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A 46-year old Ghanaian man presented with immobilizing arthralgias in all joints except the forefoot, with a periarticular swelling most pronounced around the wrists and ankles. He had erythema nodosum and hilar lymphadenopathy on chest radiograph. We diagnosed Löfgren syndrome. The polyarthralgia recovered quickly with prednisone treatment.

A 42-year-old man with no relevant medical history presented with a painless, red, disfiguring skin lesion located on the nose. He was diagnosed with lupus pernio, a rare, cutaneous subtype of sarcoidosis which is relatively resistant to therapy and is associated with systemic sarcoidosis.

Histoplasmosis is an infection caused by inhalation of spores of the fungus Histoplasma capsulatum. H. capsulatum is not present in the Netherlands but can cause severe disseminated disease in the immunocompromised traveller, with high mortality rate, especially when diagnosis is delayed. Therefore, early recognition is crucial. However, similarities with other infectious diseases, haematological malignancies and auto-immune diseases make timely diagnosis difficult.We present a case of a 39-year-old immunocompromised male traveller who presented with disseminated histoplasmosis after a trip to Central America. The diagnosis was made a few months after the first symptoms occurred. He died despite adequate treatment with liposomal amphotericin B.Disseminated histoplasmosis should be considered as a cause of unexplained fever in immunocompromised patients who travelled to endemic regions. Mortality is high, even when properly treated. Early recognition and treatment improve outcome.

In addition to its mucosal pathology, sarcoidosis of the nose may cause a range of skin abnormalities and destruction of the osteocartilaginous structures of the nose. Clinical presentation can mimic other diseases and a biopsy is often necessary. We propose a classification of nasal sarcoidosis based on disease location to help with recognition of the symptoms and, subsequently, treatment. Here we describe 4 patients with nasal sarcoidosis. In the first patient, a 53-year-old woman with a granuloma in the nasal vestibule, the lesion was excised. The second patient, a 38-year-old man with intranasal crusts, synechiae and atrophic mucosa, was treated with corticosteroid nasal drops. The third and fourth patients, a 36-year-old man with progressive widening of the nasal dorsum and a 60-year-old woman with a saddle nose, respectively, were treated with a rhinoplasty.

A 41-year-old male with a history of cutaneous sarcoidosis presented with sudden onset pain in his left foot. An X-ray showed cystic lesions in the proximal phalanges of the foot with two insufficiency fractures. The lace-like pattern of these lesions is exemplary for osseous sarcoidosis.

The clinical spectrum of neurosarcoidosis is highly diverse; virtually any neurological syndrome can present, depending upon granuloma localization. There are indications that neurosarcoidosis is insufficiently recognized as a separate clinical entity. In the absence of major prospective clinical trials, we launched a large national online registry of neurosarcoidosis patients in the Netherlands in June 2014 at www.neurosarcoidose.nl. When a patient with sarcoidosis presents with neurological symptoms that may compatible with sarcoidosis, it is important to locate sites of disease activity accessible for biopsy outside the nervous system. Small nerve fibre neuropathy is a common neurological complication of sarcoidosis. It is considered an epiphenomenon, and therefore classified as 'para-neurosarcoidosis'. Neurological symptoms causing disability are an indication for immunosuppressive therapy. There is increasing evidence for the effective treatment of refractory neurosarcoidosis using biologicals. Whether the intravenous administration of immunoglobulins or ARA290, an erythropoietin derivative with TNF-α-antagonistic and tissue-protective characteristics, is effective for small nerve fibre neuropathy in sarcoidosis is subject for study.

In view of the diminished number of CD4+ lymphocytes, the co-existence of an HIV infection and sarcoidosis seems paradoxical. Immune reconstitution inflammatory syndrome (IRIS) may be observed in response to anti-retroviral therapy (ART). According to the conventional definition, this is caused by an overwhelming immune response to an already present or to a new agent.We describe the case of a 47-year-old HIV-positive patient, who presented with an exacerbation of his sarcoidosis nine months after initiation of ART. Based on the time course and the dynamics of the CD4+ lymphocyte count, this presentation of disease can be placed in the context of IRIS.The presentation or exacerbation of sarcoidosis after initiation of antiretroviral therapy in HIV-positive patients with a low CD4+ count at start of therapy can be placed in the context of IRIS.

