Replication of association at the LPP and UBASH3A loci in a UK autoimmune Addison's disease cohort.

Autoimmune Addison's disease (AAD) arises from a complex interplay between multiple genetic susceptibility polymorphisms and environmental factors. The first genome wide association study (GWAS) with patients from Scandinavian Addison's registries has identified association signals at four novel loci in the genes LPP, SH2B3, SIGLEC5, and UBASH3A. To verify these novel risk loci, we performed a case-control association study in our independent cohort of 420 patients with AAD from the across the UK. We report significant association of alleles of the LPP and UBASH3A genes [odds ratio (95% confidence intervals), 1.46 (1.21-1.75)and 1.40 (1.16-1.68), respectively] with AAD in our UK cohort. In addition, we report nominal association of AAD with SH2B3 [OR 1.18 (1.02-1.35)]. We confirm that variants at the LPP and UBASH3A loci confer susceptibility to AAD in a UK population. Further studies with larger patient cohorts are required to robustly confirm the association of SH2B3 and SIGLEC5/SPACA6 alleles.

Identification of a Cancer-Predisposing Germline POT1 p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma.

Germline disruptive variants in Protection of Telomeres 1 (POT1) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline POT1 variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5-CD10- B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified POT1 p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the POT1 variant was germline. This likely pathogenic POT1 loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline POT1 variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic POT1 variants (i.e., autosomal dominant POT1 tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the POT1 genetic locus (7q31.33).

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.

Vitamin D status and pathway genes in five European autoimmune Addison's disease cohorts.

OBJECTIVE: While vitamin D regulates immune cells, little is known about it in autoimmune Addison's disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes. DESIGN: Cross-sectional study. METHODS: A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). RESULTS: Vitamin D deficiency (25(OH)D3 10-20 ng/mL) was highly prevalent in AAD patients (34-57%), 5-22% were severely deficient (<10 ng/mL), 28-38% insufficient (20-30 ng/mL) and only 7-14% sufficient (>30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (P = 0.03/0.003 and P = 1 × 10-5/< 1 × 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/mL) and synthesize less 1,25(OH)2D3. CONCLUSION: Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

Growth, development, and phenotypic spectrum of individuals with deletions of 2q33.1 involving SATB2.

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.

Patient satisfaction and quality of life in hypothyroidism: An online survey by the british thyroid foundation.

OBJECTIVE: Dissatisfaction with treatment and impaired quality of life (QOL) are reported among people with treated hypothyroidism. We aimed to gain insight into this. DESIGN AND PATIENTS: We conducted an online survey of individuals with self-reported hypothyroidism. RESULTS: Nine hundred sixty-nine responses were analysed. Dissatisfaction with treatment was common (77.6%), and overall QOL scores were low. Patient satisfaction did not correlate with type of thyroid hormone treatment, but treatment with combination levothyroxine (L-T4) and liothyronine (L-T3) or with desiccated thyroid extract (DTE) was associated with significantly better reported QOL than L-T4 or L-T3 monotherapies (P < .001); however, multivariate analysis inclusive of other clinical parameters failed to confirm an association between type of thyroid hormone treatment and QOL or satisfaction. Multivariate analysis showed positive correlations between satisfaction and age (P = .026), male gender (P = .011), being under the care of a thyroid specialist (P < .001), family doctor (GP) prescribing DTE or L-T4 + L-T3 or L-T3 (P < .001) and being well informed about hypothyroidism (P < .001); negative correlations were observed between satisfaction and negative experiences with L-T4 (P < .001) and expectations for more support from the GP (P < .001), for L-T4 to resolve all symptoms (P = .004), and to be referred to a thyroid specialist (P < .001). For QOL, positive correlations were with male gender (P = .011) and duration of hypothyroidism (P = .002); negative correlations were with age (P = .027), visiting the GP more than 3 times before diagnosis (P < .001), sourcing DTE or L-T3 independently (P = .014), negative experiences with L-T4 (P = .013), having expectations for L-T4 to resolve all symptoms (P < .001) and of more support from the GP (P = .006). CONCLUSIONS: Multiple parameters including prior healthcare experiences and expectations influence satisfaction with hypothyroidism treatment and QOL. Focusing on enhancing the patient experience and clarifying expectations at diagnosis may improve satisfaction and QOL.

