Superficial epidermolytic ichthyosis (SEI) is a rare keratinopathic ichthyosis (KI; see this term) characterized by the presence of superficial blisters and erosions at birth.

Summary:
Epidemiology
Less than 30 families have been reported in the literature.
Clinical description
Clinical features of SEI are similar but milder that those of epidermolytic ichthyosis (EI; see this term). SEI presents at birth or during the neonatal period with mild superficial blistering that is more frequent on flexures, shins, abdomen and extremities. After a few weeks, the skin starts to peel leaving characteristic denuded areas with normal skin (called molting/ mauserung phenomenon). A variable and mild grey rippled hyperkeratosis develops predominantly on the limbs, lower trunk and flexural areas. Blistering diminishes with age but persists through childhood and sometimes into adult life in response to trauma, heat or excessive sweating. Palmoplantar involvement is usually not observed but palmoplantar blistering, usually associated with hyperhidrosis, may sometimes occur. Skin odor is not present.
Etiology
SEI is caused by mutations in the KRT2 gene encoding keratin 2. These mutations impair keratin filament formation and weaken the structural stability of the keratinocyte cytoskeleton.
Diagnostic methods
Diagnosis is based on clinical and histological examination of skin lesions biopsies revealing acanthosis, a prominent granular layer, epidermolytic changes in the granular and upper spinous layers, hyperorthokeratosis and intracorneal blister formation. On electron microscopic examination, keratinocytes of the granular layer display structural alterations of tonofilaments. Molecular analysis, if available, reveals KRT2 mutations.
Differential diagnosis
Differential diagnosis includes epidermolytic ichthyosis, peeling skin syndrome, staphylococcal scalded skin syndrome, Alopecia-contractures-dwarfism-intellectual disability syndrome (see these terms), and atopic dermatitis.
Antenatal diagnosis
Genetic prenatal diagnosis is available for inherited ichthyoses (see this term) but it is generally not proposed for SEI due to its mild course.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to affected families. The risk for an affected parent to have an affected child is 50%.
Management and treatment
Treatment is symptomatic. Emollient and mild topical keratolytics may be used to reduce hyperkeratosis. Low dose of oral retinoids may also reduce hyperkeratosis, but must be used with caution because of their side effects and of their effect in the increase of skin fragility. Antibiotic therapy is required to treat secondary infection.
Prognosis
SEI is usually a mild disease. Life expectancy is normal and quality of life is not severely impaired.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nathalie JONCA  - Pr Juliette MAZEREEUW-HAUTIER


Superficial siderosis is a rare neurologic disease characterized by progressive sensorineural hearing loss, cerebellar ataxia, pyramidal signs, and neuroimaging findings revealing hemosiderin deposits in the spinal and cranial leptomeninges and subpial layer. The disease progresses slowly and patients may present with mild cognitive impairment, nystagmus, dysmetria, spasticity, dysdiadochokinesia, dysarthria, hyperreflexia, and Babinski signs. Additional features reported include dementia, urinary incontinence, anosmia, ageusia, and anisocoria.


A rare disorder of the anterior segment of the eye characterized by unilateral or bilateral, chronic and recurrent inflammation affecting the upper tarsal and bulbar conjunctiva, as well as the superior limbus, manifesting as a papillary reaction on the upper tarsal conjunctiva, thickening and folding of redundant superior bulbar conjunctiva, and superficial punctate epithelial keratitis with or without filament formation near the superior corneal limbus. Middle-aged women are most commonly affected and present with foreign body sensation, frequent blinking, burning sensation, and pruritus, among others.


A rare breast malformation characterized by the presence of accessory breasts with a complete ductal system, areola, and nipple in addition to two normal breasts. The accessory breast tissue mostly lies along the milk lines. It is often not recognized until puberty, when it begins to respond to regular hormonal fluctuations, and may develop the same changes as normal breasts throughout life.


Supernumerary nostril is an extremely rare congenital malformation characterized by the presence of one or more accessory nostrils, with or without accessory cartilage, located medially, above, below or laterally to the other nostrils. Unlike in polyrhinia (see this term) there is no duplication of the nasal septum/cavity. Supernumerary nostril is often associated with other congenital malformations usually of face.


Supratip dysplasia is a rare, congenital, non-syndromic, nose and cavum malformation characterized by the presence of a bulbous, soft tissue hypertrophy located in the middle-to-distal third of the nasal dorsum, in association with deformed, slightly laterally- and caudally-placed nasal alae and a scar-like atrophic skin lesion located at the nasal tip. Respiratory function is not affected.


A rare aortic malformation characterized by the narrowing of the aorta lumen (close to its origin) associated or not with stenosis of other arteries (branch pulmonary arteries, coronary arteries). This narrowing of the aorta or pulmonary branches may impede blood flow, resulting in heart murmur and ventricular hypertrophy (left ventricle in case of aorta involvement, right ventricle in case of pulmonary artery involvement).

Summary:
Epidemiology
The incidence of supravalvular aortic stenosis (SVAS) is estimated at approximately 1 in 25 000 births and the mean prevalence in the general population at 1/7 500.
Clinical description
Clinical manifestations of SVAS include ejection systolic murmur and, in some cases, symptoms of chest pain or syncope. The electrocardiogram may indicate signs of a repolarisation disorder at rest and/or signs of ischemia after a stress test.
Etiology
The narrowing results from a thickening of the artery wall, which is not related to atherosclerosis. SVAS is caused by a mutation in the elastin gene (ELN), which is located on chromosome 7q11.23. In nearly all cases, ELN mutations disrupt elastin protein synthesis, resulting in a production deficit.
Diagnostic methods
The discovery of a systolic murmur may prompt a cardiological examination, potentially showing ventricular hypertrophy. Echocardiogram may indicate a progressive ''hourglass'' narrowing of the aorta and/or pulmonary artery lumen, specific to SVAS. Angiography by retrograde femoral arterial catheterization would allow a more precise diagnosis but it may be associated with risk if the stenosis is significant. Thus, in such cases scanning is preferred. CT scan can show the location and the severity of aorta narrowing.
Differential diagnosis
SVAS can be part of the Williams-Beuren syndrome caused by microdeletion of the 7q11-q23 region, including the elastin and many contiguous genes. SVAS associated with Williams-Beuren syndrome is identical to isolated SVAS, however Williams-Beuren syndrome is also associated with a characteristic face, behavioral disorders and hypercalcemia.
Antenatal diagnosis
In a family affected by SVAS, the progressive nature of the disease makes the identification of mutation carriers important for follow-up. Prenatal ultrasound examination can allow detection of the aortic or pulmonary supravalvular stenosis.
Genetic counseling
Except for the cases with Williams-Beuren syndrome, the disease is either sporadic or familial. In familial cases it is transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity within members of the same family.
Management and treatment
Regular follow-up is recommended (every 6 months for infants and each year in children) in order to monitor the evolution of the stenosis, which can be removed by surgery. Surgical repair is indicated only for significant stenosis.
Prognosis
The prognosis of SVAS depends on the severity of the lesion and on potential associated anomalies located on the aortic valve or coronary arteries. Predictors of worse outcomes and frequent surgical intervention are the presence of diffuse lesions compared to discrete stenosis or presence of associated aortic valve disease.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Sylvie DI FILIPPO


SURF1-related Charcot-Marie-Tooth disease type 4

A subtype of Charcot-Marie-Tooth disease type 4 characterized by childhood onset of severe, progressive, demyelinating sensorimotor neuropathy manifesting with distal muscle weakness and atrophy of hands and feet, distal sensory impairment (vibration and pinprick) of lower limbs, lactic acidosis, areflexia and severely reduced motor nerve conduction velocities (25 m/s or less). Patients may also present kyphoscoliosis, nystagmus, hearing loss, cerebellar ataxia and/or brain MRI abnormalities (putaminal and periaqueductal lesions).


A rare systemic or rheumatologic disease characterized by the triad of central nervous system (CNS) dysfunction, branch retinal artery occlusions (BRAOs) and sensorineural hearing loss (SNHL) due to autoimmune-mediated occlusions of microvessels in the brain, retina, and inner ear.

Summary:
Epidemiology
Susac syndrome (SuS) prevalence is still unknown. To date more than 500 cases have been reported worldwide. Young females (20-40 years) are more affected (female: male ratio 3.5:1). The age at onset ranges from 8 to 72 years (mean age: 32 years).
Clinical description
Characteristic is a triad of encephalopathy (cognitive and behavioral disturbances, personality changes, psychosis, preceding headaches) and/or focal CNS dysfunction, visual dysfunction due to BRAO and SNHL. The components of the triad may not be concomitantly present and may develop successively. Three major disease courses have been suggested: monocyclic (fluctuating disease that self-limits after a maximum period of 2 years), polycyclic (relapses that continue beyond a 2 years period) and chronic-continuous.
Etiology
The etiology and precise pathophysiology are not yet clear. According to recent data, clonally expanding autoreactive cytotoxic CD8+ T cells cause inflammation-mediated injury of the microvascular endothelium which leads to swelling of endothelial cells, vessel occlusion in the affected organ and finally micro-ischaemic damage and dysfunction.
Diagnostic methods
The diagnosis is based on the demonstration of the typical triad. There is no singular ''marker'' of SuS. Beside the clinical examination, most relevant diagnostic tools are brain magnetic resonance imaging (MRI), retinal fluorescein angiography (FA), and audiometry. In the acute phase, T2 weighted brain MRI often shows blurry lesions in the central fibers of the corpus callosum (''snowball lesions'') which later convert into sharply defined ''punched out'' lesions. Periventricular lesions and involvement of cerebellum, brain stem and deep grey matter nuclei are also often present. FA demonstrates BRAO and fluorescein leakage, often in the retinal periphery (may then be clinically silent). Audiometry analysis reveals uni- or bilateral SNHL. Cerebrospinal fluid analysis often shows mild pleocytosis and moderate protein elevation, oligoclonal bands are uncommon. Anti endothelial cell antibodies have been reported in some cases. An early and reliable diagnosis is facilitated by application of the validated diagnostic criteria of the European Susac Consortium (EUSAC).
Differential diagnosis
Inflammatory demyelinating CNS disease (such as multiple sclerosis, acute disseminated encephalitis, neuromyelitis optica spectrum disorders), autoimmune encephalitis, and various other diseases involving CNS, retina, and inner ear (including infections, malignancies, psychotic disorders, cerebrovascular disease, migraine, Meniere disease, isolated BRAO) and a variety of autoimmune diseases such as Cogan syndrome, Eales disease, autoimmune inner-ear disease, polyarteritis nodosa, Wegener granulomatosis, Churg-Strauss syndrome, systemic lupus erythematosus, antiphospholipid syndrome, Sjögren syndrome and Behçet disease.
Management and treatment
No evidence-based treatment strategies exist. Empirically, pulsed glucocorticosteroid treatment is effective in the acute phase. In severe cases treatment may be complemented by cyclophosphamide and/or intravenous immunoglobulins (ivIG), methotrexate (MTX), azathioprine (AZA) or mycophenolate mofetil (MMF). After stabilization glucocorticosteroids should be very slowly tapered. Long term immunosuppressive treatment by MTX, AZA, MMF, and/or ivIG is usually necessary. More recently, positive experiences have been reported with monoclonal antibodies such as rituximab, natalizumab, and infliximab. Patients with severe hearing loss may benefit from cochlear implants.
Prognosis
The disease usually self-limits after 2-4 years, Late relapses after decades have been reported. The final outcome shows a large variability of disability ranging from unimpairment to dementia, deafness and blindness. The majority of patients retains variable degrees of cognitive, visual and/or hearing deficits.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Jan-Markus DÖRR