Sarcoidosis is a systemic inflammatory disease usually presenting with pulmonary symptoms. However, acute arthritis could be the presenting sign of sarcoidosis. We present a 47-year-old man with bilateral arthritis of the ankles, erythema nodosum and bilateral hilar adenopathy on the chest X-ray. This triad is known as Löfgren's syndrome, a form of acute sarcoidosis. He was first treated with an NSAID, followed by a short course of prednisone because of persisting symptoms. After six weeks the patient was asymptomatic. Further investigation showed no decline in pulmonary function. Acute arthritis in patients with sarcoidosis with or without the complete Löfgren's syndrome has a good prognosis. Usually the signs and symptoms will disappear within a few months. Unlike other forms of sarcoidosis, Löfgren's syndrome does not require histological proof of non-caseating granulomas.

Pediatric granulomatous arthritis (PGA) is an hereditary inflammatory disease that that can affect almost any part of the body, but is characterized by a clinical triad of granulomatous uveitis, arthritis and dermatitis. It is caused by gain-of-function mutations in the NOD/NACHT domain of the nucleotide oligomerisation domain 2 (NOD2) protein. This clinical entity comprises both the autosomal dominant familial form, the Blau syndrome (BS), and the sporadic form, early-onset sarcoidosis (EOS). In order to investigate the immunologic processes, involved cell types and therapeutic implications, an immunohistochemical (IHC) analysis needs to be performed. Biopsies from children suffering from this progressive disease are collected, processed and investigated, in a manner that represents the historical expertise of the department of anatomy&pathology of the KUL. Future perspectives include microdissection and RNA profiling of these specimen as well. LIST OF ABBREVIATIONS 9 GENERAL INTRODUCTION 13 1. What is a granuloma? 13 1.1 The monocyte-macrophage lineage in granulomatous inflammation. 15 1.2 Different phases of granuloma formation 18 1.2.1 The initiation phase 18 1.2.2 The accumulation phase 19 1.2.3 The effector phase 21 1.2.4 The terminal phase 21 1.3 Histopathological criteria for classification of granulomas 23 1.3.1 Common features of granulomas 25 1.3.2 Accessory features of granulomas 28 1.3.3 Rare subtypes of granulomas 30 1.4 Immunohistochemistry in study of granulomas 31 2. Pathogen sensors and innate immunity: focus on NOD2 33 3. NOD2-related granulomatous inflammatory diseases 35 3.1 Blau Syndrome, a monogenic orphan disease 36 3.2 Crohn’s disease, a multifactorial inflammatory bowel disease 38 3.3 NOD2 variants in adult sarcoidosis 39 4. Granulomatous inflammatory diseases with wild type NOD2 40 4.1 Chronic Granulomatous Disease, a primary neutrophil immune deficiency 41 4.2 Cartilage-Hair Hypoplasia, a primary lymphocyte immune deficiency 42 4.3 Infantile Onset Panniculitis with Systemic Granulomatosis, a new disease 43 4.4 Adult-type pediatric sarcoidosis 43 5. Th17 or the first major revision of the Th1-Th2 hypothesis 44 GENERAL AIM AND OBJECTIVES 49 PATIENTS AND METHODOLOGY 53 REFERENCE LIST I 59 RESULTS 73 Section 1: Granuloma histopathology: phases, stages and novel features. 73 Chapter 1.1: New insights in the histopathology of granuloma formation. 75 Chapter 1.2: Granuloma-in-follicles: a new observation. 87 Section 2: Granulomas in NOD2-related granulomatous inflammatory diseases. 99 Chapter 2.1: Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease. 101 Chapter 2.2: R702W in nucleotide oligomerization domain 2 is linked with auto-inflammatory features in classic sclerosing lung sarcoidosis. 115 Chapter 2.3: Outcome of lymphocyte emperipolesis in multinucleated giant cells in nucleotide oligomerization domain 2-related disorders. 123 APPENDIX I: Case report. 143 APPENDIX II: Pediatric sarcoidosis cases. 151 APPENDIX III: Pediatric sarcoidosis cases. 153 APPENDIX IV: Adult sarcoidosis cases. 155 GENERAL DISCUSSION 157 REFERENCE LIST II 163 SUMMARY 167 SAMENVATTING 169 CURRICULUM VITAE 171 Exclusive research topic with pioneering biomedical data and insights, obtained through international collaboration and an interdisciplinary approach. nrpages: 186 status: published

An extensive differential diagnosis exists for swelling of the fingers. One of the rare causes of such a swelling is a multisystem disorder called sarcoidosis.We describe a 40-year-old female patient who was first seen at our outpatient clinic with a painless swelling of the middle phalanx of her right middle finger. The diagnosis initially made was enchondroma, which was treated conservatively. Thirteen years later, the patient returned with pain and progressive swelling of this same finger. Physical examination and imaging revealed a giant-cell tumour of the tendon sheath, which was excised. The diagnosis of sarcoidosis was made after histological analysis.The initial manifestation of sarcoidosis is rarely observed in bone and soft tissue. For this reason, symptoms arising from such tissues will not always lead to the consideration of this diagnosis. The typical radiological abnormalities of bone combined with swelling of soft tissue should, however, give rise to the consideration of this diagnosis.

