A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma.

Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.

Outpatient synacthen testing in a large metropolitan region: a clinical audit.

AIM: To audit short synacthen tests (SSTs) performed at a single laboratory within the greater Auckland area. METHODS: Two hundred and eighty-seven SSTs conducted in 286 individuals between September 2016 and September 2019 were assessed. Test requests were not triaged. We assessed source of referrals, indications for testing, adequacy of pre-test information and test outcomes. RESULTS: Seventy-one percent of referrals were for women. Fifty-six percent were from primary care and 18% from rheumatology. One-hundred and fifteen (40%) of those referred had been taking corticosteroids within the previous three months: this information was only provided in 49 referrals. In 32% of referrals, no serum cortisol measurement had been undertaken within the previous six months. In 20% of referrals, no indication was provided. Thirty-three (11%) SSTs were abnormal. Of these, 29 were in patients taking corticosteroids. No SSTs were abnormal among 64 patients with pre-test serum cortisol >300nmol/L or >400nmol/L according to the cortisol assay in use. CONCLUSIONS: Referrals for SSTs often lack important information, such as the indication for testing and recent corticosteroid exposure. Up to one quarter of SSTs could be avoided if a serum cortisol was routinely measured prior to referral. Adopting a structured referral form that mandates provision of important clinical and biochemical data might reduce unnecessary testing.

A rare simultaneous manifestation of polyglandular autoimmune syndrome type II.

SUMMARY: Polyglandular autoimmune syndrome type II is a rare condition defined by the presence of autoimmune primary adrenal insufficiency along with autoimmune thyroid disease and/or type-I diabetes. Onset of these conditions will usually be separated by several years, though in rare instances it can occur simultaneously. This syndrome can also be associated with various non-endocrine autoimmune diseases, such as vitiligo and alopecia. Coeliac disease is less commonly associated with polyglandular autoimmune syndrome type II and is more commonly associated with polyglandular autoimmune syndrome type III. Here we describe an interesting case of a young male presenting with simultaneous manifestation of Addison's disease and Graves, with coincident asymptomatic coeliac disease, as a rare manifestation of polyglandular autoimmune syndrome type II. LEARNING POINTS: Polyglandular autoimmune syndrome type II is rare, has female predominance, and peak onset in the third and fourth decades of life. Onset of Addison's disease will usually precede or follow onset of type-I diabetes or autoimmune thyroid disease by several years in this syndrome. Simultaneous onset can occur, as in this case. Coeliac disease is uncommonly associated with this syndrome. Coeliac disease is more commonly associated with polyglandular autoimmune syndrome type III. Coeliac disease should be screened for in patients with associated autoimmune conditions, such as type-I diabetes or autoimmune thyroid disease.

An unusual case of Cushing's syndrome due to bihormonal ACTH-prolactin secreting pituitary macroadenoma with rapid response to cabergoline.

A 23-year-old man presenting with florid Cushing's syndrome was found to have high plasma ACTH and very high serum prolactin. Pituitary MRI showed a large invasive macroadenoma. Low-dose cabergoline promptly suppressed both ACTH and prolactin levels within 2 weeks, with unexpected clinical and biochemical hypocortisolism requiring hydrocortisone replacement. Secondary hypogonadism was reversed. Clinical and biochemical remission of his Cushing's syndrome together with significant shrinkage of his macroadenoma has been maintained for 1 year on cabergoline 0.5 mg twice weekly. Reduction in pituitary tumour volume and brisk fall in serum prolactin in response to low-dose cabergoline is regularly observed in patients with macroprolactinomas, but the concurrent fall in the plasma ACTH level and hypocortisolism was a pleasant surprise. We assume that he most likely has a single bihormonal adenoma that is enriched with dopamine-2 receptors.

Neurological manifestations of phaeochromocytomas and secretory paragangliomas: a reappraisal.