Susceptibility to infection due to TYK2 deficiency

A rare primary immunodeficiency characterized by increased susceptibility to intracellular bacterial and viral infection, with or without increased serum IgE. Clinical manifestations are highly variable, depending on the infection type and location, and can include recurrent otitis, sinusitis, pulmonary and cutaneous infections, meningitis and internal abscesses.


Susceptibility to localized juvenile periodontitis

A rare functional neutrophil defect characterized by increased susceptibility to aggressive periodontitis in otherwise young, healthy individuals, due to impaired polymorphonuclear leukocyte chemotaxis toward bacterial formylpeptides. The periodontitis is rapidly progressive with progredient destruction of periodontal tissue and attachment loss.


Susceptibility to respiratory infections associated with CD8alpha chain mutation

A rare primary immunodeficiency due to a defect in adaptive immunity characterized by the absence of CD8+ T cells with normal immunoglobulin and specific antibody titres in blood and susceptibility to recurrent respiratory bacterial and viral infections. Symptom severity range from fatal respiratory insufficiency to mild or asymptomatic phenotypes.


Susceptibility to viral and mycobacterial infections due to STAT1 deficiency

A rare, genetic, primary immunodeficiency due to a defect in innate immunity disorder characterized by impaired intracellular signaling from both type I and type II interferons, leading to early-onset, severe, life-threatening intracellular bacterial (typically mycobacteria) and viral (mainly herpes viruses) infections.


A rare inflammatory disease characterized by abrupt appearance of painful, edematous and erythematous papules, plaques and nodules on the skin, and frequently accompanied by fever and neutrophilia with a dense infiltration of mature neutrophils that are typically located in the upper dermis. The disease is classically associated with inflammatory disease, pregnancy, infection (mostly of the upper respiratory tract), or vaccination but may be idiopathic, associated with a hematological or visceral malignancy, or drug-induced.

Summary:
Epidemiology
Several hundred cases of Sweet syndrome have been published.
Clinical description
Classical Sweet syndrome (CSS) usually presents in women between the age of 30 and 50 years. It is often preceded by an upper respiratory tract infection and may be associated with inflammatory bowel disease. It is characterized by the abrupt onset of painful erythematous plaques or nodules, but pustules and bullae are also described. Fever is observed in 30 to 80% of cases. Approximately one-third of patients with CSS experience recurrence of the dermatosis. Malignancy-associated Sweet syndrome (MASS) can occur as a paraneoplastic syndrome in patients with an established cancer or individuals whose Sweet syndrome-related hematologic dyscrasia or solid tumor was previously undiscovered; MASS is most commonly related to acute myelogenous leukemia. The dermatosis can precede, follow, or appear concurrently with the diagnosis of the patient's cancer. Hence, MASS can be the cutaneous harbinger of either an undiagnosed visceral malignancy in a previously cancer-free individual or an unsuspected cancer recurrence in an oncology patient. Drug-induced Sweet syndrome (DISS) most commonly occurs in patients who have been treated with granulocyte-colony stimulating factor, however, numerous medications have also be associated with DISS.
Etiology
The pathogenesis may be multifactorial and still remains to be definitively established. Clinical and laboratory evidence suggests that altered expression of inflammatory effector molecules, abnormal neutrophil function and genetic predisposition have an etiologic role.
Diagnostic methods
Sweet syndrome (SS) is a diagnosis of exclusion and is based on criteria (both of the major and 2 minor criteria are required for diagnosis). Major criteria include 1) abrupt onset of typical cutaneous lesions and 2) histopathology consistent with SS. Minor criteria include 1) lesions preceded by one of the associated infections or vaccinations; accompanied by one of the associated malignancies or inflammatory disorders; associated with drug exposure or pregnancy, 2) presence of fever and constitutional signs and symptoms, 3) leukocytosis, and 4) excellent response to systemic corticosteroids.
Differential diagnosis
Differential diagnosis includes infectious disorders, inflammatory disorders (e.g. arthropod bites, halogenoderma, other neutrophilic dermatoses, Wells syndrome), and neoplastic disorders (e.g. leukemia cutis, lymphoma cutis, metastatic carcinoma).
Management and treatment
Management of SS need to take into account any associated-diseases or medications. Systemic corticosteroids are the therapeutic gold standard. After initiation of treatment with systemic corticosteroids, there is a prompt response consisting of dramatic improvement of both the dermatosis-related symptoms and skin lesions. Topical application of high potency corticosteroids or intralesional corticosteroids may be used for treating localized lesions. Other first-line oral systemic agents are potassium iodide and colchicine. Second-line oral systemic agents include indomethacin and dapsone. TNF alpha inhibitors and the IL-1 receptor antagonist (anakinra) have been used in case reports.
Prognosis
The symptoms and lesions may resolve spontaneously, without any therapeutic intervention; however, recurrence may follow either spontaneous remission or therapy-induced clinical resolution.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Emmanuel DELAPORTE


Symbrachydactyly of hands and feet is a rare, non-syndromic limb reduction defect disorder characterized by unilateral or bilateral brachydactyly, cutaneous syndactyly and global hypoplasia of the hand and/or foot, with underlying muscles, tendons, ligaments and bones being affected but without other associated limb anomalies. Patients typically present short, stiff, webbed or missing fingers and/or toes which are often replaced with small stumps (nubbins) with residual nails.


Symmetrical thalamic calcifications are clinically distinguished by a low Apgar score, spasticity or marked hypotonia, weak or absent cry, poor feeding, and facial diplegia or weakness.

Summary:
Epidemiology
It is an extremely rare condition, with about 30 cases described in the literature.
Diagnostic methods
The calcifications are revealed by computed tomography scanning.
Prognosis
The prognosis is very poor.

                            Last update:
                            July 2006


Sympathetic ophthalmia (SO) is a bilateral granulomatous anterior uveitis usually occurring within the three months following trauma or a surgical procedure involving one eye.

Summary:
Epidemiology
SO is reported to affect between 1/1000 and 1/1650 individuals with a history of a penetrating eye wound.
Clinical description
Patients present with pain, photophobia, paresis of accommodation, metamorphopsia and mild to significant visual loss. The granulomatous anterior uveitis is accompanied by posterior segment findings including moderate to severe vitritis, choroiditis, papillitis, perivasculitis, and yellow-white lesions of the retinal pigment epithelium (Dalen-Fuchs nodules). The inflammation can lead to serous retinal detachment and macular edema. Extraocular symptoms include headache, meningitis or cerebrospinal fluid pleocytosis, hearing loss, poliosis and vitiligo.
Etiology
The etiology of SO is not completely understood. The inflammation is caused by a cell-mediated immune mechanism and autoimmune inflammatory response directed against ocular self-antigens released after the initial injury. The nature of these self-antigens remains controversial. Bacterial infection may potentiate the development of SO and genetic factors may also be implicated as associations with specific major histocompatibility antigens (HLA-DR4, HLA-A11 or HLA-B40) have been reported. SO may occur after ocular trauma (47 to 65 % of patients) or contusions. Wounds involving the ciliary body are associated with the highest risk. Surgical interventions may also trigger SO, with posterior segment surgery carrying a higher risk than anterior segment surgery.
Diagnostic methods
Diagnosis of SO is mainly based on patient history and clinical presentation. Imaging studies (fluorescein or indocyanine green angiography, B-scan ultrasonography and optical coherence tomography) may be useful to confirm the diagnosis.
Differential diagnosis
Laboratory analysis can be performed to eliminate infectious uveitis. When a history of trauma has been confirmed, endophthalmitis and other forms of post-traumatic uveitis (lens-induced uveitis, post-traumatic iridocyclitis) should be included in the differential diagnosis. Other diseases associated with granulomatous uveitis, including sarcoidosis and Vogt-Koyanagi-Harada syndrome (see these terms) or uveal effusion syndrome, may also be considered in the absence of a recognized history of ocular trauma.
Management and treatment
Prompt and careful closure of all wounds decreases the risk of SO. The primary treatment is high doses of steroids (for a minimum of 3 months), followed by a taper according to the inflammatory response and maintenance therapy for 6-12 months after resolution. Immunomodulators (cyclophosphamide, azathioprine or cyclosporine) may be considered when the inflammation cannot be controlled by steroids alone. Surgical treatment remains controversial and enucleation or evisceration should only be proposed in cases of blindness or pain in the inciting eye as the visual prognosis of the sympathizing eye is variable. Late enucleation has not been shown to be beneficial.
Prognosis
Without treatment, the visual prognosis is poor with SO leading to bilateral blindness. However, prompt wound closure and efficient medical treatment improve the visual prognosis, which may then be relatively good. However, relapses and complications may occur and long-term follow-up is required.

                            Last update:
                            March 2009

                            - Expert reviewer(s):
                            Dr Christophe ORSSAUD


Symphalangism with multiple anomalies of hands and feet is a rare, genetic, congenital limb malformation disorder characterized by bilateral symphalangism of hands and feet associated with cutaneous syndactyly of digits II-V, unilateral or bilateral brachydactyly type D (i.e. short, broad terminal phalanges of the thumbs), clinodactyly of fifth toes and/or mild hypoplasia of the thenar and hypothenar eminences. There have been no further descriptions in the literature since 1981.


