Patient Demographics > Ethnicity > White

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Clare E Bonnar Centre for Diabetes, Endocrinology & Metabolism

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John F Brazil Centre for Diabetes, Endocrinology & Metabolism

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Julie O Okiro Department of Nephrology, Endocrinology & Metabolism

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Louise Giblin Department of Nephrology, Endocrinology & Metabolism

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Yvonne Smyth Department of Cardiology, Galway, Ireland

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Paula M O’Shea Department of Clinical Biochemistry, Galway University Hospitals, Saolta University Healthcare Group, Galway, Ireland

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Francis M Finucane Centre for Diabetes, Endocrinology & Metabolism

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Summary

A 32-year-old Caucasian male presented to the emergency department with a one-day history of acute severe bilateral lower limb weakness, three days after competing in a bodybuilding competition. He consumed large quantities of carbohydrate-rich foods following the competition. His past medical history was significant for anxiety, and family history was non-contributory. Examination was normal except for reduced power and hyporeflexia in both legs, despite his muscular physique. He was noted to have severe hypokalaemia (K+= 1.9 mmol/L). His thyroid function tests were consistent with thyrotoxicosis. He reported taking thyroxine and several other agents to facilitate muscle mass generation before the bodybuilding competition. His presentation was reminiscent of thyrotoxic periodic paralysis, albeit uncommon with Caucasian ethnicity. He also had transient hyperglycaemia at presentation with concomitant hyperinsulinaemia, which could be attributed to the carbohydrate load and may have exacerbated his hypokalaemia through a transcellular shift. Urine toxicology screen subsequently ruled out the use of diuretics but confirmed the presence of a long-acting beta agonist (clenbuterol) which, along with other substances, may have aggravated the hypokalaemia further. After 12 h of i.v. replacement, the potassium level normalised and leg weakness resolved. The patient agreed to stop taking thyroxine and beta agonists and was well during the clinic visit at one month follow-up. This case highlights the potential for thyrotoxicosis factitia to exacerbate hypokalaemia and muscle weakness from other causes in bodybuilders presenting with acute severe weakness, irrespective of ethnicity.

Learning points

  • In patients presenting with muscle weakness and hypokalaemia, early consideration of thyrotoxicosis is essential, even in the absence of a past history of thyroid disease or specific symptoms of thyrotoxicosis, in order to allow prompt initiation of appropriate treatment and to prevent recurrence.

  • Bodybuilders may constitute a uniquely ‘at-risk’ group for thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia, especially where there is concomitant use of beta-adrenergic agonists, even in the absence of diuretic use.

  • Although rare and usually described in patients of Asian or Polynesian ethnicity, this case highlights that thyrotoxic periodic paralysis secondary to thyrotoxicosis factitia can also occur in patients with Caucasian ethnicity.

  • We speculate that consuming large quantities of carbohydrates may induce hyperinsulinaemia, which could theoretically contribute to worse hypokalaemia, though mechanistic studies would be needed to explore this further.

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Darran Mc Donald Department of Endocrinology, St Vincent’s University Hospital, Dublin, Ireland

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Eirena Goulden Department of Endocrinology, St Vincent’s University Hospital, Dublin, Ireland

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Garret Cullen Department of Gastroenterology, St Vincent’s University Hospital, Dublin, Ireland

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John Crown Department of Oncology, St Vincent’s University Hospital, Dublin, Ireland
Department of Medicine, University College Dublin, Dublin, Ireland

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Rachel K Crowley Department of Endocrinology, St Vincent’s University Hospital, Dublin, Ireland
Department of Medicine, University College Dublin, Dublin, Ireland

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Summary

Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis.

Learning points

  • Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy.

  • Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4).

  • Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis.

  • Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption.