This brief report describes the radiographic images of a 29-year-old man with asymptomatic sarcoidosis. On a CT-scan a coalescent granuloma with a central core and peripheral nodules mimics a globular cluster galaxy; therefore it is called 'galaxy sign'. This is a classic finding in a granulomatous disease like sarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology. Standard treatment with immune suppressants such as glucocorticoids is started when vital organ function is threatened. Biotechnology has resulted in new treatments ('biologicals'), in particular monoclonal antibodies, that may be effective in the treatment of sarcoidosis. In patients with sarcoidosis, only the use of monoclonal antibodies that block tumour necrosis factor (TNF) has been studied scientifically, other biologicals hardly at all. TNF-blockers are used at present in patients with therapy refractory sarcoidosis.

A 61-year old male presented himself at the department of dermatology with an asymptomatic node next to the nose, which appeared to be a first manifestation of sarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology. Standard treatment with immune suppressants such as glucocorticoids is started when vital organ function is threatened. Biotechnology has resulted in new treatments ('biologicals'), in particular monoclonal antibodies, that may be effective in the treatment of sarcoidosis. In patients with sarcoidosis, only the use of monoclonal antibodies that block tumour necrosis factor (TNF) has been studied scientifically, other biologicals hardly at all. TNF-blockers are used at present in patients with therapy refractory sarcoidosis.

A case report and a systematic review of the literature show that neurosarcoidosis can present initially as a manic episode with psychotic features. The diagnosis of neurosarcoidosis is based on a combination of clinical features, and radiological and histopathological findings. Contrast-enhanced MRI and lumbar puncture are the most sensitive investigations for detecting neurosarcoidosis. Corticosteroids are the treatment of choice. Very few data are available concerning the efficacy of psychotropic drugs for the treatment of psychiatric symptoms caused by neurosarcoidosis.

A 33-year-old man was referred to an oral surgeon by his general practitioner because ofa bilateral swelling in both jaws. A CT-scan of the head showed enlargement of the parotid glands. After exclusion of mumps and sialolithiasis the patient was treated with oral antibiotics. The swelling failed to improve and the patient was sent to an internist. A repeated medical history revealed that he also had symptoms of sicca syndrome. Sjögren's syndrome was excluded only after negative immunoserological tests and sublabial salivary gland biopsy. A chest X-ray showed enlarged bilateral hilar lymph nodes, confirming the diagnosis of sarcoidosis. A gallium scintigraphy provided further support for this diagnosis. No treatment was initiated and the patient recovered slowly afterwards.

A 41-year-old man underwent skeletal scintigraphy due to chronic pain in the left foot and polyarthralgia. He was taking medication for gout and had previously had sarcoidosis, for which he had received corticosteroids and other therapy that was discontinued 4 years ago. Scintigraphy revealed a mass in the shaft of the left humerus that, according to biopsy, was an asymptomatic osteomyelitis caused by Mycobacterium avium. The shaft of the left humerus is an uncommon site for tuberculous osteomyelitis. A viable fistula remained after the biopsy that persisted despite pharmacologic treatment with ethambutol, rifabutin and clarithromycin. Four months later, sequestrectomy was performed with insertion of gentamicin-impregnated beads, which resulted in rapid resolution. The foot pain resolved spontaneously. The incidence of bone tuberculosis has increased over the last 2 decades. The most commonly affected sites are the spine and large joints. Infection with M. avium is sometimes involved. Because of the increasing incidence it is important to include mycobacterial infections in the differential diagnosis of focal bone lesions, especially when standard cultures are initially negative.