Symptomatic form of Coffin-Lowry syndrome in female carriers

A rare X-linked syndromic intellectual disability which in symptomatic, female carriers is characterized by a highly variable phenotype including facial dysmorphisms (prominent forehead, hypertelorism, down-slanting palpebral fissures, epicanthic folds, thick lips with everted lower vermilion, thick nasal alae, and septum), short hands with tapering fingers, short stature and skeletal findings (progressive kyphoscoliosis). Intellectual disability is mild to moderate, but intellect can also be normal. A high rate of psychiatric disorders has also been reported.


Symptomatic form of fragile X syndrome in female carriers

A rare genetic disease characterized by a variable clinical phenotype which includes similar features but is typically less severe than in affected males. Patients may present with mild to borderline intellectual disability, anxiety, social phobia, selective mutism, attention deficit hyperactivity disorder, language deficit, neurologic signs and symptoms (such as seizures, hypotonia, and clonus), ophthalmologic anomalies (strabismus, refractive errors), and facial dysmorphism (including long face, prominent forehead, large, prominent ears, and mandibular prognathism).


Symptomatic form of HFE-related hemochromatosis

A rare form of hemochromatosis characterized by inappropriately regulated intestinal iron absorption which leads to excessive iron storage in various organs and manifests with a wide range of signs and symptoms, including abdominal pain, weakness, lethargy, weight loss, elevated serum aminotransferase levels, increase in skin pigmentation, and/or arthropathy in the metacarpophalangeal joints. Other commonly associated manifestations include hepatomegaly, cirrhosis, liver fibrosis, hepatocellular carcinoma, restrictive cardiomyopathy and/or diabetes mellitus.


Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

A rare, genetic muscular dystrophy affecting female carriers and characterized by variable degrees of muscle weakness due to progressive skeletal myopathy, sometimes associated with dilated cardiomyopathy or left ventricle dilation.

Summary:
Epidemiology
The prevalence is unknown. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) primarily affect males and only a small percentage of female carriers have been reported to manifest symptoms of these diseases (24% of female carriers from families with DMD and 19% of female carriers from families with BMD).
Clinical description
Symptomatic female carriers usually present later than males with DMD or BMD. The muscle weakness is generally less severe than in affected males and is usually proximal and, unlike males, has an asymmetric distribution. The upper limbs may be weaker than the lower limbs. Myalgia and cramps have also been reported. The serum creatine kinase level is raised. Some patients may present with cardiac manifestations alone.
Etiology
DMD and BMD are both X-linked recessive diseases and are caused by dystrophin deficiency in skeletal and heart muscles due to variants in the DMD gene (Xp21.2). Females with clinical features of DMD and BMD are usually carriers of X-chromosome rearrangements and display skewed X-inactivation.
Diagnostic methods
Diagnosis can be confirmed by molecular testing of the DMD gene (Xp21.2-p21.1). Muscle biopsy shows a mosaic pattern of dystrophin expression.
Differential diagnosis
Differential diagnoses includes Turner syndrome.
Genetic counseling
The pattern of inheritance is X-linked and genetic counseling should be offered to affected families. Female siblings of a proband with DMD or BMD have a 50% risk of being carriers. Female offspring of a female carrier have a 50% risk of becoming a carrier, male offspring have 50% of inheriting DMD or BMD depending on the mutation. In female carriers, the penetrance of symptoms is variable; most carriers are asymptomatic.
Management and treatment
Management of symptomatic patients should be multidisciplinary, severely affected patients may require treatment with corticosteroids as in DMD. Physiotherapy and orthotics should be used to prevent joint contractures. Respiratory function should be monitored regularly and nocturnal hypoventilation treated with BiPAP (bilevel positive airway pressure). There should be regular cardiac monitoring of all female carriers of BMD and DMD, symptomatic and asymptomatic, with early treatment using ACE inhibitors and or beta-blockers.
Prognosis
Female carriers of DMD and BMD have been shown to be at increased risk of developing dilated cardiomyopathy, although the impact on survival is uncertain.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN


A rare non-syndromic syndactyly characterized by complete or partial webbing between the 3rd and 4th fingers and/or the 2nd and 3rd toes. Other digits may be involved occasionally. The phenotype varies widely within and between families, sometimes only the hands are affected and sometimes only the feet. Webbing between fingers may be associated with bony fusion of the distal phalanges.


A rare non-syndromic syndactyly characterized by a distinctive combination of syndactyly and polydactyly, generally affecting the 3rd and 4th fingers and the 4th and 5th toes, bilaterally, with partial or complete reduplication of a digital ray within the syndactylous web. Additional features include 5th finger clinodactyly, camptodactyly and/or brachydactyly.


A rare non-syndromic syndactyly characterized by complete and bilateral syndactyly between the 4th and 5th fingers. In most cases, it is a soft tissue syndactyly, but occasionally the distal phalanges may be fused. The middle phalanx of the fifth finger is usually hypoplastic, and the feet are not affected.


A rare non-syndromic syndactyly characterized by complete bilateral cutaneous fusion of all fingers, frequently associated with polydactyly (usually involving six digits and six metacarpals). Phalanges may fuse as a conglomerate mass of bones. Feet are occasionally affected.


A rare non-syndromic syndactyly characterized by soft tissue syndactyly of the 3rd and 4th fingers and the 2nd and 3rd toes associated with metacarpal and metatarsal fusion of the 4th and 5th digits. Shortening of fused metacarpals, ulnar deviation of fingers, interdigital cleft, camptodactyly, short distal phalanges, and absent distal interphalangeal creases have also been reported.


A rare non-syndromic syndactyly characterized by unilateral fusion of 2nd to 5th fingers, amalgamation of distal phalanges in a knot-like structure, and fusion of the 2nd and 3rd toe. Some individuals present only with webbing between the 2nd and 3rd toes, without involvement of fingers.


A rare non-syndromic syndactyly characterized by unilateral or bilateral fusion of the 4th and 5th metacarpals with no other associated abnormalities. Patients present shortened 4th and 5th metacarpals with excessive separation between their distal ends, resulting in marked ulnar deviation of the little finger and an inability to bring the 5th finger in parallel with the other fingers.


Syndactyly-camptodactyly and clinodactyly of fifth fingers-bifid toes syndrome

A rare, genetic, congenital limb malformation syndrome characterized by a unique combination of bilateral, symmetrical camptodactyly and clinodactyly of 5th fingers, mesoaxial camptodactyly of toes, and ulnar deviation of 3rd fingers. Additional variable manifestations include bifid toes and severe syndactyly, or synpolydactyly, involving all digits of hands and feet.


Syndactyly-nystagmus syndrome due to 2q31.1 microduplication

A rare, genetic, chromosomal anomaly syndrome resulting from partial duplication of the long arm of chromosome 2 characterized by congenital pendular nystagmus associated with bilateral cutaneous syndactyly between the third and fourth fingers.


A rare, genetic, congenital limb malformation syndrome characterized by complete cutaneous syndactyly between toes 1-2, ulnar polydactyly (ranging from nubbins to an almost complete additional finger) and earlobe malformations. Additionally, abnormalities along the medial border of the foot are observed on X-ray imaging. There have been no further descriptions in the literature since 1976.


Syndactyly-telecanthus-anogenital and renal malformations syndrome

A rare malformation syndrome characterized by the association of toe syndactyly, facial dysmorphism including telecanthus (abnormal distance between the eyes) and a broad nasal tip, urogenital malformations and anal atresia.


Syndrome with alpha-thalassemia as a major feature

This term refers to a group of diseases characterized by alpha-thalassemia and an associated disorder. Three conditions are included in this group: alpha thalassemia - X-linked intellectual deficit (or ATR-X syndrome), alpha-thalassemia-intellectual deficit syndrome (or ATR-16 syndrome) and alpha-thalassemia-myelodysplastic disease (or ATMDS).


A rare, genetic, syndromic intestinal disorder, characterized by congenital onset of severe watery diarrhea containing high concentrations of sodium, hyponatremia and metabolic acidosis, and generally, uni- or bilateral choanal atresia, and corneal erosions. Additional congenital malformations may include intestinal atresia, and hexadactyly.

Summary:
Epidemiology
Whilst the prevelence is unknown, less than 50 cases of both the syndromic and non-syndromic form have been reported in the literature.
Clinical description
Presentation is typically prenatal with polyhydramnios, prominent abdominal distension due to dilated fluid-filled loops of the intestine. A watery diarrhea is present after birth, independent of oral feeding (breast or formula) or nil by mouth. There are increased bowel sounds at examination, and passing of meconium is never reported. The infants become irritable and eventually apathetic, and develop moderate to severe dehydration. Rarely, there is no watery diarrhea noticed either due to severe dehydration or intestinal paralysis. This pseudo-obstruction is caused by dilated fluid-filled loops of intestine, which may result in volvulus, and requires abdominal surgery. Laboratory findings include high stool sodium levels (importantly, this can be normal when the depletion of body sodium has progressed for some time) and low serum sodium levels, metabolic acidosis and alkaline fecal pH, and low urinary sodium excretion. Histological findings reveal characteristic epithelial tufts, small crowding of enterocytes, which are often hard to find. Generally, uni- or bilateral chonal atresia is observed at birth, and most often, episodes of corneal erosions are seen. Additional congenital malformations are observed in some patients, most often intestinal atresia, and hexadactyly. In the case of unrecognized bilateral choanal atresia, aspiration and breathing difficulties can occur postnatally, in addition to the congenital diarrhea; the congenital diarrhea can go unrecognized (as the diarrhea is mistaken for urine), and severe dehydration can occur within the first days of life.
Etiology
The disorder is due to homozygous or compound-heterozygous mutations in serine peptidase inhibitor, Kunitz type 2 (SPINT2; encoded by SPINT2, 19q13.2), resulting in abrogated sodium absorption, enhanced fluid secretion and diarrhea.
Diagnostic methods
Diagnosis is suspected on clinical presentation and exclusion of the differential diagnosis. Initial diagnosis might include determination of fecal sodium, chloride and potassium. Separate sampling of watery stool and urine should be performed. Diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes the non-syndromic (classical) form of congenital sodium diarrhea (due to NHE3 or GUCY2C mutations) which is typically distinguished by the absence of congenital malformations or corneal erosions. Other differential diagnoses include anatomical bowel obstruction, congenital chloride diarrhea (distinguished by excessive fecal chloride), glucose-galactose malabsorption (which exhibits a diet-induced dehydrating diarrhea with later onset), microvillus inclusion disease and congenital tufting enteropathy (distinguished by histopathology).
Antenatal diagnosis
Diagnosis may be suspected on presentation of polyhydramnios in the third trimester. Early, targeted genetic prenatal testing is possible after identifying disease-causing variants in an index patient; however, general concerns to sampling fetal material and diagnosing genetic conditions late in pregnancy would apply.
Genetic counseling
The pattern of inheritance is autosomal recessive (AR) for SPINT2 mutations. The risk of disease transmission to offspring for AR disease is 25% where both parents are unaffected carriers.
Management and treatment
After birth, total parenteral nutrition for treatment of dehydration for at least several months is required. Sodium supplementation should be provided for treatment of severe dehydration and to maintain normal body growth by preventing total body sodium depletion. In certain cases, patients may be weaned off total parenteral nutrition. For monitoring adequate sodium supplementation, the fractional excretion of sodium (FENa) should be calculated (normal range reportedly between 0.5%-1.5%). Choanal atresia and anal intestinal atresia require surgical treatment.
Prognosis
Total parenteral nutrition carries the risk of bacteremia, and the risk of acute liver failure in very young children. Affected individuals may continue to have mild-to-moderate watery diarrhea but otherwise tend to lead a normal life. Reported complications include growth delay and hypoaldosteronism. Some patients episodically develop corneal erosions which are associated with pain and visual disturbances, and are treated with hydrating eye drops.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Andreas JANECKE


