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Open access

Sakshi Jhawar, Rahul Lakhotia, Mari Suzuki, James Welch, Sunita K Agarwal, John Sharretts, Maria Merino, Mark Ahlman, Jenny E Blau, William F Simonds and Jaydira Del Rivero

Summary

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5–15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF).

Learning points:

  • Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET.

  • Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins.

  • Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence.

  • Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.

Open access

Gemma White, Nicola Tufton and Scott A Akker

Summary

At least 40% of phaeochromocytomas and paraganglioma’s (PPGLs) are associated with an underlying genetic mutation. The understanding of the genetic landscape of these tumours has rapidly evolved, with 18 associated genes now identified. Among these, mutations in the subunits of succinate dehydrogenase complex (SDH) are the most common, causing around half of familial PPGL cases. Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation. Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants were identified retrospectively. We report the case of an asymptomatic suspected carotid body tumour found during surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant. To our knowledge, this is the first screen that detected PPGL found in a previously identified SDHA pathogenic variant carrier, during surveillance imaging. This finding supports the use of cascade genetic testing and surveillance screening in all carriers of a pathogenic SDHA variant.

Learning points:

  • SDH mutations are important causes of PPGL disease.

  • SDHA is much rarer compared to SDHB and SDHD mutations.

  • Pathogenicity and penetrance are yet to be fully determined in cases of SDHA-related PPGL.

  • Surveillance screening should be used for SDHA PPGL cases to identify recurrence, metastasis or metachronous disease.

  • Surveillance screening for SDH-related disease should be performed in identified carriers of a pathogenic SDHA variant.

Open access

Jonathan Brown and Luqman Sardar

Summary

A 68-year-old previously independent woman presented multiple times to hospital over the course of 3 months with a history of intermittent weakness, vacant episodes, word finding difficulty and reduced cognition. She was initially diagnosed with a TIA, and later with a traumatic subarachnoid haemorrhage following a fall; however, despite resolution of the haemorrhage, symptoms were ongoing and continued to worsen. Confusion screen blood tests showed no cause for the ongoing symptoms. More specialised investigations, such as brain imaging, cerebrospinal fluid analysis, electroencephalogram and serology also gave no clear diagnosis. The patient had a background of hypothyroidism, with plasma thyroid function tests throughout showing normal free thyroxine and a mildly raised thyroid-stimulating hormone (TSH). However plasma anti-thyroid peroxidise (TPO) antibody titres were very high. After discussion with specialists, it was felt she may have a rare and poorly understood condition known as Hashimoto’s encephalopathy (HE). After a trial with steroids, her symptoms dramatically improved and she was able to live independently again, something which would have been impossible at presentation.

Learning points:

  • In cases of subacute onset confusion where most other diagnoses have already been excluded, testing for anti-thyroid antibodies can identify patients potentially suffering from HE.

  • In these patients, and under the guidance of specialists, a trial of steroids can dramatically improve patient’s symptoms.

  • The majority of patients are euthyroid at the time of presentation, and so normal thyroid function tests should not prevent anti-thyroid antibodies being tested for.

  • Due to high titres of anti-thyroid antibodies being found in a small percentage of the healthy population, HE should be treated as a diagnosis of exclusion, particularly as treatment with steroids may potentially worsen the outcome in other causes of confusion, such as infection.

Open access

Yang Timothy Du, Lynette Moore, Nicola K Poplawski and Sunita M C De Sousa

Summary

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology.

Learning points:

  • Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history.

  • Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management.

  • Identification of a genetic disorder may have important implications for family planning.

