2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents

Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents

Le gigantisme hypophysaire

Pituitary gigantism is a rare but important form of overgrowth due to GH/IGF-1 excess. The initial aim of the present research was to design and implement a comprehensive cohort study of the etiology, clinical diagnosis and management of this rare disease. This work describes the findings of an international collaborative study involving the largest pituitary gigantism population described to date (208 patients) from 47 centers across the globe to explore the specific characteristics of these patients and the genetic background of pituitary gigantism. Overall, the work undertaken has permitted us to identify the clinical phenotype and treatment outcomes in patients with pituitary gigantism; these features differ significantly from those in adult somatotropinoma patients with acromegaly. Patients with gigantism presented clear a male predominance (95%) and differ in their presentation based on gender, with females presenting significantly earlier than males. Increased somatic growth in pituitary gigantism is associated with an early onset form of GH/IGF-1 hypersecretion due to pituitary tumors that are highly resistant to treatment. These characteristics point to specific molecular mechanisms in pituitary tumor formation. Until recently, pituitary gigantism has been a well-known disease but poorly understood from genetic point of view. Underlying genetic causes have been studied comprehensively and identified in half of the cases in our large international series. While complex multi-organ syndromes (such as McCune-Albright syndrome (MAS), MEN1 and Carney Complex) counted only for rare cases of pituitary gigantism (7% in total), the most frequent genetic etiologies appear to be those leading to disease isolated to the pituitary, such as AIP mutations (29%) and X-linked acrogigantism syndrome (X-LAG) (10%). The latter is a new genetic form of infant-onset acrogigantism, occurring sporadically and in familial setting, which was described for the first time during the course of this work. X-LAG remains rare and only about 33 genetically confirmed cases have been published to date. X-LAG is a dramatically aggressive disorder affecting children from a very young age (usually during the first year), who are predominantly female (70%). Despite the very young age at disease onset, X-LAG patients develop large pituitary lesions (frequently mixed GH and prolactin secreting adenomas and/or hyperplasia) with extremely elevated hormonal levels. This contributes certainly to excessively rapid somatic growth leading to severe overgrowth. The remarkable phenotype of X-LAG syndrome is underlined by an unusual genetic mechanism; it is due to a microduplication on Xq26.3 including always GPR101 gene, whereas previously described genetic mechanisms in pituitary tumorigenesis are mainly triggered by a point mutation or deletions in a single gene. Additionally, a novel genetic technology (digital droplet PCR (ddPCR)) revealed that males with X-LAG syndrome can be mosaics for the GPR101 duplication, and as few as 16% of duplicated cells could lead to severe overgrowth. Many of the tallest giants in history had a clinical history that exactly mirrors this phenotype. The molecular diagnosis of X-LAG due to a duplication in GPR101 was made using paleogenetic extraction techniques in combination with modern ddPCR on DNA successfully isolated from the century-old remains of the historical case of The Giant Constantin (2.59m) who had autopsy findings of a pituitary adenoma. It can be considered as the tallest genetically proven case of gigantism available. It was also noted that more than 50% of cases remain genetically unexplained. Importantly, these genetic subgroups have statistically significant differences in terms of features at