OBJECTIVE: To determine the frequency and range of neurological manifestations of phaeochromocytomas and secretory paragangliomas. METHODS: A retrospective review of case notes of patients admitted to Auckland Hospital from 1985 to 2011 with a discharge diagnosis of phaeochromocytoma or secretory paraganglioma. RESULTS: Ninety-three patients were admitted with a phaeochromocytoma or secretory paraganglioma. Sixty-eight patients (73%) had neurological symptoms, but only 15 patients (16%) received a neurological consultation. Neurological manifestations occurred in three main clinical contexts. First, paroxysmal symptoms occurred in 66 of 93 patients (71%). Neurological symptoms were common features of these attacks and included headache (47 patients), anxiety (24 patients), tremulousness (15 patients) and dizziness (12 patients). The headaches typically had an explosive onset. Delay in diagnosis was common. Second, 28 patients (30%) had an acute crisis, which was associated with neurological symptoms in 11 (39%) of the episodes: headache (10 patients); seizures (five patients); strokes (three patients); delirium (three patients) and subarachnoid haemorrhage (one patient). Third, five of six patients with a head and neck secretory paraganglioma had neurological symptoms related to infiltration of the middle ear or compression of cranial nerves. Reversible cerebral vasoconstriction syndrome (RCVS) was documented in three patients. CONCLUSIONS: Neurological manifestations of phaeochromocytomas and secretory paragangliomas were common, and these tumours can present with various neurological manifestations. The paroxysmal symptoms can be incorrectly attributed to other headache syndromes, panic attacks or cerebral vasculitis. RCVS may play a role in the pathogenesis of the neurological symptoms associated with acute crises and paroxysmal attacks.

Delayed puberty from partial 17-alpha hydroxylase enzyme deficiency.

An 18-year-old woman with primary amenorrhoea and pubertal delay was investigated for mild labile hypertension and secondary hypogonadism. Low renin and normal aldosterone levels combined with evidence of primary adrenal insufficiency suggested partial 17-alpha hydroxylase enzyme deficiency. The diagnosis was confirmed by measurement of 24-hour urine steroid metabolites and whole gene sequencing of CYP17A1 that demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation. Ultrasound showed bilateral small ovaries with multiple cysts. The serum anti-mullerian hormone concentration was unremarkable at 6.6 (normal <12.6 ng/ml) but the outlook for her future ovulatory potential is uncertain. Dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking normalised her hormonal profile and her blood pressure without side-effects.

Rapid development of anterotibial compartment syndrome and rhabdomyolysis in a patient with primary hypothyroidism and adrenal insufficiency.

BACKGROUND: Anterior compartment syndrome (ACS) and rhabdomyolysis are rare complications of hypothyroid myopathy. We report the case of a young man with rapid onset of ACS who presented with simultaneous primary hypothyroidism and adrenal insufficiency associated with acute renal failure, hyponatremia, and hyperkalemia. PATIENT FINDINGS: A 22-year-old man presenting with a one-month history of tiredness, hyperpigmentation, and cramps in his calves was found to have severe bilateral foot drop. Investigations revealed severe primary hypothyroidism and adrenal insufficiency, renal failure, and evidence of rhabdomyolysis with myoglobinuria. Abnormal biochemical findings included serum sodium of 110 mM, serum potassium of 6.9 mM, and serum creatine kinase (CK) of >25,000 IU/L. Magnetic resonance imaging (MRI) of his legs showed changes of myonecrosis confined to anterior tibial muscles typical of ACS. After treatment with intravenous fluids, potassium-lowering therapies, thyroxine, and hydrocortisone, his renal and metabolic function returned to normal, but irreversible bilateral foot drop persisted. SUMMARY: A young man with primary hypothyroidism, adrenal insufficiency, hyponatremia, and hyperkalemia presented with severe myopathy, such that muscle necrosis, apparently confined to the anterior tibial compartment on MRI, led to rhabdomyolysis, acute renal failure, and irreversible bilateral peroneal nerve damage. It is possible that other patients with primary hypothyroidism and marked elevations of CK without widespread myopathy or rhabdomyolysis may demonstrate evidence of differential muscle effects in the anterior compartment when assessed by MRI, but that this patient also had adrenal insufficiency raises the possibility that this was a contributing factor. CONCLUSIONS: Severe thyroid myopathy and rhabdomyolysis may be associated with anatomic susceptibility to ACS, particularly in the presence of concomitant adrenal insufficiency. MRI examination reveals a distinctive appearance of myonecrosis confined to the anterior compartment.

Are pregnant women in New Zealand iodine deficient? A cross-sectional survey.

Severe iodine deficiency in pregnancy can result in cretinism. There is growing concern that less severe iodine deficiency may also affect fetal growth and development. A handful of prior small New Zealand studies focussed on pregnant women living in Dunedin. This study utilised biochemical, clinical and dietary indices to assess iodine status of 170 women living throughout New Zealand. The median urinary iodine concentration (UIC) of the women was 38 µg/L, well below the 150 µg/L cut-off value that indicates adequate iodine status; 7% of women had goitre. Not surprisingly, iodine intake was also low at 48 µg/day. The majority of women had TSH and FT4 concentrations within pregnant reference ranges, suggesting that despite the low UIC observed in these women, thyroid hormone production appeared unaffected.

