Ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome is characterised by ichthyosis, hepatosplenomegaly and late-onset cerebellar ataxia. It has been described in two brothers. Transmission is either autosomal recessive or X-linked.


Ichthyosis-hypotrichosis syndrome is characterised by congenital ichthyosis and hypotrichosis. It has been described in three members of a consanguineous Arab Israeli family. The syndrome is transmitted as an autosomal recessive trait and is caused by a missense mutation in the ST14 gene, encoding the recently identified protease, matriptase. Analysis of skin samples from the patients suggests that this enzyme plays a role in epidermal desquamation.


Ichthyosis-intellectual disability-dwarfism-renal impairment syndrome is characterised by nonbullous congenital ichthyosis, intellectual deficit, dwarfism and renal impairment. It has been described in four members of one Iranian family. Transmission is autosomal recessive.


Ichthyosis-oral and digital anomalies syndrome is characterised by ichthyosis, unusual facies (small mouth with a thin upper lip and lower lip with a midline groove) and digital anomalies (tapered fingers with a lack of distal flexion creases and wide spacing between the second and third fingers). It has been described in two sibs born to first cousin parents. Transmission appears to be autosomal recessive.


A rare, syndromic congenital ichthyosis characterized by premature birth (at gestational weeks 30-32, in general) in addition to thick, caseous and desquamating epidermis, neonatal respiratory asphyxia, and persistent eosinophilia. After the perinatal period, a spontaneous improvement in the health of affected patients is observed and skin features (vernix caseosa-like scale) evolve into a mild presentation of flat follicular hyperkeratosis with atopy.


A rare, syndromic ichthyosis characterized by a collodion membrane at birth, generalized congenital ichthyosis, microspherophakia, myopia, ectopia lentis, short stature with brachydactyly and joint stiffness, and occasionally mitral valve dysplasia.


Idiopathic achalasia (IA) is a primary esophageal motor disorder characterized by loss of esophageal peristalsis and insufficient lower esophageal sphincter (LES) relaxation in response to deglutition.

Summary:
Epidemiology
IA is a rare disease with an annual incidence of approximately 1/200,000 to 1/59,000 and a prevalence rate recently estimated to be 1/10,000. There is no gender predilection and the peak incidence occurs between 30 and 60 years of age. There is some suspicion of differences between ethnic groups.
Clinical description
IA is characterized predominantly by dysphagia to solids and liquids, bland regurgitation often unresponsive to an adequate trial of proton pump inhibitor (PPI), and chest pain. Weight loss (usually between 5 and 10 kg) is present in most, but not all patients. Heartburn occurs in 27%-42% of IA patients. They are more likely to suffer from autoimmune disorders (diabetes mellitus, hypothyroidism, Sjögren syndrome, lupus erythematosus; see these terms).
Etiology
Although the precise etiology is unknown, it is often thought to be either autoimmune, viral immune, or neurodegenerative. Some familial cases have been reported, but the rarity of familial occurrence does not support the hypothesis that genetic inheritance is a significant etiologic factor. IA has been associated with viral infections and auto-antibodies against myenteric plexus have been found, but the causal relationship remains unclear.
Diagnostic methods
Lack of response to proton pump inhibitor therapy in a patient initially diagnosed as gastroesophageal reflux disease (GERD) should raise suspicion for motility disorders such as IA, especially if dysphagia is an accompanying complaint. The diagnosis is based on history of the disease, radiography (barium esophagogram), and esophageal motility testing (esophageal manometry). Endoscopic assessment of the gastroesophageal junction and gastric cardia is necessary to rule out malignancy. Newer diagnostic modalities such as high resolution manometry (HRM) help in predicting treatment response in achalasia based on esophageal pressure topography patterns identifying three phenotypes of achlasia (I-III) and outcome studies suggest better treatment response with types I and II compared to type III.
Differential diagnosis
A majority of patients are misdiagnosed as having reflux disease given regurgitation. The differential diagnosis of a patient with dysphagia and regurgitation includes GERD, esophageal spasm, pseudoachalasia (associated to malignancies), and possibly eosinophilic esophagitis (see this term).
Management and treatment
Although IA cannot be permanently cured, excellent outcomes are achieved in over 90% of patients. Current medical and surgical therapeutic options (pneumatic dilation, surgical myotomy, and pharmacologic agents) aim at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Either graded pneumatic dilatation (PD) or laparoscopic surgical myotomy with a partial fundoplication are recommended as initial therapy guided by patient age, gender, preference, and local institutional expertise. Botulinum toxin therapy is less effective than PD or surgical myotomy and is commonly reserved for patients who are not candidates for definitive therapies.
Prognosis
The prognosis in IA patients is excellent. Most patients with IA who are appropriately treated have a normal life expectancy but the disease does recur and the patient may need intermittent treatment.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Dr Dhyanesh PATEL  - Pr Michael VAEZI


Idiopathic acute eosinophilic pneumonia (IAEP) is an eosinophilic pneumonia of undetermined etiology that is characterized by acute febrile hypoxic respiratory failure associated with diffuse radiographic infiltrates and pulmonary eosinophilia, but without concurring allergy or infection.

Summary:
Epidemiology
The prevalence of IAEP is still unknown but <100 cases have been reported to date. A recent study has described only 3 pediatric cases in a 5 year-time frame in France. Men are affected approximately twice as frequently as women.
Clinical description
IAEP can occur at any age, even in previously healthy children, although most patients are between 20 and 40 years of age. IAEP presents itself as an acute pneumonia in previously healthy subjects and the clinical features include acute respiratory failure with fever, dry cough, progressive dyspnea, tachypnea and severe hypoxemia. Crackles on chest auscultation and marked chest wall retractions can be observed. Myalgia and abdominal pain may also be present.IAEP can be precipitated or exacerbated by smoking tobacco and cannabis.
Etiology
The pathophysiology of IAEP is still not well understood. It appears to result from damage caused by eosinophils infiltrating the lung parenchyma and releasing toxic substances such as basic proteins, lipid mediators, and cytokines.
Diagnostic methods
Diagnostic criteria for IAEP are as follows: 1) acute onset of febrile illness (usually less than 7 days), 2) diffuse bilateral pulmonary infiltrates, 3) severe hypoxemic respiratory failure (with blood oxygen saturation <90% by pulse oximetry, or PaO2<60mmHg on room air or PaO2/FiO ≤300 mmHg), 4) lung eosinophilia (bronchoalveolar lavage [BAL] fluid eosinophilia >25% or predominance of eosinophils in lung biopsy), and 5) no known causes of acute eosinophilic lung (recent onset of tobacco smoking or exposure to inhaled dust). Chest radiographs show diffuse bilateral infiltrates, air space opacities, interstitial reticulo-nodular densities and/or pleural effusion. These interstitial infiltrates usually progress to extensive alveolar and interstitial infiltrates involving all lobes in several hours. Chest computed tomography (CT) scans show diffuse areas of ground-glass attenuation, alveolar infiltrates, poorly defined nodules and interlobular septal thickening.
Differential diagnosis
Differential diagnosis includes acute interstitial pneumonia (AIP), acute lung injury (ALI), acute respiratory distress syndrome (ARDS) (see these terms), severe community-acquired pneumonia, aspiration pneumonia, acute hypersensitivity pneumonitis and fungal or parasitic infections.
Management and treatment
Complete clinical and radiological recovery without relapse may be achieved rapidly with corticosteroid therapy (between 2 and 12 weeks intravenous dosage followed by a switch to oral administration).In patients not properly treated, respiratory failure is observed, requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
Prognosis
Prognosis of IAEP is excellent as long as corticosteroid therapy is instituted promptly. Without the appropriate diagnosis and treatment, IAEP may be fatal.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Pr Jean-Christophe DUBUS


A rare immune-mediated inflammatory demyelinating disorder of the spinal cord with motor, sensory and autonomic involvement.

Summary:
Epidemiology
Annual incidence is estimated at between 1/1,000,000 and 1/250,000 depending on the study. Onset may occur at any age and both sexes may be affected.
Clinical description
The spinal cord inflammation is focal and the signs and symptoms are usually bilateral and depend on the extent and site of the lesion, with the thoracic spinal cord being the most common localization. Progression to nadir occurs between 4 hours and 21 days after onset. Motor involvement is characterized by limb weakness, stiffness and muscle spasms. If the upper spinal cord is involved then respiratory function may be impaired. Back pain, paraesthesia, numbness and neuropathic pain are common sensory manifestations. Uncomfortable band-like sensations around the torso and radicular pain have also been reported. Autonomic anomalies include sexual dysfunction, urinary urge/retention and bowel urgency/retention. Autonomic dysreflexia (ADR), resulting in rapid onset of hypertension and bradycardia, is a complication seen in patients with spinal cord lesions at T6 or above and usually with severe myelitis.
Etiology
By definition, the etiology of idiopathic acute transverse myelitis (ATM) is unknown. A history of viral illness (usually upper respiratory infection) often precedes onset of symptoms by three weeks and idiopathic ATM is believed to be associated with a late immune response against a recent microbial infection that inadvertently targets the spinal cord.
Diagnostic methods
The diagnostic approach revolves around confirming the diagnosis of myelitis (MRI revealing transverse spinal cord lesions and swelling, with longitudinally extensive lesions in some cases), and excluding secondary causes (brain MRI, serology and analysis of cerebrospinal fluid to rule out secondary ATM; see this term), which may be associated with a relapsing disease course requiring preventative treatments.
Differential diagnosis
Acute compressive lesions (such as metastases and epidural abscess) and infarction of the spinal cord should also be included in the differential diagnosis.
Management and treatment
Acute treatment may include corticosteroid therapy and plasma exchange. The benefits of intravenous immunoglobulins and cyclophosphamide remain to be established. Long-term management is mainly symptomatic and should include rehabilitative therapy.
Prognosis
The prognosis is variable and unpredictable. Recovery may begin between 2 and 12 weeks after the onset of symptoms. Full recovery (occurring in only a third of patients) may take years and permanent sequelae are frequent (moderate disability in one third of patients and severe disability in the remaining third).

