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Summary
Ovarian hyperstimulation syndrome (OHSS) usually occurs in patients undergoing assisted reproduction techniques and ovulation induction. Its variant, spontaneous ovarian hyperstimulation syndrome, a potentially life-threatening disorder, is uncommon and only a few cases have been reported in association with hypothyroidism. This study analysed five patients with untreated chronic hypothyroidism presenting with multicystic ovaries, isosexual precocious puberty, and delayed bone age; subsequently, the follow-up and regression of ovarian pathology was assessed. Two patients had presented to the emergency department with menorrhagia and hypotension, of these, one had ovarian torsion at presentation. Three patients presented to the outpatient department: one for evaluation of short stature, one for premature menarche, and another with polycystic ovaries. They were all diagnosed with long-standing, untreated chronic hypothyroidism. There was regression of the size of the cystic ovaries on subsequent follow-up. In all these patients, long-standing hypothyroidism had resulted in ovarian hyperstimulation syndrome. The potentially life-threatening complications of this syndrome may be prevented by careful screening and a strong index of clinical suspicion at the outset.
Learning points
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Long-standing, untreated primary hypothyroidism may result in spontaneous ovarian hyperstimulation syndrome.
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A high index of suspicion is required for an early and accurate diagnosis.
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The requirement for interdepartmental collaboration between gynaecology and endocrinology departments is essential for the successful management of this life-threatening but easily treatable disorder.
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Summary
Insulin autoantibody syndrome (IAS) or Hirata’s disease is a rare condition characterized by recurrent fasting hypoglycaemic and postprandial hyperglycaemic episodes. Insulin autoantibodies are diagnostic for the condition. Hirata’s disease has been seen to be associated with other autoimmune conditions. Vitiligo is a common depigmentation disorder whose exact cause is unknown but thought to have an autoimmune aetiology. Although autoimmunity plays a role in the pathogenesis of both the diseases, association between the two has not been reported till date. In our case, a 72-year-old Indian woman with vitiligo for the past 30 years presented with recurrent episodes of fasting hypoglycaemia. She was found to have very high levels of fasting insulin, C-peptide, and insulin antibody and was diagnosed with IAS. Thus, we conclude that the clinical spectrum of Hirata’s disease has to be taken as more heterogenous than previously assumed.
Learning points
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Insulin autoantibody syndrome (IAS) or Hirata’s disease is a rare condition characterized by recurrent fasting hypoglycaemic and postprandial hyperglycaemic episodes in which insulin plays a major role.
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Insulin autoantibodies are diagnostic for IAS. The endocrine insulin and its autoantibodies play a major role in the pathogenesis of the disease.
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Vitiligo is a common depigmentation disorder whose exact cause is unknown but thought to have an autoimmune aetiology.
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IAS and vitiligo are two diseases with autoimmune aetiology which has been seen to be associated with each other (the first case to be reported).
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The clinical spectrum of Hirata’s disease has to be taken as more heterogenous than previously assumed.
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On dealing with autoimmune diseases, we should also keep in mind about other diseases with autoimmune pathogenesis.
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University of Melbourne, Parkville, Victoria, Australia
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Summary
Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly.
Learning points
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Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state.
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Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity.
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AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia.
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Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN.
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Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.
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Summary
An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC)/paraganglioma is the cause of ectopic Cushing’s syndrome (CS) in 5.2% of cases reported in the literature. We present a previously healthy 43-year-old woman admitted to our hospital with cushingoid features and hypertensive urgency (blood pressure = 200/120 mmHg). Her 24-h urinary free cortisol was >4270 nmol/day (reference range (RR) = 100–380 nmol/day) with a plasma ACTH of 91.5 pmol/L (RR: 2.0–11.5 pmol/L). Twenty-four-hour urinary metanephrines were increased by 30-fold. Whole-body CT demonstrated a 3.7-cm left adrenal mass with a normal-appearing right adrenal gland. Sellar MRI showed a 5-mm sellar lesion. MIBG scan revealed intense uptake only in the left adrenal mass. She was managed pre-operatively with ketoconazole and phenoxybenzamine and underwent an uneventful left laparoscopic adrenalectomy, which resulted in biochemical resolution of her hypercortisolemia and catecholamine excess. Histology demonstrated a PCC (Grading System for Adrenal Pheochromocytoma and Paraganglioma score 5) with positive ACTH staining by immunohistochemistry. A PCC gene panel showed no mutations and there has been no evidence of recurrence at 24 months. This case highlights the difficult nature of localizing the source of CS in the setting of a co-existing PCC and sellar mass.
