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Pranav Gupta Division of Endocrinology, Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA

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Karen Loechner Division of Endocrinology, Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
Division of Endocrinology, Department of Pediatrics, Connecticut Childrens Medical Center, Farmington, Connecticut, USA

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Briana C Patterson Division of Endocrinology, Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Atlanta, Georgia, USA

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Eric Felner Division of Endocrinology, Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA

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Summary

Insulinomas are a rare cause of persistent hypoglycemia in a previously healthy child. In addition to symptoms of hypoglycemia, individuals with insulinomas usually present with a history of incessant caloric intake and weight gain due to a constant need to counter hypoglycemia. In addition to an extensive review of the literature, we report the first case of an insulinoma coexisting with reduced appetite secondary to anorexia nervosa in an adolescent female.

Learning points

  • Eliciting a detailed family history is important in hypoglycemia cases.

  • Obtaining a thorough dietary intake, weight history, and menstrual cycles (in females) and considering a psychiatric consultation for an eating disorder when indicated.

  • Although rare in the pediatric population, multiple endocrine neoplasia type 1 syndrome should be considered in the evaluation of children and adolescents with hypoglycemia who also have a family history of pituitary, pancreatic, and/or parathyroid endocrinopathies.

Open access
Adrian Po Zhu Li Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Sheela Sathyanarayan Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Salvador Diaz-Cano Departments of Cellular Pathology and Molecular Pathology, Queen Elizabeth Hospital, Birmingham, UK
Division of Cancer Studies, King’s College London, London, UK

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Sobia Arshad Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Eftychia E Drakou Department of Clinical Oncology, Guy’s Cancer Centre – Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, UK

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Royce P Vincent Department of Clinical Biochemistry, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
Faculty of Life Sciences and Medicine, School of Life Course Sciences, King’s College London, London, UK

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Ashley B Grossman Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
Barts and the London School of Medicine, Centre for Endocrinology, William Harvey Institute, London, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK

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Simon J B Aylwin Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK

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Georgios K Dimitriadis Department of Endocrinology ASO/EASO COM, King ’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK
Obesity, Type 2 Diabetes and Immunometabolism Research Group, Department of Diabetes, Faculty of Life Sciences, School of Life Course Sciences, King’s College London, London, UK
Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK

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Summary

A 49-year-old teacher presented to his general physician with lethargy and lower limb weakness. He had noticed polydipsia, polyuria, and had experienced weight loss, albeit with an increase in central adiposity. He had no concomitant illnesses and took no regular medications. He had hypercalcaemia (adjusted calcium: 3.34 mmol/L) with hyperparathyroidism (parathyroid hormone: 356 ng/L) and hypokalaemia (K: 2.7 mmol/L) and was admitted for i.v. potassium replacement. A contrast-enhanced CT chest/abdomen/pelvis scan revealed a well-encapsulated anterior mediastinal mass measuring 17 × 11 cm with central necrosis, compressing rather than invading adjacent structures. A neck ultrasound revealed a 2 cm right inferior parathyroid lesion. On review of CT imaging, the adrenals appeared normal, but a pancreatic lesion was noted adjacent to the uncinate process. His serum cortisol was 2612 nmol/L, and adrenocorticotrophic hormone was elevated at 67 ng/L, followed by inadequate cortisol suppression to 575 nmol/L from an overnight dexamethasone suppression test. His pituitary MRI was normal, with unremarkable remaining anterior pituitary biochemistry. His admission was further complicated by increased urine output to 10 L/24 h and despite three precipitating factors for the development of diabetes insipidus including hypercalcaemia, hypokalaemia, and hypercortisolaemia, due to academic interest, a water deprivation test was conducted. An 18flurodeoxyglucose-PET (FDG-PET) scan demonstrated high avidity of the mediastinal mass with additionally active bilateral superior mediastinal nodes. The pancreatic lesion was not FDG avid. On 68Ga DOTATE-PET scan, the mediastinal mass was moderately avid, and the 32 mm pancreatic uncinate process mass showed significant uptake. Genetic testing confirmed multiple endocrine neoplasia type 1.

Learning points

  • In young patients presenting with primary hyperparathyroidism, clinicians should be alerted to the possibility of other underlying endocrinopathies.

    In patients with multiple endocrine neoplasia type 1 (MEN-1) and ectopic adrenocorticotrophic hormone syndrome (EAS), clinicians should be alerted to the possibility of this originating from a neoplasm above or below the diaphragm.