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Anu JACOB  - Dr Alison L JONES


A rare osteonecrosis characterized by bone necrosis due to disrupted blood supply in the absence of a known cause. Affected bones include the femoral head, talus, vertebral body, humerus, and scaphoid, among others. Patients may initially be asymptomatic but subsequently present with gradually developing refractory pain, swelling, and reduced range of motion. If left untreated, the condition may progress to bone collapse with secondary degeneration, fragmentation, and pathological fracture, as well as osteoarthritis.


Idiopathic bilateral vestibulopathy is a rare otorhinolaryngologic disease characterized by dysfunction of both peripheral labyrinths or of the eighth cranial nerves, which presents with persistent unsteadiness of gait (particularly in darkness, during eye closure or under impaired visual conditions, or when standing/walking on uneven, soft or wobbly ground) and oscillopsia associated with head movements. The disease may be progressive, presenting no episodes of vertigo, or sequential, presenting recurrent episodes of vertigo.


Idiopathic bronchiectasis (IB) is a progressive lung disease characterized by chronic dilation of the bronchi and destruction of the bronchial walls in the absence of any underlying cause (such as post infectious disease, aspiration, immunodeficiency, congenital abnormalities and ciliary anomalies).


Idiopathic camptocormia is a postural disease characterized by an anterior flexion of the torso (during walking or standing) that resolves in the supine position and that is caused by weakness of the lumbar paraspinal muscles (spinal extensors), due to massive fatty infiltrations of posterior spinal muscles, without an identifiable etiology.


Idiopathic CD4 lymphocytopenia is a rare primary immunodeficiency disorder characterized by persistent CD4 T-cell lymphopenia (less than 300 cells/µL on multiple occasions) not associated with any other underlying primary or secondary immune deficiency. Patients typically present opportunistic infections (with cryptococcal, mycobacterial, candidal, varicella zoster virus infections and progressive multifocal leukoencephalopathy being the most prevalent), malignancies (mainly lymphoproliferative disorders), or autoimmune disorders. Some individuals are asymptomatic and incidentally diagnosed.


Idiopathic chronic eosinophilic pneumonia

A rare, severe, interstitial lung disease characterized by insidious onset with subacute or chronic non-specific respiratory manifestations (dyspnea, cough, wheezing) often associated with systemic manifestations (fatigue, malaise, weight loss) and a history of asthma (up to half of patients). Eosinophilia is present in most cases, usually in excess of 1000 cells/mm3.


Idiopathic congenital hypothyroidism is a type of primary congenital hypothyroidism (see this term) whose cause and prevalence are unknown.

Summary:
Clinical description
Clinical manifestations are those of other forms of congenital hypothyroidism (CH; see this term). Goiter is always absent.
Diagnostic methods
Ultrasound examination and thyroid scintigraphy show a thyroid gland of normal shape and size in the normal, eutopic location. Idiopathic congenital hypothyroidism can be diagnosed after exclusion of the known causes of CH.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Idiopathic copper-associated cirrhosis is a rare copper-overload liver disease characterized by a rapidly progressive liver cirrhosis from the first few years of life leading to hepatic insufficiency and harboring a specific pathological aspect: pericellular fibrosis, inflammatory infiltration, hepatocyte necrosis, absence of steatosis, poor regeneration and histochemical copper staining.


A rare acquired skeletal muscle disease characterized by severe weakness of the neck extensor muscles causing progressive reducible kyphosis of the cervical spine and the inability to hold the head up, in the absence of a known cause. Histological studies reveal a non-inflammatory myopathic picture. The clinical course is relatively benign, although cervical myelopathy may develop.


A rare biliary tract disease characterized by loss of interlobular bile ducts resulting in chronic cholestasis, without any known cause. Loss of less than 50% of interlobular bile ducts is associated with a mild disease course, while loss of the majority of ducts results in a severe form, potentially leading to cirrhosis and liver failure. Patients typically present as young or middle-aged adults with episodic jaundice, pruritus, and elevated liver enzymes.


A rare idiopathic inflammatory myopathy characterized by eosinophilic infiltration and inflammatory lesions of the skeletal muscle tissue, in the absence of an identifiable causative factor (e.g. parasitic infection, drug intake, systemic or malignant disease). Clinically patients may present focal or generalized muscle weakness and pain, difficulties to walk, motor clumsiness and/or mild bilateral Achilles tendon contracture , as well as elevated serum creatine kinase levels and peripheral blood and/or bone marrow hypereosinophilia.


A rare idiopathic gastroesophageal disease characterized by delayed gastric emptying in the absence of mechanical obstruction of the gastric outlet. Patients present symptoms including nausea, vomiting, early satiety, postprandial fullness, bloating, abdominal pain and, in more severe cases, dehydration, electrolyte disturbances, weight loss and malnutrition.


A rare cardiomyopathy characterized by progressive myocarditis with diffuse infiltration of cardiac tissue by lymphocytes, macrophages, multinuclear giant cells, and myocardial necrosis. Clinical presentation includes rapidly progressive heart failure, ventricular arrhythmias, complete heart block, and sudden cardiac death. Some patients have associated autoimmune disorders.


A rare acute encephalopathy with inflammation-mediated status epilepticus characterized by infancy-onset of refractory unilateral, mainly clonic status epilepticus during or shortly after a febrile episode without evidence of central nervous system infection, followed by permanent or transient hemiplegia with a minimum duration of one week. The majority of children develop pharmaco-resistant epilepsy a few months later. Brain imaging shows edematous swelling of the affected hemisphere at the time of the initial status, followed by hemiatrophy that does not correlate with any vascular territory.


A rare renal disease characterized by persistent excess urinary calcium excretion in the absence of an underlying systemic disease and hypercalcemia. The condition leads to an increased risk for the formation of kidney stones and nephrocalcinosis, as well as reduced bone mineral density with increased incidence of fractures in some patients.

Summary:
Epidemiology
Prevalence is estimated at 2.2-6.4% in the pediatric population and is the most common cause of calcium nephrolithiasis in childhood.
Clinical description
Idiopathic hypercalciuria (IH) mainly presents in childhood with variable clinical symptoms including abdominal or back pain, cloudy urine (more evident at the first voiding of the day), sediment in urine collection, gross or microscopic hematuria, urinary tract infections, urinary urgency, incontinence or dysuria. Calcium kidney stones occur frequently as a result of supersaturation of calcium oxalate and calcium phosphate in urine, leading to the formation of mineral plaques in the renal papillary interstitium and subsequent growth of a calcium body. Excessive calcium excretion may also result in decreased bone mineral density and disturbance of bone mineralization.
Etiology
The disorder can be caused by reduced tubular calcium reabsorption (renal IH) or by increased intestinal calcium absorption associated to a vitamin D receptor activation (absorptive IH), or as a result of both. Genetic susceptibility to absorptive IH is correlated to mutations on the ADCY10 gene (1q23.3-q24) and on the 4q33-qter segment, and a history of nephrolithiasis is frequently reported in first-degree relatives. Furthermore, pathological elevation of tissue vitamin D receptor (VDR) level is suggested as a molecular basis of IH, which may elevate intestinal calcium absorption and bone resorption, and decrease renal tubule calcium reabsorption. Environmental factors including dietary habits also influence the disease.
Diagnostic methods
Diagnosis is based on evidence of repeated hypercalciuria in the fasting or fed state, and in the absence of any underlying cause. Hypercalciuria is determined on 24-hour urine collection test, and is often associated with a calcium/creatinine ratio greater than 0.20 mg/mg. Kidney stones may be revealed by ultrasound and high resolution CT imaging of the urinary tract.
Differential diagnosis
Conditions in which urine calcium levels may be increased should be excluded, including hypercalcemia, bone metabolic diseases (e.g. primary hyperparathyroidism, Paget disease), renal tubular acidosis, metabolic acidosis, chronic renal failure, nephrocalcinosis of other origin, long-term immobilization, and drugs affecting bone metabolism (glucocorticoids, diuretics, vitamin D).
Genetic counseling
The disease follows an autosomal dominant inheritance. Genetic counselling should be provided to family members and affected parents, informing them of the 50% risk of reoccurrence. Clinical variability is explained by dietary and other environmental factors.
Management and treatment
Treatment is with dietary management ensuring daily calcium requirements (1,200 mg/day in adults or equivalent reference values for children ), preferably sourced from food, a reduced sodium intake (up to 1.5 g/day in adults or an equivalent quantity in children), moderation of animal protein, and a fluid intake of 3 to 3.5 liters daily depending on climate, lifestyle and working conditions. Thiazide diuretics and potassium citrate are commonly used to prevent persistent symptoms, recurrence of stone formation, development of nephrocalcinosis, and osteopenia and, when dietary adjustments fail, to decrease urinary calcium supersaturation. A urinary calcium: citrate ratio ≥ 0.25 is a risk marker for nephrolithiasis. Monitoring nutritional vitamin D deficiency is recommended but excessive supplementation should be avoided to prevent further excretion of urinary calcium.
Prognosis
The prognosis of IH is usually favorable when treated appropriately. However, persistent hypercalciuria in children may decrease bone formation and lead to poor bone health in adulthood with osteopenia, osteoporosis and increased risks of fractures, whereas recurrent nephrolithiasis may result in progressive renal damage.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Gema ARICETA | ERKNet*

                                * European Reference Network


A rare hematologic disease characterized by eosinophilia without evidence of clonality persisting for at least six months, for which no underlying cause can be identified. The condition is associated with signs of organ damage and dysfunction. Clinical manifestations are highly variable, depending on the organ systems involved, and include rapidly developing, life-threatening cardiovascular or neurological complications.


A rare neurologic disease characterized by an excessive daytime sleepiness with long and unrefreshing naps, and/or prolonged and undisturbed nocturnal sleep, impaired daytime alertness, and/or sleep inertia (ie, great difficulty in waking up after sleep) and where other causes have been excluded.

