Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.

OBJECTIVES: Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom. DESIGN AND PATIENTS: Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated. MEASUREMENTS: Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed. RESULTS: Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results. CONCLUSIONS: Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

SDHC phaeochromocytoma and paraganglioma: A UK-wide case series.

OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

Management of aggressive variants of papillary thyroid cancer.

PURPOSE OF REVIEW: The aim of this study was to provide a timely and relevant review of the latest findings and explore appropriate management of aggressive variants of papillary thyroid cancer (AVPTC). RECENT FINDINGS: In general, AVPTCs tend to exhibit more invasive characteristics, a lack of responsiveness to radioiodine, increased occurrences of regional spreading, distant metastases and higher mortality rates. Meanwhile, each variant showcases unique clinical and molecular profiles. SUMMARY: Given the elevated risk of recurrence postsurgery, a more aggressive strategy may be necessary when suspected preoperatively, particularly for those presenting with invasive features. Decision on the extent of surgical treatment and adjuvant therapy is individualized and made by experienced clinicians and multidisciplinary teams based on the clinical presentation, presence of aggressive features and molecular profile. Future studies on development of personalized medicine and molecular target therapy may offer tailored treatment options.

Thyroglossal duct cyst carcinoma case series-Management strategy and outcomes.

OBJECTIVE: To review the clinical presentation, diagnosis, pathology and management strategies in a modern cohort of patients with thyroglossal duct cyst carcinoma. STUDY DESIGN: Retrospective case series following PROCESS Guidelines. SETTING: Comprehensive cancer centre. METHODS: Data recorded included: gender, age at diagnosis, clinical presentation, thyroid function, diagnostic investigations, cytological results, final histology, staging and follow up status. The risk of malignancy in cytological analysis was stratified according to the Royal College of Pathologists classification in United Kingdom. RESULTS: Twelve patients were included. The majority of patients (66.7%) presented with an isolated thyroglossal duct cyst. Only 4 patients had preoperative cytological suspicion of carcinoma (sensitivity: 33.3%). At the time of presentation all patients were euthyroid. Following diagnosis of malignancy, a total thyroidectomy was performed in all patients, with the exception of 2, who had a thyroglossal duct cyst carcinoma of less than 10mm. Among the 10 patients who underwent total thyroidectomy, 7 (70%) patients had proven carcinoma in the thyroid gland, 3 with deposits of less than 10mm. The average size of the thyroid cancer deposits was 7.2mm (1-20mm). With a mean follow-up of is 44 months (5-120), all patients were alive and free of recurrence at the end of the study period. CONCLUSION: Thyroglossal duct cyst carcinoma is a rare condition and its management should be discussed in a multidisciplinary meeting. As with differentiated thyroid cancer originating in the thyroid gland, it bears extraordinary survival rates. Accordingly, the management of these cancers has shifted towards a more conservative approach although its peculiarities must be taken into account: ease of extracystic invasion and possible different lymph node invasion.

Tumour detection and outcomes of surveillance screening in SDHB and SDHD pathogenic variant carriers.

OBJECTIVE: Succinate dehydrogenase subunit (SDHx) pathogenic variants predispose to phaeochromocytoma and paraganglioma (PPGL). Lifelong surveillance is recommended for all patients to enable prompt detection and treatment. There is currently limited evidence for optimal surveillance strategies in hereditary PPGL. We aim to detail the clinical presentation of PPGL in our cohort of non-index SDHB and SDHD pathogenic variant carriers. METHODS: Retrospective analysis of medical and genetic records from a single tertiary referral centre identified SDHB or SDHD pathogenic variants in 74 non-index cases (56 SDHB and 18 SDHD). Surveillance screening for asymptomatic relatives consisted of annual plasma metanephrine measurement and whole-body MRI with contrast at 3-5 yearly intervals. RESULTS: Twenty-three out of 74 non-index patients (10 SDHB and 13 SDHD) were diagnosed with PPGL, 17 patients through surveillance screening (24 tumours in total) and 6 diagnosed prior to commencement of cascade screening with symptomatic presentation. MRI with contrast identified PPGL in 22/24 screen-detected tumours and 5/24 tumours had elevated plasma metanephrine levels. Penetrance in non-index family members was 15.2 and 47.2% for SDHB carriers and 71.6 and 78.7% for SDHD carriers at age of 50 and 70 years, respectively. CONCLUSION: Surveillance screening with combined biochemical testing and imaging enables early detection of PPGL in asymptomatic relatives with SDHx pathogenic variants. The presence of disease at first screen was significant in our cohort and hence further multi-centre long-term data are needed to inform counselling of family members undergoing lifelong surveillance.