A rare gastroenterologic disease manifesting as intractable diarrhea in the first month of life with failure to thrive and associated with facial dysmorphism, hair abnormalities, and, in some cases, immune disorders and intrauterine growth restriction.

Summary:
Epidemiology
Syndromic diarrhea (SD/THE) prevalence is <1/1,000,000. More than 100 cases have been reported worldwide.
Clinical description
Severe, persistent and intractable diarrhea most often starts within the first month after birth (at latest 6 months) and is accompanied by severe malabsorption resulting in early and relentless protein-energy malnutrition and failure to thrive. SD children in most reported cases (>70%) were below the 10th percentile of birth weight and nearly half were born preterm suffering from intrauterine growth restriction. Patients present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hair is woolly, easily removable and in some cases sparse and poorly pigmented; further analysis reveals trichorrhexis nodosa, pili torti, trichothiodystrophy and aniso- and poikilotrichosis. Liver disease, with extensive fibrosis or cirrhosis and siderosis, affects about half of the patients, and hepatomegaly may be observed. Patients are prone to frequent infections and may fail to produce antibodies upon vaccination or present low immunoglobulin levels. Skin abnormalities including café au lait spots, xerosis and rubbery skin are seen in half of the reported cases and are more prevalent with time. Cardiac abnormalities have been reported in a few cases and mild intellectual deficiency in half of patients.
Etiology
Autosomal recessive mutations in SKIV2L (40% of cases) and TTC37 (60% of cases) lead to SD/THE. These genes encode proteins that form the Ski complex, a group of proteins responsible for the 3'-5' degradation of aberrant mRNA. Many different mutations have been identified and are spread along the genes. How Ski complex defects lead to the observed phenotype has yet to be elucidated and no genotype/phenotype correlation has been established to date.
Diagnostic methods
Diagnosis is suggested by clinical features. Small intestine biopsy shows non-specific villous atrophy with variable mononuclear cell infiltration of the lamina propria, but no specific histological abnormalities involving the epithelium. Genetic testing confirms these observations.
Differential diagnosis
Differential diagnoses include all causes of chronic diarrhea, copper and iron deficiencies due to malnutrition, intestinal epithelial dysplasia, and microvillus inclusion disease.
Antenatal diagnosis
Antenatal diagnosis should be offered to the parents of an affected child once the molecular defect has been characterized.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Intractable diarrhea requires parenteral nutrition during a variable period of time ranging from a few months to over a decade. In some cases, the association of enteral with parenteral nutrition can be indicated. Immunoglobulin supplementation may be necessary and antibody production after vaccination should be monitored. Finally, some children can present with a severe liver disease, independent of parenteral nutrition, but which could be worsened by it. In cases of severe liver disease, the only therapeutic option is a liver graft.
Prognosis
Prognosis is poor with a mortality rate of up to 50%. The main complications are severe liver disease and infections. Some patients are rapidly weaned off parenteral nutrition but others remain under parenteral dependence for more than 10 years. Most of the children achieve a small final stature and half manifest mild intellectual deficit.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Catherine BADENS  - Dr Alexandre FABRE


Syndromic microphthalmia, type 5 is characterized by the association of a range of ocular anomalies (anophthalmia, microphthalmia and retinal abnormalities) with variable developmental delay and central nervous system malformations.

Summary:
Epidemiology
Less than 20 cases have been reported in the literature so far.
Clinical description
The clinical picture is highly variable, even between affected members of the same family. Ocular findings ranged from bilateral anophthalmia, to severe or mild bi- or unilateral microphthalmia and retinal dystrophy. MRI may reveal optic nerve aplasia/hypoplasia, hippocampal malformations, structural abnormalities of the pituitary gland, and agenesis of the corpus callosum. Severe developmental delay was noted in some patients, whilst others showed normal cognitive development. Pituitary dysfunction, leading to growth hormone deficiency and short stature, or combined pituitary hormone deficiency (CPHD), has also been reported.
Etiology
The syndrome is caused by heterozygous mutations in the OTX2 gene (14q22.3).
Differential diagnosis
A similar phenotype with bilateral anophthalmia and pituitary abnormalities (with additional findings of limb defects, ear anomalies and facial dysmorphism) is found in patients carrying a deletion encompassing the OTX2 gene. Patients with the full clinical spectrum of ocular anomalies, central nervous system abnormalities and pituitary abnormalities also show significant overlap with septooptic dysplasia (see this term).

                            Last update:
                            February 2010


Syndromic multisystem autoimmune disease due to Itch deficiency

A rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland.


Syndromic orbital border hypoplasia is a rare disorder observed in two families to date and characterized by agenesis of the orbital margin, varying defects of the lacrimal passages, hypoplasia of the palpebral skin and tarsal plates and atresia of the nasolacrimal duct.


A rare genetic skin disease belonging to the Mendelian Disorders of Cornification (MeDOC) characterized by a generally mild cutaneous desquamation in association with extracutaneous manifestations as part of a syndrome.

Summary:
Epidemiology
The prevalence of syndromic RXLI is estimated at 1/50,000-1/150,000. It affects almost exclusively males.
Clinical description
Cutaneous manifestations include generalized scaling of the skin commonly more pronounced on the extensor surfaces of the limbs (mostly lower extremities). Non-cutaneous manifestations may include cryptorchidism, attention-deficit and hyperactivity disorder (ADHD), and corneal opacity. Manifestations due to contiguous gene syndrome include neurological abnormalities such as epilepsy and hyposmia, intellectual disability and/or short stature. This mechanism can be observed in Kallmann syndrome, hypergonadotropic hypogonadism, ocular albinism type 1, or hypertrophic pyloric stenosis.
Etiology
RLXI is due to deletions in the steroid sulfatase STS gene located on chromosome Xp22.3. STS codes for a lipid hydrolase that participates in the regulation of permeability, barrier homeostasis and desquamation. STS mutations result in abnormal desquamation, decreased corneodesmosomal degradation and retention hyperkeratosis.
Diagnostic methods
Diagnosis is based on clinical findings and family history (scaling in male relatives, history of delayed birth). It is confirmed by biochemical analysis such as serum protein electrophoresis, and STS activity test of fibroblasts or leukocytes, and molecular/cytogenetic analyses such as polymerase chain reaction (PCR), multiple ligation-dependent probe amplification (MLPA), comparative genomic hybridization/comparative microarray analysis (CMA), and fluorescent in situ hybridization (FISH). Histology and ultrastructure of the skin is helpful for the differentiation of ichthyosis vulgaris.
Differential diagnosis
Differential diagnosis includes non-syndromic RXLI, ichthyosis vulgaris, autosomal recessive congenital ichthyosis (ARCI), namely lamellar ichthyosis, or multiple sulfatase deficiency.
Antenatal diagnosis
Maternal urine and serum steroid measurements may show decreased estrogen levels. Therefore, RXLI may be detected in utero when maternal estriol levels are measured during prenatal screening. Genetic analysis can be performed for families with an identified causing mutation.
Genetic counseling
XLRI has an X-linked recessive mode of inheritance: it affects males and is inherited through female carriers. Female patients have rarely been reported.
Management and treatment
Cutaneous therapy consists in hydrating and softening the skin with the use of lubricating bath oils and emollients containing humectants and keratolytics (e.g. urea, lactic acid, and glycolic acid). For adult patients, systemic retinoids are an option, e.g. during winter, when the ichthyosis is generally more severe. Additional supportive treatments should be proposed depending on systemic findings.
Prognosis
RXLI represents a complex form of ichthyosis whose prognosis depends on the systemic involvement (central nervous system and cognitive impairment are variable). Scaling may improve with age.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Dr Ángela HERNÁNDEZ MARTÍN


Syndromic sensorineural deafness due to combined oxidative phosphorylation defect

A rare mitochondrial disease characterized by a variable phenotype comprising congenital sensorineural deafness, intermittent or persistent hypoglycemia, and hepatic and renal dysfunction potentially progressing to organ failure. Serum lactate levels are variably increased, deficiency of mitochondrial respiratory chain complexes I, III, and IV is observed in the liver and in fibroblasts.


Syndromic X-linked intellectual disability 7

A rare, X-linked syndromic intellectual disability disorder characterized by mild to moderate intellectual disability, obesity, hypogonadism, tapering fingers and microphallus with small or undescended testes, localized to Xp11.3-Xq23. Additional variable manifestations include alopecia, dental and eyesight anomalies, speech disabilities, and decreased body strength.


SYNGAP1-related developmental and epileptic encephalopathy

A rare genetic developmental and epileptic encephalopathy (DEE) characterized by developmental delay, generalized epilepsy consisting of eyelid myoclonia with absences and myoclonic-atonic seizures, intellectual disability and autism spectrum disorder (ASD).

