Endocrinology, Neuro-Endocrine Immunology, and Clinical and Medical Immunology

All subthemes of ‘Endocrinology’ try to implement their basic research data from the bench in the patient and the population, while at the same time answering the questions from studies in the population by working at the bench.

Keeping a constant eye on the clinical relevance of basic research for the patient and population at large and vice versa, has positioned these themes at a recognized high level in the scientific community, as can be demonstrated by e.g. the scientific output and obtained grants, both from national and international sources. In the following pages, each of the themes is described in more detail.

Subtheme 1: Neuro-endocrinology

Prof. dr. L.J. Hofland, Prof. dr. W.W. de Herder, Dr. R.A. Feelders, Dr. S.J.C.C.M. Neggers, Dr. J. Hofland, Dr. A. Iyer, Dr. J.A.M.J.L. Janssen, prof. dr E.F.C. van Rossum, and Prof. dr. Dr. A.J. van der Lely, Dept. of Internal Medicine; Section of Endocrinology

This subtheme studies disorders in neuro-endocrinology, neuro-immunology and endocrine oncology. It develops new modalities for molecular imaging and treatment using peptide receptors as primary targets and aims to unravel the endocrine and immunological basis of important diseases in the community.

In particular, the research includes the following main topics:

• Pituitary tumors (Prof. dr. L.J. Hofland, Dr. R.A. Feelders, Dr. S.J.C.C.M. Neggers, Prof. dr. Dr. A.J. van der Lely): Pituitary tumors cause severe clinical syndromes due to hormonal overproduction by the tumor cells, or in case of tumors not producing hormones, due to their growth and pressure on surrounding structures. Striking examples are acromegaly due to a GH secreting pituitary adenoma and Cushing’s disease due to excessive ACTH secretion by a pituitary adenoma. The search for better diagnostic tools and novel medical therapies for these diseases is one of our main aims.
• Neuroendocrine tumors (Prof.dr. L.J. Hofland, Prof.dr. W.W. de Herder, Dr. J. Hofland, Dr. R.A. Feelders): Neuroendocrine neoplasms or NENs are diverse malignant neoplasms mainly arising from the gastrointestinal and pulmonary tracts. NENs display a unique biology with debilitating hormonal syndromes and often long-term survival despite metastatic disease. At the Erasmus MC ENETS Center of Excellence and EURACAN Group 4 ERN Center, we study the biology of NENs through translational approaches with the ultimate goal of developing novel diagnostic, predictive or prognostic biomarkers and therapeutic options for patients. Key research areas include clinical aspects of hormonal syndromes, such as the carcinoid syndrome, ex vivo NET modelling and radionuclide imaging and therapy, also known as theranostics and furthermore radionomics/multi-omics projects have been initiated. The center is the key leader, or collaborates in collaborative Dutch national or international preclinical projects as well as international multicenter clinical studies with a high impact.
• Adrenocortical tumors (Dr. R.A. Feelders, Prof.dr. L.J. Hofland): One of the research lines of the neuroendocrine group is the study of adrenal tumors. Hormone secreting adrenocortical adenomas can lead to severe clinical symptoms. Adrenocortical carcinomas are highly aggressive tumors, for which surgery is the only curative treatment modality and patients with adrenocortical carcinoma have a 5-year survival rate of 16-44%. There is a high need for effective medical therapies. The research focusses on better diagnostic tools to distinguish adrenocortical adenoma from carcinoma, on predictive and prognostic markers, as well as on novel therapeutic options.
• Ghrelin (Prof. dr. A.J. van der Lely): We have discovered that ghrelin can influence insulin sensitivity and that its unacylated form can significantly improve insulin sensitivity by antagonizing the acylated form of ghrelin, which makes the combination a candidate for treatment of the many disorders which can be characterized by an increased insulin resistance. Studies on the metabolic activities of ghrelin and the role of ghrelin receptors herein form a main arm of the current research activities.
• Glucocorticoid receptors (prof. dr. E.F.C. van Rossum): We identified a number of polymorphisms in the glucocorticoid receptor (GR)-gene that are associated with changes in the glucocorticoid sensitivity. A main research goal is the identification of the effects of these variations on numerous aspects of health and ageing.
• Cortisol in relation to cardiometabolic diseases and psychiatric diseases (prof. dr E.F.C. van Rossum, Dr A. Iyer): We are one of the few laboratories in the world who developed an innovative method to determine long-term cortisol levels using scalp hair. Studying relations between the stress hormone cortisol and the metabolic syndrome, cardiovascular disease, mental illnesses and numerous other disease was previously limited by the only available highly variable point measurements in e.g. blood and saliva. In contrast, our novel cortisol analysis in hair resulted in numerous promising insights in these stress-related diseases and yielded many possibilities to study other diseases or conditions, which are related to cortisol. Most of the findings are directly relevant for clinical practice.
• Insulin-like growth factor I (IGF-I) (Dr.J.A.M.J.L. Janssen, Prof.dr. L.J. Hofland): We recently studied genetic polymorphisms in the regulatory region of the IGF-I gene and found that both the risk of type 2 diabetes and myocardial infarction were significantly increased in non-carriers of a 192-bp allele when compared with carriers of this polymorphism. This suggests that a genetically determined exposure to low IGF-I levels plays a role in the pathogenesis of both type 2 diabetes as well as myocardial infarction. Considering the high complexity of the IGF-I system, which includes many binding proteins, we have now developed an IGF-I bioassay to determine more in detail the role of genetic variations in the IGF-I gene in relation to circulating IGF-I bioactivity.