Summary:
Epidemiology
The prevalence estimates were initially based on the proportion of patients with idiopathic hypersomnia (IH) over those with narcolepsy in the sleep medicine population. The consensus currently estimates prevalence of IH in the range of 0.002%-0.010% in the general population. A higher frequency in women is reported.
Clinical description
Symptoms frequently start during adolescence or young adulthood, but may occur at any age. Idiopathic hypersomnia with long sleep time is characterized by a prolonged (more than 10 hours) nocturnal sleep of good quality, and / or excessive daytime sleepiness with prolonged unrefreshing sleep episodes, and sometimes difficulty in awakening in the morning or after naps, with sleep inertia or drunkenness. Idiopathic hypersomnia without long sleep time is characterized by isolated excessive daytime sleepiness, with irresistible and more or less refreshing diurnal naps. Nocturnal sleep is normal or slightly prolonged but lasts less than 10 hours, and quality of awakening is often normal. Idiopathic hypersomnia is never associated with cataplexy (which would lead to a suspicion of narcolepsy type 1).
Etiology
Etiology is still unknown. There is no association with any particular HLA (human leukocyte antigen) marker or with a decrease in the orexin/hypocretin levels, as in narcolepsy type 1.
Diagnostic methods
Diagnosis is complex and must exclude other causes of sleepiness and document the excess of nighttime and daytime sleep. Definitive diagnosis is based on polysomnography completed with multiple sleep latency tests (MSLT), performed without any medication with an effect on sleep. These tests reveal a sleep of good quality and reveal a mean sleep latency of less than 8 min with a maximum of one episode of paradoxical sleep. In case of idiopathic hypersomnia with long sleep time, a 24h (or 32h) continuous sleep recording shows a nocturnal sleep episode of over 10 hours with a daytime nap of more than an hour, i.e. over 11 hours/ 24h (or over 19 hours/32h).
Differential diagnosis
Clinical examination (based on a clinical interview, a sleep diary or on actimetry) eliminates chronic insufficient sleep syndrome. Sleep recordings exclude narcolepsy, circadian rhythm disorders or fragmented night sleep due to motor or respiratory events. A psychological examination excludes hypersomnia of psychiatric origin (especially depressive symptoms). Finally, neuro-radiological tests, which are rarely performed, exclude cerebral lesions.
Genetic counseling
IH appears to be familial; however, there is no information on inheritance or penetrance.
Management and treatment
To date, no drug has authorisation for the treatment of patients affected with idiopathic hypersomnia worldwide; recommendations are based on expert opinion only. Stimulant drugs (i.e. modafinil, methylphenidate, pitolisant) have a good benefit risk ratio except for the post-awakening confusion (sleep inertia). Amphetamines are third-line therapies. Sodium oxybate could be effective on sleepiness and inertia (ongoing clinical trials).
Prognosis
The disease has a negative social and professional impact. Spontaneous evolution of the disease is variable and may remain stable, resolve or evolve to narcolepsy type 2.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Lucie BARATEAU  - Pr Yves DAUVILLIERS


Idiopathic intracranial hypertension is a neurological disorder characterized by isolated increased intracranial pressure manifesting with recurrent and persistent headaches, nausea, vomiting, progressive and transient obstruction of the visual field, papilledema. Visual loss can be irreversible.


A rare, non-syndromic, urogenital tract malformation characterized by an anatomically normal penis which has a stretched penile length of less than 2.5 SD for age, in the absence of any other abnormalities and with no known cause.


Idiopathic juvenile osteoporosis (IJO) is a primary condition of bone demineralization that presents with pain in the back and extremities, walking difficulties, multiple fractures, and radiological evidence of osteoporosis.

Summary:
Epidemiology
The exact prevalence is unknown but several hundreds of cases have been reported in the literature so far.
Clinical description
Onset usually occurs in the prepubertal period, between 8 and 12 years of age. The first sign of IJO is usually pain in the lower back, hips and feet. Knee and ankle pain, kyphosis, loss of height and a sunken chest may also be present. Low bone mineral density, vertebral collapse and metaphyseal compression fractures of the long bones are common.
Etiology
The etiology of idiopathic juvenile osteoporosis remains unknown.
Diagnostic methods
Diagnosis is based on clinical presentation, skeletal X-rays and bone density tests (dual-energy X-ray absorptiometry, dual photon absorptiometry and quantitative computed tomography).
Differential diagnosis
Osteogenesis imperfecta (see this term) is the main differential diagnosis.
Management and treatment
Management is aimed at protecting the spine and other bones from fracture. Physical therapy and exercise (avoiding weight-bearing activities), and other supportive measures are mandatory. There is no established treatment strategy. Treatments with calcium and/or vitamin D, fluoride, calcitonin, and bisphosphonates (in severe, long-lasting cases) have been reported with unequivocal efficacy.
Prognosis
The disease is self-limiting with spontaneous resolution after the onset of puberty. Rarely, in more severe cases, permanent disability (kyphoscoliosis and rib deformity) can develop.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Pr Pierre QUARTIER DIT MAIRE


Idiopathic linear interstitial keratitis is a rare, acquired ocular disease characterized by migratory or non-migratory, horizontal, linear, stromal infiltrates that may heal spontaneously. Minimal vascularization and scarring may be observed but vision loss is not associated.


Idiopathic localized lipodystrophy is a rare, acquired, localized lipodystrophy characterized by asymptomatic, well-demarcated, depressed, lipoatrophic lesions of variable size, with normal overlying skin without antecedent inflammation or a known identifiable cause (autoimmune disease, drug injection, injury, etc).


Idiopathic macular telangiectasia type 1 is a rare, acquired, eye disease characterized by unilateral (rarely bilateral) abnormally dilated and tortuous capillaries around the fovea, associated with multiple arteriolar and venular aneurysms, lipid depositions, and intra-retinal cystoid degeneration. It leads to vision loss due to macular edema with hard exudates.


Idiopathic macular telangiectasia type 3 is a rare, acquired, eye disease characterized by progressive visual loss, due to bilateral juxtafoveolar capillary occlusions, capillary telangiectasia, and minimal exudation. It is associated with systemic or cerebral vascular occlusive disease.


Idiopathic malabsorption due to bile acid synthesis defects

A dirsorder that is due to increased acid bile synthesis is an intestinal disease of unknown etiology characterized by an overproduction of bile acids which leads to chronic watery diarrhea.


Idiopathic neonatal atrial flutter (AFL) is a rare rhythm disorder, characterized by sustained tachycardia in newborns and infants with an atrial rate often at around 440 beats/minute (range 340-580). AFL may manifest as asymptomatic tachycardia, congestive heart failure or hydrops.

Summary:
Epidemiology
AFL is rare with an approximate incidence of around 1/50,000 live births in Europe.
Clinical description
AFL has a neonatal onset and the majority (72%) of patients present with symptoms within the first 48 h of life. Onset during the fetal period may be associated with hydrops fetalis and death. AFL manifests with tachycardia and congestive heart failure. AFL is sustained although conversion from atrial flutter to sinus rhythm may occur spontaneously (<24 hours). Some patients are asymptomatic and tachycardia may be noted on routine examination and monitoring.
Etiology
The etiology of AFL is unknown but immaturity of the myocardium and the high pressure in the right atrium during the perinatal period may be factors that favor the appearance of atrial re-entry.
Diagnostic methods
The diagnosis of AFL relies on surface electrocardiogram (ECG) which usually shows an atrial rate of around 440 beats/min, most often with 2:1 atrioventricular conduction (sometimes with variable AV conduction and an irregular ventricular rate of 125-280 beats/min), and saw tooth P waves in leads II, III, and aVF. The echocardiogram may show impaired ventricular function after prolonged tachycardia.
Differential diagnosis
Differential diagnosis includes multifocal atrial tachycardia (see this term) and other forms of supraventricular tachycardia.
Antenatal diagnosis
AFL may be diagnosed prenatally by fetal echocardiogram which will show an atrial rate of over 400 per minute and most often 2:1 AV conduction to give a ventricular rate of over 200 per minute.
Management and treatment
The first aim of treatment is the restoration of sinus rhythm. This is most easily achieved by transoesophageal overdrive pacing or synchronised low energy DC cardioversion using around 0.5-1 J/kg. The response to drug treatment is variable and unpredictable. Recurrence of atrial flutter in neonates is rare and prophylactic medication is usually not required. Sotalol is said to be an effective agent in the treatment of AFL in the fetus as it has excellent transplacental passage.
Prognosis
In the absence of additional arrhythmias, infants with AFL have an excellent prognosis once in sinus rhythm, with a low risk of recurrence, and chronic anti arrhythmic therapy is unlikely to be necessary.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christopher WREN


A rare primary glomerular group of diseases characterized by the triad of edema, massive, or nephrotic-range, proteinuria and hypoalbuminemia, for which there is no known cause. Depending on response to treatment, disease is distinguished into steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS), with the latter being further divided, depending on occurrence, into familial or sporadic forms.


Idiopathic non-lupus full-house nephropathy

A rare idiopathic glomerular clinical syndrome characterized by diffuse renal lesions that are indistinguishable from the lesions observed in systemic lupus erythematosus (SLE) in the absence of circulating autoantibodies and other systemic features necessary to meet the classification criteria for SLE. Patients may present with nephrotic syndrome, abnormal urinary sediment, acute renal insufficiency, progressive glomerulonephritis, and hypertension. Some patients have been reported to develop a progression to SLE over time.


A rare ophthalmic disorder characterized by idiopathic orbital inflammation in which the specific target tissue is the optic nerve sheath. Patients typically present with ocular pain, pain on eye movement, visual symptoms with loss of vision progressing over several weeks, dyschromatopsia, and variable visual field defects. Orbital signs and symptoms may be present and include ptosis, ophthalmoplegia, and exophthalmos. Optic disc edema is observed in most cases. The condition is usually unilateral.


Idiopathic panuveitis is a rare inflammatory eye disease, of unknown etiology, characterized by generalized inflammation of the uvea (iris, ciliary body, choroid), retina and vitreous with consequent ciliary spasm and posterior synechiae formation, leading to acute or chronic, unilateral or bilateral visual impairment and ocular discomfort or pain. Patients present an increased risk of development of cataracts, secondary glaucoma, cystoid macular edema and/or retinal detachment. It could potentially result in vision loss.


A rare vascular liver disease characterized by widespread or focal cystic dilatation of sinusoidal blood-filled spaces of the liver without any known cause. Lesions can vary in diameter between few millimeters and several centimeters. The condition may remain asymptomatic or manifest with complications including rupture and intraperitoneal hemorrhage, hepatomegaly, portal hypertension, cholestasis, and liver failure.