  • A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

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Lachlan M Angus Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia

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Jun Yang Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Victoria, Australia
Department of Medicine, Monash University, Victoria, Australia

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Ada S Cheung Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia

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Summary

Primary aldosteronism is one of the most common (affecting up to 10%) yet treatable causes of hypertension in our community, notable due to an associated elevated risk of atrial fibrillation, stroke and myocardial infarction compared to essential hypertension. Guidelines have focussed on improving case detection due to significant underdiagnosis in the community. While our case experienced significant delay in diagnosis, we highlight a state of protracted, persistent post-operative hypoaldosteronism which manifested with severe hyponatraemia and hyperkalaemia, necessitating long-term mineralocorticoid replacement. We discuss whether pre-operative mineralocorticoid receptor antagonists to stimulate aldosterone secretion from the contralateral gland may have prevented this complication.

Learning points

  • Hypoaldosteronism is an uncommon complication of adrenalectomy for primary aldosteronism, typically manifesting with hyperkalaemia and hyponatraemia. While most cases are transient, it may be persistent, necessitating ongoing mineralocorticoid replacement.

  • Routine electrolyte monitoring is recommended post-adrenalectomy.

  • Risk factors for hypoaldosteronism include age >50 years, duration of hypertension >10 years, pre-existing renal impairment and adrenal adenoma size >2 cm.

  • Mineralocorticoid receptor antagonists may assist in the management of hypokalaemia and hypertension pre-operatively. However, it is unclear whether this reduces the risk of post-operative hypoaldosteronism.

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Annabelle M Warren Department of Endocrinology, The Alfred Hospital, Melbourne, Victoria, Australia
Department of Endocrinology, The Austin Hospital, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia

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Peter R Ebeling Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia
Department of Endocrinology, Monash Health, Clayton, Victoria, Australia

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Vivian Grill Department of Endocrinology, Western Health, St Alban’s, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia

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Ego Seeman Department of Endocrinology, The Austin Hospital, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia

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Shoshana Sztal-Mazer Department of Endocrinology, The Alfred Hospital, Melbourne, Victoria, Australia
Women’s Health Research Program, School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, Australia

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Summary

Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended.

Learning points

  • Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss.

  • Antiresorptive therapy is contraindicated in HPP.

  • Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis.

  • Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory.

  • Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly.

  • Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

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Darija Tudor Department of Pediatrics, University Hospital of Split, Split, Croatia

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Iva Kolombo Department of Pediatrics, Šibenik General Hospital, Šibenik, Croatia

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Ana Tot Department of Pediatrics, University Hospital of Split, Split, Croatia

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Drasko Cikojevic Department of Otorhinolaryngology, University Hospital of Split, Split, Croatia

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Marko Simunovic Department of Pediatrics, University Hospital of Split, Split, Croatia
Department of Pediatrics, University of Split School of Medicine, Split, Croatia

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Veselin Skrabic Department of Pediatrics, University Hospital of Split, Split, Croatia
Department of Pediatrics, University of Split School of Medicine, Split, Croatia

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Summary

This is a case report of a child with chronic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) as a paraneoplastic manifestation of olfactory neuroblastoma (OFN). We hereby report a clinical presentation as well as a pragmatic approach to one of the most common electrolytic disorders in the pediatric population and have emphasized the necessity of involving the sinonasal area in the diagnostic procedure while evaluating possible causes of SIADH. This report indicates that the chronicity of the process along with the gradual onset of hyponatremia occurrence is responsible for the lack of neurological symptoms at the moment of disease presentation.

Learning points

  • Hyponatremia is not infrequently attributed to SIADH.

  • Paraneoplastic syndromes are uncommon but they should be considered in the differential diagnosis of pediatric SIADH.

  • Chronic insidious hyponatremia may not be associated with clear neurological symptoms despite its severity.

