Diverse presentations of Cushing's syndrome during pregnancy - A case series.

BACKGROUND: Cushing's syndrome (CS) encompasses various causes of hypercortisolism including adrenocorticotropic hormone (ACTH) secreting pituitary adenoma with or without bilateral adrenal hyperplasia, an adrenal adenoma or carcinoma, ectopic ACTH or corticotrophin-releasing hormone (CRH) secretion by a neoplasm or exogenous corticosteroid therapy. The diagnosis of CS in pregnancy presents a challenge due to overlapping clinical features of pregnancy (weight gain, striae, acne). If untreated, CS in pregnancy is associated with increased risk of maternal and fetal complications. AIMS: With fewer than 250 cases currently published, we aim to review the clinical presentations, diagnostic methods, management, and outcomes of patients with CS in pregnancy to help optimise our clinical practice. MATERIALS AND METHODS: This is a single-centre, retrospective review of woman with documented hypercortisolism receiving antenatal care at a tertiary maternity hospital in Perth between 2006 to 2022. Data were collated from electronic and chart reviews. OMNI calculator was used for birthweight calculations. Local ethics and patient consent were obtained. RESULTS: Five women and seven pregnancies were identified. Four women had a pituitary source of ACTH-dependent CS as confirmed by brain magnetic resonance imaging. One woman had an ectopic source of ACTH. Two women were diagnosed during pregnancy. All pregnancies occurring prior to treatment of the Cushing's disease were complicated by secondary hypertension and diabetes. CONCLUSION: CS represents a rare and difficult to diagnose condition in pregnancy. When untreated, maternal and fetal outcomes are compromised. Close monitoring of the associated complications with involvement of a multidisciplinary team are recommended.

Genome-wide analysis of thyroid function in Australian adolescents highlights SERPINA7 and NCOA3.

OBJECTIVE: Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance. METHODS: Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9-16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery. RESULTS: Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7-74.9%) for TSH, 67.5% (59.8-75.3%) for fT4, 59.7% (54.4-65.0%) for fT3 and 48.8% (40.6-56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4. CONCLUSION: Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests.

INTRODUCTION: Discordant thyroid function tests are routinely encountered in clinical practice. Differential diagnoses include acute thyroxine (T4) ingestion, laboratory interference from heterophilic antibodies, thyroid hormone resistance, thyroid-stimulating hormone (TSH)-secreting pituitary adenomas, and T4 protein binding abnormalities. The impact of abnormal binding proteins may be less recognized since widespread use of free T4 (FT4) assays compared to older total T4 assays. CASE REPORT: A 69-year-old female was referred for assessment of discordant thyroid function tests. Biochemistry since July 2015 showed persistently elevated FT4 levels by immunoassay ranging between 25 to 34 pmol/L with normal or slightly decreased TSH ranging between 0.05 to 2.74 mU/L. The patient was clinically euthyroid on 100 mcg daily of levothyroxine for Hashimoto's thyroiditis. FT4 measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was 19.5 pmol/L. Exome sequencing (confirmed by Sanger sequencing) detected a guanine to adenine substitution at residue 725 of the ALB gene previously associated with dysalbuminemic hyperthyroxinemia. The patient's daughter had similar thyroid function tests and the same genetic variant. FT4 results from 3 different automated immunoassays showed the Roche Cobas and Siemens Centaur platforms to be most affected by the variant, and Abbott Architect had the best agreement with LC-MS/MS. CONCLUSION: Familial dysalbuminemic hyperthyroxinemia is a potential cause of discordant thyroid function tests. Clinicians suspecting protein-binding abnormalities may further investigate using reference methods such as LC-MS/MS and equilibrium dialysis if available. The increasing accessibility of exome sequencing offers a cost-effective method of diagnosing genetic variants that cause discordant thyroid function tests.

Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients.

BACKGROUND: Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. METHODS: A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. RESULTS: A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L (<2nd percentile) had a low sensitivity (5.8%) but good positive predictive value (82.5%) for hypogammaglobulinaemia (IgG ≤5.7 g/L), with a positive predictive value of 37.5% for severe hypogammaglobulinaemia (IgG ≤3 g/L). Paraproteins were identified in 123/291 (42.3%) of patients with increased calculated globulins (≥42 g/L) who also had a serum electrophoresis performed. Significantly elevated calculated globulin ≥50 g/L (>4th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). CONCLUSIONS: Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.

