other microvascular complications as the presenting feature of T1DM is rarely known or reported in the literature. A 33-year-old healthcare worker had been seen by the opticians due to 1-week history of blurred vision. The ophthalmology assessment had confirmed proliferative retinopathy in the right eye and severe non-proliferative retinopathy in the left eye with bilateral clinically significant macular oedema. His BMI was 24.9 kg/m2. The nervous system examination revealed bilateral stocking type peripheral neuropathy. The random venous glucose was 24.9 mmol/L. Plasma ketones were 0.7 mmol/L and HbA1c was 137 mmol/mol. On further evaluation, the anti-glutamic acid decarboxylase (GAD) antibody was positive, confirming the diagnosis of T1DM. He was started on aflibercept injections in both eyes, followed by panretinal photocoagulation. Subsequent nerve conduction studies confirmed the presence of symmetrical polyneuropathy. The pathogenesis of the development of microvascular complications in T1DM is multifactorial. Usually, the development of complications is seen at least a few years following the diagnosis. The occurrence of microvascular complications at presentation is rare. This makes the management challenging and extremely important in preventing the progression of the disease.

Learning points

  • The pathogenesis of the development of microvascular complications in type 1 diabetes mellitus is multifactorial.

  • The development of complications is seen at least a few years following the diagnosis.

  • Occurrence of microvascular complications at presentation is rare.

  • This makes the management challenging and extremely important to prevent the progression of the disease.

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Joanna Chrzanowska Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases for Children and Adolescents, Wrocław Medical University, Poland

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Monika Seifert Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases for Children and Adolescents, Wrocław Medical University, Poland

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Barbara Salmonowicz Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases for Children and Adolescents, Wrocław Medical University, Poland

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Agnieszka Zubkiewicz-Kucharska Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases for Children and Adolescents, Wrocław Medical University, Poland

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Summary

The etiology of foot drop is diverse from various diseases to mechanic injuries and includes neuropathy of the peroneal nerve. Peroneal neuropathy might also be one of the forms of diabetic neuropathy, very rarely reported as the first sign of diabetes. We describe three cases of children with newly diagnosed type 1 diabetes (TID) who developed unilateral peroneal nerve palsies and tibial nerve palsies, presenting clinically as a foot drop. In two of our cases, the symptoms of foot drop occurred shortly after starting treatment for severe diabetes ketoacidosis. In the third patient, food drop was a reason for the initial medical consultation, but eventually, TID was diagnosed. The presented cases highlight that neuropathy can be observed not only as a chronic complication of T1D, but it can also appear at the time of disease manifestation. The incorrect position of the lower limb during a keto coma may contribute to the development of neuropathy.

Learning points

  • Neuropathy can be observed not only as a chronic complication of type 1 diabetes (T1D), but it can also appear at the time of disease manifestation.

  • The incorrect position of the lower limb causing external pressure during a keto coma may contribute to the development of neuropathy.

  • It is important to examine the glycemia in patients with acute peroneal neuropathy, as this kind of peripheral neuropathy can be associated with newly diagnosed T1D. Normalization of glycemia might lead to rapid neuronal recovery.

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Clemens Gardemann FH Münster Oecotrophologie, Münster, Germany
Clinic for Pediatrics and Adolescent Medicine/Metabolism Laboratory, Universitätsklinikum Münster, Münster, Germany

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Sonja Knowles FH Münster Oecotrophologie, Münster, Germany

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Thorsten Marquardt Clinic for Pediatrics and Adolescent Medicine/Metabolism Laboratory, Universitätsklinikum Münster, Münster, Germany

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Summary

Traditional guidelines for type 1 diabetics do not restrict carbohydrates to improve clinical outcomes for patients. This paper highlights the favorable blood glucose control outcomes when a type 1 diabetic focuses on caloric intake from protein and healthy fats instead of the traditional carbohydrate-focused meals. We followed a male type 1 diabetic in his 20s adopting a ketogenic diet through a process of slowly lowering total daily carbohydrate intake. Diabetes-related biomarkers were measured throughout the process. Diabetes-related biomarkers saw massive improvements and ended up in the official non-diabetic range. Total daily insulin requirements dropped by 70%. The patient also experienced great improvements in his quality of life. This study demonstrates the possibility of improving diabetes-related biomarkers through dietary changes, which have positive effects on health outcomes in patients living with this disease.