Simultaneous Kidney and Parathyroid Transplantation in the Management of Genetic Hypoparathyroidism in a Child.

Background: Genetically determined hypoparathyroidism can lead to life-threatening episodes of hypocalcemia and, more rarely, to end-stage kidney disease at a young age. Parathyroid allotransplantation is the only curative treatment, and in patients already receiving immunosuppression for kidney transplantation, there may be little additional risk involved. We report the first such case in a child. Methods: An 11-y-old girl, known to have hypoparathyroidism secondary to an activating pathogenic variant in the calcium-sensing receptor, developed end-stage kidney disease and was started on intermittent hemodialysis. Since the age of 2.5 y, she had been receiving treatment with exogenous synthetic parathyroid hormone (PTH). In June 2019, at the age of 11.8 y, she received a living-donor kidney and simultaneous parathyroid gland transplant from her father. The kidney was implanted into the right iliac fossa, followed by implantation of the parathyroid gland into the exposed rectus muscle. Results: The kidney graft showed immediate function while the intrinsic serum PTH level remained low at 3 ng/L. Exogenous PTH infusion was reduced on day 6 posttransplantation to stimulate PTH production by the new gland, which resulted in improving intrinsic PTH concentrations of 28 ng/L by day 9. Twelve months after transplantation, PTH levels remain in normal range and the kidney graft function is stable with a serum creatinine of 110 µmol/L. Conclusions: Simultaneous living donation and transplantation of a kidney and a parathyroid gland into a child is safe and feasible and has the potential to cure primary hypoparathyroidism as well as kidney failure.

Cardiac valve disease and low-dose dopamine agonist therapy: an artefact of reporting bias?

INTRODUCTION: Chronic low-dose cabergoline treatment for microprolactinoma may cause cardiac valve pathology, but the evidence is contradictory. We investigated whether the expectation of the echocardiographer could influence the report. METHODS: Transthoracic echocardiograms from 40 patients aged 49·3 ± 9·6 (mean ± SD) years (Men:Women 7:33) on long-term cabergoline and bromocriptine therapy (duration 9·94 ± 4·5 years) were randomly assigned to two groups of echocardiographers so that each echocardiogram was reported twice. One group was told that 'the patients were control subjects' (Group A) and the other that 'the patients were on dopamine agonist therapy which is known to cause valve disease' (Group B). An observer who was blind to the group scored the reports for regurgitation at each valve (scores 0-4; max 16 per case). RESULTS: Mean total regurgitation score was significantly higher in Group B (1·43 ± 1·28; P = 0·014) than in Group A (0·73 ± 1·30). The difference was mainly from reporting trivial regurgitation: (mitral 16 vs 5, P = 0·005; tricuspid 17 vs 6, P = 0·007 and pulmonary 8 vs 1, P = 0·013). Mild regurgitation was uncommon (mitral 1 vs 1 and tricuspid 3 vs 6). Moderate regurgitation occurred in only one case and was associated with restriction of the leaflets consistent with the effects of cabergoline. Valve thickening was not reported in Group A, but in 9 (23%) mitral and 4 (10%) aortic valves in Group B. CONCLUSION: Long-term, low-dose dopamine agonist therapy rarely causes cardiac valve disease, but operator bias can lead to over-reporting of both valve thickening and trivial regurgitation.

Thyroid disorders in subfertility and early pregnancy.