presentation/diagnosis, however all pituitary giants, including the genetically negative group, have aggressive clinical characteristics. Further studies were focused on the association of genetic events, in particular AIP mutations, with the aggressive phenotype of somatotropinomas that are resistant to conventional treatment. The clinical experience in patients with pituitary gigantism that have failed previous therapy with first generation somatostatin analogues, showed the role of other treatment options (pegvisomant, paseriotide) in hormonal and tumoral control in genetically negative and AIP mutated cases. A severe disease burden was highlighted in a comprehensive autopsy and genetic analysis in an adult male patient with a complex clinical profile of MAS including pituitary gigantism. The pathological findings and the presence of GNAS1 mutation in a mosaic state in different endocrine and non-endocrine tissues, combined with the clinical description of this case in the medical records, illustrated the challenges in treatment and consequences of disease activity. Crucially, the results derived from our large pituitary gigantism cohort and our further studies in specific genetically predisposed forms (such as X-LAG, AIP mutation– or MAS– related cases) pointed out that pituitary gigantism is a severe therapeutic challenge, requiring a multimodal treatment approach. However, one of the major findings of our research shows that early recognition and effective management in terms of sustained hormonal control and pituitary tumor shrinkage are essential for limiting the pathological effects on height and multi-organ disease burden.Le gigantisme hypophysaire est une forme rare d’une surcroissance importante due à l'excès de GH et IGF-1. Le but initial de nos travaux était d’organiser une étude complète sur l'étiologie, le diagnostic clinique et la prise en charge de cette maladie rare. Nous décrivons les résultats d'une collaboration internationale impliquant la plus grande population de gigantisme hypophysaire décrite à ce jour (208 patients) de 47 centres à travers le monde pour explorer les caractéristiques spécifiques de ces patients et le contexte génétique du gigantisme hypophysaire. La présentation clinique montre une maladie sévère et invalidante qui affecte généralement la population jeune (enfants, adolescents et jeunes adultes). Dans l'ensemble, ce travail a permis d'identifier le phénotype clinique et les résultats du traitement chez les patients atteints de gigantisme hypophysaire; ces caractéristiques sont différentes de celles bien établies chez les adultes atteints d’acromégalie due à une adénome somatotrope. Les patients atteints de gigantisme présentaient une nette prédominance masculine (95%) et différaient dans leur présentation en fonction du sexe, les femmes se présentant significativement plus tôt que les hommes. Une croissance accrue est associée à une forme précoce d'hypersécrétion de GH / IGF-1 due à des tumeurs hypophysaires très résistantes au traitement. Ces caractéristiques sont les conséquences des mécanismes moléculaires impliqués dans la formation de tumeurs hypophysaires. Jusqu'à très récemment, le gigantisme hypophysaire était une maladie bien connue visuellement, mais mal comprise du point de vue génétique. Les causes génétiques ont été étudiées et révélées dans presque la moitié des cas dans notre grande série internationale. Alors que les syndromes complexes multi-organes (tels que le syndrome de McCune-Albright (MAS), NEM1, et Complex du Carney) ne comptaient que pour de rares cas de gigantisme hypophysaire (7%), les étiologies génétiques les plus fréquentes semblent être celles conduisant à adénomes hypophysaire familiaux isolées (FIPA), comme les mutations AIP (29%) et le syndrome du X-linked acrogigantism (X-LAG) (10%). Ce dernier est une nouvelle forme génétique d'acrogigantisme infantile, apparaissant de