Subtheme 2: Role of the thyroid gland in disease

Dr. W. Edward Visser, Department of Internal Medicine, Section of Endocrinology, Rotterdam Thyroid Center, prof. dr. R.P. Peeters, dr. Marco Medici, dr. Marcel Meima Department of Internal Medicine, Section of Endocrinology, Rotterdam Thyroid Center

Thyroid hormone signalling is indispensable for normal development and function of many tissues. The thyroid gland mainly produces the precursor hormone T4 (thyroxine), which is deiodinated to the bioactive form T3 in peripheral tissues. According to the current paradigm, cellular thyroid hormone signalling is governed at multiple levels: 1) plasma membrane transport, 2) intracellular metabolism and 3) genomic actions via nuclear thyroid hormone receptors (TRs).

Over the last decades, our group has identified a number of disorders arising from defects in key players of thyroid hormone signaling. Mutations in the thyroid hormone transporter MCT8 result in a disorder with severe neurological and metabolic consequences (Groeneweg, Lancet Diab Endocrinol 2020). Following translational studies in our lab, we led a multicenter international trial in which the effects of a T3 analog was investigated in such patients (Groeneweg, Lancet Diab Endocrinol 2019). Based on the promising results, a second international trial has started and the first steps towards registration of this molecule for MCT8 deficiency have been taken. Furthermore, we and others identified the first patients with a defective TR who manifested with developmental delays and growth retardation (Van Mullem, NEJM 2013). We are currently exploring the mechanisms of disease employing a wide array of cutting edge technologies.

At present, we are utilizing patient-derived induced pluripotent stem cells to model the different disorders (e.g. MCT8 deficiency, RTHa etc). At present, the focus is on differentiation towards various neural cell lineages.

Based on a large genome wide association study, a few novel candidates in thyroid hormone regulation (AADAT, SLC17A4) were identified (Teumer, Nat Comm 2018). At present, we are investigating the physiological role of these newly discovered genes.

We aim to use our knowledge on cellular thyroid hormone regulation not only for the benefit of patients with rare thyroid hormone signaling disorders but also for common primary thyroid disorders. At present, we coordinate a national randomized controlled trial in which the addition of T3 to the standard T4 therapy in patients with hypothyroidism is studied.

In the Thyroid Group we cover fundamental, translational and clinical studies along with research lines in epidemiology (thyroid and aging, thyroid and pregnancy; see chapter 15, Theme 12).

Subtheme 3: Calcium and Bone related research

Prof. dr. A.G. Uitterlinden, Department of Internal Medicine, Section of Endocrinology

Calcium and bone metabolism research focuses on the regulation of skeletal and calcium homeostasis and the development and progression of diseases in particular during ageing. The eventual goal is by integration of molecular and cell biological, experimental animal models, epidemiological and genetic epidemiological and clinical research to achieve improved diagnostics and treatment of skeletal diseases and disturbances in calcium metabolism. The current therapies for osteoporosis are predominantly directed to inhibit bone resorption and thereby progression. There is, however, a great need for anabolic therapies that stimulate bone formation because bone loss has already occurred at the moment that the consequences of osteoporosis become overt. In line with this, the improvement of early diagnosis is of great importance.

Four major interrelated research lines directed to etiology, diagnostics and treatment of calcium and bone related diseases can be identified.