Lower serum 25-hydroxyvitamin D is associated with colorectal and breast cancer, but not overall cancer risk: a 20-year cohort study.

Studies of the relationship between circulating 25-hydroxyvitamin D (25(OH)D) and cancer risk have been inconsistent. We hypothesized that serum 25(OH)D was associated with total non-skin cancer incidence and mortality, and/or specifically with colorectal, lung, breast or prostate cancer in an Australian cohort. Serum 25(OH)D was measured in 3818 participants (2166 females) in the 1994/1995 Busselton Health Survey aged 25 to 84 years at baseline. Cancer mortality and events over 20 years follow-up were determined by data linkage. The mean serum 25(OH)D concentration was 60.6 ±â€¯18.0 nmol/L, with 28%, 54% and 18% of participants in the lower (<50 nmol/L), middle (50-75 nmol/L) and higher (≥75 nmol/L) vitamin D status groups, respectively. During follow-up (excluding the first 2 years), 212 participants died from non-skin cancer and 634, 110 and 44 participants had non-skin, colorectal and lung cancer events, respectively; 113 women had breast cancer and 122 men had prostate cancer events. For colorectal cancer, lower circulating 25(OH)D was associated with significantly higher risk compared with the middle group (covariate-adjusted HR 1.62, 95% CI 1.04, 2.53). For breast cancer, women with a higher 25(OH)D level had lower risk than women in the middle group (HR 0.38, 95% CI 0.16, 0.89) and the lower group (HR 0.37, 95% CI 0.15, 0.89). Serum 25(OH)D was not associated with overall cancer death or event, or with lung or prostate cancer. In this community-based cohort, lower 25(OH)D levels were associated with increased risk of colorectal and breast cancer, but not overall cancer risk.

Direct infant UV light exposure is associated with eczema and immune development.

BACKGROUND: Suboptimal vitamin D levels during critical periods of immune development have emerged as an explanation for higher rates of allergic diseases associated with industrialization and residing at higher latitudes. OBJECTIVE: We sought to determine the effects of early postnatal vitamin D supplementation on infant eczema and immune development. METHODS: By using a double-blind randomized controlled trial, newborn infants were randomized to receive vitamin D supplementation (400 IU/d) or a placebo until 6 months of age. Some infants also wore personal UV dosimeters to measure direct UV light (290-380 nm) exposure. Infant vitamin D levels were measured at 3 and 6 months of age. Eczema, wheeze, and immune function outcomes were assessed at 6 months of age. RESULTS: At 3 (P < .01) and 6 (P = .02) months of age, vitamin D levels were greater for the vitamin D-supplemented group than the placebo group, but there was no difference in eczema incidence between groups. Infants with eczema were found to have had less UV light exposure (median, 555 Joules per square meter [J/m2; interquartile range, 322-1210 J/m2]) compared with those without eczema (median, 998 J/m2 [interquartile range, 676-1577 J/m2]; P = .02). UV light exposure was also inversely correlated with IL-2, GM-CSF, and eotaxin production to Toll-like receptor ligands. CONCLUSION: This study is the first to demonstrate an association between greater direct UV light exposures in early infancy with lower incidence of eczema and proinflammatory immune markers by 6 months of age. Our findings indicate that UV light exposure appears more beneficial than vitamin D supplementation as an allergy prevention strategy in early life.

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

Vitamin D and cancer mortality in elderly women.