façon sporadique et familiale, décrite pour la première fois dans ce travail. L’X-LAG reste une maladie rare et seulement environ 33 cas confirmés génétiquement ont été publiés à ce jour. X-LAG est un maladie extrêmement agressive affectant les enfants dès leur plus jeune âge (généralement au cours de la première année), avec une prédominance chez les femmes (70%). Malgré le jeune âge au début de la maladie, les patients X-LAG développent des grandes lésions hypophysaires (ce sont souvent des adénomes mixtes qui sécrètent de la GH et de la prolactine et/ou une hyperplasie) avec des taux hormonaux extrêmement élevés. Ceci contribue certainement à une croissance excessivement rapide conduisant à une taille finale extrême. Le phénotype remarquable de l’X-LAG est dû à un mécanisme génétique inhabituel; il est dû à une microduplication sur Xq26.3 incluant toujours le gène GPR101, alors que les autres mécanismes génétiques bien décrits précédemment dans la tumorigenèse hypophysaire sont déclenchés par une mutation ponctuelle ou des délétions dans un seul gène. De plus, une nouvelle technologie génétique (digital droplet PCR (ddPCR)) a révélé que les mâles atteints du syndrome X-LAG peuvent être des mosaïques pour la duplication GPR101, et que 16% seulement des cellules dupliquées pourraient conduire à une croissance extrême. Les plus grands géants de l'histoire avaient une présentation clinique qui reflète exactement ce phénotype. Le diagnostic moléculaire de X-LAG dû à une duplication du GPR101 a été fait par la technique paléogénétique en combinaison avec le ddPCR moderne sur l'ADN obtenu à partir du squelette centenaire d'un cas historique du Géant Constantin (2.59m) et qui a eu un adénome hypophysaire selon les résultats d'autopsie. Compte tenu de la description clinique de ce cas dans les archives historiques, il peut être considéré comme le plus grand cas de gigantisme génétiquement prouvé disponible. Plus de 50% des cas restent génétiquement inexpliqués. Les groupes de géants avec des causes génétiques différentes et ceux qui ont été génétiquement négatifs, présentent des caractéristiques distinctes au diagnostic, mais tous les géants hypophysaires, y compris le groupe génétiquement négatif, ont un phénotype agressif. Des études ultérieures se sont concentrées sur l'association d'événements génétiques, en particulier de mutations AIP, avec le phénotype agressif du somatotropinome résistant au traitement conventionnel. L'expérience clinique chez les patients atteints de gigantisme hypophysaire qui n’ont répondu au traitement antérieur avec des analogues du somatostatine de première génération, a montré le rôle d'autres options thérapeutiques (pegvisomant, paseriotide) dans le contrôle hormonal et tumoral dans les cas génétiquement négatifs et AIP mutés. La morbidité sévère a été mise en évidence lors d'une autopsie complète et d'une analyse génétique chez un patient adulte avec un profil clinique complexe de MAS géant. Les résultats pathologiques et la présence de la mutation GNAS1 dans un état mosaïque dans différents tissus endocriniens et non endocriniens, combinés avec la description clinique de ce cas dans le dossier médical, ont illustré les défis du traitement et les conséquences de l'activité de la maladie. Fondamentalement, les résultats de notre grande série de patients atteints du gigantisme hypophysaire et nos études ultérieures dans des formes spécifiques génétiquement prédisposées (comme les cas X-LAG, AIP positifs ou MAS) ont montré que le gigantisme hypophysaire est un challenge thérapeutique nécessitant une approche de traitement multimodal. En plus, nous avons montré qu'une reconnaissance précoce et une prise en charge efficace en termes de contrôle hormonal constant et de diminution du volume de tumeur hypophysaire sont essentielles pour limiter les effets pathologiques sur la taille finale et la charge de morbidité multi-organes