• Molecular mechanisms of bone cell differentiation and regulation of bone formation and resorption. The aim is:
  • to identify novel therapeutic targets and therapies for osteoporosis and to obtain new insights into mesenchymal stem cell differentiation important for tissue engineering, and
  • to assess new leads for the identification and characterization of risk determinants (see Research line 2) by genomic and proteomic approaches.
• Identification and characterization of risk determinants for osteoporosis.
  • to analyse genes/proteins identified in Research line 1 as risk determinants, and
  • to identify new markers by serum protein profiling of individuals with specific osteoporotic characteristics (e.g. fractures).

This research can be perfectly coupled to the genome wide association studied that are planned to be performed within the Rotterdam Study.

• Relationship of osteoporosis and osteoarthritis and the significance for development of osteoarthritis.

In the clinic severe forms of osteoporosis and osteoarthritis seem to exclude each other, however, there also seem to be overlapping aetiological mechanisms. The aim is to include in the research lines 1 and 2 also the osteoporosis — osteoarthritis relationship and to assess differences but also to analyse common mechanisms.

• Calcium homeostasis in relation to bone metabolism and osteoporosis.

The aim is to investigate changes in calcium homeostasis and bone metabolism during aging by human population and experimental animal studies. The combination of human population and experimental animal studies provide the opportunity to analyse the epidemiological observations at a more mechanistic level. These studies will provide new insights into the calcium and skeletal homeostasis and potential novel therapeutic and diagnostic targets which are coupled to research lines 1 and 2.

Subtheme 4: Metabolism and Reproduction

Dr.ir. J.A. Visser, Prof. dr. A.J. van der Lelij, Dept. of Internal Medicine; Section of Endocrinology

The research of the Metabolism and Reproduction group is directed at gonadal and metabolic dysfunction. Through a combination of physiological, genetic and signal transduction studies our group aims to understand the role of steroid hormones, peptide hormones, and growth factors in the interaction between gonadal function and metabolism (such as reproductive aging, PCOS) and metabolism (including metabolic aging). The hormones studied include estrogens, androgens and glucocorticoids, ghrelin and unacylated ghrelin, and TGFβ family members such as anti-Müllerian hormone and bone-morphogenetic proteins. An important focus of our studies is on white and brown adipose tissue functioning, insulin sensitivity and lipids.

Additionally, we aim to understand the sex differences in metabolic dysfunction. The ultimate goal is to unravel the mechanisms by which hormones and growth factors contribute to metabolic disorders, such as obesity, diabetes, and cardiovascular disease in order to identify novel risk markers and novel therapeutic targets.

Within our group we have three interrelated research lines. All lines use a combination of molecular, cellular and animal research and studies in humans.

• The sex-specific regulation of the activity of fat metabolism (Dr. Aldo Grefhorst & Dr. ir. Jenny A. Visser).

There are clear differences between men and women in fat distribution and the development of obesity and associated metabolic diseases. This suggests that sex-specific approaches may be needed to combat obesity and associated diseases. By detailed investigation of the differences between male and female metabolism and the role of sex steroids herein, we aim to understand sex differences in metabolism, especially in the white adipose tissue (WAT), brown adipose tissue (BAT) and the liver. We and others have shown in animal experiments that females have more active BAT than males. Furthermore we recently showed that the TGFβ family member BMP8b might be involved in this sex-difference in BAT activity, because BAT of female mice had a higher BMP8b expression than BAT of male mice. Since the brain plays an important role in the regulation of metabolism, we also study how sex steroids act in the brain to control the function of peripheral metabolic tissues.

• The development of un-acylated ghrelin (UAG) as a drug to combat obesity and its accompanying physiological aberrations (Dr. Patric Delhanty & Prof. dr. Aart Jan van der Lely).

The acylated form of ghrelin (AG) is known as the hunger hormone that induces obesity and insulin resistance. Un-acylated ghrelin (UAG) is the naturally occurring non-acylated form of ghrelin and an increasing number of studies suggest that UAG is a functional inhibitor of AG. An analogue of UAG is currently in phase I clinical trials to discover if it can reverse the effects of obesity and/or diabetes. However, despite evidence for biological activity of UAG on various cell types and in animals and humans, and that inhibition of a range of signaling pathways block its activity, we still do not know its precise mechanism of action, since a receptor for UAG has not yet been discovered. One of our main ongoing research themes is to investigate the mechanism of action of UAG and its analogues in animal models of obesity and insulin resistance, as well as mice that have had the ghrelin gene deleted. The goal is to identify discrete physiological effects which could impact on these pathologies, such as effects on energy metabolism, as well as sites of action, for example the pancreas, adipose tissue and brain.