Disorders of thyroid function are common in pregnancy and have implications for foetal and maternal health. Thyroid autoimmunity, as evidenced by the presence of elevated levels of anti-thyroid antibodies (anti-TPO and anti-Tg antibodies) is associated with an increased risk of miscarriage, though the mechanism remains poorly understood. There has been considerable focus on the implications and optimal management of pregnant women with thyroid disease, especially those undergoing assisted reproduction. Pregnancy results in significant changes in thyroid physiology and these need to be understood by clinicians involved in the care of pregnant women. Guidelines for the use of thyroxine and target thyroid function tests have been produced by international bodies but it is recognised that these predominantly reflect expert opinion rather than established evidence-based practice. Importantly a number of key clinical trials have been performed to aid understanding, particularly of the consequences of hypothyroidism for mother and baby, and the effectiveness of thyroid hormone use in autoimmune and subclinical hypothyroidism. This review summarises the current knowledge base and guidance for practice relating to thyroid disorders in pregnancy and subfertility.

Glucocorticoid management of adrenal insufficiency in the United Kingdom: assessment using real-world data.

Background and objectives Glucocorticoids are used to manage adrenal insufficiency (AI). We describe treatments used in the United Kingdom and real-world clinical outcomes for each treatment. Methods We used 2010-2016 primary care data from The Health Improvement Network (THIN). Descriptive analyses were conducted, and differences in variables between patients prescribed immediate-release hydrocortisone (IR HC), prednisolone or modified-release hydrocortisone (MR HC) were assessed using Fisher's exact test. Results Overall, 2648 patients were included: 1912 on IR HC (72%), 691 on prednisolone (26%) and 45 (2%) on MR HC. A total of 1174 (44.3%) had primary and 1150 (43.4%) had secondary AI. Patients on prednisolone were older (P < 0.001) and had a greater history of smoking (292/691, P < 0.001) and CVD (275/691, P < 0.001). Patients on MR HC had more PCOS (3/45, P = 0.001) and diabetes (27/45, P = 0.004). The number of GP visits/patient/year was 6.50 in IR HC, 9.54 in prednisolone and 9.11 in MR HC cohorts. The mean number of A&E visits and inpatient and outpatient hospital admissions ranged from 0.42 to 0.93 visits/patient/year. The mean number of adrenal crises/patient/year was between 0.02 and 0.03 for all cohorts. Conclusion IR HC is most commonly used for the management of AI in the United Kingdom, followed by prednisolone. Few patients receive MR HC. The prednisolone and MR HC cohorts displayed a greater prevalence of vascular risk factors compared with IR HC. The occurrence of AC and primary and secondary resource use were similar between treatment cohorts, and they indicate significant resource utilisation. Improved treatment and management of patients with AI is needed.

MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and treatment.

Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.

Suboptimal rise in awakening-induced cortisol is an accurate marker of cortisol insufficiency in patients with normal renal function (eGFR >60 mL/min).

Background The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient-based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min). Method Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol:creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1 + S2 + S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3. Results Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs . S2 and S3 in controls ( P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs . controls ( P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%). Conclusion Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient-based screening test for exclusion of cortisol insufficiency.

The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population.

Context: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective: We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design: We performed a case-control study. Setting: This study was performed at a hospital clinic. Patients: Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements: Our study determined the prevalence of a metabolic syndrome in our cohort. Results: A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (± standard deviation) age was 33.2 ± 1.0 years. Compared with age-, sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 ± 1.2 mmol/L vs control, 4.9 ± 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 ± 17.0 pmol/L vs control, 14.2 ± 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 ± 1.2 mmol/L) compared with control subjects (1.3 ± 0.8 mmol/L; P < 0.001), but total cholesterol, high-density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 ± 18 mm Hg vs control subjects, 129 ± 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 ± 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions: Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation.

Making (mis) sense of asymptomatic marked hypercalcemia in pregnancy.

We describe a rare case of homozygous inactivating calcium-sensing receptor mutation detected during pregnancy and mimicking primary hyperparathyroidism. In pregnancy, the differential diagnosis of hypercalcaemia requires a cautious approach as physiological changes in calcium homeostasis may mask rare genetic conditions.

The epidemiology of pituitary adenomas in Iceland, 1955-2012: a nationwide population-based study.