Summary:
Epidemiology
This disorder has an estimated prevalence of <1/1 000 000.
Clinical description
Presentation is of developmental delay, identified in the first months of life, associated with hypotonia and subsequent neurodevelopmental plateauing or regression. Generalized epilepsy is present in most with seizure onset typically at 2-3 years (ranges from 4 months to 7 years) with a distinctive epilepsy syndrome, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Drop attacks due to eyelid myoclonia evolving to myoclonic-atonic or atonic seizure can be present. Other generalized seizure types, variably combined, and reflex seizures triggered by eating or eyes closure may occur. The spectrum of seizure severity varies, with drug-resistant seizures in about half of patients. Moderate to severe intellectual disability becomes progressively evident in most, associated with ASD in about half of the patients. Behavioral disorders, including oppositional and defiant behavior with aggression, self-injury, and temper tantrums, are seen in most. Subtle dysmorphic facial features may be present in some, including slightly prominent eyebrows with medial flaring, hypertelorism, full nasal tip, slightly upturned nasal tip, short philtrum, cupid bow upper lip, broad mouth with diastemata of the upper teeth, and small pointed chin. Other associated features comprise high pain threshold, eating and sleeping problems, ataxia or gait abnormalities, and orthopedic abnormalities. Brain imaging is usually normal with possible nonspecific findings.
Etiology
The SYNGAP1 gene (6p21.32) encodes the synaptic Ras-GTPase-activating protein 1, mainly expressed in the synapses of excitatory neurons. Loss of function mutations in SYNGAP1 impairs neuronal homeostasis and development. This disorder is caused by heterozygous pathogenc SYNGAP1 variants or chromosome 6p21.32 microdeletions encompassing the SYNGAP1 gene.
Diagnostic methods
The diagnosis is suspected in a patient with developmental delay or intellectual disability, ASD and generalized epilepsy with generalized epileptiform abnormalities on EEG. The genetic identification of pathogenic SYNGAP1 variants (next generation sequencing) or chromosome 6p21.32 microdeletions (aCGH ) confirms the diagnosis.
Differential diagnosis
The phenotype of SYNPAG1-related encephalopathy might overlap with that of other neurodevelopmental disorders and DEEs. Seizures semiology, trigger factors and EEG patterns can help to differentiate this syndrome and orient the genetic testing.
Antenatal diagnosis
Once a pathogenic SYNGAP1 variant has been identified, prenatal testing is possible for a pregnancy at increased risk.
Genetic counseling
The pattern of inheritance is autosomal dominant. Whilst pathogenic variants occur de novo in almost all cases, parental mosaicism is possible. In such cases, genetic counseling is recommended as the risk of recurrence in affected families is higher than the general population.
Management and treatment
Management requires a multidisciplinary approach and tailored treatments addressing the specific symptoms. Anti-seizure medications and ketogenic diet are used for the management of seizures. Non-pharmacological interventions comprise physical, occupational, speech, and feeding therapy, as well as individualized educational plans.
Prognosis
Life expectancy is unknown due to under diagnosis in adult age. However, adult patients are known, demonstrating that survival into adulthood is possible. Prognosis is poor, resulting in severe cognitive deficits in most, associated with behavioral disorders of variable degree, and persisting seizures in half of the cases.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Sara MATRICARDI  - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


Synovial sarcoma is an aggressive soft tissue sarcoma (see this term), occurring most commonly in adolescents and young adults (15 to 40 years), usually localized near the large joints of the extremities but also in the head and neck, mediastinum and viscera (lung, kidney etc), clinically presenting as a deep seated swelling or a painful mass often with an initial indolent course and is characterized by its local invasiveness and a propensity to metastasize. The origin of synovial sarcoma is likely from multipotent mesenchymal cells and not synovium (contrary to its name).


A rare non-malignant adnexal neoplasm that originates from the apocrine or eccrine sweat glands and is characterized histologically by cystic, papillary, and ductal invaginations into the dermis lined by double-layered outer cuboidal and luminal high columnar epithelium and connected to the epidermis. Dilated capillaries and a dense infiltrate of plasma cells are characteristic. Clinically, lesions are asymptomatic with a heterogeneous, non-distinctive appearance ranging from skin-colored to pink papules or plaques, occurring most commonly in the head and neck area.

Summary:
Epidemiology
To date, approximately 730 cases have been reported in the literature. The condition has been reported worldwide.
Clinical description
Syringocystadenoma papilliferum (SCAP) may be present at birth (50% of cases) or develop around puberty (15-30% of cases). SCAP typically presents as slow developing, non-specific, smooth, skin-colored to pink papule, verruca or nodule, which may be exudative. It may also be seen as hairless plaques, smooth or raised, usually less than 4 cm in diameter, skin-colored to brown. It is rarely pigmented. In the majority of cases, it is asymptomatic, but it may grow progressively and has been occasionally associated with pruritus, pain, and/or bleeding. Three clinical types have been described: the plaque type, the linear type and the solitary nodular type. The plaque type usually presents as an alopecia plaque on the scalp which may increase in size at puberty and often transforms to nodular or verrucous lesions. The linear type consists of multiple pink to reddish, firm papules or umbilicated nodules, 1-10 mm in diameter, and is extremely rare. The solitary type includes dome-shaped, pedunculated nodules, 5-10 mm in diameter, with a predilection for the trunk, shoulder and axillae. Rarely, segmental variants are found. In 75% of cases, SCAP is located on the head or cervical region and less frequent in other regions, or on a postoperative scar. SCAP develops in existing nevus sebaceous in about one-third of cases, 10% of which are associated with he development of basal cell carcinoma and more rarely other carcinomas. SCAP can also be associated with other benign lesions. Transition to malignancy is rare but, possible. Syringocystadenocarcinoma papilliferum is the malignant counterpart to this lesion and may develop in a long-standing case of SCAP.
Etiology
The etiology of SCAP has not been elucidated. It seems to arise from the pluripotent cells with the potential to exhibit either apocrine or eccrine lineage, although apocrine differentiation is more common. The pathogenesis of SCAP remains unclear although, both in sporadic cases and lesions arising in nevus sebaceous, the human papillomavirus (HPV) DNA and mutations in the RAS/mitogen-activated protein kinase signaling pathway have been detected. BRAF V600E mutation or activating mutations in HRAS (or in one case KRAS) have been reported in sporadic forms.
Diagnostic methods
Diagnosis is suspected on clinical presentation of non-distinctive lesions and confirmed on biopsy showing the characteristic histology. Immunohistochemically, the tumor cells stains positively for carcinoembryonic antigen. Dermatoscopy is not diagnostic.
Differential diagnosis
The differential diagnosis is broad, requiring histological confirmation of cases. The main diagnostic issue is the distinction of SCAP from hidradenoma papilliferum. Other conditions to be considered include basal cell carcinoma, cutaneous lymphoma, factitious dermatitis, viral warts, subcutaneous fungal infection, linear verrucous nevus, pyogenic granuloma, warty dyskeratoma, inverted follicular keratosis, as well as eccrine nevus, nevus comedonicus, cylindroma, and basaloid follicular hamartoma.
Management and treatment
Treatment involves complete surgical excision. However, recurrence is common. Carbon dioxide laser treatment can be useful for lesions in anatomic areas not favorable for excision and grafting. SCAP has also been successfully treated with Mohs micrograhic surgery.
Prognosis
The condition is mostly benign but extensive lesions may have an impact on quality of life and transformation to malignancy cannot be ruled out.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Alexander KATOULIS  - Pr Efstathios RALLIS


A rare medullar disease characterized by cerebrospinal fluid (CSF)-filled cavities (syrinx) inside the spinal cord as a result of an obstruction to CSF flow, either at the craniovertebral junction (Chiari malformation) or in the perimedullary subarachnoid spaces (arachnoiditis).

Summary:
Epidemiology
Estimated prevalence is 8.4/100,000. Cases of autosomal recessive familial syringomyelia have been reported with an estimated incidence of 2% of all syringomyelia cases.
Clinical description
Although syringomyelia can lead to disruption of neural connections in the spinal cord and to neurological damage, 50% of patients (when all types of syrinxes are considered) will experience no or only mild disability. In symptomatic patients, onset is usually marked by pain and sensory disturbances, varying from complete absence of sensation, pins and needles or temperature sensing alterations, to increased sensation to stimuli. Although there are no clear clinical clues at neurological examination, a 'cape-like' sensory dissociation (loss of the ability to distinguish between hot and cold with intact light-touch sensation in the upper limbs and torso), as well as reduced upper limb reflexes, are quite specific initial findings when present. Motor symptoms usually range from varying degrees of weakness to spasticity and loss of autonomy. Alterations in bladder and sexual function may also be present.
Etiology
Syringomyelia is due to obstruction of CSF flow either at the craniovertebral junction (e.g. Chiari malformation) or in the perimedullary subarachnoid spaces (e.g. arachnoiditis). Chiari malformations can be associated with other craniovertebral junction malformations (e.g. basilar invagination) or neural tube defects (Chiari II malformation). Spinal arachnoiditis can be either idiopathic or secondary (postinfectious, posttraumatic, posthemorrhagic, postoperative).
Diagnostic methods
Neurological examination and MRI are required for diagnosis. MRI is the gold standard and reveals a fluid filled cavity with variable degrees of vertical and horizontal extension within the spinal cord ranging from involvement of one level up to extension over the entire spinal cord. The signal characteristics on MRI are usually quite similar to those of CSF.
Differential diagnosis
The differential diagnosis includes persistent or dilated central canal (hydromyelia, slits), myelomalacia, tumoral cysts, myelitis, amyotrophic lateral sclerosis and multiple sclerosis.
Management and treatment
Management consists of long-term follow up and surgery in cases of progressive neurological deterioration. The goal of surgery is to restore CSF flow either at the craniovertebral junction in case of Chiari malformation (foramen magnum decompression) or in the perimedullary subarachnoid spaces in case of arachnoiditis (arachnoidolysis). If not possible, or in case of failure, a shunting procedure can be performed to drain the syrinx, either to the peritoneal space (syringoperitoneal shunt) or pleural space (syringopleural shunt).
Prognosis
Around 50% of Chiari malformation type I patients with syringomyelia remain neurologically stable. In cases with progressive deterioration, surgical intervention usually prevents clinical progression. In cases of posttraumatic syringomyelia due to spinal cord compression, reconstruction of the spinal canal appears to yield similar results. Prognosis is worse for cases in which the only surgical option is direct shunting of the syrinx, as this often leads to neurological deficit and recurrence. Persistent or dilated central canal, which is not a syringomyelia, has a benign natural history with usually no progression neither clinically nor radiologically.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Dr Steven KNAFO  - Dr Silvia MORAR


Systemic capillary leak syndrome (SCLS) is a severe systemic disease due to increased capillary permeability, characterized by episodes of hypotension, edema and hypovolemia.