Open access

Chloe Broughton, Jane Mears, Adam Williams and Kathryn Lonnen

Summary

Pituitary adenomas can be classified as functioning or non-functioning adenomas. Approximately 64% of clinically non-functioning pituitary adenomas are found to be gonadotroph adenomas on immunohistochemistry. There are reported cases of gonadotroph adenomas causing clinical symptoms, but this is unusual. We present the case of a 36-year-old female with abdominal pain. Multiple large ovarian cysts were identified on ultrasound requiring bilateral cystectomy. Despite this, the cysts recurred resulting in further abdominal pain, ovarian torsion and right oophorectomy and salpingectomy. On her 3rd admission with abdominal pain, she was found to have a rectus sheath mass which was resected and histologically confirmed to be fibromatosis. Endocrine investigations revealed elevated oestradiol, follicle-stimulating hormone (FSH) at the upper limit of the normal range and a suppressed luteinising hormone (LH). Prolactin was mildly elevated. A diagnosis of an FSH-secreting pituitary adenoma was considered and a pituitary MRI revealed a 1.5 cm macroadenoma. She underwent transphenoidal surgery which led to resolution of her symptoms and normalisation of her biochemistry. Subsequent pelvic ultrasound showed normal ovarian follicular development. Clinically functioning gonadotroph adenomas are rare, but should be considered in women presenting with menstrual irregularities, large or recurrent ovarian cysts, ovarian hyperstimulation syndrome and fibromatosis. Transphenoidal surgery is the first-line treatment with the aim of achieving complete remission.

Learning points:

  • Pituitary gonadotroph adenomas are usually clinically non-functioning, but in rare cases can cause clinical symptoms.

  • A diagnosis of a functioning gonadotroph adenoma should be considered in women presenting with un-explained ovarian hyperstimulation and/or fibromatosis.

  • In women with functioning gonadotroph adenomas, the main biochemical finding is elevated oestradiol levels. Serum FSH levels can be normal or mildly elevated. Serum LH levels are usually suppressed.

  • Transphenoidal surgery is the first-line treatment for patients with functioning gonadotroph adenomas, with the aim of achieving complete remission.

Open access

Ellena Cotton and David Ray

Summary

A young woman carrying germline DICER1 mutation was discovered to have a pituitary microprolactinoma when she became amenorrhoic. The mutation was identified as a result of family screening following the early death of the patient’s daughter with ovarian cancer. The patient was in follow-up screening for thyroid disease, and investigations were initiated when she became amenorrhoic. MR scan revealed a 6 mm diameter pituitary microadenoma and raised prolactin. The prolactin was efficiently suppressed with low-dose cabergoline, and her menstrual cycles resumed. Dicer is an RNase enzyme, which is essential for processing small non-coding RNAs. These molecules play pleiotropic roles in regulating gene expression, by targeting mRNA sequences for degradation. DICER1 plays different roles depending on cell context, but is thought to be a functional tumour suppressor gene. Accordingly, germline mutation in one DICER1 allele is insufficient for oncogenesis, and a second hit on the other allele is required, as a result of postnatal somatic mutation. Loss of DICER1 is linked to multiple tumours, with prominent endocrine representation. Multinodular goitre is frequent, with increased risk of differentiated thyroid cancer. Rare, developmental pituitary tumours are reported, including pituitary blastoma, but not reports of functional pituitary adenomas. As DICER1 mutations are rare, case reports are the only means to identify new manifestations and to inform appropriate screening protocols.

Learning points:

  • DICER1 mutations lead to endocrine tumours.

  • DICER1 is required for small non-coding RNA expression.

  • DICER1 carriage and microprolactinoma are both rare, but here are reported in the same individual, suggesting association.

  • Endocrine follow-up of patients carrying DICER1 mutations should consider pituitary disease.

Open access

Benjamin Kwan, Bernard Champion, Steven Boyages, Craig F Munns, Roderick Clifton-Bligh, Catherine Luxford and Bronwyn Crawford

Summary

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members.

Learning points:

  • ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.

  • In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.

  • CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.

  • Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.

