Hypertension with hidden causes:the cognitive and behavioral profile of an adult female with chronic stress and 16p11.2 microdeletion

This case report aims to alert physicians to neuropsychological features and chromosomal variants that may underly resistant hypertension. We present a 35-year-old female patient with hypertensive crisis (BP 260/160 mmHg), initially treated with a combination of calcium antagonists, beta blockers, diuretics and angiotensin-converting enzyme (ACE)-inhibitors, though with little improvement. Cushing's syndrome, Conn's syndrome, and glucocorticoid receptor deficiency were ruled out. Multidisciplinary examination of medical history and (hetero)anamneses including psychosocial factors revealed mild dysmorphic body features, developmental delay, early diagnosis of autism spectrum disorder, a history of being bullied at school, little peer contact, learning disabilities, and special education. Neuropsychological assessment demonstrated below average to low average intelligence quotient, cognitive impairments, and psychopathology. Parallel genetic analyses revealed a rare 16p11.2 microdeletion syndrome. These concurrent examinations explained the patient's life-long high stress levels. After psychological treatment, with additional support at home, her blood pressure lowered to normal levels and antihypertensive drugs were no longer needed.</p

What endocrinologists can do to prevent cardiovascular complications in adults with Prader-Willi syndrome:Lessons from a case series

Context: Prader-Willi syndrome (PWS) is a complex rare genetic syndrome. Mortality in patients with PWS is 3% per year. In nearly half of the patients, the cause of death is of cardiopulmonary origin. Prevention, diagnosis and treatment of cardiovascular (CV) disease in PWS adults is complicated by the behavioral phenotype, reduced ability to express physical complaints, high pain threshold and obesity. Objective: To describe the challenges in prevention, diagnosis and treatment of CV disease in PWS adults, in order to increase awareness and improve medical care. Methods: Retrospective study of medical records of adults visiting the Dutch PWS reference center. Results: We describe the challenges encountered during diagnosis and treatment of four PWS adults with heart failure. All had pre-existent peripheral edema. CV risk factors in these patients were obesity (n=4), type 2 diabetes mellitus (n=2), hypertension (n=2), hypogonadism (n=3) and sleep apnea (n=2). Remarkably, all patients were younger than 40 years during their first cardiac decompensation. All patients presented with progressive shortness of breath and/or orthopnea and progressive pitting edema. In 117 controls with PWS without CV problems, 31% had leg edema. Conclusion: Diagnosing CV problems in PWS adults is challenging. Peripheral edema is common in PWS adults without CV morbidity, which makes edema in general a poor marker for heart failure. However, when edema is of the pitting kind and progressive, this is a strong predictor of cardiac decompensation. We provide practical recommendations for diagnosing and treating CV problems in this vulnerable patient population.</p

Understanding the impact of tuberous sclerosis complex:development and validation of the TSC-PROM

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to measure the impact of TSC manifestations on daily functioning. The aim of this study was to develop a TSC-specific PROM for adults that captures the impact of TSC on physical functions, mental functions, activity and participation, and the social support individuals with TSC receive, called the TSC-PROM. METHODS: COSMIN methodology was used to develop a self-reported and proxy-reported version. Development and validation consisted of the following studies: PROM development, content validity, structural validity, internal consistency, and construct validity. The International Classification of Functioning and Disability was used as a framework. Content validity was examined by a multidisciplinary expert group and cognitive interview study. Structural and construct validity, and internal consistency were examined in a large cohort, using confirmatory factor analysis, hypotheses testing, and Cronbach's alpha. RESULTS: The study resulted in an 82-item self version and 75-item proxy version of the TSC-PROM with four subscales (physical functions 18 and 19 items, mental functions 37 and 28 items, activities and participation 13 and 14 items, social support 13 items, for self version and proxy version respectively). Sufficient results were found for structural validity with sufficient unidimensionality for each subscale. With regard to construct validity, 82% of the hypotheses were met for the self version and 59% for the proxy version. The PROM showed good internal consistency (Cronbach's alpha 0.78-0.97). CONCLUSIONS: We developed a PROM for adults with TSC, named TSC-PROM, showing sufficient evidence for reliability and validity that can be used in clinical and research settings to systematically gain insight into their experiences. It is the first PROM in TSC that addresses the impact of specific TSC manifestations on functioning, providing a valuable, patient-centered addition to the current clinical outcomes.</p