OBJECTIVE: Pituitary adenomas (PA) are among the most common human neoplasms. To describe the epidemiology and assess the disease burden of clinically significant PAs, population-based studies are needed. Iceland has a small well-defined population. The aim of this study is to describe the epidemiology of PAs in Iceland over an expanded period of time. DESIGN: This is a retrospective observational study, including all PAs diagnosed in Iceland from 1955 to 2012. METHODS: Extensive clinical information was gathered in a database. Prevalence rates for all PA subtypes were calculated along with standardized incidence rates (SIR). Sex ratios and relationships with adenoma size, age, and symptoms were assessed. RESULTS: We identified 471 individuals: 190 men and 281 women. Total prevalence in 2012 was 115.57/100, 000, prolactinomas were most prevalent (54.37/100, 000) followed by non-functioning adenomas (NFPAs) (42.32/100 ,000). Throughout the period, NFPAs were most common (43.0%) followed by prolactinomas (39.9%) and 11.3% had acromegaly and 5.7% Cushing's disease. Women are diagnosed younger with smaller adenomas. Total SIR has increased significantly and is now 5.8/100 000 per year. CONCLUSION: In this nationwide study spanning six decades, we have confirmed PAs rising prevalence and incidence rates noted in recent studies. We demonstrated higher overall prevalence and incidence rates than ever previously recorded with an increasing predominance of NFPAs, which is not explained by incidental findings alone. There is a relationship with the introduction of imaging modalities, but the vast majority of patients are symptomatic at diagnosis. This underlines the importance of increased awareness, education, and appropriate allocation of resources for this growing group of patients.

Clinical and endocrine responses to pituitary radiotherapy in pediatric Cushing's disease: an effective second-line treatment.

Transsphenoidal surgery (TSS) is considered first-line treatment for Cushing's disease (CD). Options for treatment of postoperative persisting hypercortisolemia are pituitary radiotherapy (RT), repeat TSS, or bilateral adrenalectomy. From 1983 to 2001, we treated 18 pediatric patients (age, 6.4-17.8 yr) with CD. All underwent TSS, and 11 were cured (postoperative serum cortisol, <50 nM). Seven (39%) had 0900-h serum cortisol of 269-900 nM during the immediate postoperative period (2-20 d), indicating lack of cure. These patients (6 males and 1 female; mean age, 12.8 yr; range, 6.4-17.8 yr; 4 prepubertal; 3 pubertal) received external beam RT to the pituitary gland, using a 6-MV linear accelerator, with a dose of 45 Gy in 25 fractions over 35 d. Until the RT became effective, hypercortisolemia was controlled with ketoconazole (dose, 200-600 mg/d) (n = 4) and metyrapone (750 mg-3 g/d) +/- aminoglutethimide (1 g/d) or o'p'DDD (mitotane, 3 mg/d) (n = 3). All patients were cured after pituitary RT. The mean interval from RT to cure (mean serum cortisol on 5-point day curve, <150 nM) was 0.94 yr (0.25-2.86 yr). Recovery of pituitary-adrenal function (mean cortisol, 150-300 nM) occurred at mean 1.16 yr (0.40-2.86 yr) post RT. At 2 yr post RT, puberty occurred early in one male patient (age, 9.8 yr) but was normal in the others. GH secretion was assessed at 0.6-2.5 yr post RT in all patients: six had GH deficiency (peak on glucagon/insulin provocation, <1.0-17.9 mU/liter) and received human GH replacement. Follow-up of pituitary function 7.6 and 9.5 yr post RT in two patients showed normal gonadotropin secretion and recovery of GH peak to 29.7 and 19.2 mU/liter. The seven patients were followed for mean 6.9 yr (1.4-12.0 yr), with no evidence of recurrence of CD. In conclusion, pituitary RT is an effective and relatively rapid-onset treatment for pediatric CD after failure of TSS. GH deficiency occurred in 86% patients. Long-term follow-up suggests some recovery of GH secretion and preservation of other anterior pituitary function.

Skeletal consequences of discontinuation of growth hormone at final height.