A rare bone disease characterized by bone resorption affecting the distal phalanx, most commonly the terminal tuft, in the absence of a known cause. Patients present with shortening of the affected fingers or toes, associated with nail abnormalities (dystrophic or hypertrophic nails) and skin changes (such as ulceration or pigment anomalies).


A rare idiopathic interstitial pneumonia characterized by prominent subpleural and parenchymal fibroelastosis and pleural fibrosis, predominantly involving the upper lobes. Signs and symptoms include non-productive cough, dyspnea, and recurrent respiratory infections. Pneumothorax is a frequently reported complication. Pulmonary function test reveals a restrictive pattern and reduced diffusing capacity. Computed tomography shows pleural thickening with signs of fibrosis (traction bronchiectasis, architectural distortion, and loss of volume), and reticulation.


Idiopathic posterior uveitis is a rare, potentially sight-threatening, ocular disease, not attributed to any specific ocular or systemic cause, characterized by focal, multifocal or diffuse non-infectious inflammation in the posterior uvea (i.e. choroiditis, chorioretinitis, retinitis and neuroretinitis). Visual morbidity due to complications (including cystoid macular edema and choroidal neovascularization) has been reported.


Idiopathic pulmonary arterial hypertension (IPAH) is a sporadic form of pulmonary arterial hypertension (PAH, see this term) characterized by elevated pulmonary arterial resistance leading to right heart failure. IPAH is progressive and potentially fatal and not associated with an underlying condition or family history of PAH.

Summary:
Epidemiology
Prevalence of PAH, in all of its forms, is estimated at around 1/67,000. IPAH is one of the most commonly diagnosed forms.
Clinical description
Clinical manifestations of IPAH are similar to other forms of PAH regardless of its etiology. IPAH develop in adults and in rare cases in children; women are twice as likely as men to be affected. The diagnosis is often made in patients in their mid-forties. Initial symptoms include dyspnea, fatigue, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, right ventricular heave, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. 70% of patients present heart failure (classed as New York heart association functional classification (NYHA FC) III or IV). More rarely, clubbing of digits and Raynaud phenomenon may be observed. Hemoptysis has also been reported.
Etiology
IPAH is caused by vascular remodeling of small pulmonary arteries due to unknown causes. Mutations in PAH predisposing genes are identified in about 15% to 20% of PAH patients initially considered to have an idiopathic form of the disease. IPAH patients carriers of a mutation in PAH predisposing gene have to be reclassified in ''heritable PAH'' (see this term). The main genetic risk factor of PAH is mutations in BMPR2gene (2q33). Mutations in ACVRL1>(12q13), ENG>(9q34), KCNK3 >(2p23),CAV1 (7q31), TBX4(17q21) have been identified in few cases.
Genetic counseling
Genetic counseling has to been proposed to all IPAH patients and mutations in PAH predisposing genes have to be searched. All PAH predisposing gene are transmitted in an autosomal dominant manner with an incomplete penetrance. In the cases of BMPR2 mutations, the penetrance is estimated to be 42% in female mutation carriers and 14% in male mutation carriers.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Barbara GIRERD  - Pr David MONTANI


Idiopathic pulmonary artery dilatation is a rare developmental defect during embryogenesis characterized by the dilatation of the main pulmonary artery, with or without dilatation of the right and left pulmonary artery branches, and not attributed to any other cardiac, pulmonary and/or arterial wall disease. It may present with exertional dyspnea, fatigue, cough, hemoptysis, palpitation and chest pain, but may also be asymptomatic. In serious cases, trachea constriction due to postural changes may lead to attacks of cyanosis with severe dyspnea. Sudden cardiac death has been reported in some cases.


An interstitial lung disease with a poor prognosis, that is characterized by the progressive formation of scar tissue within the lungs in the absence of any known cause.

Summary:
Epidemiology
Idiopathic pulmonary fibrosis (IPF) incidence appears to be increasing. Reported incidences range from 0.2 per 100.000 per year to 94 per 100.000 per year. The prevalence is estimated to be higher in men than in women.
Clinical description
The mean age at presentation is 66 years. IPF initially usually manifests with symptoms of breathlessness on exertion and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones. Clubbing is found in approximately 50% of IPF patients typically exertional dyspnea progresses over a period of months to years. In practice patients are often misdiagnosed.
Etiology
The etiology is not yet completely understood. The current conceptual model is that environmental factors may cause microscopic damage in the lungs and that in susceptible people this may lead to a disturbed healing reaction that will result in an ongoing process of scar formation in the lung. This will ultimately lead to loss of lung function.
Diagnostic methods
IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images. If these are non-conclusive a lung biopsy can be considered, though potential implications and associated risks should always be weighed and discussed. The diagnosis of IPF can be made by defined criteria that have been published in guidelines endorsed by several professional societies.
Differential diagnosis
Differential diagnosis includes other idiopathic interstitial pneumonias, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis + and other environmental (sometimes occupational) exposures. In a subgroup of patients with pulmonary fibrosis, despite thorough investigations, no definite diagnosis can be made and this group is than labeled as unclassifiable- pulmonary fibrosis.
Genetic counseling
In patients that present one or more family members with pulmonary fibrosis, genetic counseling should be considered.
Management and treatment
Pharmacological management: Two medications, pirfenidone and nintedanib, are recommended in the current international guidelines for the treatment of IPF. These medication slow down disease progression, as measured by decline in forced vital capacity by approximately 50% and are safe. Besides these, multiple new molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medications. These non pharmacological management approaches aim to improve or maintain quality of life and sometimes also life longer. Preventative measures as smoking cessation, influenza and pneumococcal vaccination are recommended. Supplemental oxygen is recommended for patients with an oxyhemoglobin saturation of less than 88% and reduces exertional dyspnea and improves exercise capacity for patients. Pulmonary rehabilitation and measures aimed at symptom relieve improve health related quality of life for patients. In a subgroup of patient lung transplantation may be an option.
Prognosis
The median survival without treatment is 2 to 5 years from the time of diagnosis.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr María MOLINA-MOLINA  - Dr M.S. [Marlies] WIJSENBEEK


Idiopathic pulmonary hemosiderosis is a respiratory disease due to repeated episodes of diffuse alveolar hemorrhage without any underlying apparent cause, most often in children. Anemia, cough, and pulmonary infiltrates on chest radiographs are found in majority of the patients.


Idiopathic recurrent pericarditis is a rare autoinflammatory syndrome defined as recurrence of pericardial inflammation of unknown origin following the first episode of acute pericarditis and a symptom-free interval of 4-6 weeks or longer. Recurrent attacks of chest pain may be the sole presentation or the chest pain may be accompanied by pericardial friction rub, electrocardiographic or echocardiographic changes, pericardial effusion and increased C-reactive protein. Cardiac tamponade is a rare, life-threatening complication.


A rare neurologic disease characterized by unpredictable, transient and spontaneous unresponsiveness lasting from hours to days, with a frequency of three to seven attacks per year, in the absence of readily discernible toxic, metabolic or structural causes.


Idiopathic spontaneous coronary artery dissection

A rare vascular disease characterized by idiopathic detachment of the layers of the walls of coronary arteries, creating a false lumen which limits the main coronary flow, leading to myocardial ischemia. Clinical manifestations include acute coronary syndromes, especially ST-segment elevation myocardial infarction (STEMI), syncope, cardiogenic shock, or sudden cardiac death. The condition typically affects young women.


Idiopathic steroid-resistant nephrotic syndrome

A rare, idiopathic nephrotic syndrome characterized by the triad of proteinuria, hypoalbuminemia and edema in patients who do not respond, or only partially respond, to the initial trial of corticosteroids. Patients may be multidrug resistant or may be sensitive to second-line immunosuppressive therapy.

Summary:
Epidemiology
The annual incidence of idiopathic nephrotic syndrome is estimated at 1/34,000 children, although this varies according to ethnicity or the country of origin. Steroid-resistance is described in 2.1-27.3% of children with idiopathic nephrotic syndrome, with annual incidence estimated at 1/390,000. In most regions, there is a male predominance, although reported ratios vary between 1.0 and 3.8.
Clinical description
Children with nephrotic syndrome generally present with signs of edema, for instance with swollen eyes, abdomen, scrotum, and/or ankles. Evaluation by a pediatrician/pediatric nephrologist will confirm the diagnosis of idiopathic nephrotic syndrome. Some criteria may increase the chance of becoming steroid-resistant, such as hematuria, hypertension and/or acute kidney injury at presentation, as well as having a positive family history for kidney disease or signs of extra-renal manifestations. Histologically, children with steroid-resistant nephrotic syndrome (SRNS) present most frequently with focal segmental glomerulosclerosis, less frequently with diffuse mesangial sclerosis, and more rarely with minimal change disease.
Etiology
After exclusion of the genetic forms, SRNS may result from a circulating permeability factor; such a factor is still unidentified, but its presence may result in a relapse of nephrotic syndrome after kidney transplantation. SRNS can also be secondary to an infection (such as CMV or HIV) or an underlying kidney disease (such as IgA nephropathy, membranous nephropathy or a collagenopathy).
Diagnostic methods
SRNS is established when treatment with corticosteroids does not result in a full remission within 4-6 weeks. In such patients, it is essential to search for an underlying genetic cause, underlying kidney disease (by performing a kidney biopsy) and by excluding other causes of the SRNS (laboratory work up for i.e. sickle cell disease, HIV, SLE, HepB, malaria, parvovirus B19).
Differential diagnosis
Genetic forms of SRNS should be excluded, as this has an important impact on subsequent therapies. Underlying kidney disease (membranous nephropathy, membranoproliferative glomerulonephritis, C3 glomerulopathy, IgA nephropathy, lupus nephritis, Alport syndrome/collagen IV glomerulopathy, amyloidosis, thrombotic microangiopathy), circulating permeability factor, infectious causes (cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepatitis B, malaria, parvovirus B19, syphilis), sickle cell disease, and malignancy (mainly lymphoma) should also be excluded.
Management and treatment
Treatment of a child with SRNS is based on reduction of proteinuria, immunosuppressive treatment, and supportive therapy. All children with SRNS should be treated with either an ACE inhibitor or an angiotensin-receptor blocker. Children in whom a genetic diagnosis is disproven and who have a GFR>30 ml/min/1.73m2, should receive immunosuppressive treatment, using calcineurin inhibitors, while corticosteroids are slowly tapered and discontinued. For current treatment schedules, please refer to international guidelines on treatment of SRNS. Supportive therapy consists of salt restriction and, on indication, diuretics to control edema. Albumin infusions are restricted to patients with symptomatic hypovolemia. Standard antibiotic prophylaxis is not recommended. Dysregulation of thyroid function, lipid levels, and calcium, magnesium, and vitamin D levels may occur, and should be treated accordingly. Thromboprophylaxis may be indicated in children with central venous catheters or with a history of thromboembolic events.
Prognosis
Children with SRNS who respond to immunosuppressive treatment and reach complete remission may remain in remission, or exhibit a relapse-remitting course, which is usually steroid-sensitive. Multi-drug resistant SRNS cases generally do continue to kidney failure. There is a high risk of post-renal transplant relapse which may occur within a day after kidney transplantation.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Pr M.F. [Michiel] SCHREUDER | ERKNet* - Dr Marina VIVARELLI | ERKNet*