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Ryizan Nizar Department of Diabetes and Endocrinology, Southmead Hospital, North Bristol NHS Trust, Bristol, UK

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Nathan W P Cantley Department of Clinical Biochemistry, Southmead Hospital, North Bristol NHS Trust, Bristol, UK

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Jonathan C Y Tang Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, UK

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Summary

A 33-year-old gentleman of Egyptian heritage presented with a 21 years history of unexplained and recurrent hypercalcaemia, nephrolithiasis, nephrocalcinosis, and myocarditis. A similar history was also found in two first-degree relatives. Further investigation into the vitamin D metabolism pathway identified the biochemical hallmarks of infantile hypercalcaemia type 1 (IIH). A homozygous, likely pathogenic, variant in CYP24A1 was found on molecular genetic analysis confirming the diagnosis. Management now focuses on removing excess vitamin D from the metabolic pathway as well as reducing calcium intake to achieve serum-adjusted calcium to the middle of the reference range. If undiagnosed, IIH can cause serious renal complications and metabolic bone disease.

Learning points

  • Infantile hypercalcaemia type 1 (IIH) is an autosomal recessive disorder characterised by homozygous mutations in the CYP24A1 gene that encodes the 24-hydroxylase enzyme used to convert active vitamin D metabolites such as 1,25-(OH)2-vitamin D into their inactive form.

  • IIH should be questioned in individuals presenting with a history of unexplained hypercalcaemia, especially if presenting from childhood and/or where there is an accompanying family history of the same in first and/or second degree relatives, causing complications such as nephrocalcinosis, pericarditis, and calcium-based nephrolithiasis.

  • Associated biochemistry of IIH is persistent mild to moderate hypercalcaemia, normal or raised 25-(OH)-vitamin D and elevated 1,25-(OH)2-vitamin D. An elevated ratio of 25-(OH)-vitamin D to 24,25-(OH)2-vitamin D can be a useful marker of defects in the 24-hydroxylase enzyme, whose measurement can be facilitated through the supra-regional assay service.

  • Management should focus on limiting the amount of vitamin D introduced into the body either via sunlight exposure or supplementation in addition to calcium dietary restriction to try and maintain appropriate calcium homeostasis

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Paraskevi Kazakou Endocrine Unit, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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George Simeakis Endocrine Unit, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Maria Alevizaki Endocrine Unit, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Katerina Saltiki Endocrine Unit, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Summary

Medullary thyroid carcinoma (MTC) has a varying clinical course; distant metastases are frequently present even at diagnosis. We present two MTC cases with unusual metastatic sites. Two female patients are presented with slow progressive MTC. The first case developed distant metastases 23 years after diagnosis and underwent locoregional therapies. At the same time a breast mass developed representing MTC metastasis. Treatment with vandetanib led to long-term disease stabilization. The second patient is presented with metastases in the pancreas 13 years after diagnosis. Shortly, a painful mass developed in the mandible and metastasis of MTC was diagnosed. Disease progression was recorded 20 months after the initiation of local and systemic therapy. Such cases have only rarely been reported in the literature and highlight the need for prompt recognition of unexpected MTC metastases.

Learning points

  • Unusual sites of metastasis may appear in patients with medullary thyroid carcinoma (MTC) years after the initial diagnosis.

  • Although rare, unexpected MTC metastases highlight the need for prompt recognition and appropriate treatment.

  • Local recurrences accompanied by inappropriately low calcitonin levels should prompt further investigation for possible distant metastatic disease.

  • Systemic treatment with tyrosine kinase inhibitors may be effective even in patients with unusual metastases from MTC.

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Stamatina Ioakim School of Medicine, University of Milan, Milan, Italy

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Vasilis Constantinides Centre of Endocrine Surgery, Evangelistria Medical Centre, Nicosia, Cyprus
University of Nicosia Medical School, Nicosia, Cyprus

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Meropi Toumba Child Endocrine Care, Department of Pediatrics, Aretaeio Hospital, Nicosia, Cyprus
Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

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Theodoros Lyssiotis Histopathology and Cytology Medical Centre, Nicosia, Cyprus

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Angelos Kyriacou CEDM, Centre of Endocrinology, Diabetes and Metabolism, Limassol, Cyprus
Department of Diabetes, Endocrinology & Obesity Medicine, Salford Royal NHS Foundation & University Teaching Trust, Salford, UK
Medical School, European University of Cyprus, Nicosia, Cyprus