Molecular Genetics of Rare Growth and Puberty Disorders in Finland

Growth and pubertal development are complex and interconnected processes, disruption of which leads to abnormal development of the adult height or secondary sexual characteristics or both, and often causes notable distress and even adverse health effects for the individual. Growth and pubertal development are both dependent on hormones secreted from the pituitary gland. Growth hormone (GH), secreted from the pituitary somatotropes, is required for growth of the bones and cartilage and achievement of the adult height. Formation of GH-secreting pituitary tumors, somatotropinomas, leads to excessive GH secretion and acromegaly or gigantism, which are both characterized by exaggerated growth, either at peripheral body parts or at the long bones depending on the onset of GH excess. In a proportion of cases, a germline gene defect can predispose to somatotropinoma formation. The ability to reproduce is achieved in puberty once the sex organs and other sexual characteristics mature into the adult form. The onset of pubertal development occurs upon the reactivation of the hypothalamic-pituitary-gonadal axis after quiescency following the previous activation phase in infancy. In the pubertal reactivation, increased gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus triggers the secretion of gonadotropins from the pituitary. Premature activation of gonadotropin secretion leads to central precocious puberty (CPP), where the pubertal development begins before the age of eight in girls or the age of nine in boys. In turn, deficient gonadotropin secretion leads to congenital hypogonadotropic hypogonadism (CHH), characterized by delayed, absent, or partial puberty. If defective sense of smell co-occurs with CHH, the condition is named Kallmann syndrome (KS). Despite multiple genes are implicated in the disorders of pituitary hormone secretion, a great proportion of patients miss a molecular genetic diagnosis. The aim of this thesis was to discover defects in specific genes and evaluate their roles in disorders of growth and pubertal development, which originate from aberrant GH or gonadotropin secretion. The disorders were gigantism, acromegaly, CPP, and CHH. Variants in the potassium channel gene KCNQ1 have been previously implicated in growth hormone deficiency, and co-expression of the mutated KCNQ1 with the potassium channel subunit KCNE2 has decreased adrenocorticotropin secretion from a pituitary tumor cell line. KCNQ1 and KCNE2 were screened for germline variants in 49 Finnish patients and four patients of other ethnicities with acromegaly, who represented the phenotypic model opposite to growth hormone deficiency. In KCNQ1, deep intronic and common synonymous variants were identified, and one heterozygous variant with unknown significance in KCNE2 was found in three patients. The frequency of the KCNE2 variant was significantly higher among the patients compared to controls. Two Polish and one Finnish CPP patient as well as their family members were screened for variants in MKRN3, a maternally imprinted gene suggested to function as a pubertal brake. Novel, deleterious variants segregating with CPP in a paternally inherited manner were identified in both families. The first MKRN3 variant in Finnish CPP patients and the first long-term effects of a variant in this gene in a boy with CPP are described. Twenty-four Finnish patients with normosmic CHH or KS were screened for variants in the microRNA genes MIR7-3, MIR141, MIR429, and MIR200A-C, which were predicted to regulate CHH-related genes based on evidence from animal models, literature, or bioinformatic analyses or all. A common, heterozygous variant in MIR200A was detected in one patient. The genetic basis of KS in a Finnish patient with a de novo 2.38 Mb deletion in 9q31.2 and no likely pathogenic variants in a KS gene targeted sequencing panel was investigated with whole genome linked-read sequencing, whole exome sequencing, and RNA sequencing. In the whole genome linked-read sequencing, the deletion was found to encompass six protein-coding genes, including ZNF462, consistent with his Weiss-Kruszka syndrome. The deletion did not cover the nearby KS candidate gene PALM2AKAP2, expression of which was not suppressed by