                                * European Reference Network


Idiopathic steroid-sensitive nephrotic syndrome with secondary steroid resistance

A rare, idiopathic nephrotic syndrome characterized by pediatric onset of proteinuria, hypoalbuminemia and edema. Patients respond successfully to the initial standard course of corticosteroids, but are resistant to standard therapy for a subsequent relapse and following this relapse remain steroid-resistant.


Idiopathic steroid-sensitive nephrotic syndrome

A rare primary glomerulopathy of unknown cause characterized by edema, nephrotic-range proteinuria and hypoalbuminemia that responds to standard prednisone treatment within 4-6 weeks.

Summary:
Epidemiology
The annual incidence of idiopathic nephrotic syndrome varies by ethnicity and region ranging from 1/5,900-85,000 children, of which 70-98% are steroid sensitive. The disease is less frequently reported in adults. It has a male predominance (approximately 2:1) in young children.
Clinical description
Disease onset can occur at any age, but mostly between 2 - 6 years, frequently preceded by an upper respiratory tract infection. Patients typically present with edema, mainly periorbital and of lower extremities. Anasarca may develop with pleural and pericardial effusion, ascites, abdominal pain (due to hypoperfusion) and cold extremities with hypotension. Intravascular volume depletion and oliguria are present, and concomitant factors, (sepsis, diarrhea, diuretic use) can lead to acute kidney injury. Proteinuria typically has a relapsing and remitting course of varying frequency, and can be steroid-dependent in certain cases (relapsing during steroid therapy or within 15 days of its discontinuation). Urinalysis reveals nephrotic-range proteinuria and blood chemistry results show reduced serum albumin and total protein, reduced total calcium with ionized calcium usually normal, markedly decreased IgG levels, and hyperlipidemia. Hemoconcentration leads to increased hematocrit levels and thrombocytosis. A state of hypercoagulability (due to hypovolemia, hyperdyslipidemia, thrombocytosis) leads to an increased risk of, usually venous, thrombosis.
Etiology
Etiology is thought to be immune-mediated, although exact mechanism leading to disruption of the glomerular filtration barrier and proteinuria is unknown.
Diagnostic methods
Diagnosis is based on clinical manifestations, laboratory findings, and response to prednisone. Although renal biopsy is usually not performed, it may be advisable in the presence of atypical features (e.g. onset age < 1 or > 12 years, gross hematuria, low serum complement C3, marked hypertension, renal failure without severe hypovolemia), if prolonged therapy with calcineurin inhibitors is required or if the patient's clinical course is particularly difficult. Renal biopsy will most frequently show minimal changes with a negative immunofluorescence (so-called minimal change disease), though occasionally it may show other pictures.
Differential diagnosis
Differential diagnoses include membranous nephropathy, IgA nephropathy, renal vasculitis, C3 glomerulopathy and post-infectious glomerulonephritis.
Management and treatment
At onset, management includes symptomatic care with, in severe cases, albumin infusions. In children, prednisone (60mg/m2/day) is the mainstay of therapy. If the patient presents frequent relapses or steroid-dependent disease, second-line steroid-sparing immunosuppression with various agents, including antiproliferatives, levamisole, calcineurin inhibitors, mycophenolate mofetil and, more recently, rituximab, is prescribed.
Prognosis
Prognosis is variable. After remission of the first episode, the risk of relapse is negligible in 30% of patients. Approximately 20%-30% progress to infrequent relapses (rarely more than 3-4 episodes in total) with prednisone alone. The remaining 40%-50%, mostly children < 5 years of age, have a frequently relapsing or steroid-dependent course. Rarely, patients with initially steroid-sensitive nephrotic syndrome develop secondary steroid resistance, leading to progressive renal failure. In forms that remain steroid-responsive, renal function is typically preserved. Long-term outcome is heavily influenced by side effects of protracted administration of steroids and second-line steroid-sparing agents. The disease tends to resolve following puberty, but a significant percentage, around 10-15% of patients, will continue to present this disease in adulthood.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Marina VIVARELLI | ERKNet*

                                * European Reference Network


Idiopathic syringomyelia is a rare, non-syndromic central nervous system malformation characterized by a longitudinally oriented fluid-filled cavity inside the spinal cord parenchyma or the central canal, without any readily identifiable cause. It is usually associated with pain, sensory and/or musculoskeletal disturbances, but it can also be an incidental and asymptomatic finding.


A rare isolated nail anomaly characterized by brittle, thin, rough, opaque appearing nails with excessive longitudinal ridging. In a less severe form, the nails retain their luster and present with superficial ridging and multiple small geometric pits. In both varieties, superficial scaling of the nail plate and hyperkeratosis of the cuticles, as well as koilonychia and onychoschizia are observed. Any number of nails may be affected, and fingernails are more often affected than toenails. Spontaneous improvement of the condition may occur.


A rare panuveitis characterized by uni- or bilateral abnormal fluid accumulation within the suprachoroidal space, resulting in internal choroidal elevation, in the absence of any known cause, such as decreased intraocular tension, intraocular tumor, intraocular inflammation or nanophtalmos. Patients typically present a protracted, relapsing-remitting course of visual acuity loss and fundus examination shows annular celio-choroidal detachment and shifting, serous retinal detachment.


Idiopathic ventricular fibrillation, non Brugada type

A rare, genetic, cardiac rhythm disease characterized by ventricular fibrillation in the absence of any structural or functional heart disease, or known repolarization abnormalities. The presence of J waves is associated with a higher risk of nocturnal ventricular fibrillation events and a higher risk of recurrence.


Idiopathic/heritable pulmonary arterial hypertension

A form of pulmonary arterial hypertension (PAH) characterized by elevated pulmonary arterial resistance leading to right heart failure; it is progressive and potentially fatal. The majority cases have an identifiable genetic cause, but a significant proportion are idiopathic.


A rare autoimmune bullous skin disease characterized by painful and pruritic vesiculopustular eruptions resulting from circulating IgA antibodies against keratinocyte cell surface components. The lesions are typically found at the periphery of erythematous annular plaques and favor intertriginous regions. Histologically and immunologically, IgA pemphigus can be subdivided into subcorneal pustular dermatosis and intraepidermal neutrophilic IgA dermatosis.


A rare systemic autoimmune disease characterized by infiltrates of IgG4-positive plasma cells and lymphocytes in the adventitia of the aorta, resulting in thickening of perivascular tissue or formation of soft tissue masses surrounding the aorta and its major branches (potentially complicated by inflammatory aortic aneurysm), associated with elevated serum IgG4 levels. Preferential location is the infra-renal portion of the abdominal aorta. In addition, medium-sized blood vessels can be involved, and the condition may occur together with IgG4-related disease in other parts of the body. Clinical symptoms are unspecific and include chest or back pain and fever.


IgG4-related dacryoadenitis and sialadenitis

IgG4-related dacryoadenitis and sialoadenitis (Mikulicz disease) is an IgG4-related sclerosing disease (see this term) characterized by persistent, usually painless, bilateral enlargement of the lacrimal, parotid, and submandibular glands associated with elevated levels of serum immunoglobulin (Ig) G4 and with lymphocyte and IgG4-positive plasmacyte infiltration. It predominantly causes mouth and eye dryness but can also affect other organs such as the lungs, liver, and kidneys, and be accompanied by complications such as autoimmune pancreatitis (AIP), retroperitoneal fibrosis, and tubulointerstitial nephritis (see these terms).


A rare renal disease occurring in the setting of a systemic IgG4 related disease (IgG4-RD). The disorder is characterized by a fibrosing tubulointerstitial nephritis consisting of predominantly IgG4+ plasma cells with/without glomerulonephritis, retroperitoneal fibrosis and hydronephrosis.

Summary:
Epidemiology
The disease prevalence is unknown.
Clinical description
The clinical manifestations include tubulointerstitial nephritis (TIN) and membranous glomerulonephritis with or without TIN. Other glomerular disease is reported (IgA nephropathy, membranoproliferative glomerulonephritis, mesangioproliferative glomerulonephritis). Radiological abnormalities include mass lesions and diffusely enlarged kidneys. Presentation may be on routine imaging, with acute or chronic kidney disease, or with nephrosis depending on underlying lesion. Hydronephrosis may occur due to obstruction from IgG4-related retroperitoneal fibrosis.Other extra renal manifestations of IgG4-RD may also be present (e.g. salivary glands, hypophysis, hepatobiliary system, lungs).
Etiology
The etiology is unknown.
Diagnostic methods
The disease is diagnosed with characteristic imaging and renal biopsy findings (lymphocytic infiltration with predominantly IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis). Diagnostic criteria have been outlined.
Differential diagnosis
The differential diagnosis depends on presentation. For example, the differential for presentation with TIN includes: medications, autoimmune disease (e.g. Sjogren's syndrome, Sarcoid), malignancy (e.g. lymphoproliferative disease), and infection (e.g. Tuberculosis).
Management and treatment
Not supported by randomized controlled trials. Lymphocytic infiltration is usually quickly responsive to steroids. Some patients require immunosuppressants such as Rituximab.
Prognosis
Relapse is common, and progressive renal impairment can occur, including the need for renal replacement therapy.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Rhys EVANS | ERKNet*

                                * European Reference Network


A rare systemic autoimmune disease characterized by an aggressive fibroinflammatory process with infiltration of IgG4-positive plasma cells in the mediastinum, potentially resulting in compression and functional impairment of vital mediastinal structures, and associated with elevated serum IgG4. Clinical symptoms are unspecific and include pain or symptoms due to mass effect. The condition may occur together with IgG4-related disease in other parts of the body.