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Summary

Our objective is to demonstrate the importance of considering microcalcifications even without evidence of nodules as a potential sign of malignancy. Current guidelines, such as those of the British Thyroid Association, acknowledge the clinical significance of microcalcifications only when found within nodules. In this case, they are considered a suspicious feature, classifying the nodules as U5 (i.e. high risk) where fine-needle aspiration biopsy (FNAB) is warranted, following the high likelihood of cancer in these nodules. In addition, there is a dearth of evidence of ultrasound scan (USS) detection of microcalcifications in the thyroid gland outside of nodules, along with their associated clinical implications. Yet, this clinical manifestation is not so infrequent considering that we do encounter patients in the clinic showing these findings upon ultrasound examination. Three patients who presented to our clinic with thyroid-related symptoms were shown to have areas of microcalcifications without a nodule upon sonographic evaluation of their thyroid gland. These incidentally detected hyperechoic foci were later confirmed to correspond to areas of papillary thyroid carcinoma (PTC) on histopathological examination of resected tissue following thyroidectomy. Four more cases were identified with sonographic evidence of microcalcifications without nodules and given their clinical and other sonographic characteristics were managed with active surveillance instead.

Learning points

  • Echogenic foci known as microcalcifications may be visible without apparent association to nodular structures.

  • Microcalcifications without nodules may not be an infrequent finding.

  • Microcalcifications are frequently indicative of malignancy within the thyroid gland even without a clearly delineated nodule.

  • Empirically, the usual guidelines for the management of thyroid nodules can be applied to the management of microcalcifications not confined to a nodule, but such a finding per se should be classified as a ‘high-risk’ sign.

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

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Avinaash Maharaj Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Federica Buonocore Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

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Gabriel Angel Martos-Moreno Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain

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Jesús Argente Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
CEI UAM + CSIC, IMDEA Food Institute, Madrid, Spain

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John C Achermann Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK

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Li F Chan Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Lou A Metherell Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

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Summary

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

Learning points

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

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

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

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Fiona Melzer Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany

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Corinna Geisler Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany

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Dominik M Schulte Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany
Department of Medicine 1, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Schleswig-Holstein, Kiel, Germany

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Matthias Laudes Institute of Diabetes and Clinical Metabolic Research, Kiel, Germany
Department of Medicine 1, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Schleswig-Holstein, Kiel, Germany

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Summary

Familial partial lipodystrophy (FPLD) syndromes are rare heterogeneous disorders especially in women characterized by selective loss of adipose tissue, reduced leptin levels and severe metabolic abnormalities. Here we report a 34-year-old female with a novel heterozygotic c.485 thymine>guanine (T>G) missense variant (p.phenylalanine162cysteine; (Phe162Cys)) in exon 4 of the peroxisome proliferator-activated receptor gamma (PPARG) gene, developing a non-ketotic diabetes and severe hypertriglyceridemia with triglyceride concentrations >50 mmol/L. In this case, a particular interesting feature in comparison to other known PPARG mutations in FPLD is that while glycaemic control could be achieved through standard anti-diabetic medication, hypertriglyceridemia did neither respond to fibrate nor to omega-3-fatty acid therapy. This might suggest a lipid metabolism driven phenotype of the novel PPARG c.485T>G missense variant. Notably, recombinant leptin replacement therapy (metreleptin (Myalepta®)) was initiated showing a rapid and profound effect on triglyceride levels as well as on liver function tests and satiety feeling. Unfortunately, severe allergic skin reactions developed at the side of injection which could be covered by anti-histaminc treatment. We conclude that the heterozygous PPARG c.485T>G variant is a yet undescribed molecular basis underlying FPLD with difficulties predominantly to control hypertriglyceridemia and that recombinant leptin therapy may be effective in affected subjects.

Learning points

  • Heterozygous c.485T>G variant in PPARG is most likely a cause for FPLD in humans.

  • This variant results in a special metabolic phenotype with a predominant dysregulation of triglyceride metabolism not responding to standard lipid lowering therapy.

  • Recombinant leptin therapy is effective in rapidly improving hypertriglyceridemia.

Open access