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[This corrects the article DOI: 10.3389/fendo.2023.1168648.].
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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 260/160âmmHg), 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.
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Transtorno do Espectro Autista , Hipertensão , Humanos , Adulto , Feminino , Transtorno do Espectro Autista/tratamento farmacológico , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/uso terapêutico , CogniçãoRESUMO
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.
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Esclerose Tuberosa , Adulto , Humanos , Inquéritos e Questionários , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/psicologia , Reprodutibilidade dos Testes , Autorrelato , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida/psicologiaRESUMO
Background: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria. Methods: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS. Results: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively). Conclusion: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensão , Síndrome de Prader-Willi , Insuficiência Renal Crônica , Humanos , Adulto , Masculino , Adulto Jovem , Feminino , Estudos de Coortes , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Estudos Retrospectivos , Creatinina , Albuminúria/epidemiologia , Albuminúria/etiologia , Hipertensão/complicações , Hipertensão/epidemiologia , Doenças Cardiovasculares/epidemiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , AlbuminasRESUMO
CONTEXT: Turner syndrome (TS) is a rare chromosomal disorder characterized by gonadal dysfunction, short stature, and heart defects, among other features. Women with TS often suffer from severe fatigue, for which they are typically referred to endocrinologists. The diagnostic work-up is generally time-consuming and invasive, and it rarely solves the problem. To prevent the personal and financial burden of unnecessary diagnostic procedures, it is crucial to understand fatigue in TS. OBJECTIVE: To explore the association between fatigue and endocrine and non-endocrine comorbidities in a-for rare disorders-large group of women with TS. METHODS: 170 genetically confirmed women with TS who attended the TS Reference Center underwent a systematic health screening, including a structured interview, complete physical examination, biochemical measurements, perceived stress and fatigue questionnaires, and additional tests when indicated. RESULTS: Median (interquartile range) age was 32.6 (23.9-41.4) years. Severe fatigue was experienced by 1 in 3 women with TS. Liver enzyme disturbances and body mass index were significantly associated with higher fatigue scores. Perceived stress was highly correlated with fatigue. CONCLUSION: There was no association between fatigue and most endocrine and non-endocrine disorders, which implies that fatigue is only partly explained by somatic disorders. The high correlation between perceived stress and fatigue suggests that TS-related neuropsychological processes may play an important role in the etiology of fatigue in women with TS. We provide a practical algorithm for the endocrine, non-endocrine, and psychological approach to fatigue in women with TS.
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Síndrome de Turner , Adulto , Feminino , Humanos , Índice de Massa Corporal , Estudos de Coortes , Comorbidade , Síndrome de Turner/complicações , Síndrome de Turner/epidemiologiaRESUMO
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.
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Adenocarcinoma , Síndrome de Prader-Willi , Adolescente , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Pai , Hiperfagia , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/epidemiologia , Estudos RetrospectivosRESUMO
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.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Síndrome de Prader-Willi , Humanos , Síndrome de Prader-Willi/complicações , Diabetes Mellitus Tipo 2/complicações , Estudos Retrospectivos , Endocrinologistas , Obesidade/complicações , Obesidade/epidemiologia , Insuficiência Cardíaca/complicações , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/complicaçõesRESUMO
Prader-Willi syndrome (PWS), the most common form of syndromic obesity, is a complex neurodevelopmental genetic disorder including obesity with hyperphagia, endocrine and metabolic disorders and also psychiatric disorders. The most frequent endocrine disturbances include hypogonadism and growth hormone (GH) deficiency. Hypothyroidism and central adrenal insufficiency can also be observed but are less frequent. The transition of individuals with PWS from adolescence to adult life is challenging because of multiple comorbidities and complex disabilities. Individuals and caregivers face psychological, medical and social issues. This period of profound changes is thus prone to disruptions, and the main risks being the worsening of the medical situation and loss to follow-up of the individuals. Medical care may be poorly adapted to the needs of individuals because of a lack of knowledge concerning the syndrome and also lack of the necessary specific skills. A multidisciplinary panel composed of several experts in PWS met in November 2021 during an European Reference Network on Rare Endocrine Conditions (Endo-ERN) webinar. They presented complementary aspects of PWS from the perspective of the transition including psychiatric, pediatric and adult endocrinological and parent's and patient's points of view and shed light on the best way to approach this pivotal period.