Cardiac sarcoidosis was diagnosed in 3 patients: 2 men aged 52 and 51 years, respectively, and a woman aged 55 years. Both men had ventricular tachycardia. In the first man, a right-ventricle biopsy revealed a non-caseating granuloma. The second man had active granulomatous cardiac infiltration, according to a gallium scintigram. The first man recovered after receiving immunosuppression, heart-failure medication, and an implantable defibrillator; the second received the same plus radio-frequency catheter ablation, but experienced serious heart failure. The woman was being treated for pulmonary sarcoidosis but complained of progressive cardiac symptoms. She recovered after receiving heart-failure medication, immunosuppression, and a biventricular pacemaker. Sarcoidosis is a multi-system granulomatous disorder of unknown aetiology with cardiac involvement in 20 to 30% of patients, resulting in severe morbidity and mortality. With the help ofgadolinium MRI and positron emission tomography (PET), these conditions can be detected at an earlier stage, which allows for improved evaluation of the efficacy of available therapies. The use of resynchronisation therapy and implantable defibrillators has improved the prognosis of patients with cardiac sarcoidosis.

A 43-year-old man presented with a nodular tattoo lesion on his right upperarm. Histologically it resembled the granulomatous reaction seen in systemic sarcoidosis. Further evaluation revealed asymmetrical hilar lymphadenopathy with no interstitial lung disease. Since the patient was a heavy smoker, bronchus carcinoma could not be excluded and cervical mediastinoscopy was performed in order to obtain a lymph-node biopsy. This confirmed the diagnosis of systemic sarcoidosis. The patient was treated by local application of corticosteroids, but with little result. Skin lesions in scars or tattoos may be the first symptom of systemic sarcoidosis. Skin biopsy for histological confirmation of the diagnosis is recommended, as is further investigation to evaluate other organ systems which may be affected.

Diffuse parenchymal lung disorders (DPLD) can develop in a variety of systemic disorders. Schematically grouped, these include connective tissue disorders, vasculitis, neoplastic disorders, sarcoidosis and a group of inherited or other rare miscellaneous disorders. This overview focuses on sarcoidosis, systemic sclerosis and Churg Strauss vasculitis. Pulmonary involvement occurs in more than 90% of all patients with sarcodosis. Grading into 4 stages is based on the chest radiograph. Forms characterised by an acute clinical onset or a low grade lung involvement have the highest spontaneous remission rate. The cause of sarcoidosis remains unknown. The diagnosis therefore is descriptive, based on the combination of clinical observations, chest X ray, and the histological documentation of non-caseating epitheloid granulomas in tissue biopsies. Treatment with steroids is only indicated if organ involvement leads to functional impairment. Lung fibrosis is the most important complication of both the "limited" and "diffuse cutaneous form" of systemic sclerosis, involving 90% of all patients. The histological pattern is that of "Usual Interstitial Pneumonia" (UIP) or "Non-specific Interstitial Pneumonia" (NSIP). The pathogenesis of the disorder is thought to consist of an abnormal, excessive regenerative response to an auto-immune mediated lung injury. Churg Strauss vasculitis is characterised by asthma, blood eosinophilia and vasculitis of the small vessels. The affected vessels wall shows signs of fibrinoid necrosis and are infiltrated by eosinophils. pANCA (anti-myeloperoxidase) is considered to play a role in the pathogenesis of the disease. Concern has risen that CysLT1 receptor antagonists might induce production of pANCA. To date, this has not been substantiated.

Sarcoidosis presenting as a liver disease is uncommon. Hepatic sarcoidosis was diagnosed in three male patients aged 80, 64 and 69 years. They all presented with aspecific symptoms such as weight loss. Further investigation revealed liver disease, and liver biopsies demonstrated the presence of non-caseating granulomas. However, non-caseating granulomas can be associated with a great number of disorders and are therefore not specific. Other causes were excluded before the diagnosis of hepatic sarcoidosis was established with reasonable certainty. The diagnosis was finally confirmed on the basis of medical history, laboratory tests and histology. Sarcoidosis presenting as symptomatic liver disease can be treated with corticosteroids and probably with ursodeoxycholic acid as well. These three patients were treated with corticosteroids. The first patient died a year later from a cerebral infarct, the second one after a few months from a (non-sarcoidotic) cerebral haemorrhage and the third one after eight years from hepatic failure.

Sarcoidosis is a chronic generalized benign granulomatous disorder of perhaps an autoimmune character which can afflict many organs. The insidious form prevails, a (sub)acute onset covers about one third of cases. In most patients the lungs are involved; tissue damage by granulomas and inflammatory cells causes a reduction of respiratory capacity, with dyspnoea as a result. Other often-affected organs are larger joints, skin and eyes. The diagnosis is based on the symptoms, thoracic x-ray and histology. In most cases prednisone is the drug of first choice. It is tantalizing to have to decide whether to treat or not. The decision is based on the severity of the process in vital organs.