Sclerosing mesenteritis (SM) is a rare pathological disease causing inflammation of the adipose tissue of the small bowel mesentery and is commonly associated with abdominal pain, diarrhea, nausea, weight loss, bloating and loss of appetite. The two subforms include mesenteric panniculitis (where inflammation and fatty necrosis are dominant features) and retractile mesenteritis (where fibrosis and retraction dominate).


A rare, inflammatory eye disease characterized by IgG4-immunopositive lymphocyte and plasmacyte infiltration and collagenous fibrosis of affected tissue and elevated serum levels of IgG4. Clinical presentation includes mass lesion or swelling of the involved structures, commonly involving lacrimal gland and duct, infraorbital and supraorbital nerves, extraocular muscles and orbital soft tissues. A systemic involvement is common.


A rare, brain inflammatory disease characterized by thickening of the dura mater of the cranium or spine with at least two histiopatholgical features of IgG4-related disease: dense lymphoplasmacytic infiltrate, storiform fibrosis, and/or obliterative phlebitis. Patients typically have non-specific CSF findings, and might be without systemic involvement or serum IgG4 elevation. Clinical manifestation are caused by mechanical compression of nerve or vascular structure, leading to functional deficit, most commonly headache, cranial nerve palsies, vision problems and motor weakness.


A rare systemic autoimmune disease characterized by mass-forming, potentially destructive inflammation and fibrosis in the soft tissues of the retroperitoneum, associated with elevation of serum IgG4 levels and infiltration of IgG4-positive plasma cells in at least one organ or site. Most frequent locations are peripheral to the abdominal aorta, as well as the iliac and renal arteries. Clinical symptoms are unspecific and include abdominal pain, back pain, and edema of the lower extremities. The condition may occur together with IgG4-related disease in other parts of the body.


A rare systemic autoimmune disease characterized by cholestasis and diffuse cholangiographic abnormalities with circular and symmetrical bile duct wall thickening, and elevated serum IgG4 levels. Characteristic histopathological findings include dense infiltration of IgG4-positive plasma cells and extensive fibrosis in the bile duct wall. A marked response to steroid therapy is typical. Patients present with jaundice, cholangitis, pruritis, and sometimes associated findings of autoimmune pancreatitis, sialadenitis, and retroperitoneal fibrosis.


IgG4-related submandibular gland disease

A rare IgG4-related disease characterized by a benign tumor-like chronic inflammatory lesion of the submandibular gland. Histologic features are periductal fibrosis, acinar atrophy, obliterative phlebitis, dense lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, and formation of lymphoid follicles. Lobular architecture is preserved. Patients most commonly present with unilateral, painless swelling of the submandibular gland. Serologic analysis reveals elevated IgG4 levels.


A rare systemic autoimmune disease characterized by mass-forming lesions with a lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells and storiform fibrosis, often displaying obliterative phlebitis, and usually accompanied by elevated serum IgG4. Almost any organ may be affected, with pancreas, salivary gland, and orbit being the most common. Multi-organ involvement (synchronously or metachronously) is typical. Many patients show lymphadenopathy, most often involving the mediastinal, intra-abdominal, axillary, and cervical nodes. Symptoms are usually attributable to the mass effect of the lesions.


A fibroinflammatory disorder of the thyroid gland, occuring more frequently in females, characterized a large, hard thyroid mass, and presenting with pressure symptoms (breathing difficulties and dysphagia) or voice hoarseness and aphonia (impingement of recurrent laryngeal nerve). It can often be associated with extracervical fibroinflammatory disorders such as retroperitoneal fibrosis, primary scleroisng cholangitis and autoimmune diseases such as Hashimoto struma, Addison disease, and Biermer disease.


IL21-related infantile inflammatory bowel disease

A rare autosomal recessive primary immunodeficiency characterized by infancy onset of severe inflammatory bowel disease with life-threatening diarrhea and failure to thrive, oral aphthous ulcers, and recurrent severe upper and lower respiratory tract infections with finger clubbing. Laboratory examination reveals increased IgE and decreased IgG levels, as well as reduced numbers of circulating CD19+ B-cells including IgM+ naive and class-switched IgG memory B-cells, with a concomitant increase in transitional B-cells, while T-cell numbers and function are normal.


Ileal neuroendocrine tumor is a rare, primary, malignant, epithelial neoplasm of the small intestine arising from enterochromaffin cells in the ileum (usually the terminal ileum). Clinical behavior depends on the histologic grade, but initially it is generally characterized by vague abdominal symptoms (cramping, bloating, diarrhea) with insidious onset, although sometimes it could present with signs of bowel obstruction/perforation or gastrointestinal bleeding. Diagnosis in advanced stages with regional or distant spread is common, but signs of carcinoid syndrome (flushing, sweating, diarrhea) are usually not apparent until hepatic metastasis has occurred.


Ileal pouch anal anastomosis related faecal incontinence

A rare intestinal disorder characterized by the inability to control the passage of rectal contents (feces, gas) through the anus following ileal pouch-anal anastomosis surgery. Fecal incontinence is usually more frequent during the night than during daytime. The condition generally worsens over time, with a significant negative impact on the quality of life of the patient.


A rare genetic disease characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (such as cryptorchidism, posterior hypospadias, and micropenis). Patients may present shortly after birth with severe adrenal insufficiency. Additional manifestations include postnatal growth failure and delayed bone age, mild developmental delay, macrocephaly, mild facial dysmorphism (with frontal bossing, wide nasal bridge, and small, low-set ears), epiphyseal dysplasia, and hypercalcemia/hypercalciuria, among others.


Imerslund-Grasbeck syndrome (IGS) or selective vitamin B12 (cobalamin) malabsorption with proteinuria is a rare autosomal recessive disorder characterized by vitamin B12 deficiency commonly resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood.

Summary:
Epidemiology
The syndrome was first described in Finland and Norway where the prevalence is about 1/200 000.
Clinical description
Other manifestations include failure to thrive and grow, infections and neurological damage. Mild proteinuria (with no signs of kidney disease) is present in about half of the patients. Anatomical anomalies in the urinary tract were observed in some Norwegian patients. Vitamin B12 absorption tests show low absorption, not corrected by administration of intrinsic factor. The symptoms appear from 4 months (not immediately after birth as in transcobalamin deficiency) up to several years after birth.
Etiology
The cause is a defect in the receptor of the vitamin B12-intrinsic factor complex of the ileal enterocyte. In most cases, the molecular basis of the selective malabsorption and proteinuria involves a mutation in one of two genes, cubilin (CUBN) on chromosome 10 or amnionless (AMN) on chromosome 14. Both the proteins are components of the intestinal receptor for the vitamin B12-intrinsic factor complex and the receptor mediating the tubular reabsorption of protein from the primary urine.
Management and treatment
Management includes life-long vitamin B12 injections, and with this regimen, the patients stay healthy for decades. However, the proteinuria persists. In diagnosing this disease, it is important to be aware that cobalamin deficiency affects enterocyte function; therefore, all tests suggesting general and cobalamin malabsorption should be repeated after abolishment of the deficiency.

                            Last update:
                            May 2006


A rare inborn error of metabolism characterized by elevated levels of imino acids (proline, hydroxyproline) and glycine in urine due to defective reabsorption in the kidney. The condition is considered benign and not associated with any specific clinical phenotype. Mode of inheritance is autosomal recessive.


Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome

A rare immune dysregulation disease with immunodeficiency characterized by severe, progressive infantile onset inflammatory bowel disease with pancolitis, perianal disease (ulceration, fistulae), recurrent respiratory, genitourinary and cutaneous infections, arthritis and a high risk of B-cell lymphoma.


Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome

A rare genetic immune disease characterized by early onset of recurrent bacterial, viral, and fungal infections, chronic inflammatory bowel disease, gastritis, and inflammatory polyarthritis. Patients present with diarrhea, vomiting, hepatosplenomegaly, mouth ulcers, perianal abscesses, chronic lung disease with bronchiectasis, and failure to thrive. Occurrence of a skin rash associated with lymphocytic vasculitis has also been reported. Immunologic abnormalities include variable T-cell lymphopenia, decreased natural killer cells, and decreased B-cells with variable hypogammaglobulinemia.


A rare immunodysregulatory disease characterized by refractory diarrhea, endocrinopathies, cutaneous involvement, and infections.

