Related Disciplines > Genetics
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Second Department of Internal Medicine, Papanikolaou General Hospital, Thessaloniki, Greece
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Summary
We report a case of a female with hemihypertrophy, who developed five recurrences of pheochromocytomas until the age of 35. Timely follow-up of the patient's blood pressure assisted in early diagnosis and treatment of recurrent tumors.
Learning points
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Recurrent benign pheochromocytomas should raise suspicion of a genetic syndrome.
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A pheochromocytoma at a young age has a high propensity to recur and strict follow-up is mandatory.
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Summary
A 22-year-old female student presented with a history of recurrent pancreatitis. The commonest causes of pancreatitis, including drugs, gallstones, corticosteroids, excess alcohol and hypertriglyceridaemia, were excluded. She was found to have an elevated serum calcium level that was considered to be the cause of her pancreatitis, with a detectable serum parathyroid hormone (PTH). An initial diagnosis of primary hyperparathyroidism was made. However, two neck explorations failed to reveal a parathyroid adenoma. She was referred to our unit three years later as her episodes of pancreatitis were becoming more frequent and her calcium level remained persistently elevated. Her investigations were as follows: elevated adjusted calcium level of 2.79 mmol/l (2.2–2.58), PTH level of 4.2 pmol/l (0.6–6.0), low 24 h urine calcium of 0.3 mmol/l and a urine calcium:creatinine ratio of <0.003. A clinical diagnosis of familial hypocalciuric hypercalcaemia (FHH) was made and confirmed on genetic testing that showed a c.1703 G>A mutation in the calcium-sensing receptor gene. Although the hypercalcaemia of FHH is usually without sequelae due to the generalised changes in calcium sensing, in the presence of this complication she was started on cinacalcet 30 mg daily. She had one further episode of pancreatitis with calcium levels ranging between 2.53 and 2.66 mmol/l. Her cinacalcet was gradually increased to 30 mg three times daily, maintaining her calcium levels in the range of 2.15–2.20 mmol/l. She has not had a further episode of pancreatitis for more than 2 years.
FHH is usually a benign condition with minimal complications from hypercalcaemia. Pancreatitis has been reported rarely, and no clear management strategy has been defined in these cases. Cinacalcet was successfully used in treating recurrent pancreatitis in a patient with FHH by maintaining calcium levels in the lower part of the reference range. Whether or not this is an effective long-term treatment remains yet to be seen.
Learning points
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FHH is an important differential diagnosis for hypercalcaemia.
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FHH can rarely cause pancreatitis.
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No clear strategy is available to help in the management of patients with pancreatitis due to FHH.
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Cinacalcet was effective in lowering serum calcium levels and reducing the frequency of pancreatitis in our patient with FHH.
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Summary
Isolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet.
Learning points
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Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.
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Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.
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Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.
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Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.
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Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.
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Summary
Hypokalaemia may present as muscle cramps and Cardiac arrhythmias. This is a condition commonly encountered by endocrinologists and general physicians alike. Herein, we report the case of a 43-year-old gentleman admitted with hypokalaemia, who following subsequent investigations was found to have Gitelman's syndrome (GS). This rare, inherited, autosomal recessive renal tubular disorder is associated with genetic mutations in the thiazide-sensitive sodium chloride co-transporter and magnesium channels in the distal convoluted tubule. Patients with GS typically presents at an older age, and a spectrum of clinical presentations exists, from being asymptomatic to predominant muscular symptoms. Clinical suspicion should be raised in those with hypokalaemic metabolic alkalosis associated with hypomagnesaemia. Treatment of GS consists of long-term potassium and magnesium salt replacement. In general, the long-term prognosis in terms of preserved renal function and life expectancy is excellent. Herein, we discuss the biochemical imbalance in the aetiology of GS, and the case report highlights the need for further investigations in patients with recurrent hypokalaemic episodes.
Learning points
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Recurrent hypokalaemia with no obvious cause warrants investigation for hereditary renal tubulopathies.
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GS is the most common inherited renal tubulopathy with a prevalence of 25 per million people.
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GS typically presents at an older age and clinical suspicion should be raised in those with hypokalaemic metabolic alkalosis associated with hypomagnesaemia.
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Confirmation of diagnosis is by molecular analysis for mutation in the SLC12A3 gene.
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Summary
background: Congenital hyperinsulinism (CHI) is a rare genetic disorder characterised by inappropriate insulin secretion in the face of severe hypoglycaemia. There are two histological subtypes of CHI namely diffuse and focal. Diffuse CHI is most common due to recessive mutations in ABCC8/KCNJ11 (which encode the SUR/KIR6.2 components of the pancreatic β-cell KATP channel) whereas focal CHI is due to a paternally inherited ABCC8/KCNJ11 mutation and somatic loss of heterozygosity for the 11p allele inside the focal lesion. Fluorine-18-l-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA-PET/CT) is used in the pre-operative localisation of focal lesions prior to surgery. Diffuse CHI if medically unresponsive will require a near total pancreatectomy whereas focal CHI will only require a limited lesionectomy, thus curing the patient from the hypoglycaemia.
Aims: To report the first case of genetically confirmed CHI in Singapore from a heterozygous paternally inherited ABCC8 mutation.