Natural History of Adrenal Steroidogenesis in Autoimmune Addison's Disease Following Diagnosis and Treatment.

CONTEXT: The natural history of adrenal function in autoimmune Addison disease once diagnosed and treated has not been systematically studied, but several case reports of recovery from established adrenal failure suggest it may not be uniform. OBJECTIVE: To ascertain steroidogenic function in autoimmune Addison disease immediately following diagnosis and during prolonged treatment. DESIGN: We studied peak serum cortisol in response to ACTH1-24 in 20 newly diagnosed autoimmune Addison disease patients at first presentation and then again within a month. We also studied 37 patients with established Addison disease (for between 7 months and 44 years) in a medication-free state, measuring peak serum cortisol responses to ACTH1-24 and the urine LC-MS steroid metabolome. RESULTS: Adrenal steroidogenesis declined rapidly after steroid replacement treatment for newly diagnosed Addison disease was started, with a peak serum cortisol falling from 138 ±â€…19 nmol/L (SEM) at presentation to 63 ±â€…13 nmol/L over 4 weeks (P < 0.003).Six of 37 participants (16%) with established Addison disease had detectable serum cortisol and urine glucocorticoid and mineralocorticoid metabolites during repeat testing, indicating variable degrees of residual adrenal function. CONCLUSION: Autoimmune Addison disease is a heterogeneous condition, showing a rapid decline in adrenal steroidogenesis during the first few weeks following diagnosis, but low-level residual function in a minority of patients, which appears to persist for many years.

Cytogenetic and molecular diagnostic testing associated with prenatal and postnatal birth defects.

Genetic testing is beneficial for patients and providers when in search of answers to medical problems related to the prenatal or early postnatal period. It can help to identify the cause or confirm a diagnosis associated with developmental delay, intellectual disability, dysmorphic features, heart defects, multiple malformations, short stature, stillbirth, neonatal death, or fertility problems. Genetic testing can be used to rule out single-gene or chromosome abnormalities. Different diagnostic cytogenetic and molecular genetic techniques are applied in clinical genetics laboratories, from conventional ones to the state of the art chromosomal microarrays and next-generation sequencing. Each of the genetic techniques or methods has its strengths and limitations, however different methods complement each-other in trying to identify the genetic variation(s) responsible for a medical condition, especially the ones related to birth defects.

Practices in synagogues regarding Jewish genetic disease education.

Approximately one in three Ashkenazi Jews are carriers for an autosomal recessive Jewish genetic disease (JGD). However, studies indicate that most Jews are uneducated on this topic and obstetricians do not routinely offer carrier screening to Jewish patients. Both the Reform and Conservative movements of Judaism call for JGD education to take place within the synagogue; however, little is known about the extent of this education occurring today. An online survey was created for Reform and Conservative rabbis to assess the types of JGD education taking place within the synagogue. Additionally, the survey included questions to assess JGD knowledge and possible factors that could predict counseling activity and knowledge level. Of the 94 participants, 91% had provided education about JGDs to congregants, with 98.8% providing this education during premarital counseling sessions. For most respondents, explaining recessive inheritance pattern and carrier screening was the extent of the discussion. Additionally, the majority of rabbis scored below 50% on the knowledge portion of the survey, with an average score of 1.9/4. There were no statistically significant differences between JGD education in Reform vs. Conservative synagogues, and there were no statistically significant predictors of knowledge score or JGD education frequency. In conclusion, while the number of rabbis discussing this topic is encouraging, discussion topics were found to be limited and their knowledge of JGDs was found to be poor.

Residual Adrenal Function in Autoimmune Addison's Disease-Effect of Dual Therapy With Rituximab and Depot Tetracosactide.