Summary:
Epidemiology
Immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome prevalence is unknown. The disease has probably been underestimated, and milder clinical phenotypes surviving to adult life are being described.
Clinical description
IPEX syndrome most commonly develops during the first few days or weeks of life and affects exclusively boys. It classically manifests with the sequential appearance of the triad of enteropathy, autoimmune disease (particularly Type I diabetes mellitus), and cutaneous involvement, but the clinical features and severity of the disease can vary considerably between individuals. Severe autoimmune enteropathy manifests with intractable secretory diarrhea leading to malabsorption, electrolyte disturbance and failure to thrive. Vomiting, ileus, gastritis or colitis can also be observed. Patients also present with autoimmune endocrinopathies, generally insulin-dependent diabetes mellitus (type 1 DM) often in infancy or early childhood, but also thryroiditis leading to hypothyroidism or hyperthyroidism. Skin involvement consists of a generalized pruriginous eruption resembling eczema, psoriasis, and/or atopic or exfoliative dermatitis. Less frequently, alopecia or onychodystrophy can be observed. Patients may develop autoimmune cytopenias, thrombocytopenia, hemolytic anemia and neutropenia. Autoimmune involvement may also lead to pneumonitis, hepatitis, nephritis, myositis, splenomegaly and/or lymphadenopathy. Local or systemic infections (e.g. pneumonia, Staphylococcus aureus infections, candidiasis) may occur but seem to be due to loss of skin and gut barriers, immunosuppressive therapies, and poor nutrition rather than a primary immunodeficiency. Neurological findings including peripheral neuropathy, myopathy and hypotonic are described.
Etiology
IPEX syndrome is caused by mutations in the FOXP3 gene (Xp11.23). This gene codes for a forkhead transcription factor which controls the development and function of CD4+ CD25+ regulatory T cells, a major lymphocyte population involved in self-tolerance and downregulation of immune responses.
Diagnostic methods
Diagnosis is based on clinical examination, family history, and laboratory findings revealing autoimmune enteropathy (anti-enterocyte, harmonin and villin autoantibodies), type 1 DM (antibodies against insulin, pancreatic islet cells, or anti-glutamate decarboxylase), thyroiditis (anti-thyroglobulin and anti-microsome peroxidase antibodies) and cytopenia (anti-platelets and anti-neutrophils antibodies, positive Coombs test). Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes Wiskott-Aldrich and Omenn syndromes, susceptibility to viral and mycobacterial infections, CD25 deficiency, IL10R deficiency, STAT5b deficiency, transient neonatal diabetes, severe combined immunodeficiency or intermediate forms of combined immunodeficiency, X-linked thrombocytopenia and pancreatic hypoplasia or agenesis.
Antenatal diagnosis
Prenatal diagnosis from chorionic villus samples is possible after determination of the fetal sex by karyotype analysis for families in which the disease-causing mutation has been identified.
Genetic counseling
Transmission is X-linked recessive. There is a 50% risk of transmission when the fetus is a male. 50% of females will be carriers.
Management and treatment
The only curative treatment for IPEX is hematopoietic stem cell transplantation (HSCT), which is much more successful when performed in the early stages of the disease. Supportive measures include monotherapy or combined immunosuppressive therapy with glucocorticoids (prednisone and methylprednisolone), cyclosporin A (CSA), tacrolimus, azathriopine, rapamycin, lifelong insulin and thyroid hormones supplementation in case of organ failure, topical CSA for skin manifestations, and parenteral nutrition for severe cases of enteropathy.
Prognosis
Without timely diagnosis and treatment, the disease is usually fatal within the first 2 years of life in severe cases. Increasingly, patients survive into childhood when treated with appropriate immunosuppression. With HSCT, life expectancy is likely to be normal, and disease progression halted, although feeding difficulties may persist for many months post HSCT. Neurodevelopment is usually normal.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Immune hydrops fetalis (IHF), a form of HF, describes the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities due to maternal rhesus (Rh) incompatibility.

Summary:
Epidemiology
The incidence of IHF has decreased greatly since the introduction of RhoD immune globulin in the 1960's and has wide regional variability. The incidence in the U.K. is estimated to be at about 1/3,000 births. IHF accounts for about 10-20% of all cases of HF.
Clinical description
IHF presents during the gestational period (50% between 18-34 weeks of gestation, 50% between 34 weeks and term) and is characterized by the accumulation of fetal fluid manifesting as pericardial effusion, pleural effusion, ascites and subcutaneous edema in the fetus. The mother might notice decreased fetal movements prior to diagnosis. Fetal tachycardia, polyhydramnios and antenatal hemorrhage are often associated with HF. Mothers may develop massive anasarca, hypertension, and proteinuria (described as mirror syndrome). Death of the fetus is due to pulmonary hypoplasia and heart failure. Surviving newborns may present with respiratory distress, pale skin, jaundice, severe edema (mostly localized to the abdomen) and enlarged liver and spleen.
Etiology
IHF occurs when the mother's immune system causes a breakdown of red blood cells in the fetus (erythroblastosis fetalis). This results in destruction of fetal red blood cells by maternal IgG antibodies that cross the placenta. In feto-maternal Rh incompatibility, the maternal blood is Rh-negative and the fetal blood is Rh-positive. Rh alloimmunisation develops if maternal IgG antibodies cross the placenta, binding to antigens present on the fetal erythrocytes and causing hemolysis. Usually anti-D, anti-E, and antibodies directed against other Rh antigens comprise the majority of involved antibodies. The majority of the cases of Rh isoimmunisation lead to a mild to moderate fetal or neonatal hemolytic disease but about 20-25% of cases result in IHF.
Diagnostic methods
Diagnosis is usually by ultrasound during the 2nd to 3rd trimester of gestation. Ultrasound can detect fluid collections but if there is limited accumulation it may not be diagnosed. Having a placenta thickness of 5 mm or more, especially with a ''ground glass'' appearance on ultrasound may also be indicative of the presence of this condition. Maternal laboratory tests such as blood typing (to see if they are Rh negative), antibody screens for TORCHES-CLAP (Toxoplasma gondii; Rubella virus; Cytomegalovirus; Herpes simplex virus; Enterovirus; Syphilis; Chickenpox virus; Lyme disease; Aids; Parvovirus B19), hemoglobin electrophoresis, and an alpha-fetoprotein (AFP) test can also aid in diagnosing IHF.
Differential diagnosis
The many disorders associated with HF are differential diagnoses such as congestive heart failure, hepatitis B, Parvovirus B19 infection, hypercalcemia, hypernatremia, hypothrombinemia, hypothyroidism and diabetes (in mother) and neonatal hemochromatosis. A few conditions mimic full-blown HF such as obstructed or mature bowel, fetal abdominal cysts and an obstructed urinary system (in the end stages).
Antenatal diagnosis
Prenatal diagnosis is by ultrasound.
Management and treatment
Rh iso-immunization can usually be prevented by giving the mother an intramuscular injection of Rho(D) immune globulin. For those who develop IHF, intrauterine treatment can involve thoraco-amniotic drainage, antiarrhythmic drugs (ex. digoxin, sotalol, propranolol) to treat arrhythmia, and blood transfusion when anemia is present. If the fetus comes to term it should be delivered at a tertiary care center where the neonate can receive oxygen supplementation, medications for the kidneys and removal of excessive fluid from around the lungs and abdomen as necessary. Exchange transfusion or phototherapy can treat neonatal jaundice.
Prognosis
In most cases, prognosis is poor with a perinatal mortality rate ranging from 55-98%, but it is influenced by numerous factors.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Dr Carlo BELLINI


A rare autoimmune coagulation disorder characterized by isolated thrombocytopenia (a platelet count <100,000/microL), in the absence of any underlying disorder that may be associated with thrombocytopenia.

Summary:
Epidemiology
The annual incidence is estimated at between 1/25,600-37,000 in Europe, with a female to male ratio of 1.3:1. Although immune thrombocytopenia (ITP) can occur at any age, incidence shows an age-specific bimodal distribution for men with two incidence peaks observed in boys (under 18 years old) and among those older than 60 years of age.
Clinical description
ITP exposes to a risk of bleeding. It is defined as severe when the presence of bleeding symptoms at presentation is sufficient to warrant treatment or when the occurrence of new bleeding symptoms requires additional therapeutic intervention. It is asymptomatic in one-third of cases. Mucocutaneous hemorrhage with purpura is the most frequent clinical manifestation, usually occurring when the platelet count is below 30,000/microL. Severe visceral bleeding (hematuria, gastrointestinal hemorrhage or cerebromeningeal bleeding) is mainly observed when thrombocytopenia is below 10,000/microL and is rare, occurring mainly in elderly with comorbidities or in children in whom the disease is often self-limited; however, most children do not have severe bleeding problems despite very low platelet counts. Depending on the disease duration, ITP is classified into newly diagnosed, persistent (duration of 3-12 months) and chronic (duration of more than 12 months). Persistence or chronicity occurs in about 30 % of children compared with about 70% of adults.
Etiology
The etiology is unknown. However, the disease origin is not genetic as familial cases are exceptional. Platelet destruction, mediated by autoantibodies mainly in the spleen, is associated both with impaired platelet production and with T-cell-mediated effects.
Diagnostic methods
A presumptive diagnosis is made when the history, physical examination, complete blood count and examination of the peripheral blood smear do not suggest other etiologies for the thrombocytopenia. There is no `gold standard' test that can reliably establish the diagnosis. A positive response to intravenous immunoglobulin (IVIg) and/or steroids is supportive of the diagnosis. In ITP the bone marrow is normal, and bone marrow aspiration is indicated mainly in patients over 60 years' of age, in case of anomalies of other cell lines, when thrombocytopenia is refractory to first-line treatments, or when other diagnoses are suspected such as myelodysplastic syndromes (MDS). In addition to the morphologic assessment, cytogenetic testing should be considered if an MDS is suspected.
Differential diagnosis
The differential diagnosis should include causes of secondary ITP (drug-induced), autoimmune diseases (such as systemic lupus erythematosus), HIV infection and hepatitis C. In elderly patients, MDS should be ruled out. In children, inherited thrombocytopenias are often misdiagnosed with ITP. ITP can be associated with genetic immunodeficiency syndromes (typically common variable immunodeficiency) and is observed mainly in children and young adults.
Management and treatment
The therapeutic strategy should be adapted both to the severity of the disease and to the patient's age. At diagnosis, children with mild or even moderate bleeding can be managed with monitoring. Treatment is rarely indicated in adults with platelet counts above 20 to 30x10exp9/L in the absence of bleeding. Corticosteroids (oral prednisone or short course of dexamethasone) are the standard first-line treatment. Use of intravenous immunoglobulins should be reserved for patients with severe bleeding (bleeding score could be used to help the physicians for IVIg indication) who are unresponsive to prednisone or for the rare patients with contra-indications to steroids. In case of chronic severe ITP, splenectomy has been used as the reference treatment for a long time. However, biologics (such as rituximab, eltrombopag, romiplostim) and even immunosuppressants (such as mycophenolate mofetil) can now be considered as an alternative to splenectomy as second-line treatment for patients refractory to first-line treatments. The respective place between these different second-line therapeutic options is still debated; ultimately, treatment should be personalized according to the patient's characteristics.
Prognosis
The mortality rate is generally below 2%, but may exceed 10% in the rare patients refractory to first- and second-line treatments (including splenectomy).