The goal here is to more precisely define the biological function of UAG and give clues to its mechanism of action. An important related research aim is to discover the UAG receptor using cell-lines known to respond to UAG. Approaches we are using include investigation of signal transduction pathways, receptor-ligand interactions and proteomic techniques.

• The interaction between female fertility and metabolism (Dr. ir. Jenny A. Visser)

This research line focuses on the regulation of ovarian function and the interaction with metabolism as in reproductive aging and polycystic ovary syndrome (PCOS). Ovarian folliculogenesis is a dynamic process that declines with increasing age ultimately resulting in menopause.

Menopause not only leads to a loss of estrogens but also of ovarian growth factors. In contrast, in PCOS ovarian production of androgens and growth factors is increased. Both conditions, menopause and PCOS, are associated with an increase in metabolic risk factors. Using mouse models with altered gonadal function (AMH knockout mice, DHT-induced PCOS mouse model), we have recently shown that gonadal growth factors regulate the function of white and brown adipose tissue and lead to sex-specific differences in glucose tolerance. The aim of our studies is to understand the underlying mechanisms by which gonadal growth factors contribute to the (sex-specific) regulation of metabolism and to identify the gonadal factors involved.

MSc. students who are interested to participate in one of the research lines of the subthemes of ‘Endocrinology and Ageing’ are encouraged to contact one of the working group leaders.

Autoimmune diseases of the neuro-endocrine system are leading causes of morbidity, psychosocial burden and economic loss in our western society. Neuro-endocrine autoimmune diseases in which the Dept. of Immunology is in particular interested are type I diabetes (T1D), autoimmune thyroid diseases (AIT), multiple sclerosis (MS), Guillain-Barré syndrome (GBS) and systemic sclerosis). Other autoimmune diseases of interest are rheumatoid arthritis (RA), Sjögren’s syndrome and psoriasis. The Dept. also studies psychiatric diseases that are related or associated to these autoimmune diseases, such as bipolar disorder (BD), other mood disorders ( major depressive disorder,MDD; post partum psychosis, PPP), and schizophrenia(SCZ). In addition, the department studies chronic fatique as long term sequel of COVID-19/SARS-CoV2 infection. The premise is that an activated inflammatory response system (IRS) drives all these pathologic processes, yet differences occur between these complex diseases due to a difference in eliciting or protecting co-factors of genetic and environmental character, such as e.g. the polymorphisms in the HLA system, iodine consumption, smoking, gut infections, pregnancy and stress. The neuro-endocrine system is an important regulator of the IRS, both via the HPA-axis and the vagus nerve.

In the research the Dept. of Immunology predominantly focusses:

• On aberrant pro- and anti-inflammatory set points of monocytes/macrophages/dendritic cells and of Th1, Th17 and T regulatory cells as important causes of the activation of the IRS. Aberrations of these cells are studied in T1D, AIT, BD, MDD, PPP, SCZ, MS, atherosclerosis and COVID19. At present a large scale EU program (19 partners from 10 EU countries.) is coordinated by Prof Drexhage, which has as short title MOODINFLAME and this program views mood disorders as ‘low-grade special inflammations of the brain’.
• On molecular mimicry between auto-antigens and environmental antigens as another important cause of autoimmune diseases, such as GBS.

Further focuses are the amelioration of MS, AIT and RA during pregnancy, the exacerbation of these diseases and of mood disorders in the post-partum period and the immune regulation exerted by pregnancy-related and lactation related hormones and peptides. Our research covers a broad area ranging from patient cohort studies via functional in vitro and genetic analyses of patient material to several animal disease models in rodents and non-human primates.

Via our research we hope to develop better diagnostic procedures and treatment modalities. We perform our research in close collaboration with clinical researchers who are well trained in immunology, endocrinology and neuroscience. This allows the joint construction of scientifically relevant research questions and well-characterized patient cohorts.

Subtheme 1: The immune system and psychiatric disease

Prof. dr, H.A. Drexhage and dr. W.A. Dik (Department of Immunology, Laboratory Medical Immunology)

In our research over the past 5-10 years we have identified various functional abnormalities of monocytes/macrophages/dendritic cells and T cells in T1D, AIT and Sjögren’s syndrome. This research was performed on patient materials (serum and leukocyte preparations) and — in parallel — in animal models of these autoimmune diseases, in particular the NOD mouse and the BB-DP rat. We have also assessed the role of these monocyte/macrophage/dendritic cell and T cell abnormalities in defective tolerance induction.