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Context: Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures. To prevent the personal and financial burden of this disabling fatigue, it is crucial to know the causes. Objective: To explore somatic causes and provide practical recommendations for the approach to fatigue in adults with NF1. Design: Cross-sectional. All adults with NF1 (N = 133) who visited our Endocrinology department underwent a systematic health screening, including a medical questionnaire, structured interview, complete physical examination, biochemical measurements and additional tests if indicated. Main outcome measure: Prevalence of endocrine and non-endocrine health problems between NF1 adults with and without fatigue. Results: In our cohort, 75% of NF1 adults experienced fatigue. The most frequent endocrine disorders were vitamin D deficiency (28%), obesity (18%) and hypothyroidism (8%). The most frequent non-endocrine internal disorder was high blood pressure (42%). None of the disorders differed significantly between adults with and without fatigue. Conclusions: Endocrine and non-endocrine disorders were equally present in our cohort of NF1 adults with and without fatigue. This suggests that the high prevalence of fatigue in NF1 adults is not explained by these somatic disorders. An alternative explanation for fatigue might be deficits in cognitive functioning and other neuropsychological processes in NF1. Based on our results and review of the literature, we provide a clinical algorithm for the approach to fatigue in NF1 adults, including somatic and psychological assessment.
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Hipertensão , Neurofibromatose 1 , Adulto , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/epidemiologia , Estudos Transversais , Cognição , CausalidadeRESUMO
CONTEXT: Prader-Willi syndrome (PWS) is a rare complex genetic syndrome, characterized by delayed psychomotor development, hypotonia, and hyperphagia. Hormone deficiencies such as hypogonadism, hypothyroidism, and growth hormone deficiency are common. The combination of hypotonia, low physical activity, and hypogonadism might lead to a decrease in bone mass and increase in fracture risk. Moreover, one would expect an increased risk of scoliosis due to hypotonia and low physical activity. OBJECTIVE: To study the prevalence and risk factors for skeletal problems (reduced bone mineral density, fractures, and scoliosis) in adults with PWS. METHODS: We retrospectively collected patient characteristics, medical history, medication, biochemical measurements, dual-energy X-ray absorptiometry scans, and spinal X-rays and reviewed the current literature. RESULTS: We included 354 adults with PWS (median age 31 years; 43% males), of whom 51 (14%) had osteoporosis (T-score below -2.5) and 143 (54%) had osteopenia (T-score -1 to -2.5). The most prevalent modifiable risk factors for osteoporosis were hypogonadism, insufficient dairy intake, sedentary lifestyle, and corticosteroid use. Male sex was associated with osteoporosis (P = .005). Growth hormone treatment was not associated with osteoporosis. A history of vertebral fractures was present in 10 (3%) and nonvertebral fractures in 59 (17%). Scoliosis was present in 263 (80%), but no modifiable risk factors were identified. CONCLUSION: Besides scoliosis, osteoporosis is common in adults with PWS. Based on the literature and the risk factors for osteoporosis found in our cohort, we provide practical clinical recommendations to avoid skeletal complications in these vulnerable patients.