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Bertrand GODEAU


A rare form of idiopathic inflammatory myopathy characterized by acute or subacute, severe, symmetrical, proximal muscle weakness usually associated with muscle-specific antibodies (anti-HMGCR or anti-SRP). Histopathological characteristics include myocyte necrosis and regeneration without significant inflammation, and C5b-9 deposition on non-necrotic myofibers.

Summary:
Epidemiology
The incidence of idiopathic inflammatory myopathy as a whole ranges from 1.16 to 19/million/year and the prevalence ranges from 2.4 to 33.8 per 100 000 inhabitants. Although the prevalence and annual incidence are not known, immune-mediated necrotizing myopathy (IMNM) represents roughly 10% of the idiopathic inflammatory myopathies.
Clinical description
Age of onset typically ranges from 30 to 70 years of age, although pediatric onset is possible. The main presenting feature of IMNM is subacute severe symmetrical proximal myopathy with a markedly elevated creatine kinase (CK) level. The main clinical symptom is upper and lower limb weakness causing difficulty in moving from a sitting position, climbing stairs, or lifting objects. The neck flexor, pharyngeal, and respiratory muscles may also be involved. Other manifestations include fatigue, weight loss, dysphagia and dyspnea. Interstitial lung disease and cardiac involvement have also been reported (especially in patients with anti-SRP antibodies).
Etiology
The disease is thought to be related to an immune response possibly triggered by drug therapy (statins), viral infections, or cancer. The pathophysiological mechanisms are partially deciphered. A specific genetic background has been identified (HLA-DRB1*11:01 allele in adult patients with anti-HMGCR autoantibodies). The production of autoantibodies is a major feature of the disease. Several studies point toward a direct pathogenic role of these autoantibodies, potentially through the activation of the complement cascade.
Diagnostic methods
Diagnosis is based on the clinical picture with the presence of auto-antibodies (anti-SRP or anti-HMGCR) and/or a muscle biopsy showing minimal or no inflammatory infiltrates and marked muscle necrosis, unlike other inflammatory myopathies. Electromyography (EMG) shows myopathic findings. Creatine kinase (CK) levels are often more than 10 times above the upper limit of normal at the time of onset of muscle weakness. Magnetic resonance imaging (MRI) may show diffuse or patchy edema within muscles and damage-like muscle fatty replacement. Anti-SRP and anti-HMGCR autoantibodies are frequently associated with this condition. Currently, seronegative IMNM represents 20-30% of the cases.
Differential diagnosis
Differential diagnoses include other inflammatory myopathies. In children, the progressive form of the disease may mimic muscular dystrophy.
Management and treatment
Treatment of the underlying cause, if identified, is essential (statin withdrawal, or malignancy). IMNM patients generally respond well to multiple-agent, long-term immunosuppressive therapies starting by high dose corticosteroids. The therapeutic strategy relies on an induction therapy combining high dose corticosteroids and other immunosuppressive agents (methotrexate, rituximab or intravenous immunoglobulins (IVIg)), followed by a maintenance therapy with the lowest tolerated dose of corticosteroids and the immunosuppressive agent. The maintenance therapy should be administered for at least 2 years in which there is well-controlled disease. Exercise is recommended to improve muscle strength. Response to therapy should be assessed clinically on the basis of muscle strength and biologically on CK levels.
Prognosis
IMNM is the most severe idiopathic inflammatory myopathy in terms of muscle damage, and relapses are frequent. Early age of onset is a poor prognosis factor for muscle strength recovery. There is an association with cancer risk in patients with seronegative IMNM and, to a lesser extent, in patients with anti-HMGCR IMNM.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE


Immune-mediated thrombotic thrombocytopenic purpura

A rare, non-hereditary thrombotic thrombocytopenic purpura (TTP), characterized by profound peripheral thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and single or multiple organ failure of variable severity.

Summary:
Epidemiology
The annual incidence of TTP is estimated at 0.25 to 1/250, 000. Immune-mediated TTP is much more common than congenital TTP, accounting for over 95% of all TTP cases, and has a 3:1 female-to-male ratio.
Clinical description
Disease onset is typically sudden and occurs in adulthood (median age 40 years). Prodromic manifestations including fatigue, arthralgias, myalgias and abdominal and/or lumbar pain are frequently observed around the time of diagnosis. Thrombotic microangiopathy is associated with MAHA, consumptive peripheral thrombocytopenia and variable organ injury due to disseminated microvascular thrombosis. Manifestations due to cerebral (headache, confusion, seizure, focal deficiency, altered mental state and coma; 50-80% of cases), cardiac (infarction, congestive heart failure, arrhythmias, cardiogenic shock, and sudden cardiac arrest), and gastrointestinal (abdominal pain, nausea, vomiting, and diarrhea) involvement are observed. Renal involvement is usually mild. The disease course is variable. Patients may suffer from only one acute TTP episode; however, relapses have been reported in 30-40% of patients. Immune-mediated TTP is usually idiopathic but rarely may occur in association with a connective tissue disease (mostly systemic lupus erythematosus and Sjögren's syndrome), infections (typically HIV infection), or after ticlopidine intake. Patients with a history of immune-mediated TTP are at risk of a relapse during pregnancy.
Etiology
The majority of cases of immune-mediated TTP are associated with the presence of autoantibodies directed against the von Willebrand factor-cleaving protease, ADAMTS13, resulting in a severe (< 10% of normal activity) ADAMTS13 deficiency. A trigger, including physical stress (surgery), infections, drug intake or a pregnancy, may precipitate the disease.
Diagnostic methods
Biological features are consistent with hemolysis (high reticulocyte count, indirect bilirubin and LDH levels and a low haptoglobin level). The direct antiglobulin test is negative whereas peripheral blood smear reveals schistocytes. A very low platelet count (≤ 30 000/mm3) and mild renal involvement (serum creatinine ≤ 200 µmol/L) can predict a severe acquired ADAMTS13 deficiency. A severe decrease in ADAMTS13 activity (< 10% normal levels) in the presence of anti-ADAMTS13 autoantibodies confirms diagnosis.
Differential diagnosis
The main differential diagnoses are congenital TTP and atypical hemolytic uremic syndrome as well as antiphospholipid syndrome, Evans syndrome, disseminated intravascular coagulation, cobalamin deficiency and, in pregnant patients, HELLP syndrome.
Management and treatment
The treatment of immune-mediated TTP is based on a triplet regimen of therapeutic plasma exchange (TPE; with 1.5 x plasma volume exchange), immunosuppression with corticosteroids and B-cell depletion (rituximab), and caplacizumab, an inhibitor of vWF-platelet interaction. This treatment should be initiated as soon as the clinical diagnosis of TTP is made or suspected and should be continued daily until remission. Steroids, in the absence of uncontrolled infection, are often used as adjuvant first line therapies. Thromboprophylaxis may be introduced when platelet count is above 50,000/mm3. Whilst exacerbations and refractory disease are rare with the triplet regimen, this can be managed with a more intensive treatment including twice-daily TPE. For patients in clinical remission but with a persistently undetectable ADAMTS13 activity, preemptive administrations of rituximab prevents relapse.
Prognosis
In the absence of treatment, TTP is a rapidly fatal disease (mortality rate > 90%); however, the introduction of TPE has led to a decrease in the rate of mortality to 10-15%. With the recent addition of caplacizumab, mortality may further decrease to < 10%. Even with optimal management, neurological (attention deficit, memory loss) and physical (fatigue) sequelae may persist. A systematic long-term follow-up is required for all patients, due to the risk of relapse. Patients may also develop additional autoimmune diseases.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Paul COPPO


Immunodeficiency by defective expression of MHC class I

A rare autosomal recessive primary immunodeficiency characterized by severe reduction in the cell surface expression of HLA class I molecules, typically resulting in childhood-onset of chronic bacterial infections of the respiratory tract evolving to widespread bronchiectasis and respiratory insufficiency. Sterile necrotizing granulomatous skin lesions mainly involving the extremities and the mid-face may be observed in some patients. Severe viral infections do not occur as part of the condition. Atypical variants without respiratory or cutaneous manifestations, as well as asymptomatic individuals have been reported.


Immunodeficiency by defective expression of MHC class II

A rare autosomal recessive primary immunodeficiency characterized by absence of HLA class II molecules on the surface of immune cells, leading to severely impaired cellular and humoral immune response to foreign antigens, severe CD4+ T-cell lymphopenia, and hypogammaglobulinemia. The disease clinically manifests with early onset of severe and recurrent infections mainly of the respiratory and gastrointestinal tract, protracted diarrhea with failure to thrive, and autoimmune disease, and is frequently fatal in childhood.


Immunodeficiency due to a classical component pathway complement deficiency

A rare primary immunodeficiency due to a deficiency in either complement components C1q, C1r, C1s, C2 or C4 characterized by increased susceptibility to bacterial infections, particularly with encapsulated bacteria, and increased risk for autoimmune disease. Most commonly, these include systemic lupus erythematosus (SLE), SLE-like disease, Henoch-Schonlein purpura, polymyositis and arthralgia. Disease severity is variable and dependent on the complement affected.


Immunodeficiency due to a late component of complement deficiency is a primary immunodeficiency due to an anomaly in either complement components C5, C6, C7, C8 or C9 and is typically characterized by meningitis due to often recurrent meningococcal infections. The prognosis is generally favorable.


A rare genetic primary immunodeficiency due to a defect in adaptive immunity characterized by severe immunodeficiency, presenting with profound susceptibility to viral, fungal and bacterial infections due to impaired CD25-mediated T-regulatory cell function, in association with severe autoimmune disease, such as alopecia universalis, erythrodermia, and autoimmune thyroiditis and enteropathy.


Immunodeficiency due to ficolin3 deficiency is a rare, genetic, immunodeficiency due to a complement cascade protein anomaly characterized by low or undetectable serum ficolin3 levels, susceptibility to infections, and possibly autoimmunity. The presentation is variable, from perinatal necrotizing enterocolitis and recurrent skin infections with Staphylococcus aureus to childhood-onset recurrent pulmonary infections leading to brain abscesses and pulmonary fibrosis, to membranous nephropathy. In some patients, clinical consequences of ficolin3 deficiency were not clear.