CONTEXT: In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy, and poorer quality of life. OBJECTIVE: The objective of this article is to restore adrenocortical steroidogenic function in recent-onset AAD. DESIGN: An open-label, multicenter trial of immunotherapy and trophic stimulation in new-onset AAD was conducted. Serial measurement of serum and urine corticosteroids at baseline and throughout a 72-week follow-up period was performed. SETTING: This study was conducted at the.endocrine departments and clinical research facilities at 5 UK tertiary centers. PATIENTS: Thirteen participants (9 female, 4 male; age 19-64 years) were included with AAD confirmed by high adrenocorticotropin, low circulating cortisol (basal < 100 nmol/L or post-tetracosactide < 300 nmol/L), and positive serum 21-hydroxylase antibodies. INTERVENTION: All participants received dual therapy with B-lymphocyte-depleting immunotherapy (rituximab 1 g given twice) and repeated depot tetracosactide (1 mg on alternate days for 12 weeks). MAIN OUTCOME MEASURE: Restoration of normal GC secretion (stimulated cortisol > 550 nmol/L) at week 48 was the main outcome measure. RESULTS: Ten of 13 (77%) participants had detectable stimulated serum cortisol (26-265 nmol/L) at trial entry. Following intervention, 7 of 13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325 nmol/L at week 18 in 1 participant. Increased steroid metabolites, assayed by urine gas chromatography-mass spectrometry at week 12 and week 48, was detected in 8 of 13 (62%) individuals, reflecting an increase in endogenous steroidogenesis. Four of 13 had residual adrenal function at 72 weeks. CONCLUSION: Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients, and this has the potential to be exploited to improve adrenal function.

The current state of genetic counseling assistants in the United States.

Genetic counseling assistants (GCAs) have the potential to address the high demand for genetic counselors by promoting task-sharing, increasing genetic counselor efficiency, and allowing for higher level duties to be optimized by genetic counselors. However, little research has been published on the role of GCAs. This study explored current tasks of GCAs in the United States, the appropriateness of those tasks, the perceived impact on the profession, and how these findings compared between genetic counselors with and without GCAs. Full members of the National Society of Genetic Counselors (NSGC) with and without experience working with GCAs were recruited via the NSGC Student Research listserv to complete an online survey and 271 surveys were analyzed. Participants working in both clinical and laboratory settings and in all primary specialties reported working with GCAs (n = 131); GCAs were reported to frequently perform clerical tasks but were involved less often in clinical tasks such as calling patients with genetic test results. There was no difference between participants with GCAs and those without GCAs in tasks they reported GCAs are or may be performing, yet participants without GCAs believed GCAs performed more tasks on average than those with GCAs reported (p < 0.001). Participants did not differ on the appropriateness of tasks, reporting clerical tasks as more appropriate for GCAs than clinically involved tasks, with the exception of calling patients with variant of uncertain significance (VUS) results in which more participants working with GCAs reported it as an appropriate task (13%) than those without GCAs (4%; p < 0.05). Review of open-ended responses revealed themes pertaining to primary limitations, benefits, and concerns of the GCA role. The most commonly reported concern about GCAs was their poorly defined scope of practice (n = 182). Other reported limitations included a heavy workload, lack of training, and lack of experience for GCAs while the benefits of working with GCAs included increased time available for higher level duties, patient volumes, and efficiency. These data provide genetic counselors, their institutions, and the NSGC with a more generalizable understanding of current GCA roles on a national level, across specialties. Additionally, these data may help establish a scope of practice for GCAs by creating a baseline job description for genetic counselors and their institutions interested in implementing a GCA into their practice to increase patient access to genetic counseling services. It is recommended that further research objectively quantify the value added by GCAs using efficiency metrics and further clarify the role of laboratory GCAs.

AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF. METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning. RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels. CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.

Analysis of BAFF gene polymorphisms in UK Graves' disease patients.

OBJECTIVE: B lymphocyte activating factor (BAFF), a member of the tumour necrosis factor superfamily, is essential for B cell activation, differentiation and survival. Elevated circulating BAFF levels have been found in patients with several autoimmune conditions, including Graves' disease. In addition, BAFF gene variants have been associated with Graves' disease in a Taiwanese cohort, and with several other autoimmune conditions in non-Taiwanese populations. DESIGN AND METHODS: We performed a case-control association study to investigate two BAFF polymorphisms (rs9514828 and rs4000607) in a UK cohort of 444 patients with Graves' disease. Genotype frequencies were compared to those from 447 local controls and more than 5000 healthy controls from the Wellcome Trust case-control consortium (WTCCC2). RESULTS: There was a significant difference in the frequency of the AA genotype at rs4000607 between the Graves' disease cohort and both the local controls (P = 0.045) and the WTCCC2 controls (P = 4.56 × 10-6 ). Furthermore, the frequency of the A allele was found to be increased in the Graves' disease group compared to WTCCC2 controls (P = 0.02, OR 1.20 (95% CI 1.03-1.41). No association was observed at the rs9514828 locus. CONCLUSION: Dysfunction of the humoral immune system is an obligatory pathophysiological component of Graves' disease, hence BAFF is an excellent functional candidate gene. We have demonstrated, for the first time, a significant association of the BAFF polymorphism rs4000607 with Graves' disease in a UK cohort. Further work to elucidate the role of BAFF in the pathogenesis of Graves' disease is now warranted.