Mortality and morbidity in Cushing's syndrome in New Zealand.

OBJECTIVE: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. However, recent operative series suggest low morbidity and mortality for CS, whereas population-based surveys report elevated mortality rates. We investigated the mortality and morbidity of CS in New Zealand. DESIGN: A nationwide retrospective survey of patients with CS between 1960 and 2005 managed at the four main endocrinology services. PATIENTS: A total of 253 patients with CS were identified, excluding adrenal carcinoma and malignant ectopic CS. MEASUREMENTS; The primary outcome was the standardized mortality ratio (SMR), comparing the observed number of deaths with the expected number for the population matched for age, sex and duration of follow-up. Secondary outcomes were the change in prevalence of co-morbidities at presentation and at final follow-up. RESULTS: The approximate prevalence and incidence of CS was 79/million and 1·8/million/y. The mean age at presentation was 39 year, and median duration of follow-up was 6·4 year (range 0-46). Overall, 89% achieved biochemical cure at last follow-up, with >90% achieving biochemical cure for CS from adrenal adenoma and pituitary causes. Thirty-six patients died during follow-up compared with 8·8 expected deaths (SMR 4·1, 95%CI 2·9-5·6). While hypertension, sexual dysfunction, myopathy and mild psychiatric illness were significantly reduced after treatment, hypertension, diabetes mellitus, moderate or major psychiatric illness, and osteoporosis were common at final follow-up. CONCLUSION: CS is associated with both high mortality and a high prevalence of co-morbidities, even when biochemical cure rates are between 80% and 90%.

Hot flushes, hypertension and haemodialysis.

Hypertension is common in patients with end stage renal disease. However, in patients non-responsive to standard measures to control the blood pressure, non-renal causes should be considered. We present the case of a patient on haemodialysis with difficult to control blood pressure.

Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out.

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age

A case of low cortisol-binding globulin: use of plasma free cortisol in interpretation of hypothalamic-pituitary-adrenal axis tests.

We investigated a patient with suspected hypopituitarism who showed subnormal cortisol responses to stimulation tests with adrenocorticotrophic hormone (ACTH) and hypoglycaemia, but normal ACTH and 11-deoxycortisol responses in the metyrapone test. Cortisol-binding globulin (CBG) was measured by enzyme-linked immunosorbent assay (ELISA), and was used to calculate plasma free cortisol and free cortisol index. The patient had a low plasma CBG concentration. Reinterpreted in terms of free cortisol and free cortisol index, his responses to ACTH were normal. We conclude that despite subnormal total cortisol responses to ACTH and hypoglycaemia, the patient had a normal hypothalamic-pituitary-adrenal (HPA) axis. Measurement of CBG concentration and calculation of free cortisol or free cortisol index can help avoid false interpretations of dynamic tests of the HPA axis based on plasma total cortisol.

Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.

CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

Resistance to thyroid hormone in a patient with thyroid dysgenesis.

We report a patient with the unusual coincidence of two rare congenital disorders, lingual ectopy of the thyroid gland and resistance to thyroid hormone (RTH), resulting in impaired thyroid hormone production and action, respectively. The proposita had a positive thyrotropin (TSH) newborn screening test (350 mU/L, confirmed) with normal thyroxine (T4) and no clinical signs of hypothyroidism. A scintiscan revealed lingual but no orthotopic thyroid tissue. Levothyroxine (LT4) replacement failed to reduce TSH and was discontinued after four months owing to significantly elevated free T4. Her physical and mental development was unremarkable, and she was considered to be clinically euthyroid throughout childhood, even though she received either no T4 or a dose insufficient to lessen hyperthyrotropinemia. At the age of 15 years, T4 was gradually increased to a supraphysiological dose of 300 microg/d, resulting in the normalization of the serum TSH level, and subjective improvements in her ability to concentrate. The proposita's mother was clinically euthyroid, had a palpable diffuse goiter, and thyroid function tests consistent with RTH. This diagnosis was confirmed by detection of a heterozygous mutation (R320H) in the thyroid hormone receptor-beta (TR-beta) gene found in both the proposita and her mother. Under the high-dose T4 regimen, the patient's TSH and free T4 values resembled those of untreated patients with TRbeta R320H mutation, suggesting that a compensated state could be achieved, at least at the pituitary level. In the proposita, treatment of hyperthyrotropinemia is clearly mandatory because of potential complications inflicted by TSH-stimulated growth of the lingual tissue. To our knowledge, this represents the first report of congenital hypothyroidism secondary to thyroid dysgenesis complicated by coincidental RTH.

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas.

Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.