Summary:
Epidemiology
SCLS has been reported in less than 150 cases since its first description in 1960.
Clinical description
Mean age of onset is 45 and pediatric or geriatric cases are rare. The disease is characterized by alternance of crises and quiescent phases. Delay between crises is a few weeks to several years. They have been reported following infection, mostly of the upper airways, during perimenstrual or post-partum periods and, more rarely, after intense physical effort. They last days or weeks, can be of variable severity, from grade 1 (hypotension responding to oral hydration) to grade 4 (fatal attacks), and have a 3-step evolution. Crises may start with prodromes such as generalized weakness, fatigue, myalgias, orthostatic hypotension, possible digestive (diarrea, abdominal pain) and ENT (rhinorrhea, cough) manifestations, occasional fever and weight gain. The leak phase follows with oliguria, arterial hypotension and rapid development of edema of the face or the upper limbs but sparing the lungs. Hypotension may lead to hypovolemic shock with preserved consciousness. In the post-leak phase, massive edema resorption leads to polyuria and weight loss. Biological features are a characteristic association of hemoconcentration with hypoalbuminemia without albuminuria, hyperleukocytosis and a proteinemia drop in the 350-750 kDa range. Chronic cases have been reported with a continuous generalized edema, visceral effusions, hypotension and hemoconcentration being more subtle. Complications may occur in acute and post-leak phases: in the former, they include compartment syndrome with rhabdomyolysis, cardiac arrythmias, thrombosis, pancreatitis, pericarditis (see this term), seizures, cerebral edema or thickening of the myocardium. Rhabdomyolysis and fatal pericarditis may also occur in the post-leak phase, but cardiovascular overload is more frequent. Fatal acute lung edema has also been reported at this stage. Renal failure may result from hypoperfusion-induced acute tubular necrosis and rhabdomyolysis.
Etiology
SCLS is caused by capillary hyperpermeability of unknown etiology. Several physiopathological hypotheses have been considered such as an inflammation-mediated mechanism or a damage of the capillary endothelium by the monoclonal gammopathy.
Diagnostic methods
Diagnosis is based on physical and biological examination, recurrence of crises, association of hemoconcentration with hypoalbuminemia being strong indicators. The presence of an anomalous monoclonal immunoglobulin termed paraprotein is suggestive but not diagnostic.
Differential diagnosis
Differential diagnosis includes sepsis, anaphylaxis, any other cause of capillary leakage and inferior vena cavainterruption (see this term). Chronic cases might be misdiagnosed as Gleich syndrome, venous stasis, protein-losing enteropathy and nephrotic syndrome.
Management and treatment
There is no curative treatment, thus management is symptomatic and prophylactic. Intravenous fluids administration is not recommended as it fails to increase arterial pressure and worsens edema, furthermore it increases the risk of vascular overload in the post-leak phase. Oral electrolyte-containing fluids can reduce the attack severity if taken early, thus patient education to detect early signs of prodrome is crucial. Beta-adrenergic agonists (terbutaline) and phosphodiesterase inhibitors (theophylline) have shown good results in few cases but have serious side effects; intra-venous immunoglobulines are a promising prophylactic strategy.
Prognosis
Despite progress in diagnosis and management that has prolonged the survival of patients, prognosis remains poor as mortality reaches 30-40% after 10 years.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Pr Zahir AMOURA


Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood

A rare and very aggressive neoplastic disease emerging after a primary acute or chronic active EBV infection. It presents with persisting fever and malaise, hepatosplenomegaly with or without lymphadenopathy, liver failure, severe pancytopenia and a rapid progression towards multi-organ failure and hemophagocytic syndrome with a fatal issue. It is characterized by clonal proliferation of EBV-infected T cells with an activated cytotoxic phenotype.


Systemic mastocytosis with associated hematologic neoplasm

An advanced form of systemic mastocytosis (SM) characterized by the abnormal accumulation of neoplastic mast cells (MCs) in one or more extracutaneous organs, mainly the bone marrow, associated with another hematologic neoplasm of non MC nature.

Summary:
Epidemiology
Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is suggested to represent between 10-40% of all cases of SM, for which the prevalence in Europe is estimated between 1/7,700 and 1/10,400.
Clinical description
The disease typically affects adults and the elderly. Although the SM compartment is predominantly of the indolent type (ISM), in rare cases it is aggressive SM (ASM) or mast cell leukemia (MCL). The associated hematologic neoplasms (AHN) most commonly encountered are myeloid neoplasms and are rarely lymphoid neoplasms.When the SM compartment is indolent, the biological and clinical signs, and the prognosis, are dominated by the AHN. In contrast, when the SM compartment is an ASM or MCL, it is difficult to quantify the relative contribution of mastocytosis to typical B- (reflecting a high mast cell burden) and C- (reflecting organ(s) dysfunction(s)) findings. Of note, the SM compartment is often involved in MC mediator-related symptoms such as recurrent syncope, headache, flushing, gastro-intestinal tract symptoms and, in severe cases, life-threatening anaphylactic shock. Skin involvement, mainly with urticaria pigmentosa (UP) is frequently observed.
Etiology
In the vast majority of cases, an acquired and activating mutation in KIT, mostly KITD816V, can be found in the abnormal MCs of the SM compartment as well as in the malignant cells of certain AHN types. However, SM-AHN is often a complex, multi-mutated disease; reported mutations for SM-CMML or SM-MDS include, TET2, ASXL1, and SRSF2 among others.
Diagnostic methods
It is critical to determine the type of the two malignancies (SM and AHN). Diagnosis of the SM compartment is with the WHO consensus criteria. The SM is then categorized as ISM, ASM or MCL, although this may be difficult. Further testing (phenotyping, cytogenetics, molecular biology) are mandatory to characterize the nature of the AHN.
Differential diagnosis
In the case where the AHN component is of myeloid nature, the two major differential diagnoses are myelomastocytic leukemias and myeloid neoplasms with expression of mast cell lineage antigens or related gene defects. Waldenström macroglobulinemia may be considered in certain circumstances. These diseases do not fulfill the SM criteria.
Genetic counseling
The disease is due to somatic mutations, genetic counseling is not required.
Management and treatment
Each component is treated as per the guidelines for SM and AHN, irrespective of the presence of the other component. Since it is difficult to clearly delineate which component is responsible for the clinical issues/organ damage, all patients with SM-AHN should be treated as having high-risk disease. Midostaurin is approved for treatment in Europe and the USA, and whilst it is promising with partial remission of the SM-compartment, complete remission has not been reported. Patients who achieve a complete remission of their AHN, or exhibit a significant response after treatment, should be considered for allogeneic stem cell transplantation (allo-SCT) to consolidate their response. However, use of allo-SCT is often limited by age, poor performance, or other factors. For these patients, palliative therapy with hydroxyurea is required. MC mediator-related symptoms often requires supportive therapy, including H1 and H2-receptor antagonists.
Prognosis
Currently the overall median survival of 24 months is reported. However, the prognosis of SM-AHN depends both on the nature (aggressiveness) of the SM and the AHN component, with longer median survival reported in SM-MPN patients (31 months) and shorter survival in SM‐CMML (15 months), SM‐MDS (13 months), and SM‐AML (11 months). In addition, multi-mutated disease can negatively impact disease prognosis.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Michel AROCK


A heterogeneous group of rare, acquired and chronic hematological malignancies related to an abnormal accumulation/proliferation of neoplastic mast cells (MCs) in one or several organs, mainly the bone marrow (BM), associated frequently with skin involvement.

Summary:
Epidemiology
The prevalence in Europe is estimated between 1/7,700 and 1/10,400. Systemic mastocytosis (SM) preferentially affects Caucasians and there is no sex predominance.
Clinical description
SM is mainly observed in adults (average age at diagnosis is 60 years) and is very rare in the pediatric population. SM can be divided into five variants: indolent SM (ISM), smoldering systemic mastocytosis (SSM), aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL), the later 3 variants being collectively termed advanced SM (advSM). In ISM, there are no signs of high mast cell burden (B-findings) and no organ dysfunction (C-findings). SSM is a slowly progressive SM with B-findings. By contrast, advSM variants are characterized by (multiple) C-findings.
Etiology
Most patients with SM present activating mutations in KIT, the receptor of the stem cell factor, in their neoplastic MCs. Of note, a recurrent KIT mutation (D816V; exon 17 of the KIT gene) located in the phosphotransferase domain of the receptor is detectable in most patients (> 80% of all SM patients), including those with advSM. Other less frequent mutations affect exons 2, 8, and 9 encoding for the extracellular domain or exons 13 and 14 encoding for Kinase Domain 1 of KIT. Whatsoever, the various KIT mutations encountered in SM result in uncontrolled activation of the receptor, making the migration, survival and activation of MCs independent of stem cell factor.
Diagnostic methods
Consensus criteria for the diagnosis of systemic mastocytosis established by the WHO include one major criterion - the presence of aggregates of at least 15 MCs identified in BM or other extracutaneous organ biopsies (usually revealed after tryptase staining of biopsies) - and four minor criteria: the presence of more than 25% of MCs with atypical morphology in BM smears (spindle-shaped, degranulated and/or multinucleated MCs); aberrant immunophenotype of MCs which frequently abnormally express non-mast cell markers (CD25 and/or CD2); presence of a point mutation in codon 816 of the KIT gene in BM; peripheral blood or other extracutaneous organs; and increased level of serum tryptase (above 20 ng/mL). For diagnosis of SM, at least the major and one minor criterion or at least three minor criteria are fulfilled. The disease is then categorized, as described above, according to the presence of B-findings and C-findings.
Differential diagnosis
Differential diagnoses of SM include all the other causes of mast cell activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy (most cases) or another reactive inflammatory disease process is present (and is considered to be the causative etiology); and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. As well, differential diagnoses include other forms of mastocytosis (cutaneous mastocytosis, mast cell sarcoma), endocrine disorders (adrenal tumors, VIPoma,, Zollinger-Ellison syndrome), some gastrointestinal pathologies, allergies, other myeloproliferative diseases that affect bone marrow, histiocytosis, hypereosinophilic syndrome and Waldenström macroglobulinemia.
Genetic counseling
SM is usually a sporadic disease, although a few familial cases have been reported so far, for which no genetic counseling is available.
Management and treatment
Management depends on the type of SM. Treatment of ISM and stable SSM is typically symptomatic (antihistamines, corticosteroids or disodium cromoglyylcate). For advanced SM treatment is symptomatic (antihistamines anti-H1 and H2) and antiproliferative with non-targeted (e.g interferon alpha) or targeted cytoreductive therapy with KIT tyrosine kinase inhibitors. Hydroxyurea (HU) is given in patients with SM-AHN. Allogeneic stem cell transplantation (allo-SCT) is rarely used and reserved for fit patients with very aggressive, life-threatening advSM and a suitable donor.
Prognosis
Prognosis depends on the type of SM.