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Fraturas Ósseas , Hipogonadismo , Osteoporose , Síndrome de Prader-Willi , Escoliose , Humanos , Adulto , Masculino , Feminino , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/epidemiologia , Síndrome de Prader-Willi/tratamento farmacológico , Densidade Óssea , Escoliose/etiologia , Escoliose/complicações , Hipotonia Muscular , Estudos Retrospectivos , Osteoporose/etiologia , Osteoporose/complicações , Hipogonadismo/etiologia , Hipogonadismo/complicações , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Hormônio do Crescimento/uso terapêuticoAssuntos
Deficiência Intelectual , Adulto , Humanos , Pessoal de Saúde , Medicina Interna , Atenção à SaúdeRESUMO
Prader−Willi syndrome (PWS) is a complex, rare genetic disorder caused by a loss of expression of paternally expressed genes on chromosome 15q11.2-q13. The most common underlying genotypes are paternal deletion (DEL) and maternal uniparental disomy (mUPD). DELs can be subdivided into type 1 (DEL-1) and (smaller) type 2 deletions (DEL-2). Most research has focused on behavioral, cognitive and psychological differences between the different genotypes. However, little is known about physical health problems in relation to genetic subtypes. In this cross-sectional study, we compare physical health problems and other clinical features among adults with PWS caused by DEL (N = 65, 12 DEL-1, 27 DEL-2) and mUPD (N = 65). A meta-analysis, including our own data, showed that BMI was 2.79 kg/m2 higher in adults with a DEL (p = 0.001). There were no significant differences between DEL-1 and DEL-2. Scoliosis was more prevalent among adults with a DEL (80% vs. 58%; p = 0.04). Psychotic episodes were more prevalent among adults with an mUPD (44% vs. 9%; p < 0.001). In conclusion, there were no significant differences in physical health outcomes between the genetic subtypes, apart from scoliosis and BMI. The differences in health problems, therefore, mainly apply to the psychological domain.
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OBJECTIVE: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin-stimulating hormone (α-MSH) and desacetyl-α-melanocortin-stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. METHODS: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. RESULTS: The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. CONCLUSION: The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.
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Hormônio Adrenocorticotrópico , Pró-Opiomelanocortina , Insuficiência Adrenal , Humanos , Hiperfagia/genética , Obesidade/genética , Pró-Opiomelanocortina/genética , Pró-Proteína Convertase 2 , alfa-MSHRESUMO
Introduction: Transition from paediatric to adult endocrinology can be challenging for adolescents, their families and healthcare professionals. Previous studies have shown that up to 25% of young adults with endocrine disorders are lost to follow-up after moving out of paediatric care. This poses a health risk for young adults, which can lead to serious and expensive medical acute and long-term complications. Methods: In order to understand and prevent dropout, we studied electronic medical records of patients with endocrine disorders. These patients were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our hospital in 2013-2014 and should have made the transfer to adult care at the time of the study. Results: Of 387 adolescents, 131 had an indication for adult follow-up within our university hospital. Thirty-three (25%) were lost to follow-up. In 24 of them (73%), the invitation for the adult OPC had never been sent. We describe the failures in logistic processes that eventually led to dropout in these patients. Conclusion: We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Of all dropouts, 73% could be attributed to the failure of logistic steps. In order to prevent these dropouts, we provide practical recommendations for patients and paediatric and adult endocrinologists.
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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.
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Hipotireoidismo , Imunoglobulinas , Feminino , Hormônio do Crescimento , Humanos , Hipotireoidismo/genética , Imunoglobulinas/genética , Masculino , Proteínas de Membrana/genética , Mutação , FenótipoRESUMO
In children with Prader−Willi syndrome (PWS), the standard growth hormone (GH) dose often results in high immunoreactive IGF-I levels. These high immunoreactive IGF-I levels lead to concern because their long-term effects are unknown. As a result, clinicians have to lower the GH dose, which worsens body composition and quality of life. As clinical features do not seem to correspond to immunoreactive IGF-I values, it is questionable whether immunoreactive IGF-I is a suitable marker for GH dosing, or whether another parameter better reflects IGF-I bioavailability and bioactivity. We, therefore, investigate serum immunoreactive IGF-I, free IGF-I and IGFBP-3 levels in 70 GH-treated children with PWS. Our study showed that, although immunoreactive IGF-I levels were high (>2 SDS) in the vast majority of prepubertal and pubertal children, free IGF-I SDS levels were <0 SDS in most and <1 SDS in all. Free IGF-I correlated with the immunoreactive IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio. We conclude that there is a major discrepancy between immunoreactive and free IGF-I levels. While in the majority of GH-treated children with PWS, immunoreactive IGF-I levels were high, free IGF-I levels were <0 SDS in most. Our data appear to be very reassuring and suggest that free IGF-I levels should also be taken into consideration when the immunoreactive IGF-I levels are >2 SDS in GH-treated children with PWS.