In our research we also found a heightened risk for T1D and AIT in bipolar disorder patients and their family members (twins and children) and vice-versa, e.g. more mood disorders in patients with AIT and T1D. It is also known that endocrine autoimmune diseases and mood disorders are associated with a higher risk for atherosclerosis. Our studies and observations thus pointed in the direction of a shared vulnerability factor for endocrine autoimmune diseases, mood disturbances and atherosclerosis. We presently study the combination of a pro-inflammatory activated monocyte/macrophage/dendritic cell system, an activated T helper cell system and a defective regulator cell system as the shared abnormal vulnerability factor between mood disorders, autoimmunity and COVID-19/SARS-CoV2 infection.

To approach the problem on a molecular level we have identified genes aberrantly ex-pressed in monocytes of T1D, AIT, SCZ, MDD, PPP and BD patients. These gene products are linked to the previous found functional monocyte abnormalities and around 50 key aberrant genes have now been selected. We have designed custom made (RQ-PCR) arrays for these genes and test the ability of these arrays to distinguish in the lab various subtypes of T1D, to identify pre-diabetic individuals and individuals at risk for the development of MDD and SCZ. In addition, we test the ability of these arrays to identify patients that are at risk of developing chronic fatigue after COVID-19/SARS-CoV2 infection. We also target these key molecules with novel drugs (anti-cytokines, 2nd generation COX-2 inhibitors, KMO-inhibitors) in an attempt to correct the pro-inflammatory set point of the immune system to lower the risk for the development of the afore-mentioned diseases.

These studies are conducted in in a multidisciplinary setting. This includes collaborations with other departments within Erasmus MC (e.g. Psychiatry, Pulmonary Medicine, Internal Medicine) as well as other national and international partners.

Subtheme 2: Pathogenesis of the Guillain-Barré syndrome

Dr. B.C. Jacobs (Depts. of Neurology and Immunology, Erasmus MC)

The Guillain-Barré syndrome (GBS) is the most common form of acute neuromuscular pa-resis. Patients with GBS have a rapidly progressive immune-mediated neuropathy result-ing in severe paresis of limb and respiratory muscles, from which patients may die. Re-search in our group showed that GBS is a molecular mimicry mediated disease in which preceding infections trigger the production of toxic cross-reactive antibodies to neural structures. In about 40% of patients these antibodies are directed to neural glycolipids or gangliosides. Campylobacter jejuni is the predominant cause of infection in GBS and lipo-oligosaccharides from these bacteria indeed exactly mimic gangliosides. Infusion with immunoglubulins is an effective treatment in GBS, although the mechanism of action of this treatment is unknown.

Four important issues remain unsolved in GBS:

• What are the immuno-targets in patients without anti-ganglioside antibodies? Pilot studies have identified new targets, but these need to be tested in the available large cohorts of patients, in relation to neurological deficits and prognosis.
• What is the cellular mechanism driving the production of these cross-reactive anti-bodies? Our recent studies indicate that C. jejuni directly activates dendritic cells and B-cells. This in vitro model for GBS will therefore enable us to determine the responsi-ble cellular pathways.
• Can genetic host factors explain why only 1 in 1000 persons with a Campylobacter infection develops GBS? We are studying single nucleotide polymorphisms in immune response genes, which may determine this abnormal response to infection.
• Which mechanism of action is responsible for the therapeutic effect of immu-nogloblulins? Several serological and cellular models have been developed to identify the effective fractions of these immunoglobulins and clarify the mechanisms of action.

At the Erasmus MC there is a unique collaboration between the departments of Neurology, Immunology, Medical Microbiology & Infectious Diseases regarding GBS research. Central to this collaboration is the patient-related laboratory research, which gives us excellent opportunity to address these four study objectives and in which students are gladly invited to participate.

Clinical and Medical immunology encompasses a broad field of immune-mediated diseases, including Inborn Errors of Immunity (IEI), auto-immune diseases and auto-inflammatory conditions. Moreover, it has been demonstrated over the past years that many pathways involved in the pathogenesis of these immune diseases play a role in other diseases, which makes clinical and medical immunology an ever-expanding field of research and novel therapeutic developments. Within our research we focus on the so-called ‘from bedside to bench and back to bedside’ approach. Our research is therefore strongly patient driven. Based on clinical problems we encounter in daily practice we try to better understand genetics and disturbances in immunobiological pathways that give rise to immune mediated diseases. Moreover, we evaluate complications of these diseases, also related to other specialties. This has led to a network of research in which many other departments are involved. Important goals of our research topics include: unraveling immunobiological pathways involved in immune-mediated diseases, the development and implementation of novel, targeted, personalized treatment options for rare immune-mediated diseases, and improving the diagnostic work-up for immune mediated diseases.