the deletion. The patient carried no rare variants in thirty-two known KS genes in the whole exome sequencing and displayed no abnormal splicing of fifteen KS genes expressed in peripheral blood leukocytes. He is the first reported patient with a 9q31.2 deletion, KS, and Weiss-Kruszka syndrome. Screening of sixteen other Finnish KS patients for variants in PALM2AKAP2 revealed no likely pathogenic defects in this gene. In conclusion, the thesis produced new information on the association of KCNQ1, KCNE2, and the selected microRNA gene variants with disorders of aberrant pituitary hormone secretion. The results demonstrate that germline variants in KCNQ1 or KCNE2 do not seem to account for somatotropinoma formation and that variants in the microRNA genes are unlikely causes of CHH. In turn, deletions in 9q31.2 appear to underlie KS, but based on the results, variants in the KS candidate gene PALM2AKAP2 do not seem to contribute to the condition in the investigated cohort. In addition, novel variants in MKRN3 were identified, and they were found to underlie CPP in Finnish patients for the first time. Finally, an interesting finding was that male carriers of MKRN3 variants may reach their target height without treatment.Väitöstyön tavoitteena oli selvittää tiettyjen geenien vaihtelun merkitystä akromegaliassa, ennenaikaisessa murrosiässä ja synnynnäisessä hypogonadotrooppisessa hypogonadismissa. Kasvu ja murrosiän kehitys ovat riippuvaisia aivolisäkkeen erittämistä hormoneista. Joskus ituradan geenivirhe voi käynnistää kasvuhormonia erittävän aivolisäkkeen kasvaimen muodostumisen, mikä edelleen johtaa hormonin liikaeritykseen ja akromegaliaan. Murrosiän kehitykseen tarvitaan gonadotropiineja, joiden erityksen käynnistyminen liian varhain johtaa ennenaikaiseen murrosikään eli murrosiän alkamiseen tytöillä alle 8-vuotiaana ja pojilla alle 9-vuotiaana. Gonadotropiinien puutteellinen eritys taas johtaa synnynnäiseen hypogonadotrooppiseen hypogonadismiin (HH), joka ilmenee viivästyneenä, puuttuvana tai osittaisena murrosikänä. Hypogonadotrooppista hypogonadismia kutsutaan Kallmannin syndroomaksi (KS), jos potilaalla on myös puutteellinen hajuaisti. Kolmessa ensimmäisessä osatyössä KCNQ1- ja KCNE2-geenit tutkittiin 53 akromegaliapotilaalta, mikroRNA-geenit MIR7-3, MIR141, MIR429 ja MIR200A-C yhteensä 24 suomalaiselta HH- tai KS-potilaalta ja MKRN3-geeni puolalaiselta ja suomalaiselta perheeltä, joilla esiintyi ennenaikaista murrosikää. KCNQ1:stä löydettiin todennäköisesti harmittomia variantteja ja KCNE2:sta kolmelta akromegaliapotilaalta merkitykseltään tuntematon variantti, joka oli merkittävästi yleisempi tutkittujen potilaiden kuin kontrollien joukossa. Todennäköisesti harmiton variantti MIR200A:ssa löydettiin yhdeltä KS-potilaalta ja MKRN3:sta löytyi molemmilta perheiltä ennen raportoimaton ja ennenaikaista murrosikää isältä perittynä aiheuttava variantti. Myös MKRN3:n variantin pitkäaikaisvaikutukset pojalla, jolla on ennenaikainen murrosikä, raportoidaan. Neljäs osatyö selvitti suomalaisen KS-potilaan sairauden geneettistä perustaa. Hänellä olleen 9q31.2-kromosomin deleetion havaittiin kattavan kuusi geeniä, muun muassa ZNF462:n, jonka puutos selitti hänen Weiss-Kruszkan syndroomansa. Deleetio ei vaikuttanut sen lähellä sijaitsevan KS:n ehdokasgeeni PALM2AKAP2:n ilmentymiseen. Potilaalta ei löytynyt harvinaisia variantteja 32 tunnetussa KS-geenissä, ja silmukointianalyysin tulos oli tutkittujen geenien osalta normaali. Potilas on ensimmäinen, jolla on raportoitu 9q31.2-kromosomin deleetio sekä Kallmannin ja Weiss-Kruszkan syndroomat. PALM2AKAP2:sta ei 16 muulla suomalaisella KS-potilaalla löytynyt todennäköisesti tautia aiheuttavia variantteja. Väitöstyö tuotti uutta tietoa KCNQ1-, KCNE2- ja tutkittujen mikroRNA-geenien varianttien yhteydestä poikkeaviin aivolisäkehormonien erityksen sairauksiin. Tulosten perusteella KCNQ1- ja KCNE2-geenien variantit ovat epätodennäköisiä akromegalian ja tutkittujen mikroRNA-geenien variantit HH:n aiheuttajia. Kuitenkin deleetiot 9q31.2-kromosomissa näyttävät voivan aiheuttaa Kallmannin syndroomaa, mutta ehdokasgeeni PALM2AKAP2:n variantit eivät liittyneet tautiin tutkituilla. Työssä löydettiin myös uusia MKRN3-geenin variantteja, joiden havaittiin aiheuttavan ennenaikaista murrosikää Suomessa ensi kertaa