  • Although relatively rare compared with sporadic cases, thymic carcinoids secondary to MEN-1 may also be associated with EAS.

  • Electrolyte derangement, in particular hypokalaemia and hypercalcaemia, can precipitate mild nephrogenic diabetes insipidus.

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Joana Lima Ferreira Endocrinology Department, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal

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Francisco Simões de Carvalho Endocrinology Department, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal

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Ana Paula Marques Endocrinology Department, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal

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Rosa Maria Príncipe Endocrinology Department, Hospital Pedro Hispano, Matosinhos Local Health Unit, Matosinhos, Portugal

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Summary

Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.

Learning points:

  • Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.

  • Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.

  • APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.

  • APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.

  • Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.

  • Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

Open access
Satyanarayana V Sagi Department of Diabetes and Endocrinology, Peterborough City Hospital, Peterborough, UK

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Hareesh Joshi Department of Diabetes and Endocrinology, Peterborough City Hospital, Peterborough, UK

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

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

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Ashwini Swamy Department of Diabetes and Endocrinology, Peterborough City Hospital, Peterborough, UK

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Jeyanthy Rajkanna Department of Diabetes and Endocrinology, Peterborough City Hospital, Peterborough, UK

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Nazir A Bhat Department of Ear, Nose and Throat, Peterborough City Hospital, Peterborough, UK

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Firas J S Haddadin Department of Diabetes and Endocrinology, Queen Elizabeth Hospital, King’s Lynn, UK

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Samson O Oyibo Department of Diabetes and Endocrinology, Peterborough City Hospital, Peterborough, UK

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Soo-Mi Park Department of Clinical Genetics, Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK

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Summary

Familial hypocalciuric hypercalcaemia (FHH) is a dominantly inherited, lifelong benign disorder characterised by asymptomatic hypercalcaemia, relative hypocalciuria and variable parathyroid hormone levels. It is caused by loss-of-function pathogenic variants in the calcium-sensing receptor (CASR) gene. Primary hyperparathyroidism (PHPT) is characterised by variable hypercalcaemia in the context of non-suppressed parathyroid hormone levels. Unlike patients with FHH, patients with severe hypercalcaemia due to PHPT are usually symptomatic and are at risk of end-organ damage affecting the kidneys, bone, heart, gastrointestinal system and CNS. Surgical resection of the offending parathyroid gland(s) is the treatment of choice for PHPT, while dietary adjustment and reassurance is the mainstay of management for patients with FHH. The occurrence of both FHH and primary hyperparathyroidism (PHPT) in the same patient has been described. We report an interesting case of FHH due to a novel CASR variant confirmed in a mother and her two daughters and the possible coexistence of FHH and PHPT in the mother, highlighting the challenges involved in diagnosis and management.

Learning points:

  • Familial hypocalciuric hypercalcaemia (FHH) and primary hyperparathyroidism (PHPT) can coexist in the same patient.

  • Urinary calcium creatinine clearance ratio can play a role in distinguishing between PHPT and FHH.

  • Genetic testing should be considered in managing patients with PHPT and FHH where the benefit may extend to the wider family.

  • Family segregation studies can play an important role in the reclassification of variants of uncertain significance.

  • Parathyroidectomy has no benefit in patients with FHH and therefore, it is important to exclude FHH prior to considering surgery.

  • For patients with coexisting FHH and PHPT, parathyroidectomy will reduce the risk of complications from the severe hypercalcaemia associated with PHPT.

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Thien Vinh Luong Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark

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Lars Rejnmark Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

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Anne Kirstine Arveschoug Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark

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Peter Iversen Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, Aarhus, Denmark

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Lars Rolighed Department of Otorhinolaryngology, Aarhus University Hospital, Aarhus, Denmark

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Multiple endocrine neoplasia 1 (MEN1) is a rare genetic syndrome characterized by the manifestation of tumors in endocrine glands most often in the parathyroid gland (PG). Treatment may involve several parathyroidectomies (PTX), especially in young patients, which increases the risk of postoperative complications. We present a 16-year-old patient with a family history of MEN1 syndrome. The patient started to show biochemical signs of hyperparathyroidism (HPT) and hypercalcemia at the age of 10. One and a half years later a PTX was successfully performed with removal of the two left PGs. However, a rise in plasma parathyroid hormone and ionized calcium was observed 4 years later. Preoperative noninvasive imaging with 99mTc-sestamibi scintigraphy showed no definitive parathyroid adenoma. A 11C-methionine position emission tomography combined with MRI (MET-PET/MRI) was then performed and detected a focus posterior to the lower part of the right thyroid lobe. Intraoperative angiography with fluorescence and indocyanine green dye was used to assess the vascularization of the remaining PGs. The lower right PG was removed. The patient was discharged with normalized biochemical values and without postoperative complications. Recurrence of primary HPT is frequent in MEN1 patients which often necessitates repeated operations. Our case report showed that the use of advanced noninvasive preoperative imaging techniques and intraoperative fluorescent imaging are valuable tools and should be taken into consideration in selected cases to avoid postoperative complications. To our knowledge, this is the first case where MET-PET/MRI has been used to detect parathyroid pathology.