Two patients, a woman aged 66 and a man aged 56 years, with an inflammatory syndrome, weight loss, joint pain and abdominal lymphadenopathy received long-term treatment with corticosteroids for alleged sarcoidosis. No long-term remission was induced and the patients were referred for a second opinion. Eventually the diagnosis of Whipple's disease was established 5 years after the appearance of the first symptoms in the case of the female patient and 4 years after in the case of the male patient. Both patients showed a marked clinical improvement after treatment with trimethoprim-sulfamethoxazole. An atypical presentation of alleged sarcoidosis should suggest the possibility of Whipple's disease, especially in the case of gastrointestinal symptoms and the failure to respond to corticosteroids, and warrants duodenal biopsy. The presence of granulomas with an elevated angiotensin-converting enzyme level is not pathognomonic for sarcoidosis. It is vitally important to distinguish the two disorders, as Whipple's disease is an infectious disorder that requires antibiotic therapy to prevent a fatal outcome.

Two patients, a man aged 23 and a woman aged 42 years, complained of fatigue and arthralgia respectively. A particularly high serum activity of angiotensin-converting enzyme (ACE) was established during the diagnostic work-up, although sarcoidosis was considered to be unlikely. This led to a series of diagnostic procedures, some invasive, to confirm the diagnosis of sarcoidosis. The diagnosis was not made in either of these patients. The fatigue appeared to be self-limiting and the arthralgia was due to arthrosis. Eventually it was discovered that these patients had a familial elevation of serum ACE activity. The elevation of ACE levels has limited specificity for sarcoidosis (85%) and is therefore of no value in the diagnostic workup, if the a priori probability for sarcoidosis is low.

An extremely high level of serum angiotensin-converting enzyme (ACE) activity was found in eight individuals, women aged 31, 60, 42 and 67 years, and men aged 50, 47, 23 and 50 years. They had consulted a specialist due to a wide range of non-specific complaints or abnormalities (fatigue, dyspnoea, arthralgia, kidney stones with high urinary calcium, neurological symptoms and an elevated blood alkaline phosphatase activity level). As each of these complaints could be a symptom of sarcoidosis, the ACE activity was measured. However, sarcoidosis was not diagnosed in any of these patients. A subsequent analysis revealed that all eight individuals had family members with a similar elevation of ACE. Therefore, the increase in ACE activity was familial. Patients with this disorder have serum ACE levels of between 3 and 7 times the upper limit of normal, whereas in the case of sarcoidosis, serum ACE levels rarely exceed three times this limit. Familial ACE hyperactivity is not accompanied by clinical symptoms. It is caused by a point mutation in the ACE gene, which results in the cell-bound ACE being more readily loosened from the cell surface into the circulatory system.

Sarcoidosis is a multi-systemic disease of unknown aetiology, immunopathologically and histologically characterised by a macrophage/T-helper I cell-mediated non-caseating granulomatous inflammation process. In the development of granulomas, an imbalance between pro-inflammatory and anti-inflammatory cytokines plays an important role, possibly initiated by an as yet unidentified (exogenous) stimulus. The clinical outcome of the disease process is unpredictable, and appears to be determined by the cytokine production of the inflammatory cells in the granuloma. Fifty to seventy percent of the patients recover without medication within a period of time which cannot be predicted, the other 30 to 50% of patients are treated during the course of the disease with corticosteroids (with varying degrees of success), either alone or in combination with cytostatic or immunosuppressive agents. Based on recent developments in the field of immunomodulation and on current knowledge of the immunopathogenesis of sarcoidosis, there appear to be opportunities for specific immunotherapy which should be evaluated in controlled studies.

A 39-year-old man presented with fever, arthritis of knees and wrists, periarticular ankle inflammation, erythema nodosum, bilateral hilar adenopathy and diffuse pulmonary parenchymal changes, due to Löfgren's syndrome.