BACKGROUND: There is increasing evidence that vitamin D deficiency is a risk factor for cancer, however it remains uncertain whether vitamin D deficiency also predisposes to death from cancer. The aim of the study was to determine the association between serum 25-hydroxy-vitamin D (25 (OH) D) concentrations and cancer-specific mortality in a community-based cohort of older post-menopausal women. METHODS: Cox proportional regression analyses were conducted to examine the association between serum 25 (OH) D concentrations and the risk of overall and site-specific cancer mortality in a cohort of elderly women. RESULTS: Over a median follow-up time of 10 years, a total of 84 cancer deaths were observed. Women with lower serum 25 (OH) D concentrations were at an increased risk of cancer death, but not for incident cancer. The excess risk for cancer death was observed with serum 25 (OH) D concentration less than 64 nmol/L (the median value) [adjusted HR: 1.61 (95% CI: 1.02 - 2.54, p = 0.04]. For every 30 nmol/L reduction in serum 25 (OH) D concentrations, there was a 30% increase in the overall risk of cancer death [adjusted HR: 1.33; 95% CI: 1.03 - 1.72, p = 0.02]. The excess risk appeared to be site-specific and greatest in those with haematological cancers [adjusted HR: 2.13: 95% CI: 1.0 - 4.55, p = 0.05]. CONCLUSIONS: In elderly women, lower serum 25 (OH) D concentrations appear to be an independent risk factor for cancer-specific mortality, but not a risk factor for the development of cancer.

X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

A distinctive colour associated with high iodine content in malignant pleural effusion from metastatic papillary thyroid cancer: a case report.

INTRODUCTION: Pleural effusions are a common clinical problem and affect about one million people in the United States and United Kingdom each year. Over 60 causes of pleural effusion have been identified; establishing the definitive aetiology can be difficult, and often requires invasive procedures. Guidelines state that macroscopic examination of the fluid should be the first step in determining the aetiology of a pleural effusion. Papillary thyroid carcinoma is an uncommon cause of malignant pleural effusion, with only 10 cases reported in the literature, their physical characteristics and composition having been rarely described. We describe for the first time a distinctive brown colour of the malignant effusion (despite centrifugation) from a rare case of metastatic papillary thyroid cancer to the pleura, associated with a high pleural fluid iodine content. Such a characteristic may be useful in expediting diagnosis of a malignant pleural effusion in the appropriate clinical context. CASE PRESENTATION: We present the case of a 71-year-old Caucasian man with metastatic papillary thyroid cancer; a large, long-standing, right-sided pleural effusion and a 83-fold higher pleural thyroglobulin level compared to corresponding serum, supporting this malignancy as the cause of the patient's effusion. The pleural fluid had a distinctive pigmentation similar to iodine-containing antiseptic preparations. Biopsy during medical thoracoscopy confirmed metastatic papillary thyroid carcinoma. Analysis of pleural fluid showed a pleural thyroglobulin level over 80 times that of serum levels (29,000µg/L versus 350ug/L). Pleural fluid iodine content was 23,000ug/L and may account for the fluid's distinctive pigment, as iodine is an essential component in thyroglobulin and thyroid hormone synthesis. CONCLUSIONS: Pleural fluid pigmentation may aid diagnosis in the appropriate clinical setting. A distinctive iodine-like brown colour of pleural fluid may represent elevated iodine content and should raise consideration of metastatic thyroid cancer as a cause for a pleural effusion.

Optimizing the multimodal approach to pancreatic cyst fluid diagnosis: developing a volume-based triage protocol.

BACKGROUND: The objective of this study was to develop a triage algorithm to optimize diagnostic yield from cytology, carcinoembryonic antigen (CEA), and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) testing on different components of a single pancreatic cyst fluid specimen. The authors also sought to determine whether cell block supernatant was suitable for CEA and KRAS testing. METHODS: Fifty-four pancreatic cysts were triaged according to a volume-dependent protocol to generate fluid (neat and supernatant) and cell block specimens for cytology, comparative CEA, and KRAS testing. Follow-up histology, diagnostic cytology, or a combined clinicopathologic interpretation was recorded as the final diagnosis. RESULTS: There were 26 mucinous cystic lesions and 28 nonmucinous cystic lesions with volumes ranging from 0.3 mL to 55 mL. Testing different components of the specimens (cell block, neat, and/or supernatant) enabled all laboratory investigations to be performed on 50 of 54 cyst fluids (92.6%). Interpretive concordance was observed in 17 of 17 cases (100%) and in 35 of 40 cases (87.5%) that had multiple components tested for CEA and KRAS mutations, respectively. An elevated CEA level (>192 ng/mL) was the most sensitive test for the detection of a mucinous cystic lesion (62.5%) versus KRAS mutation (56%) and "positive" cytology (61.5%). KRAS mutations were identified in 2 of 25 mucinous cystic lesions (8%) in which cytology and CEA levels were not contributory. CONCLUSIONS: A volume-based protocol using different components of the specimen was able to optimize diagnostic yield in pancreatic cyst fluids. KRAS mutation testing increased diagnostic yield when combined with cytology and CEA analysis. The current results demonstrated that supernatant is comparable to neat fluid and cell block material for CEA and KRAS testing.