Learning points
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An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC) is an important item to be considered in all patients presenting with ectopic Cushing’s syndrome (CS).
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In exceptionally rare cases, patients with ectopic CS may present with multiple lesions, and a systematic approach considering all potential sources is crucial to avoid misdiagnosis.
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CS with a large adrenal mass but lacking contralateral adrenal atrophy should raise suspicion of an ACTH-dependent process.
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In patients with clinical suspicion of PCC, clinicians should be mindful of the use of steroids and beta-blockers without appropriate alpha blockade as they may precipitate an adrenergic crisis.
Search for other papers by Pranav Gupta in
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Division of Endocrinology, Department of Pediatrics, Connecticut Childrens Medical Center, Farmington, Connecticut, USA
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Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, 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
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Eliciting a detailed family history is important in hypoglycemia cases.
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Obtaining a thorough dietary intake, weight history, and menstrual cycles (in females) and considering a psychiatric consultation for an eating disorder when indicated.
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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.
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Summary
Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves’ disease (GD). Additional/concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 µg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range <1.75). MRI revealed an enhancing lesion infiltrating the left superior rectus, with concurrent characteristic muscle belly involvement bilaterally. Orbital biopsy showed atypical lymphoid cells (CD20+), suggesting marginal zone lymphoma. CT thorax and abdomen, fluorodeoxyglucose-positron emission tomography and bone marrow examination were normal. The patient was administered orbital radiotherapy for her localised lymphoma and carbimazole was continued. TED is the most common cause of orbital involvement overall and in GD. However, additional or alternative pathology may be present which requires evaluation. MRI can be a useful adjunct in these patients. Orbital lymphoma needs to be staged with workup for disseminated disease. Radiotherapy is the treatment of choice for localized disease. The index case provides evidence for synchronous presentation of dual pathology and highlights the importance of astute clinical examination as well as keeps a low threshold for MRI in selected cases.
Learning points
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Thyroid eye disease can co-exist with other ocular pathology, especially in elderly individuals.
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Eccentric proptosis, absent lid lag and restriction of eye movements (suggesting tendon involvement) should alert towards the presence of alternative pathology.
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Orbital imaging using MRI not only has greater sensitivity in diagnosing radiologically bilateral disease in patients who have unilateral involvement clinically but is also useful to identify concurrent neoplasms.
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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Summary
A 62-year-old Asian British female presented with increasing tiredness. She had multiple co-morbidities and was prescribed steroid inhalers for asthma. She had also received short courses of oral prednisolone for acute asthma exacerbations in the last 2 years. Unfortunately, the frequency and dose of steroids for asthma was unclear from history. Her type 2 diabetes mellitus (DM) control had deteriorated over a short period of time (HbA1c: 48–85 mmol/mol). Blood tests revealed undetectable cortisol and ACTH (<28 mmol/L, <5.0 ng/L). Renin, electrolytes and thyroid function were within normal limits. A diagnosis of secondary adrenal insufficiency, likely due to long-term steroid inhaler and recurrent short courses of oral steroids for asthma exacerbations was made. Patient was commenced on hydrocortisone 10 mg, 5 mg and 5 mg regimen. Steroid inhaler was discontinued following consultation with respiratory physicians. Despite discontinuation of inhaled steroids, patient continued not to mount a response to Synacthen®. Upon further detailed history, patient admitted taking a ‘herbal’ preparation for chronic osteoarthritic knee pain. Toxicology analysis showed presence of dexamethasone, ciprofloxacin, paracetamol, diclofenac, ibuprofen and cimetidine in the herbal medication. Patient was advised to discontinue her herbal preparation. We believe the cause of secondary adrenal insufficiency in our patient was the herbal remedy containing dexamethasone, explaining persistent adrenal suppression despite discontinuation of all prescribed steroids, further possibly contributing to obesity, hypertension and suboptimal control of DM. In conclusion, a comprehensive drug history including herbal and over-the-counter preparations should be elucidated. Investigation for the presence of steroids in these preparations should be considered when patients persist to have secondary adrenal insufficiency despite discontinuation of prescribed steroid medications.