UWOMJ Volume 79, Issue 1, Spring 2010

Schulich School of Medicine & Dentistryhttps://ir.lib.uwo.ca/uwomj/1016/thumbnail.jp

The role of the aryl hydrocarbon receptor interacting protein (AIP) in pituitary tumorigenesis: A proteomic approach for explaining the clinical behaviour of AIP mutation-associated pituitary adenomas

A subset of familial and sporadic pituitary adenomas is due to germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP). A systematic follow-up of cases and families with AIP mutation (AIPmut)-associated pituitary adenomas is lacking. The product of this novel tumour suppressor gene is a ubiquitously expressed co-chaperone of the heat shock proteins HSPA8 and HSP90, but besides of pituitary adenomas, there is no clear association of AIPmuts to other neoplasms. The molecular processes leading to pituitary tumorigenesis in the presence of AIPmuts and the mechanism for tissue-specific tumour suppressor function are unclear. This research work describes the clinical features of AIPmut positive familial and sporadic pituitary adenomas in a large international cohort of patients, aiming to increase the knowledge about this condition and focusing on the screening-led detection of pituitary adenomas. To define the repertoire of interactions of AIP in the pituitary gland and to determine which interactions are lost by AIP mutants, a proteomic screening for molecular partners of AIP in a pituitary cell line was conducted. The stability of a panel of missense AIP mutant proteins and the mechanism of protein degradation were evaluated in half-life studies, and the relationship between protein stability and phenotype was analysed. A number of novel features of AIPmut positive pituitary disease were identified, drawing attention to the high percentage of positive clinical screening of the apparently unaffected AIPmut carriers. The AIP tumour suppressor function is apparently mediated by its interaction with molecular chaperones, perhaps modifying their affinity for specific client proteins. AIP could exert an additional anti-tumorigenic action by regulating cytoskeletal organisation. AIP is processed via ubiquitination and proteasomal degradation, probably mediated by the FBXO3- containing SKP1-CUL1-F-BOX protein complex E3 ubiquitin-ligase. Enhanced proteasomal degradation conferred shorter half-life to most of the AIP mutants tested, with implications for the clinical presentation.National Council of Science and Technology (CONACYT) and the Secretariat of Public Education (SEP) Mexico, Barts and The London Charity

Cushing syndrome and disease:a study of the diagnosis, treatment, clinical consequences, and Health-related Quality of Life associated with these medical conditions

Introduction Cushing syndrome and disease are classified as rare diseases. The estimated incidence of CS (2021), was 10 to 15 per million people worldwide per year and can occur in any age group, mostly diagnosed in females with a median age of 41 years. The mortality rate is reported to be between 2-4 times higher than the general population. This study was conducted following my diagnosis of CS to compare other patients experiences of these medical conditions with my own, and the clinical consequences following a diagnosis and treatment of CS. Methods A HRQoL survey was conducted on members of the Pituitary Associations using a disease-specific on-line questionnaire. Quantitative and Qualitative analysis was performed. Semi-structured interviews were also conducted on a range of Health Professions disciplines. Results The study population was 86. The 71 female members median age was 42 and the 15 males was 39.4 years. The results showed a strong correlation between age and QoL scores, (rConclusions The wide clinical spectrum of CS produces medical dilemmas as symptoms vary and therefore patients can be sent to a range of Physicians prior to a definitive diagnosis. The prolonged consequences of excess cortisol affected my own and their HRQoL, even after remission, mainly due to the persistence of physical and neuropsychological morbidity. There remains a lack of psychological support and Health Professionals awareness. A patient’s perspective should be recognised to be an integral part of the management of CS

Cushing syndrome and disease: a study of the diagnosis, treatment, clinical consequences, and health-related quality of life associated with these medical conditions

Introduction: Cushing syndrome and disease are classified as rare diseases. The estimated incidence of CS (2021), was 10 to 15 per million people worldwide per year and can occur in any age group, mostly diagnosed in females with a median age of 41 years. The mortality rate is reported to be between 2-4 times higher than the general population. This study was conducted following my diagnosis of CS to compare other patients experiences of these medical conditions with my own, and the clinical consequences following a diagnosis and treatment of CS. Methods: A HRQoL survey was conducted on members of the Pituitary Associations using a disease-specific on-line questionnaire. Quantitative and Qualitative analysis was performed. Semi-structured interviews were also conducted on a range of Health Professions disciplines. Results: The study population was 86. The 71 female members median age was 42 and the 15 males was 39.4 years. The results showed a strong correlation between age and QoL scores, (r<1, P < .03). The median length of time for a diagnosis of CS was 5.4 years (females), and 3.7years for the males. The median number of Physicians consulted prior to a diagnosis was 2. The results showed a strong correlation between the number of Physicians and their QoL scores, (r .78, P < .05). Both genders reported physical and psychological conditions. Conclusions: The wide clinical spectrum of CS produces medical dilemmas as symptoms vary and therefore patients can be sent to a range of Physicians prior to a definitive diagnosis. The prolonged consequences of excess cortisol affected my own and their HRQoL, even after remission, mainly due to the persistence of physical and neuropsychological morbidity. There remains a lack of psychological support and Health Professionals awareness. A patient’s perspective should be recognised to be an integral part of the management of CS