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Prader-Willi syndrome (PWS) is a rare neuroendocrine genetic syndrome. Characteristics of PWS include hyperphagia, hypotonia, and intellectual disability. Pituitary hormone deficiencies, caused by hypothalamic dysfunction, are common and hypogonadism is the most prevalent. Untreated hypogonadism can cause osteoporosis, which is already an important issue in PWS. Therefore, timely detection and treatment of hypogonadism is crucial. To increase understanding and prevent undertreatment, we (1) performed a cohort study in the Dutch PWS population, (2) thoroughly reviewed the literature on female hypogonadism in PWS and (3) provide clinical recommendations on behalf of an international expert panel. For the cohort study, we retrospectively collected results of a systematic health screening in 64 female adults with PWS, which included a medical questionnaire, medical file search, medical interview, physical examination and biochemical measurements. Our data show that hypogonadism is frequent in females with PWS (94%), but is often undiagnosed and untreated. This could be related to unfamiliarity with the syndrome, fear of behavioral changes, hygienic concerns, or drug interactions. To prevent underdiagnosis and undertreatment, we provide practical recommendations for the screening and treatment of hypogonadism in females with PWS.
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Patients with complex rare genetic syndromes (CRGS) have combined medical problems affecting multiple organ systems. Pediatric multidisciplinary (MD) care has improved life expectancy, however, transfer to internal medicine is hindered by the lack of adequate MD care for adults. We have launched an MD outpatient clinic providing syndrome-specific care for adults with CRGS, which, to our knowledge, is the first one worldwide in the field of internal medicine. Between 2015 and 2020, we have treated 720 adults with over 60 syndromes. Eighty-nine percent of the syndromes were associated with endocrine problems. We describe case series of missed diagnoses and patients who had undergone extensive diagnostic testing for symptoms that could actually be explained by their syndrome. Based on our experiences and review of the literature, we provide an algorithm for the clinical approach of health problems in CRGS adults. We conclude that missed diagnoses and needless invasive tests seem common in CRGS adults. Due to the increased life expectancy, an increasing number of patients with CRGS will transfer to adult endocrinology. Internist-endocrinologists (in training) should be aware of their special needs and medical pitfalls of CRGS will help prevent the burden of unnecessary diagnostics and under- and overtreatment.
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Prader-Willi syndrome (PWS) is a complex genetic syndrome characterized by hyperphagia, intellectual disability, hypotonia and hypothalamic dysfunction. Adults with PWS often have hormone deficiencies, hypogonadism being the most common. Untreated male hypogonadism can aggravate PWS-related health issues including muscle weakness, obesity, osteoporosis, and fatigue. Therefore, timely diagnosis and treatment of male hypogonadism is important. In this article, we share our experience with hypogonadism and its treatment in adult males with PWS and present a review of the literature. In order to report the prevalence and type of hypogonadism, treatment regimen and behavioral issues, we retrospectively collected data on medical interviews, physical examinations, biochemical measurements and testosterone replacement therapy (TRT) in 57 Dutch men with PWS. Fifty-six (98%) of the patients had either primary, central or combined hypogonadism. Untreated hypogonadism was associated with higher body mass index and lower hemoglobin concentrations. TRT was complicated by behavioral challenges in one third of the patients. Undertreatment was common and normal serum testosterone levels were achieved in only 30% of the patients. Based on the Dutch cohort data, review of the literature and an international expert panel discussion, we provide a practical algorithm for TRT in adult males with PWS in order to prevent undertreatment and related adverse health outcomes.