                            Last update:
                            July 2019

                            - Expert reviewer(s):
                            Pr Michel AROCK


Systemic monochloroacetate poisoning is a rare, life-threatening intoxication with monochloroacetic acid (mainly through the skin, but also by inhalation or ingestion). It is characterized by vomiting, diarrhea and central nervous system (CNS)-excitability (disorientation, delirium, convulsions) as early signs of systemic poisoning, followed by CNS-depression, coma and cerebral edema. Additional signs include heart involvement (severe myocardial depression, shock, arrhythmias, nonspecific myocardial damage), severe metabolic acidosis, hypokalemia, hypocalcemia and progressive renal failure leading to anuria. Myoglobinemia and leukocytosis may occur. Manifestations may be delayed for 1-4 hours.


Systemic polyarteritis nodosa (PAN; see this term) is a chronic systemic necrotizingvasculitis of adults and childrenaffecting small- and medium-sized vessels and characterized by formation of microaneurysms leading to serious generalized disease and multi-organ involvement.


A rare disorder of carnitine cycle and carnitine transport that is characterized classically by early childhood onset cardiomyopathy often with weakness and hypotonia, failure to thrive and recurrent hypoglycemic hypoketotic seizures and/or coma.

Summary:
Epidemiology
Systemic primary carnitine deficiency (SPCD) exact prevalence is unknown and varies depending on ethnicity. The estimated prevalence is 1/20,000 - 1/70,000 newborns in Europe and the USA while the estimated incidence in Japan is 1/40,000 births. In the Faroe Islands, the prevalence is 1/1,300 and the incidence is 1/720.
Clinical description
Disease onset typically occurs in infancy between the ages of 3 months to 2 years. Infants often present with hypoketotic hypoglycemia, poor feeding, irritability, lethargy, and hepatomegaly, triggered by fasting stress or common illnesses including gastroenteritis and respiratory tract infections. Roughly half of clinically presenting patients present with muscle hypotonia and progressive childhood cardiomyopathy leading to heart failure. Anemia is sometimes observed as carnitine plays a role in red blood cell metabolism. Adulthood presentation is associated with minor symptoms like fatigue and decreased stamina but dilated cardiomyopathy and arrhythmias and sudden cardiac death have also been reported. Asymptomatic adults are also described. During pregnancy, minor symptoms as well as cardiac arrhythmias can worsen.
Etiology
SPCD is caused by mutations in the SLC22A5 gene on chromosome 5q31.1 that encodes the plasma membrane sodium-dependent high affinity carnitine transporter (OCTN2) which is expressed in most tissues including cultured fibroblasts, lymphocytes, muscle, kidney, gut and heart. OCTN2 is necessary for L-carnitine transport across the plasma membrane and L-carnitine is necessary for transporting long chain fatty acids into the mitochondria for fatty acid oxidation. When fat cannot be used for fatty acid oxidation due to SPCD, glucose is consumed (resulting in hypoglycemia) and the fat released from adipose tissue accumulates in the liver, heart and skeletal muscle (leading to hepatic steatosis and lipid myopathy).
Diagnostic methods
Diagnosis is based on a finding of very low plasma free and total carnitine concentrations (<5-10 micromol/L) and confirmed by demonstrating significantly reduced carnitine transport in skin fibroblasts or biallelic pathogenic mutations in the SLC22A5 gene. There is lipid myopathy with microvesicular lipid accumulation found in the muscle and liver as well as elevated liver transaminases and hyperammonemia. A marked renal loss of carnitine even in the presence of very low plasma and tissue carnitine concentrations is also noted. Newborn screening is available in Austria, Denmark, Hungary, Iceland, Portugal, Spain and Israel.
Differential diagnosis
Differential diagnoses include other fat oxidation defects such as medium chain acyl-CoA dehydrogenase deficiency and very long chain acyl-CoA dehydrogenase deficiency.
Genetic counseling
SPCD is an autosomal recessive disorder and genetic counseling can be offered to families with a known mutation.
Management and treatment
Carnitine therapy is the standard treatment. Oral levocarnitine (L-carnitine) supplementation of 100-400 mg/kg/day in three divided doses is usually required. Oral carnitine treatment is required for lifelong treatment of the disease.
Prognosis
The prognosis is extremely good as long as oral carnitine supplementation is maintained.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                             Joanne CROFT  - Dr Simon OLPIN


Systemic sclerosis (SSc) is a generalized disorder of small arteries, microvessels and connective tissue, characterized by fibrosis and vascular obliteration in the skin and organs, particularly the lungs, heart, and digestive tract. There are two main subsets of SSc: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) (see these terms). A third subset of SSc has also been observed, called limited Systemic Sclerosis (lSSc) or systemic sclerosis sine scleroderma (see these terms).

Summary:
Epidemiology
The prevalence is estimated at about 1/6,500 adults. Women are predominantly affected (F/M sex ratio around 4:1).
Clinical description
The disease usually manifests between 40 and 50 years of age. Raynaud's phenomenon is often the first sign of the disease. The other signs usually appear a few months later in the diffuse cutaneous subset and some years later in the limited cutaneous subset. In the limited cutaneous subset, skin involvement is limited to the hands, face, feet and forearms while in the diffuse subset it rapidly becomes generalized. Esophageal dysmotility is common and provokes gastroesophageal reflux and sometimes dysphagia. Life-threatening complications can occur such as pulmonary fibrosis and, less frequently, pulmonary arterial hypertension. The limited SSc patients have no skin involvement but only Raynaud's phenomenon, and are at risk of organ involvement.
Etiology
The exact cause of SSc is unknown. The disease originates from an autoimmune reaction which leads to overproduction of collagen. In some cases, SSc is associated with exposure to chemicals (including silica, solvents and hydrocarbons).
Diagnostic methods
Diagnosis is based on typical clinical manifestations and on evidence of specific microangiopathy with giant loops on capillaroscopy. Blood tests show typical antinuclear autoantibodies. The extent of the disease should be evaluated by computed tomography (CT), electrocardiogram, echocardiography, radiography of the hands and esophageal and gastric fibroscopy if needed.
Differential diagnosis
Differential diagnoses include Sharp syndrome, systemic lupus erythematosus, antiphospholipid syndrome, polyarteritis nodosa, polymyositis, and rheumatoid arthritis (see these terms).
Management and treatment
Management is mostly symptomatic. Raynaud's phenomenon can be treated with calcium channel blockers. Proton pomp inhibitors are given for gastric reflux. Low doses of corticosteroids with immunosuppressive agents are needed in cases with recent and severe cutaneous involvement or in progressive lung fibrosis. Pulmonary vasodilators are given in case of pulmonary arterial hypertension. Patients require regular clinical follow-up with early pulmonary function tests and echocardiography.
Prognosis
The prognosis depends on the subset of SSc. The prognosis for limited cutaneous SSc is relatively good (10-year survival rate of 80-90%). However, pulmonary arterial hypertension, which occurs in about 10% of cases, and severe lung fibrosis, may lead to a more severe prognosis. The prognosis for diffuse cutaneous SSc is more severe (10-year survival rate of 60-80%) because of the higher risk of life-threatening complications: renal crisis, severe digestive involvement, severe lung fibrosis, and, sometimes, severe heart involvement and pulmonary arterial hypertension.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Eric HACHULLA


Systemic-onset juvenile idiopathic arthritis

A rare pediatric rheumatological disease characterized by the variable occurrence of chronic arthritis, intermittent high spiking fever, maculopapular rash during fever episodes, hepatomegaly and/or splenomegaly, lymphadenopathy, and serositis.

Summary:
Epidemiology
Juvenile idiopathic arthritis (JIA) is one of the most common pediatric chronic diseases, with a yearly incidence between 1.6 and 23 new cases per 100,000 children. Systemic-onset JIA accounts for roughly 10-20% of all JIA patients, with incidence estimated at 1/166,000 and prevalence at 1/32,000 in the prediatric population. Frequency is higher in some countries; for example in parts of Asia, sytemic-onset JIA may account for up to 30-40% of all JIA cases.
Clinical description
Onset usually occurs between 3 and 5 years of age. The clinical signs include fever with oscillating temperatures over a 24-hour period and peaks of over 39°C or more. The fever peaks are associated with the transient occurrence of an evanescent macular rash. Any joint, small or large, may be affected at disease onset, and involvement is nearly symmetrical and may be oligo- or polyarticular. Arthritis tends to increase in severity over time, and thus may not appear until later in the disease course. The course of the disease varies between individuals, ranging from a monocyclic disease course, to recurrent predominantly systemic disease course, to a progressive polyarthritis that could lead to severe and destructive joint disease.
Etiology
Whilst the underlying mechanisms and triggering factors are not fully understood, IL-1 and IL-6 play a major role in the pathogenesis of the disease.
Diagnostic methods
Diagnosis is based on clinical and biological findings in a child under the age of 16 presenting with fever for at least 3 consecutive days and 2 major criteria (arthritis and evanescent rash) or 1 major and 2 minor criteria ((1) generalized lymph node enlargement and/or hepatomegaly or splenomegaly (2) serositis (3) arthralgias lasting 2 weeks or longer (4) leukocytosis > 15.000/mm3 with neutrophilia) A confirmed diagnosis requires exclusion of other causes of the symptoms.
Differential diagnosis
The differential diagnoses is extensive and includes bacterial infections (including occult bacterial infection, brucellosis, Lyme disease, cat scratch disease, tuberculosis, and infectious mononucleosis), malaria, malignancies (such as leukemia, lymphoma, and neuroblastoma), viral infections, hereditary recurrent fever syndromes, other inflammatory diseases (such as systemic lupus erythematosus, systemic vasculitis, Kawasaki disease, Behçet disease, inflammatory bowel disease, Sweet syndrome, PFAPA, Takayasu arteritis, Castleman syndrome, rheumatic fever, and polyarteritis nodosa), connective tissue diseases, and periodic fever syndromes.
Management and treatment
Management by a specialized multidisciplinary team is required. Treatment is typically first with non-steroidal anti-inflammatory drugs (NSAIDs) and, if the inflammation is not controlled, followed by high dose corticosteroids. Treatment with cytokine inhibitors (anakinra, canakinumab, and tocilizumab) has shown to be highly effective. Furthermore, these drugs can help mitigate damage caused by the inflammatory process. Generally, complications such as macrophage activation syndrome, limitations in functional outcome by arthritis and long-term damage from chronic inflammation continue to be a major issue in patients' care, but have decreased since the use of biological treatment.
Prognosis
The disease course is long with major impact on quality of life. The risk of complications due to the illness or medication has been significantly reduced by the early use of biological treatment. Nowadays, osteopenia and osteoporosis, growth impairment, erosive arthritis, and secondary or reactive amyloidosis have almost disappeared. Currently, therapeutic strategies using anakinra (a recombinant IL-1 receptor antagonist), JAK inhibitors, and IL-6 inhibitors are also being studied. In severe case, where these is no response to these treatments or to high-dose corticosteroid therapy, intensive care becomes quickly necessary.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Chantal DESLANDRE