Learning points

  • The adaptation of a ketogenic diet improved diabetes-related biomarkers in this patient.

  • Diabetes-related biomarkers, such as HbA1c, are the main risk factors for developing complications in diabetics.

  • The ketogenic diet is a feasible approach to minimizing the risk of developing complications in diabetics.

  • Total daily insulin requirements dropped by 67% adapting a ketogenic diet.

  • The patient experienced enormous changes in the quality of life after adapting to the new diet.

  • The safe and physiological state of ketosis might be associated with additional benefits for the patient

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Nam Quang Tran Department of Endocrinology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
Department of Endocrinology, University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam

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Chien Cong Phan Department of Imaging, University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam

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Tran Bao Vuong Department of Endocrinology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam

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Thang Viet Tran Department of Endocrinology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
Department of Endocrinology, University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam

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Phat Tung Ma Department of Endocrinology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
Department of Endocrinology, University Medical Center at Ho Chi Minh City, Ho Chi Minh City, Vietnam

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Summary

Mitochondrial diseases are a group of rare diseases presenting with heterogeneous clinical, biochemical, and genetic disorders caused by mutations in the mitochondrial or nuclear genome. Multiple organs can be affected, particularly those with high energy demand. Diabetes is a common endocrine manifestation of mitochondrial diseases. The onset of mitochondrial diabetes can be latent or acute, and the presenting phenotype can be type 1- or type 2-like. Studies show that diabetes ais associated with latent progression of cognitive decline in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Herein, we report a case of rapid cognitive decline after the acute onset of diabetes in a patient with MELAS syndrome. The patient was a 36-year-old woman who was hospitalized due to hyperglycemic crisis and seizures. She was diagnosed with MELAS syndrome two years previously, and had gradually progressing dementia and hearing loss. However, following the acute onset of diabetes, she developed rapid cognitive decline and loss of ability to perform daily activities. In conclusion, the acute onset of diabetes could be an associated risk factor for rapid cognitive decline in patients with MELAS syndrome. Thus, these patients as well as healthy carriers with related genetic mutations should undergo diabetes education and screening tests. Moreover, clinicians should be aware of the possibility for acute onset of hyperglycemic crisis, particularly in the presence of triggering factors.

Learning points

  • Diabetes is a common endocrine manifestation of mitochondrial diseases, presenting with a type 1- or type 2-like phenotype depending on the level of insulinopenia.

  • Metformin should be avoided in patients with mitochondrial diseases to prevent metformin-induced lactic acidosis.

  • Mitochondrial diabetes can manifest before or after the onset of MELAS syndrome.

  • In patients with MELAS syndrome, diabetes can initially manifest with a life-threatening severe hyperglycemic crisis and can cause rapid cognitive decline.

  • Diabetes screening tests (e.g. hemoglobin A1c, oral glucose tolerance test, or random blood glucose level measurement) should be performed either systematically or in the presence of symptoms, particularly after triggering events.

  • Genetic testing and counseling should be provided to patients and their families for the purpose of better understanding the inheritance, progression, and possible outcomes of the disease.

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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.

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Osamu Horikawa Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

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Satoshi Ugi Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
Department of Medicine, Omihachiman Community Medical Center, Omihachiman, Shiga, Japan

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Tomofumi Takayoshi Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan

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Yasushi Omura Department of Internal Medicine, Kohka Public Hospital, Kohka, Shiga, Japan

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Maya Yonishi Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

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Daisuke Sato Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

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Yukihiro Fujita Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

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Tomoya Fuke Department of Medicine, Saiseikai Shiga Hospital, Ritto, Shiga, Japan

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Yushi Hirota Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan

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Wataru Ogawa Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan

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Hiroshi Maegawa Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

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Summary

A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 μU/mL; 60 min: 953 μU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother’s diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years.

Learning points

  • Type A insulin resistance syndrome is caused by mutations in the insulin receptor (INSR) gene and results in severe insulin resistance.

  • Genetic evaluation should be considered in adolescents or young adults with dysglycemia when an atypical phenotype, such as severe insulin resistance, or a relevant family history is observed.

  • Clinical courses may differ even if the same genetic mutation is found in a family.

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