Learning points:

  • MEN1 patients will develop parathyroid disease, which eventually will lead to surgical treatment with removal of the pathological glands.

  • Preoperatively usage of MRI combined with PET tracers such as 11C-methionine and 18F-Fluorocholine are able to detect parathyroid pathology with a higher sensitivity than conventional imaging.

  • Techniques using intraoperatively angiography with fluorescence and florescent dyes allow surgeons to verify the vascularization of each parathyroid gland.

  • Optimization of noninvasive preoperative imaging techniques and intraoperative fluorescent imaging are valuable tools and should be taken into consideration when performing PTX consecutively in the same patient to avoid postoperative complications.

Open access
Jane J Tellam Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
University of Queensland, Herston, Queensland, Australia

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Ghusoon Abdulrasool Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
University of Queensland, Herston, Queensland, Australia
Pathology Queensland, Australia

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Louise C H Ciin Gold Coast University Hospital, Southport, Queensland, Australia
Griffith University, Southport, Queensland, Australia

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Summary

Distinguishing primary hyperparathyroidism (PHPT) from familial hypocalciuric hypercalcaemia (FHH) can be challenging. Currently, 24-h urinary calcium is used to differentiate between the two conditions in vitamin D replete patients, with urinary calcium creatinine clearance ratio (UCCR) <0.01 suggestive of FHH and >0.02 supportive of PHPT. A 26-year-old Caucasian gentleman presented with recurrent mild hypercalcaemia and inappropriately normal parathyroid hormone (PTH) following previous parathyroidectomy 3 years prior. He had symptoms of fatigue and light-headedness. He did not have any other symptoms of hypercalcaemia. His previous evaluation appeared to be consistent with PHPT as evidenced by hypercalcaemia with inappropriately normal PTH and UCCR of 0.0118 (borderline low using guidelines of >0.01 consistent with PHPT). He underwent parathyroidectomy and three parathyroid glands were removed. His calcium briefly normalised after surgery, but rose again to pre-surgery levels within 3 months. Subsequently, he presented to our centre and repeated investigations showed 24-h urinary calcium of 4.6 mmol/day and UCCR of 0.0081 which prompted assessment for FHH. His calcium-sensing receptor (CASR) gene was sequenced and a rare inactivating variant was detected. This variant was described once previously in the literature. His mother was also confirmed to have mild hypercalcaemia with hypocalciuria and, on further enquiry, had the same CASR variant. The CASR variant was classified as likely pathogenic and is consistent with the diagnosis of FHH. This case highlights the challenges in differentiating FHH from PHPT. Accurate diagnosis is vital to prevent unnecessary surgical intervention in the FHH population and is not always straightforward.

Learning points:

  • Distinguishing FHH from PHPT with co-existing vitamin D deficiency is difficult as this can mimic FHH. Therefore, ensure patients are vitamin D replete prior to performing 24-h urinary calcium collection.

  • Individuals with borderline UCCR could have either FHH or PHPT. Consider performing CASR gene sequencing for UCCR between 0.01 and 0.02.

  • Parathyroid imaging is not required for making the diagnosis of PHPT. It is performed when surgery is considered after confirming the diagnosis of PHPT.

Open access
Maria Cabrer Endocrine Unit, Hospital Comarcal d’Inca, Inca, Spain

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Guillermo Serra Endocrine Unit, Hospital Universitari Son Espases, Palma, Spain

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María Soledad Gogorza Endocrine Unit, Hospital Universitari Son Espases, Palma, Spain

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Vicente Pereg Endocrine Unit, Hospital Universitari Son Espases, Palma, Spain

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Summary

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic syndrome that may present with hypocalcemia due to primary hypoparathyroidism (PH) at any age. We report a new diagnosis of 22q11.2DS in a 57-year-old man who presented with symptomatic hypocalcemia. It is important to consider genetic causes of hypocalcemia due to PH regardless of age.