Sleep-related hypermotor epilepsy and peri-ictal hypotension in a patient with syntaxin-1B mutation.

STX1B is a gene that encodes syntaxin-1B. STX1B mutations have recently been implicated in fever-associated epilepsy syndromes. However, these have not previously been reported in sleep-related hypermotor epilepsy. A 20-year-old man with a strong family history of epilepsy was investigated in our epilepsy monitoring unit due to uncontrolled epilepsy, compatible with sleep-related hypermotor epilepsy. Electroclinical and polygraphic physiological recordings revealed left frontal epileptiform discharges and prominent peri-ictal hypotension. Normal MRI using an epilepsy protocol prompted a search for a genetic epilepsy, which revealed a likely pathogenic mutation in the STX1B gene. The patient remained seizure-free after treatment optimization with carbamazepine. This case suggests that a sleep-related hypermotor epilepsy phenotype can be associated with syntaxin-1B gene mutation, and testing for this gene should be considered in such patients. Furthermore, it may also be concluded that autonomic dysfunction, characterized by peri-ictal hypotension, can also occur in this discorder. [Published with video sequences on www.epilepticdisorders.com].

Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations.

PURPOSE: Smooth muscle dysfunction syndrome (SMDS) due to heterozygous ACTA2 arginine 179 alterations is characterized by patent ductus arteriosus, vasculopathy (aneurysm and occlusive lesions), pulmonary arterial hypertension, and other complications in smooth muscle-dependent organs. We sought to define the clinical history of SMDS to develop recommendations for evaluation and management. METHODS: Medical records of 33 patients with SMDS (median age 12 years) were abstracted and analyzed. RESULTS: All patients had congenital mydriasis and related pupillary abnormalities at birth and presented in infancy with a patent ductus arteriosus or aortopulmonary window. Patients had cerebrovascular disease characterized by small vessel disease (hyperintense periventricular white matter lesions; 95%), intracranial artery stenosis (77%), ischemic strokes (27%), and seizures (18%). Twelve (36%) patients had thoracic aortic aneurysm repair or dissection at median age of 14 years and aortic disease was fully penetrant by the age of 25 years. Three (9%) patients had axillary artery aneurysms complicated by thromboembolic episodes. Nine patients died between the ages of 0.5 and 32 years due to aortic, pulmonary, or stroke complications, or unknown causes. CONCLUSION: Based on these data, recommendations are provided for the surveillance and management of SMDS to help prevent early-onset life-threatening complications.

Tremelimumab-Induced Graves Hyperthyroidism.

Tremelimumab and ipilimumab are monoclonal antibodies directed against the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and have been used as immunotherapies against immune checkpoints that suppress T-cell activation. Anti-CTLA-4 antibody-based therapies have been shown to be effective in treating various cancers including metastatic melanoma. However, a few immune-related adverse events including hypophysitis and thyroid disorder have been reported, mostly developed within the first year of receiving treatment. We report a case of tremelimumab-induced Graves hyperthyroidism in a 55-year-old man who was diagnosed with metastatic melanoma after 8 years of tremelimumab therapy. He had no personal or family history of thyroid or autoimmune diseases. His biochemical profile was in keeping with Graves disease, with raised serum free thyroid hormones, suppressed thyroid-stimulating hormone concentration, and raised thyrotropin receptor antibody level. He was treated with carbimazole as part of the block and replace therapy, without complications. Tremelimumab therapy was temporarily discontinued and recommenced when he was rendered biochemically euthyroid. There has been no further relapse of Graves hyperthyroidism since the discontinuation of block and replace therapy. The mechanistic profile of anti-CTLA-4-induced thyroid dysfunction and the long-term endocrine safety of this therapeutic approach remain unclear. It is important to monitor thyroid functions in patients receiving anti-CTLA-4 therapies, as their effects on endocrine systems could be more latent or prolonged than the data from current clinical trials suggest. Antithyroid drug therapy was safe and effective alongside anti-CTLA-4 therapy without compromising antitumour treatment efficacy.