Methods/Results: A term male infant presented with severe hyperinsulinaemic hypoglycaemia (HH) after birth and failed medical treatment with diazoxide and octreotide. Genetic testing (paternally inherited mutation in ABCC8/p.D1472N) suggested focal disease, but due to the unavailability of 18F-DOPA-PET/CT to confirm focal disease, a partial pancreatectomy was performed. Interestingly, histology of the resected pancreatic tissue showed changes typical of diffuse disease.
Conclusion: Heterozygous paternally inherited ABCC8/KCNJ11 mutations can lead to diffuse or focal CHI.
Learning points
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HH is a cause of severe hypoglycaemia in the newborn period.
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Paternal mutations in ABCC8/KCNJ11 can lead to diffuse or focal disease.
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18F-DOPA-PET/CT scan is the current imaging of choice for localising focal lesions.
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Gallium-68 tetra-aza-cyclododecane-N N′N″N-‴-tetra-acetate octreotate PET scan is not a useful imaging tool for localising focal lesions.
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The molecular mechanism by which a heterozygous ABCC8 mutation leads to diffuse disease is currently unclear.
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Focal lesions are curable by lesionectomy and so genetic studies in patients with HH must be followed by imaging using 18F-DOPA-PET/CT scan.
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The Medical School, Newcastle University, Newcastle NE24HH, UK
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The Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle-upon-Tyne NE1 3BZ, UK
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Summary
Aim: Differentiating familial cranial diabetes insipidus (CDI) from primary polydipsia can be difficult. We report the diagnostic utility of genetic testing as a means of confirming or excluding this diagnosis.
Patient and methods: The index case presented at 3 months with polydipsia. He was diagnosed with familial CDI based on a positive family history combined with what was considered to be suspicious symptomatology and biochemistry. He was treated with desmopressin (DDAVP) but re-presented at 5 months of age with hyponatraemia and the DDAVP was stopped. Gene sequencing of the vasopressin gene in father and his offspring was undertaken to establish the underlying molecular defect.
Results: Both father and daughter were found to have the pathogenic mutation c.242T>C (p.Leu81Pro) in exon 2 of the AVP gene consistent with a diagnosis of familial diabetes insipidus. The index case did not have the pathogenic mutation and the family could be reassured that he would not require intervention with DDAVP.
Conclusions: Gene sequencing of AVP gene can have a valuable role in predicting whether or not a child is at risk of developing CDI in future. This can help to prevent family uncertainty and unnecessary treatment with its associated risks.
Learning points
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Differentiating patients with familial cranial diabetes insipidus from those with primary polydipsia is not always straightforward.
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Molecular genetic analysis of the vasopressin gene is a valuable way of confirming or refuting a diagnosis of familial CDI in difficult cases and is a valuable way of identifying individuals who will develop CDI in later childhood. This information can be of great value to families.
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Summary
We present the case of a 30-year-old female who was diagnosed with hereditary phaeochromocytoma secondary to a rare gene mutation in exon 8 of the RET oncogene. This genetic mutation was picked up as part of an extended genetic screen using a method known as next generation sequencing. Detection of this genetic mutation prompted further screening for the manifestation of multiple endocrine neoplasia type 2A (MEN2A). The patient subsequently underwent a thyroidectomy with histology confirming C-cell hyperplasia.
Learning points
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Genetic analysis is an important step in the diagnostic work up of phaeochromocytoma.
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Extended genetic analysis is important when there is a strong suspicion of hereditary phaeochromocytoma.
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Mutations in exon 8 of the RET gene are associated with phaeochromocytoma as part of MEN2A syndrome.
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Summary
A 19-year-old woman was diagnosed with osteogenesis imperfecta (OI). She had sustained numerous low-trauma fractures throughout her childhood, including a recent pelvic fracture (superior and inferior ramus) following a low-impact fall. She had the classical blue sclerae, and dual energy X-ray absorptiometry (DEXA) bone scanning confirmed low bone mass for her age in the lumbar spine (Z-score was −2.6). However, despite these classical clinical features, the diagnosis of OI had not been entertained throughout the whole of her childhood. Sequencing of her genomic DNA revealed that she was heterozygous for the c.3880_3883dup mutation in exon 50 of the COL1A1 gene. This mutation is predicted to result in a frameshift at p.Thr1295, and truncating stop codon 3 amino acids downstream. To our knowledge, this mutation has not previously been reported in OI.
Learning points
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OI is a rare but important genetic metabolic bone and connective tissue disorder that manifests a diverse clinical phenotype that includes recurrent low-impact fractures.
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Most mutations that underlie OI occur within exon 50 of the COL1A1 gene (coding for protein constituents of type 1 pro-collagen).
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The diagnosis of OI is easily missed in its mild form. Early diagnosis is important, and there is a need for improved awareness of OI among health care professionals.
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OI is a diagnosis of exclusion, although the key diagnostic criterion is through genetic testing for mutations within the COL1A1 gene.
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Effective management of OI should be instituted through a multidisciplinary team approach that includes a bone specialist (usually an endocrinologist or rheumatologist), a geneticist, an audiometrist and a genetic counsellor. Physiotherapy and orthopaedic surgery may also be required.