Learning points:

  • It is important to discard genetic cause of primary hypoparathyroidism in a patient without autoimmune disease or prior neck surgery.

  • A new diagnosis of a hereditary disease has familial implications and needs genetic counselling.

  • It is also important to discard other syndrome’s comorbidities.

Open access
Rowena Speak Departments of Oncology and Metabolism, University of Sheffield

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Jackie Cook Department of Genetics, Sheffield Children’s Hospital, Sheffield, UK

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Barney Harrison Endocrine Surgery, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

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John Newell-Price Departments of Oncology and Metabolism, University of Sheffield
Endocrinology

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Mutations of the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.2, cause multiple endocrine neoplasia type 2A (MEN2A). Patients with mutations at the codon 609 usually exhibit a high penetrance of medullary thyroid cancer (MTC), but a sufficiently low penetrance of phaeochromocytoma that screening for this latter complication has been called to question. Patients with other RET mutations are at higher risk of younger age onset phaeochromocytoma if they also possess other RET polymorphisms (L769L, S836S, G691S and S904S), but there are no similar data for patients with 609 mutations. We investigated the unusual phenotypic presentation in a family with MEN2A due to a C609Y mutation in RET. Sanger sequencing of the entire RET-coding region and exon–intron boundaries was performed. Five family members were C609Y mutation positive: 3/5 initially presented with phaeochromocytoma, but only 1/5 had MTC. The index case aged 73 years had no evidence of MTC, but presented with phaeochromocytoma. Family members also possessed the G691S and S904S RET polymorphisms. We illustrate a high penetrance of phaeochromocytoma and low penetrance of MTC in patients with a RET C609Y mutation and polymorphisms G691S and S904S. These data highlight the need for life-long screening for the complications of MEN2A in these patients and support the role for the screening of RET polymorphisms for the purposes of risk stratification.

Learning points:

  • C609Y RET mutations may be associated with a life-long risk of phaeochromocytoma indicating the importance of life-long screening for this condition in patients with MEN2A.

  • C609Y RET mutations may be associated with a lower risk of MTC than often quoted, questioning the need for early prophylactic thyroid surgery discussion at the age of 5 years.

  • There may be a role for the routine screening of RET polymorphisms, and this is greatly facilitated by the increasing ease of access to next-generation sequencing.

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

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

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

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Summary

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

Learning points

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

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

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

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Katsumi Taki Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Yamanashi, 403-0005, Japan

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Takahiko Kogai Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, 321-0293, Japan

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Junko Sakumoto Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, 321-0293, Japan

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Takashi Namatame Clinical Research Center, Dokkyo Medical University, Tochigi, 321-0293, Japan

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Akira Hishinuma Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, 321-0293, Japan

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Summary

A de novo heterozygous inactivating mutation of calcium-sensing receptor (CASR) gene typically causes neonatal hyperparathyroidism (NHPT) with moderate hypercalcemia and hyperparathyroid bone disease. We present a case of asymptomatic hypocalciuric hypercalcemia with a de novo heterozygous mutation in CASR, S591C, which is primarily reported to be responsible for NHPT. A 54-year-old female was referred for investigation of asymptomatic hypercalcemia that was initially found in the 1980s but without a history of bone disease during the perinatal period. She had moderate hypercalcemia (12.4 mg/dl) and relative hypocalciuria (fractional extraction of calcium 1.07%) but normal intact parathyroid hormone and serum 1,25-dihydroxyvitamin D3. Pedigree analysis revealed that she carried a de novo heterozygous mutation of S591C, which she transmitted to an affected child with moderate hypercalcemia but not to other children, who had normal serum calcium levels. A de novo heterozygous CASR mutation that is responsible for NHPT may also present in individuals with asymptomatic hypocalciuric hypercalcemia. Caution is required when predicting course and outcome in a pedigree with CASR mutation, as well as incidental hypercalcemia, because of its variable phenotypes.

Learning points

  • The phenotype and severity of CASR mutations are thought to be dependent on genotypes.

  • We report an asymptomatic case of the de novo heterozygous S591C mutation in CASR, which has previously been reported as a responsible mutation of NHPT with bone diseases.

  • Variable phenotypes of CASR raise a cautionary note about predicting outcome by genotyping in a pedigree with CASR mutation.

Open access