Subtheme 1: Inborn errors of immunity (IEI, primary immunodeficiencies)

Dr. V.A.S.H. Dalm, dr. H. IJspeert, dr. W.A. Dik (Department of Internal Medicine, Section of Clinical Immunology and Department of Immunology, Laboratory Medical Immunology)

Inborn Errors of Immunity (IEI, previously recognized as Primary Immune Deficiencies) are rare, inborn errors of (parts) of the human immune system, which give rise to complex and heterogeneous clinical phenotypes. Clinical features include an increased risk of infections, auto-immune disease, auto-inflammatory complications and (hematological) malignancies. At current over 450 IEIs are described based on monogenetic defects, however in the majority of patients no known genetic defect is described. In ongoing projects we aim to identify the burden, cause and therapeutic options of non-infectious complications in IEI patients, including granulomatous disease, skin, endocrine, neurodevelopmental, fertility and psychiatric disorders. Moreover, IEI as part of syndromic disorders including Jacobsen syndrome and Netherton syndrome have been identified and novel therapeutic options are evaluated. Current area of interest includes the identification of novel genetic defects resulting in IEI, evaluation of pathways involved in pathogenesis, in vitro analysis of therapeutic efficacy of novel compounds and implementation of new therapeutic strategies in clinical practice, providing a targeted, personalized therapy in IEI patients. Finally, attention is on studies on Quality of Life and implementation of Value Based Health Care program as well as development of patient-centered and individualized care programs are studied.

MSc students will be able to have their own, first-author research project of their choice, focusing on the following topics:

1. Identification of novel pathogenic genetic defects in patients with IEI, which includes genetic evaluation of specific patients or patient groups and in depth analysis of the biological and clinical relevance of the found genetic defect, which could result in the evaluation of potential novel targeted treatment options for these patients
2. Unravelling the pathogenesis of granulomatous disease in patients with IEI using in depth cellular and molecular analysis in order to provide a potential basis for novel treatment options
3. Evaluation of non-immune complications in patients with IEI. It has been recognized that many patients with IEI suffer from complications in other organ systems. In these projects we evaluate the presence of psychiatric, neurodevelopmental, gastrointestinal tract, fertility complications in patients with IEI
4. The role of Value Based Health Care in patients with IEI

Subtheme 2: Systemic autoimmunity, auto-inflammation, Graves’ ophthalmopathy, inflammation and fibrosis

Dr. P.L.A. van Daele, dr. Z. Brkic, dr. W.A. Dik, dr. M.A. Versnel (Department of Internal Medicine, Section of Clinical Immunology and Department of Immunology, Laboratory Medical Immunology)

Systemic autoimmune diseases like systemic lupus erythematosus (SLE), systemic sclerosis (Ssc) and primary Sjögren’s Syndrome (pSS) have a subset of patient with systemically elevated type I Interferon (IFN) activation. As treatment options for these diseases are limited type I IFN is considered an interesting treatment target. The overall aim of this research line is to unravel the role of type I IFN in the pathogenesis, determine the prevalence of systemic IFN activation, to relate the presence of this activation to clinical symptoms and response to treatment and finally to therapeutically target IFN activation in patients with systemic autoimmune diseases.

Another group of diseases with systemic activation of type I IFN is the so-called interferonopathies. These diseases are characterized by a mutation of single genes involved in type I IFN signaling. Yet, recognizing, diagnosing and treating these diseases can be troublesome. . The aim of this study is to evaluate the applicability of laboratory tests that reflect type I IFN type pathway activation in the diagnostic work-up and treatment evaluation of these diseases.

Graves ophthalmopathy (GO) and SSc are auto-immune diseases characterized by inflammation and fibrosis. Inflammatory reactions are normally resolved in a phase of scar formation involving the activation of fibroblasts. Fibroblasts are anyway involved in the inflammatory process by providing a scaffold for the inflammation. In addition there is an intensive molecular cross talk between tissue fibroblasts and resident and infiltrating immune cells during the inflammatory process. In certain immune pathological conditions these interactions are aberrant and result in abnormal inflammation and fibrosis, e.g. in GO and SSc.

GO and SSc are our current models for further study, here we focus on receptor antibodies, IFN activation and other immune stimulators for fibroblasts and the resulting stimulation of kinase pathways in fibroblasts. Attempts are made to intervene in such pathways (both clinically and in the laboratory) with kinase inhibitors such as Imatinib mesylate, AMN107 and Dasanitib.