Sézary syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma characterized by a triad of erythroderma, lymphadenopathy and circulating atypical lymphocytes (Sézary cells).

Summary:
Epidemiology
SS has an annual incidence rate of 1/10,000,000 and represents 3% of all cutaneous lymphomas.
Clinical description
SS develops most frequently in men, in most cases during their fifth decade of life and progresses rapidly. SS correspond to stages IVA2 and IVB of T-cell cutaneous lymphoma (see this term). Patients present with a scaling erythroderma and infiltration often manifesting with leonine facies and severe pruritus. Alopecia, ectropium, mild palmoplantar keratoderma and nail onychodystrophy may be present. Lymphadenopathy and hepatosplenomegaly are observed. Patients often shiver and complain of chills and general fatigue.
Etiology
SS has been linked to a wide range of chromosomal anomalies, in particular rearrangements in the 6q23-27 region leading to alterations in the MYB proto-oncogene and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2), but its etiology remains unclear.
Diagnostic methods
Criteria that define SS are currently the following: an absolute Sézary cell count of 1,000 cells/mm3 or greater (B2 stage); an increase in CD3 or CD4 positive cells resulting in a CD4/CD8 ratio of 10 or greater; aberrant expression of pan T cell markers (i.e. deficient CD7 expression on T cells); increased relative or absolute lymphocyte counts with evidence of an identical T cell clone in the blood and skin by Southern blot or PCR technique. Skin biopsy may be not conclusive.
Differential diagnosis
Differential diagnosis includes adverse drug reactions, classical mycosis fungoides and other forms of primary cutaneous T cell lymphoma (see these terms) as well as other causes of erythroderma such as psoriasis, atopic dermatitis and pityriasis rubra pilaris (see this term).
Management and treatment
Assessment includes chest X-ray, computed tomography scan, magnetic resonance imaging and PET scan and an initial lymph node biopsy. Bimonthly extracorporeal photopheresis treatment may be combined with low doses of methotrexate, bexarotene or interferon-alpha. In advanced or non-responsive cases, chemotherapy with liposomal doxorubicine, gemcitabine or alemtuzumab may be considered. In cases of relapse, treatment may include total skin electron beam therapy and allogeneic stem cell transplantion.
Prognosis
Prognosis is poor, with median survival of patients being approximately 5 years, and is dependent upon initial presentation and evolution.

                            Last update:
                            August 2013

                            - Expert reviewer(s):
                            Pr Martine BAGOT


T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta

A rare T-B+ severe combined immunodeficiency characterized by a T cell-negative, B cell-positive, natural killer (NK) cell-positive immune phenotype. Patients present in infancy or early childhood with recurrent infections. Clinical manifestations may vary in severity depending on the underlying molecular defect, resulting in early death without bone marrow transplantation in some patients.


T-B+ severe combined immunodeficiency due to CD45 deficiency

A rare T-B+ severe combined immunodeficiency characterized by markedly decreased numbers of T-cells and normal or increased numbers of B-cells and natural killer (NK) cells. Hypogammaglobulinemia has also been reported. Patients generally present in infancy with recurrent infections, failure to thrive, rash, fever, hepatosplenomegaly, lymphadenopathy, and pancytopenia.


T-B+ severe combined immunodeficiency due to gamma chain deficiency

Severe combined immunodeficiency (SCID) due to gamma chain deficiency, also called SCID-X1, is a form of SCID (see this term) characterized by severe and recurrent infections, associated with diarrhea and failure to thrive.

Summary:
Epidemiology
It accounts for approximately 50% of SCID cases and is the most common form of SCID in Europe. The annual incidence varies among the populations but it is estimated at approximately 1/200,000 births. The disease occurs in males.
Clinical description
SCID-X1 manifests during the first months of life with severe and often life threatening viral, bacterial or fungal infections (e.g. Pneumocystis jiroveci pneumonitis, disseminated BCG infection if previously vaccinated), and failure to thrive. Chronic diarrhea is a frequent finding. Some patients may have skin rashes and abnormalities of liver function. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. Immunological findings are lymphopenia with the absence of T and NK cells, hypogammaglobulinemia, and normal or increased B cell count.
Etiology
SCID-X1 results from a defect in the IL2RG gene encoding the common gamma chain.
Genetic counseling
Transmission is X-linked.

                            Last update:
                            March 2013

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency

A rare T-B+ severe combined immunodeficiency characterized by markedly decreased numbers of T-cells and normal or increased numbers of B-cells and natural killer (NK) cells. Patients generally present in infancy with recurrent infections, failure to thrive, fever, diarrhea, and dermatitis.


T-B+ severe combined immunodeficiency due to JAK3 deficiency

Severe combined immunodeficiency (SCID) T-B+ due to JAK3 deficiency is a form of SCID (see this term) characterized by severe and recurrent infections, associated with diarrhea and failure to thrive.

Summary:
Epidemiology
Annual incidence is between 1/100,000 and 1/1,000,000 live births depending on the population.
Clinical description
The disease shares the same clinical picture as SCID due to gamma chain deficiency (see this term). Patients present in the first few months of life with the classical clinical features of SCID, i.e. chronic diarrhea, failure to thrive, recurrent respiratory infections and/or generalized infections due to opportunistic pathogens. Patients may present with skin rash, abnormalities of liver function, and pancytopenia. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. The disease is characterized by a lack of circulating T and NK (Natural Killer) cells and normal number of B lymphocytes.
Etiology
SCID due to JAK3 deficiency results from a defect in the JAK3 gene encoding an intracellular tyrosine kinase, the Janus activating kinase 3 required for cytokine-mediated signaling.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            March 2013

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


T-B+ severe combined immunodeficiency (SCID; see this term) is a group of rare monogenic primary immunodeficiency disorders characterized by a lack of functional peripheral T lymphocytes with presence of B lymphocytes, resulting in early-onset severe respiratory viral, bacterial or fungal infections, diarrhea and failure to thrive.


T-B- severe combined immunodeficiency (SCID; see this term) is a group of rare monogenic primary immunodeficiency disorders characterized by a lack of functional peripheral T and B lymphocytes, resulting in recurrent early-onset severe respiratory viral, bacterial or fungal infections, diarrhea and failure to thrive. Hypersensitivity to ionizing radiation is a characteristic feature of some of its sub-types.


T-cell immunodeficiency with epidermodysplasia verruciformis

A rare primary immunodeficiency characterized by increased susceptibility to infection by human papillomavirus, presenting in childhood with disseminated flat wart-like cutaneous lesions. Burkitt lymphoma has also been reported. Whilst total T-cell counts are normal, there is impaired TCR signaling, profound peripheral naive T-cell lymphopenia with memory T-cells displaying an exhaustion phenotype.


T-cell immunodeficiency with thymic aplasia

A rare primary immunodeficiency with autosomal or X-linked recessive inheritance, characterized by thymic aplasia in the absence of other congenital abnormalities, with profound T-cell deficiency, while serum immunoglobulin levels are normal or increased. Patients present with chronic or recurrent infections in infancy including candidiasis, skin, pulmonary and urinary tract infections, chronic diarrhea, and failure to thrive.


T-cell large granular lymphocyte leukemia (T-cell LGL leukemia) is a lymphoproliferative malignancy that arises from the mature T-cell (CD3+) lineage.


A rare mature T-cell neoplasm characterized by proliferation of small to medium-sized prolymphocytes with a mature post-thymic T-cell phenotype, involving the peripheral blood, bone marrow, lymph nodes, liver, spleen, and sometimes the skin. T-cell receptor genes are clonally rearranged. Patients typically present with hepatosplenomegaly, generalized lymphadenopathy, high leukocyte count with normal serum immunoglobulins, anemia, and thrombocytopenia. HTLV-1 serology is negative. The disease course is aggressive with generally poor prognosis.


T-cell/histiocyte rich large B cell lymphoma (THRLBCL) is a rare variant of diffuse large B-cell lymphoma (DLBCL; see this term), mainly affecting middle-aged men and often not being discovered until an advanced disease stage, with involvement of the spleen, liver and bone marrow occurring at a greater frequency than in DLBCL. It is often difficult to diagnose due to its similarity with other lymphoid diseases such as classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma (see these terms) and has an aggressive clinical course.


A rare systemic disease characterized by acute or subacute onset of thrombocytopenia, anasarca (edema, pleural effusion, ascites), and systemic inflammation (fever and/or elevated C-reactive protein). Minor diagnostic categories are Castleman's disease-like features on lymph node biopsy, reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow, progressive renal insufficiency, and mild organomegaly including hepatosplenomegaly and lymphadenopathy. Most patients show elevated levels of serum alkaline phosphatase, while marked polyclonal hypergammopathy is rare.