Assessment of thyroid function during pregnancy: first-trimester (weeks 9-13) reference intervals derived from Western Australian women.

OBJECTIVE: To establish first-trimester-specific reference intervals for thyroid function tests in pregnant Australian women. DESIGN, SETTING AND PARTICIPANTS: Serum samples were collected from 2159 pregnant women (9-13 weeks' gestation) attending a private pathology practice for first-trimester screening during October and November 2006. Levels of serum thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured by chemiluminescent immunoassay (Abbott ARCHITECT analyser). MAIN OUTCOME MEASURES: Reference intervals based on 2.5th and 97.5th percentiles for TSH, fT4 and fT3, after exclusion of 338 women with positive TPOAb or TgAb tests; comparison with reference intervals for non-pregnant women (TSH, 0.40-4.0 mU/L; fT4, 9-19 pmol/L; fT3, 3.0-5.5 pmol/L). RESULTS: Derived reference intervals for thyroid function tests during the first trimester of pregnancy were: TSH, 0.02-2.15 mU/L; fT4, 10.4-17.8 pmol/L; and fT3, 3.3-5.7 pmol/L. If the non-pregnant TSH reference range was applied to the study participants, 344 women (16.0%) whose serum TSH concentration was within the first-trimester-specific reference range would be misclassified as having subclinical hyperthyroidism, and 98 women (4.5%) with a TSH concentration above the first-trimester-specific upper reference limit would not be identified. CONCLUSIONS: The reference interval for TSH during the first trimester of pregnancy differs substantially from that for non-pregnant women, and applying the general laboratory reference range to pregnant women results in misclassification of thyroid status for 20.5% of women. Australian pathology laboratories should adopt pregnancy-specific reference intervals for thyroid function tests.

Concomitant compostite adrenal phoechromocytoma, multipte gastric stromal tumours and pseudohermaphrodism in a patient with von Recklinghausen's disease.

Although pheochromocytoma occurs in 1% of patients with von Recklinghausen's disease, composite tumors in this syndrome are much rarer, with isolated case reports in the literature. Most gastrointestinal stromal tumors (GISTs) are solitary and sporadic. Multiple GISTs however, are associated with clinical syndromes particularly von Recklinghausen's disease. We believe this is the first report of composite adrenal pheochromocytoma and multiple GISTs occurring in an 82 year old woman with neurofibromatosis type 1 (NF1), manifested by clitoral and subcutaneous neurofibromas, epilepsy and Lisch nodules. The extreme clitoromegaly raised concerns of pseudohermaphrodism at presentation.

Hepatic iron loading in patients with compound heterozygous HFE mutations.

AIM: To assess the severity of hepatic iron loading in patients with a compound heterozygous C282Y/H63D HFE genotype. METHODS: A total of 246 patients were referred to the Hepatology Clinic at a tertiary hospital for HFE genotyping and further assessment of elevated serum transferrin saturation and/or ferritin results, either with or without abnormal liver function tests. Subjects of the study were 19 patients compound heterozygous for HFE who had liver biopsy, quantitative liver iron estimation and liver histopathology. RESULTS: Mild iron overload [hepatic iron concentration between 30 and 100 micromol/g dry weight], was present in 16/19 compound heterozygous patients, three patients had values within the reference range. As well as the compound heterozygous HFE genotype, 18/19 patients were found to have had at least one additional risk factor for developing either iron loading or liver disease. CONCLUSION: Compound heterozygous patients show no more than mild liver iron loading. The decision whether or not to recommend liver biopsy in C282Y/H63D patients with abnormal serum iron indices and/or liver function tests should be based on the need to evaluate liver damage rather than solely to assess liver iron loading.