MSc students will be able to have their own, first-author research project of their choice, focusing on the following topics:

1. Unraveling the role of type I IFN in the pathogenesis of systemic autoimmune diseases.
2. Study the clinical relevance of assessing type I IFN activation in auto-inflammatory disorders and systemic autoimmune diseases.
3. Study the interaction between mast cells and orbital fibroblasts to further unravel the immunopathobiology of Graves’ ophthalmopathy in order to provide a basis for novel treatment options to disrupt mast cell fibroblast interactions

Most of our studies are conducted in in a multidisciplinary setting, combining knowledge of both clinical and laboratory specialists. This includes collaborations with other departments within Erasmus MC (e.g. Internal Medicine, section of Clinical Immunology, Internal Medicine, section of Endocrinology, Rheumatology, Pediatric Rheumatology, Ophthalmology) as well as other national collaborators (e.g. Rotterdam Eye Hospital).

Patients with complex rare genetic syndromes (CRGS), by definition, have combined medical problems affecting multiple organ systems for which they require multidisciplinary medical care. Up to 89% percent of the syndromes are associated with endocrine problems. Until recently, children with CRGS often did not reach adult age. However, improvement of pediatric medical care has significantly increased the life expectancy and an increasing number of children with CRGS now reach adult age. Unfortunately, little is known about the medical problems that occur during adulthood in patients with CRGS. This lack of knowledge often results in over- and underdiagnosis and over- and undertreatment. The result: suboptimal patient care, medical complications, and high healthcare costs.

Within the department of Internal Medicine – Endocrinology, we have launched a specialized multidisciplinary outpatient clinic for adults with CRGS (the Center for Adults with Complex Rare Genetic Syndromes).

Our center is the only center for adults with CRGS in the world, when it comes to internal medicine. This gives us the unique opportunity to study medical problems in adults with CRGS in a relatively large number of patients. In the Center for Adults with CRGS, we combine unique multidisciplinary care with clinical and fundamental research. The research of all “Genetic and Developmental Endocrinology” subthemes is carried out at the Center for Adults with CRGS. If you wish to know more about one of the subthemes, please contact dr. Laura C.G. de Graaff (l.degraaff@erasmusmc.nl).

Subtheme 1: Prader-Willi syndrome
Prader-Willi syndrome (PWS) is a rare and complex disorder, which is caused by lack of expression of the paternally expressed genes on chromosome 15q11.2-q13. The syndrome is characterized by intellectual disability, hypotonia, and hypothalamic dysfunction. Due to the hypothalamic dysfunction, individuals with PWS experience insatiable appetite, abnormal pain perception, and several pituitary hormone deficiencies, among others.

PWS is well studied in children, but in adults this is not the case. As the syndrome is very rare with an incidence of 1:16.000 – 1:20.000 live births, we closely work together with other PWS experts from all over the world. Previous research of our group focused on missed diagnoses and health problems in adults with PWS, the hypothalamic-pituitary-adrenal axis in adults with PWS, the effects of multidisciplinary care and growth hormone treatment during childhood on health problems in adults with PWS, the effects of growth hormone treatment during adulthood , and the genetics of Prader-Willi like syndrome.

Ongoing clinical research of our group focuses on the genetics of PWS, the prevalence of malignancies in patients with PWS, and on cardiovascular pathology, hypogonadism, bone health, and thyroid function in adults with PWS. Besides clinical research, we also do fundamental research. Ongoing fundamental research focuses on the bioactivity of IGF-I in individuals with PWS and on the use of new assays to measure bioactive IGF-I. For this research, we collaborate with the Diagnostic Laboratory of Endocrinology (head: Dr. Sjoerd van den Berg)

The aim of this subtheme is to further unravel the adult manifestations of Prader-Willi syndrome, both from a clinical and fundamental point of view.

Subtheme 2: Neurofibromatosis type 1
Neurofibromatosis type 1 (NF1) is a rare disorder caused by mutations in the NF1 gene on chromosome 17q11.2 with an incidence of 1:2.500 live births. NF1 is characterized by neurofibromas, café-au-lait spots, and learning difficulties, among others. Besides, adults with NF1 often suffer from unexplained severe fatigue, sometimes accompanied by hypertension and palpitations.

Within the Center for Adults with CRGS, we are currently investigating the causes of this disabling fatigue in adults with NF1. In this study we investigate whether the fatigue can be explained by previously undetected organ dysfunction or endocrine deficiencies, or by neurocognitive problems. For this unique combined somatic and neurocognitive research, we collaborate closely with the Vincent van Gogh Institute, Center for Neuropsychiatry.