Diagnosis is central to medicine. In spite of tremendous diagnostic technological advances, no infallible test exists and in the complex diagnostic process the physician may well get lost. The ultimate feedback on the accuracy of diagnosis is the autopsy. Five patients illustrate that the autopsy may disclose unexpected results. The first patient was a 9-year-old girl who suffered from daily abdominal spasmodic pain but each time recovered. She died suddenly; autopsy revealed intestinal intussusception. A 46-year-old man who was treated for hypertension developed pain in the chest and the lower back, but there were no other signs of myocardial infarction. He died suddenly; autopsy revealed a dissecting aortic aneurysm with rupture in the left pleural cavity. A 21-year-old woman, an excellent swimmer, drowned during a swim in the sea. Autopsy revealed severe widespread coronary disease with multiple myocardial infarction. A 32-year-old Surinam woman developed acute coma and died from cardiorespiratory arrest. At autopsy she had massive pulmonary embolism and generalized lymphadenopathy due to sarcoidosis. The last patient, a 32-year-old woman suffered from fatigue after her fourth child was born. She was admitted with severe dyspnoea and her chest X-ray showed interstitial fibrosis. She died presently and autopsy revealed metastatic colon carcinoma with pulmonary lymphangitis carcinomatosa. Systematic reviews of the results of autopsies show no decline in the percentage of false diagnoses and/or unexpected findings in spite of the enormous growth of the diagnostic armamentarium. Although we may radiologically 'slice' the body in incredible detail or investigate human cells at the molecular level, the autopsy has by no means become obsolete and is an invaluable tool for quality control and teaching.

Dermatophytosis is the most common equine skin disease. Mycotic-like lesions that do not disappear are suspected of being sarcoids. The clinical symptoms and therapeutic interventions for both affections are discussed. A short review of the differential diagnoses is presented.

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology, most commonly affecting young adults. The course and the prognosis may correlate with the mode of onset. An acute onset with erythema nodosum heralds a self-limiting course and spontaneous resolution, whereas an insidious onset may be followed by relentless, progressive fibrosis.

Two male patients with a testicular carcinoma and a female with a mammary carcinoma, all associated with pulmonary sarcoidosis are described. This coincidence is very rare, but clinically relevant as enlarged mediastinal and hilar lymph nodes might suggest metastatic disease or metastasis after a curative treatment. The role of mediastinoscopy in obtaining a histological diagnosis is stressed. A causal relationship between sarcoidosis and malignant diseases has not yet been established.

In 2 patients arrhythmias and conduction disorders were the first symptoms at presentation of cardiac sarcoidosis. One patient with severe conduction disorders showed normalisation of the EKG during steroid treatment. The other patient developed an overall cardiomyopathy and the arrhythmia was treated with conventional drugs. The frequency of cardiac involvement in sarcoidosis is much higher than that of clinical symptoms of sarcoid heart disease. Cardiac sarcoidosis is increasingly diagnosed in the last few decades. In most cases, it presents with sudden death, arrhythmia, conduction disorders or cardiomyopathy. The main diagnostic pathological feature is evidence of noncaseating granulomas, but mononuclear cell infiltration and focal interstitial fibrosis have also been found. The basal part of the interventricular septum is particularly prone to involvement. If conventional therapy in clinically important cases proves inadequate, steroid therapy should be added. It is recommended to make an EKG in every patient presenting with sarcoidosis even in the absence of cardiac symptoms. Sarcoid heart disease should be considered in every patient with diagnostic sarcoidosis and heart disease but also in every case of difficult heart disease without an obvious aetiology. Because of the relatively early age at onset, life expectancy is shortened.

Squamous cell carcinomas of the bovine eye and equine sarcoids are briefly reviewed. A single injection of BCG into the tumour results in permanent regression of the lesion in 37 per cent of the cattle, regression followed by recurrence of the tumour in 26 per cent and in progressive growth of the tumour in 37 per cent of the cases. Recurrence may be prevented by repeated injection into the lesion. From 50 to 60 per cent of the cows will remain free from tumours. Equine sarcoids show a complete regression in 70-80 per cent of the cases. Tumours on the limbs show a less satisfactory response (lower rates of success, more complications) than do tumours in other areas of the body.

The history of illness of an eight-year-old boy is presented. Fifteen days old he had been hospitalized because of vomiting, diarrhoea and prolonged jaundice. Alpha 1-antitrypsin deficiency (genotype PiZZ) was diagnosed. At the age of nearly eight complaints started, such as headache, apathy, nausea and vomiting. Sarcoidosis was diagnosed on account of hypercalcemia (3.48-3.68 mmol/l), an elevated serum angiotensin converting enzyme (60 U/l), a positive Kveim test and the fact that other diseases could be excluded. The prognosis of a combination of a serious alpha 1-antitrypsin deficiency and sarcoidosis is discussed. This combination, as far as we have been able to trace, has not been described before.

Sarcoidosis seldom occurs in children. The illness has variable clinical manifestations. Diagnosis is often delayed because of the variable clinical manifestations and the sporadic occurrence. The case history of one patient is described. The presentation, diagnostical approach. therapy and course of sarcoidosis is discussed.