Open access

Yang Timothy Du, Angus Rutter and Jui T Ho

Summary

A 40-year-old man with achondroplasia presented with symptoms of hypogonadism, low libido and gynaecomastia. He was found to have hypergonadotropic hypogonadism, and karyotype and fluorescent in situ hybridisation analysis showed SRY-positive 46, XX disorder of sex development (DSD). He was tested to have the common activating mutation of the FGFR3 gene implicated in achondroplasia, indicating that he had the two rare conditions independently, with an extremely low incidence of 1 in 400 million. This, to the best of our knowledge, is the first report of an individual having these two rare conditions concurrently. This case highlights that individuals with achondroplasia should have normal sexual development, and in those presenting with incomplete sexual maturation or symptoms of hypogonadism should prompt further evaluation. We also propose a plausible link between achondroplasia and 46, XX DSD through the intricate interactions between the SRY, SOX9 and FGFR9 gene pathways.

Learning points:

  • The SOX9 and FGF9 genes, which are upregulated by the SRY gene, are important in both sex determination in the embryo, as well as endochondral bone growth.

  • Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.

  • Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.

Open access

Michelle Maher, Federico Roncaroli, Nigel Mendoza, Karim Meeran, Natalie Canham, Monika Kosicka-Slawinska, Birgitta Bernhard, David Collier, Juliana Drummond, Kassiani Skordilis, Nicola Tufton, Anastasia Gontsarova, Niamh Martin, Márta Korbonits and Florian Wernig

Summary

Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population. It is estimated that 5% of pituitary adenomas occur in a familial setting, either in isolated or syndromic form. Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas. It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma. We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms. Initially, the adenoma showed biochemical response but poor tumour shrinkage in response to cabergoline; therefore, transsphenoidal surgery was performed. Following initial clinical improvement, tumour recurrence was identified 15 months later. Interestingly, re-initiation of cabergoline proved successful and the lesion demonstrated both biochemical response and tumour shrinkage. Our patient’s SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing. Re-inspection of the histopathological report of the prolactinoma confirmed cells with vacuolated cytoplasm. This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing. Surprisingly, immunohistochemistry of this pituitary adenoma demonstrated normal SDHB expression, despite loss of SDHB expression in the patient’s father’s paraganglioma.

Learning points:

  • Pituitary adenomas may be the presenting and/or sole feature of SDHB mutation-related disease.

  • SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.

  • Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.

  • Immunohistochemistry may not always predict the presence of SDHx mutations.

Open access

Gordon Sloan, Tania Kakoudaki and Nishant Ranjan

Summary

We report a case of a 63-year-old man who developed diabetic ketoacidosis (DKA) associated with canagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor. He presented acutely unwell with a silent myocardial infarction, diverticulitis and DKA with a minimally raised blood glucose level. Standard therapy for DKA was initiated. Despite this, ketonaemia persisted for a total of 12 days after discontinuation of canagliflozin. Glucosuria lasting for several days despite discontinuation of the medications is a recognised phenomenon. However, this is the longest duration of ketonaemia to be reported. The cause of prolonged SGLT-2 inhibition remains uncertain. Deviation from the normal DKA treatment protocol and use of personalised regimens may be required in order to prevent relapse into ketoacidosis while avoiding hypoglycaemia in those that develop this condition.

Learning points:

  • Diabetic ketoacidosis (DKA) may develop in the presence of lower-than-expected blood glucose levels in patients treated with a sodium glucose co-transporter 2 (SGLT-2) inhibitor.

  • Certain individuals prescribed with SGLT-2 inhibitors may be more at risk of DKA, for example, those with a low beta cell function reserve, excessive alcohol consumption and a low carbohydrate diet.

  • In order to reduce the risk of SGLT-2 inhibitor-associated DKA, all patients must be carefully selected before prescription of the medication and appropriately educated.

  • Increased serum ketone levels and glucosuria have been reported to persist for several days despite discontinuation of their SGLT-2 inhibitor.

  • Physicians should consider individualised treatment regimens for subjects with prolonged DKA in the presence of SGLT-2 inhibition.