Medical treatment and monitoring for disorders of cortisol and adrenocorticotrophin excess and deficiency

Background: Disorders of cortisol secretion have high mortality and morbidity if inadequately treated. Medical treatment is an essential part of patient management and has improved prognosis and morbidity, however, there are unanswered questions about effectiveness, safety, accuracy and monitoring. The hypothesis in this thesis was that medical treatments can restore physiological cortisol and adrenocorticotrophin hormone (ACTH) levels in patients with disorders of cortisol excess and deficiency. Methods: Five studies examined the treatment and monitoring of cortisol secretion disorders. Two studies examined medical treatment of cortisol and ACTH excess, Cushings syndrome (CS) and Nelson’s syndrome (NS), two studies examined new methods for replacing cortisol in children with adrenal insufficiency and one study examined potential for a novel biomarker of cortisol replacement in congenital adrenal hyperplasia (CAH). Results: Study 1, demonstrated that medical therapy with the steroidogenesis enzyme inhibitor metyrapone was effective in restoring eucortisolaemia and reducing hypercortisolaemia in 50-80% of patients with CS. Study 2, demonstrated that medical therapy with pasireotide, a multi-receptor somatostatin analogue, reduced plasma ACTH levels in patients with Nelson’s syndrome. Study 3, showed that it is possible to replace cortisol with hydrocortisone through nasogastric tubes, however, there are variable drug loses due to interaction with the administering equipment and the study provided practical solutions. Study 5, showed that a novel formulation of hydrocortisone granules administered sprinkled on soft food (applesauce or yoghurt) are bioequivalent to granules delivered directly to the back of the tongue. Study 4, showed that haemoglobin and haematocrit are positively correlated with androgen and steroid precursor levels in women with CAH and provide a novel biomarker. Conclusions. Medical therapy for cortisol excess and deficiency can be improved. Metyrapone and pasireotide are effective in improving cortisol and ACTH levels in patients with CS and Nelson’s syndrome, respectively. The replacement of cortisol in paediatric adrenal insufficiency can be done through nasogastric tubes if required and with food to improve accurate dosing in neonates, infants and children. Markers of erythropoiesis may be used as a biomarker to monitor disease control in women with CAH

Genetic obesity:Disorders and diagnostics

Obesity is a common disease with serious consequences for the health and well-being of patients. In a small proportion of people with excessive weight, a change in genetic material is the main cause of the obesity. In this thesis, the results of genetic testing for these rare obesity disorders are described. Because of the high prevalence of obesity, it is currently impossible to perform genetic diagnostics in all people with obesity. An improved insight in the clinical phenotype of patients with a genetic obesity disorder is therefore needed to determine which patients should undergo genetic testing. Moreover, the impact of diagnosing these disorders is described in this thesis. Increased knowledge about the underlying mechanisms offers great opportunities for the development of novel drug therapy for obesity

Topics in Osteoporosis

Osteoporosis affects the osteo-articular system. However, there are hormonal, kidney related, gastrointestinal and neuromuscular factors among other, that can be involved in the etiopathogenesis of the disease. In the other hand, for osteoporosis prevention there are many lifestyle conditions that are very important, as dietary habits, physical activity, drugs and caffeine intake, smoking, associated diseases, etc. Based on the above, treatment and prevention of osteoporosis have to be addressed in a multidisciplinary and integral approach. The knowledge about bone metabolism and the related disorders represents an extensive field that is currently increasing through many investigations conducted in the world. The purpose of this book is to show several reviews and original investigations related with osteoporosis