Besides fatigue, thyroid noduli seem to be more prevalent among patients with NF1. The exact prevalence and clinical relevance of these thyroid noduli are unknown and guidelines on how to approach this health problem in patients with NF1 are lacking. In this study, we investigate the clinical significance of these noduli and develop an algorithm for the approach of thyroid noduli in adults with NF1.

Subtheme 3: Disorders of Sex Development
Disorders of Sex Development (DSD) is a group of congenital conditions associated with atypical development of internal and external gonadal and/or genital structures. In some DSD, the physical appearance does not match with the sex chromosomes. For example, in Complete Androgen Insensitivity Syndrome, the physical appearance is female, whereas the sex chromosomes are male (XY). In other forms of DSD, there is a variation in the number of sex chromosomes. Examples are XXY (Klinefelter syndrome), XO (Turner syndrome), XXX (Triple-X syndrome), XXXX (Tetra-X syndrome), XXYY or XXXXY syndrome. In this subtheme we will mainly focus on Turner syndrome (TS) and Klinefelter syndrome (KS).

TS is characterized by complete or partial monosomy X, leading to a 45,X karyotype. TS is associated with short stature, increased risk of cardiac and renal malformations, incomplete pubertal development, infertility, and neurocognitive alterations, among others. Many women with TS have unexplained severe fatigue and unexplained elevations of liver enzymes.

Regarding TS, we investigate the internal causes of fatigue in women with TS and relate this to their Health Related Quality of Life. Furthermore, we explore the different internal causes for elevated liver enzymes in order to develop algorithms for diagnostics and treatment of both health problems.

KS is characterized by one or more extra X-chromosomes, leading to for example a 47,XXY karyotype. KS is associated with tall stature, small testicular volume, low testosterone levels, gynecomastia, and neurocognitive problems, among others. Equally to TS, many men with KS have unexplained severe fatigue and Quality of Life is often impaired.

Ongoing research on KS focuses on fatigue, Quality of Life, and perceived stress in men with KS. In a large observational cohort study, we explore the relationship between long-term testosterone levels (hair testosterone) and fatigue, Quality of Life and perceived stress in men with KS.

Due to the extremely low prevalence of the disorders we see in our center, we use study designs that are especially suitable to investigate rare disorders, like “N-of-1” studies. One of the “N-of-1” studies is about the effect of testosterone treatment in a patient with 17-beta-hydroxysteroid dehydrogenase type 3 deficiency, which is an ultra-rare type of DSD.

Subtheme 4: Other complex rare genetic syndromes
At the Center for Adults with CRGS, we have seen over 700 patients with 61 different CRGS during the last five years. In the previous subthemes we have described three types of CRGS. However, we also perform studies that do not focus on a single syndrome and studies in which we investigate syndromes that only occur in a very small number of patients.

Examples of studies in this subtheme are an overview of syndrome-specific manifestations and medical pitfalls of various ultra-rare syndromes at adult age, the safety of vitamin D supplements in adults with Williams-Beuren syndrome, the occurrence of multiple syndromes within one individual, and the development of an artificial intelligence tool to improve the recognition of intellectual disability among the general population.

Fundamental research
Although improving patient care is our main focus, basic science can also ‘learn’ from patients with rare genetic disorders. Their disorders can be considered a kind of ‘experiment of nature’. If a patient is missing a specific protein gene or protein, we can learn about the role of that protein based on the patients symptoms. If we want to learn about the role of the X chromosome in certain processes in the body, a patient with tetra-X syndrome (four X-chromosomes) can teach us a lot. For fundamental research, we collaborate with the Neuroscience Lab (head: Ass. Prof. Geeske van Woerden) and the Laboratory of Metabolism and Reproduction (head: Ass. Prof. Jenny Visser).

Subtheme 5: Congenital pituitary disorder
The HYPOPIT study is an ongoing fundamental research line about congenital hypopituitarism. In a large cohort of patients with various types of congenital pituitary hormone deficiencies we study the role of different genes, proteins, and transcription factors on pituitary organogenesis and function.

In the past, we studied Dutch patients with congenital hypopituitarism for variants in PROP1, HESX1, POU1F1, LHX3, LHX4, OTX2, SHH and HHIP. We screened patients with isolated Growth Hormone Deficiency for variants in GH1, GHRHR, HMGA2 and CDK6. More recently, our research focused on the role of the GPR101 gene in congenital hypopituitarism, the phenotypic significance of a near-complete GLI2 deletion in a patient with combined pituitary hormone deficiency, and on the usefulness of genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies. Current research focuses on IGSF1 and on the added value of Whole Exome Sequencing in this intriguing disorder.