Malignancies in Prader-Willi Syndrome:Results From a Large International Cohort and Literature Review

CONTEXT: Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of the PWS critical region, a cluster of paternally expressed genes on chromosome 15q11.2-q13. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health. OBJECTIVE: To investigate the prevalence and risk factors of malignancies in patients with PWS and to provide clinical recommendations for cancer screening. METHODS: We included 706 patients with PWS (160 children, 546 adults). We retrospectively collected data from medical records on past or current malignancies, the type of malignancy, and risk factors for malignancy. Additionally, we searched the literature for information about the relationship between genes on chromosome 15q11.2-q13 and malignancies. RESULTS: Seven adults (age range, 18-55 years) had been diagnosed with a malignancy (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, stomach adenocarcinoma, biliary cancer, parotid adenocarcinoma, and colon cancer). All patients with a malignancy had a paternal 15q11-13 deletion. The literature review showed that several genes on chromosome 15q11.2-q13 are related to malignancies. CONCLUSION: Malignancies are rare in patients with PWS. Therefore, screening for malignancies is only indicated when clinically relevant symptoms are present, such as unexplained weight loss, loss of appetite, symptoms suggestive of paraneoplastic syndrome, or localizing symptoms. Given the increased cancer risk associated with obesity, which is common in PWS, participation in national screening programs should be encouraged.</p

Case Report: A Detailed Phenotypic Description of Patients and Relatives with Combined Central Hypothyroidism and Growth Hormone Deficiency Carrying IGSF1 Mutations

In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants

Bone mineral density during 3 years of growth hormone in previously GH-treated young adults with PWS

Objective: In children with Prader-Willi syndrome (PWS), growth hormone ( GH) treatment has positive effects on bone mineral density (BMD). Two 1-year studies did not show a differe nce between GH or placebo on BMD in young adults with PWS. However, there are no studies investigating BM D during longer-term GH treatment in young adults with PWS. Design: Open-label, a prospective study in 43 young adults with PWS. Methods: BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA. Results: In the total group, estimated mean (95% CI) of BMD TB remained similar during 3 years of GH, being -0.76 (-1.11 to -0.41) SDS at start and -0.90 (-1.27 to -0.54) SDS after 3 years (P = 0.11), as did BMADLS, being -0.36 (-0.72 to 0.01) SDS and -0.46 (-0.77 to -0.16) SDS, respectively (P = 0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMAD LSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT). Conclusions: During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMD TBSDS, probably due to insufficient SSRT. We recommended to continue GH treatment in young adults with PWS a nd to start SSRT during adolescence unless puberty progresses normally

Thyroid Function in Adults with Prader-Willi Syndrome;: a Cohort Study and Literature Review

Prader–Willi syndrome (PWS) is a complex genetic syndrome combining hypotonia, hyperphagia, a PWS-specific neurocognitive phenotype, and pituitary hormone deficiencies, including hypothyroidism. The low muscle mass associated with PWS causes a low energy expenditure due to a low basal metabolic rate. Combined with increased energy intake due to hyperphagia, this results in a high risk of obesity and associated cardiovascular disease. To reduce the high mortality in PWS (3% yearly), exercise is extremely important. As hypothyroidism can impair exercise tolerance, early detection is crucial. We performed a literature search for articles on hypothyroidism in PWS, measured thyroid hormone (TH) levels in 122 adults with PWS, and performed a medical file search for medication use. Hypothyroidism (low free thyroxin) was present in 17%, and often central in origin (80%). Triiodothyronine levels were lower in patients who used psychotropic drugs, while other TH levels were similar. One in six patients in our cohort of adults with PWS had hypothyroidism, which is more than in non-PWS adults (3%). We recommend yearly screening of free thyroxin and thyroid-stimulating hormone levels to avoid the negative effects of untreated hypothyroidism on basal metabolic rate, body mass index, and cardiovascular risk. Additionally, we recommend measuring TH concentrations 3–4 months after the start of growth hormone treatment