In light of the well-described adult growth-hormone (GH) deficiency syndrome, the traditional clinical practice of discontinuation of GH therapy in GH-deficient adolescent patients at completion of linear growth requires re-evaluation. Peak bone mass, an important determinant of the subsequent risk of osteoporosis-related fracture in later life, occurs several years after the completion of linear growth. Given that GH has important anabolic actions on bone, discontinuation of GH therapy at the completion of linear growth may have adverse consequences for the attainment of peak bone mass in adolescent GH-deficient patients. This paper discusses the role of GH in the attainment of peak bone mass and some of the accumulating evidence that cessation of GH at final height may compromise bone mineral accretion in GH-deficient adolescent patients.

Plasma insulin-like factor 3 (INSL3) in male patients with osteoporosis and Klinefelter's syndrome.

Insulin-like factor 3 (INSL3) is a peptide hormone produced in leydig cells of the testes. Its role in the adult male is unknown but INSL3 and its receptor RXFP2 have been linked to bone cell differentiation. It is speculated that low levels of INSL3 could be responsible for low bone mineral density in patients with primary osteoporosis and Klinefelter's Syndrome. The aim of this study was to assess plasma INSL3 in patients with osteoporosis and Klinefelter's Syndrome compared to healthy males. Fourteen healthy males, 21 males with osteoporosis (4 primary and 17 secondary) and 4 patients with Klinefelter's Syndrome were studied. Plasma INSL3, testosterone, LH, FSH and Sex hormone-binding globulin were evaluated. Plasma INSL3 concentrations were similar in osteoporosis patients compared to healthy controls (0.72 vs. 0.69 ng/mL, p = 0.26). INSL3 was significantly higher in patients with primary osteoporosis (n = 4) compared to age-matched healthy controls (n = 8) (0.845 vs. 0.665 ng/mL, p = 0.021). INSL3 levels in Klinefelter's Syndrome patients were significantly lower compared to healthy controls (0.39 vs. 0.69 ng/mL, p = 0.01). Plasma INSL3 levels were lower in Klinefelter's Syndrome reflecting testicular failure. INSL3 levels were not lower in men with osteoporosis. The relationship between INSL3, its receptor and bone metabolism requires further study.

Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort.

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. OBJECTIVE: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. RESEARCH DESIGN AND METHODS: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. RESULTS: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. CONCLUSIONS: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

Co-morbidities, management and clinical outcome of auto-immune Addison's disease.

There are no consensus guidelines on the optimum long-term care of patients with primary adrenal failure. Published data suggest increased morbidity and mortality in patients treated with current therapy. Investigations of bone mineral density (BMD) in adults with adrenal failure have reported conflicting results. The objectives of this study were to determine the prevalence of auto-immune and other co-morbidities, describe the treatment regimens and to assess the BMD of adults with auto-immune Addison's disease (AAD). A retrospective, cohort study of adults with primary adrenal failure was used. Electronic and paper records were used to collect demographic, biochemical, BMD data and details of other co-morbidities. 48 patients (35% male; 65% female; 50 ± 16, years, mean ± SD) with primary adrenal failure were identified. There was high prevalence of other auto-immune co-morbidities (hypothyroidism 58%, vitamin B(12) deficiency 29%, type 1 diabetes 10%). The presence of cardiovascular risk factors including dyslipidaemia (65% had total cholesterol >5 mmol/l) and excess weight (65% had a BMI >25 kg/m(2)) were high. Using WHO criteria, 17.9 and 53.5% of patients had spinal osteoporosis and osteopenia, respectively, at the spine. This did not relate to the duration or dose of glucocorticoid replacement. Our data shows a high prevalence of both auto-immune and non-autoimmune co-morbidities in patients with AAD. In addition to common auto-immune diseases, patients should be screened for other cardiovascular risk factors. Further studies are needed to assess the cause of the observed increased prevalence of reduced BMD at the lumbar spine. There is a need for internationally agreed long-term management guidelines.

Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients.

CONTEXT: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size. OBJECTIVE: Our objective was to establish the health status of adults with CAH. DESIGN AND SETTING: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom. PATIENTS: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18-69) years. MAIN OUTCOME MEASURES: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts. RESULTS: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised. CONCLUSIONS: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.