Learning points:
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The likelihood of complementary and alternative medicines (CAMs) in medication-induced secondary adrenal insufficiency should be considered in any patient presenting with potential symptoms of adrenal insufficiency.
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If the contents of CAM preparation cannot be ascertained, toxicology screening should be considered.
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Patients should be advised to stop taking CAM preparation when it contains steroids and hydrocortisone replacement therapy commenced, with periodic reassessment of adrenal function, and then if indicated weaned accordingly.
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Patients should be informed about the contents of CAM therapies, so they can make a truly informed choice regarding the risks and benefits.
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This case also highlights a need to increase regulatory processes over CAM therapies, given their propensity to contain a number of undisclosed medications and potent steroids.
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Summary
In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases.
Learning points:
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CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.
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CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.
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Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.
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Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.
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Summary
Combined pituitary hormonal deficiency (CPHD) is a rare disease that results from mutations in genes coding for transcription factors that regulate the differentiation of pituitary cells. PROP1 gene mutations are one of the etiological diagnoses of congenital panhypopituitarism, however symptoms vary depending on phenotypic expression. We present a case of psychosis in a 36-year-old female with congenital panhypopituitarism who presented with paranoia, flat affect and ideas of reference without a delirious mental state, which resolved with hormone replacement and antipsychotics. Further evaluation revealed that she had a homozygous mutation of PROP1 gene. In summary, compliance with hormonal therapy for patients with hypopituitarism appears to be effective for the prevention and treatment of acute psychosis symptoms.
Learning points:
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Patients with PROP1 gene mutation may present with psychosis with no impairment in orientation and memory.
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There is currently inadequate literature on this topic, and further study on the possible mechanisms of psychosis as a result of endocrine disturbance is required.
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Compliance with hormonal therapy for patients with hypopituitarism appears to be effective for prevention and treatment of acute psychosis symptoms.
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Summary
Carney complex (CNC) is a rare autosomal dominant syndrome characterized by pigmented lesions of the skin and mucosae along with cardiac, endocrine, cutaneous, and neural myxomatous tumors. Mutations in the PRKAR1A gene have been identified in ∼70% of the CNC cases reported worldwide. A 30-year-old male was referred to the endocrinology clinic with suspected acromegaly. He had a history of recurrent atrial myxoma for the past 8 years for which he underwent repeated surgeries. Presently, he complained of having headache, excessive snoring, sweating, and also noticed increase in his shoe size. Evaluation for acromegaly revealed elevated levels of GH in random as well as in suppressed condition. Magnetic resonance imaging scan revealed enlarged sella with microadenoma in the left anterior pituitary. Screening of PRKAR1A gene was carried out for the patient, his parents and siblings who were available and willing to undergo the test. The patient was diagnosed to have the rare CNC syndrome characterized by recurrent atrial myxoma and acromegaly due to a novel 22 bp insertion mutation in PRKAR1A which was predicted to be deleterious by in silico analysis. Screening the available family members revealed the absence of this mutation in them except the elder brother who also tested positive for this mutation. The present study reports on a novel PRKAR1A insertion mutation in a patient with acromegaly and left atrial myxoma in CNC.
Learning points
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Identification of a novel deleterious PRKAR1A insertion mutation causing CNC.
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It is important that patients with cardiac myxoma be investigated for presence of endocrine overactivity suggestive of CNC.
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PRKAR1A mutation analysis should be undertaken in such cases to confirm the diagnosis in the patients as well as first degree relatives.
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This case highlights an important aspect of diagnosis, clinical course, and management of this rare condition.
