Squamous cell carcinoma of the oral cavity

A rare head and neck tumor characterized by a firm infiltrative neoplasm with squamous differentiation, arising from the mucosal epithelium, and most commonly located in the tongue, floor of the mouth, or gingiva, but also the buccal mucosa or any other area of the oral cavity, depending on prevailing risk factors (such as smoking, alcohol consumption, and tobacco chewing). Patients present with a variably white, erythematous, mixed, nodular, or ulcerated lesion, which may cause discomfort, pain, or reduced mobility of the tongue. The tumor is aggressive with a propensity for local invasion and early lymph node metastasis.


Squamous cell carcinoma of the oropharynx

A rare head and neck tumor characterized by a malignant epithelial neoplasm with evidence of squamous differentiation, which may arise in association with high-risk HPV in a subset of cases. HPV-positive tumors have a strong predilection for the base of tongue and the palatine tonsils and typically present at an advanced clinical stage with cervical lymphadenopathy. They are associated with significantly better prognosis than HPV-negative tumors, which more commonly involve the soft palate, manifest as sore throat and difficulty in swallowing or a neck mass, and occur in older patients. Smoking and alcohol consumption are important risk factors.


A rare urogenital tumor characterized by origin from squamous epithelial cells of the penis, most commonly the glans or inner surface of the prepuce. Macroscopically, the tumors can appear either papillary or flat and ulcerating. Histological subtypes include usual squamous cell carcinoma as the most common type, as well as basaloid, warty, verrucous, papillary, and mixed carcinomas. Patients may initially be asymptomatic but present with itching, bleeding, discharge, foul odor, and pain, as the disease progresses. Regional lymph node involvement is common, while distant metastases occur only late in the disease. Risk factors include HPV infection, smoking, poor hygiene, and HIV infection. Neonatal circumcision is implicated as strongly protective.


A rare epithelial tumor of the rectum, arising from squamous cells in the rectal epithelium, without the presence of squamous-lined fistulous tracts in the rectum or a proximal extension of SCC of anal or gynecological origin. The reported symptoms are often nonspecific, such as anorexia, weight loss, lower abdominal pain, rectal bleeding and changes of bowel habits.


Squamous cell carcinoma of the small intestine is an extremely rare, malignant, epithelial tumor of the small intestine (most often localized in the duodenum). Presenting symptoms are often nonspecific, such as weight loss, epigastric pain, anorexia, weakness, fatigue, vomiting and abdominal distension, and vary depending on localization of the tumor. Gastrointestinal bleeding and perforation may occur in advanced cases.


A rare epithelial tumour of stomach, defined histopathologically as keratinizing cell masses with pearl formation, mosaic pattern of cell arrangement, intercellular bridges, and high concentrations of sulphydryl or disulphide bonds, arising directly from gastric mucosa, without esophageal involvement. It is characterized by preferential location in the upper third of the stomach, high probability of lymphovascular and serosal invasion and late onset of clinical symptoms associated with poor prognosis including nonspecific symptoms of abdominal pain, dysphagia, vomiting, melena or hematochezia, haematemesis and weight loss.


SRD5A3-CDG is a rare, non X-linked congenital disorder of glycosylation due to steroid 5 alpha reductase type 3 deficiency characterized by a highly variable phenotype typically presenting with severe visual impairment, variable ocular anomalies (such as optic nerve hypoplasia/atrophy, iris and optic nerve coloboma, congenital cataract, glaucoma), intellectual disability, cerebellar abnormalities, nystagmus, hypotonia, ataxia, and/or ichthyosiform skin lesions. Other reported manifestations include retinitis pigmentosa, kyphosis, congenital heart defects, hypertrichosis and abnormal coagulation.


SSR4-CDG is a form of congenital disorders of N-linked glycosylation characterized by neurologic abnormalities (global developmental delay in language, social skills and fine and gross motor development, intellectual disability, hypotonia, microcephaly, seizures/epilepsy), facial dysmorphism (deep set eyes, large ears, hypoplastic vermillion of upper lip, large mouth with widely spaced teeth), feeding problems often due to chewing difficulties and aversion to food with certain textures, failure to thrive, gastrointestinal abnormalities (reflux or vomiting) and strabismus. The disease is caused by mutations in the gene  SSR4 (Xq28).


An acute arboviral infection caused by a virus of the Flaviviridae family transmitted by an infected mosquito, and characterized by the onset of flulike symptoms such as fever, malaise, headache, cough, and sore throat that can progress to meningitis or encephalitis with symptoms like nausea, vomiting, confusion, stiff neck, disorientation, irritability, tremors, and convulsions. Photophobia, cranial nerve palsies, and even coma may occur.


STAG1-related intellectual disability-facial dysmorphism-gastroesophageal reflux syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, variable degrees of intellectual disability, and facial dysmorphism (including high nasal bridge, deep-set eyes, and wide mouth), often associated with feeding difficulties and/or gastroesophageal reflux. Additional reported manifestations are seizures, hypotonia, autistic features, and joint laxity. Brain imaging may show non-specific features (such as cerebral atrophy).


Stapes ankylosis with broad thumbs and toes is a very rare genetic bone disorder characterized by ankylosis of stapes, broad thumbs and halluces, conductive hearing loss and hyperopia.


Staphylococcal necrotizing pneumonia is a rare, bacterial, pulmonary infectious disease, caused by a Panton-Valentine leukocidin-producing Staphylococcus aureus strain, characterized by severe respiratory failure, extensive, rapidly progressing pneumonia and hemorrhagic lung necrosis. Patients typically present with influenza-like symptoms, such as fever, cough, and chest pain, as well as hemoptysis, hypotension, leukopenia, and severe respiratory symptoms that rapidly evolve to acute respiratory distress syndrome and septic shock. High mortality is associated.


A rare staphylococcal toxemia caused by epidermolytic toxins of Staphylococcus aureus and characterized by the appearance of widespread erythematous patches, on which large blisters develop. Upon rupture of these blisters, the skin appears reddish and scalded. The lesions typically begin in the face and rapidly expand to other parts of the body. The disease may be complicated by pneumonia and sepsis. It most commonly affects newborns and infants.


A rare bacterial infectious disease characterized by staphylococcal epidermolytic toxin-mediated scarlatiniform exanthema accentuated in the flexural areas, as well as fever and affection of the general condition. The exanthema progresses to desquamation in large flaps, while blistering is not observed. Enanthema, strawberry tongue or palatal petechiae are absent. The condition has mainly been reported in children and young adults.


Staphylococcal toxic shock syndrome (staphylococcal TSS) is an acute disease mediated by the production of superantigenic toxins, characterized by high fever, skin rash followed by skin peeling, hypotension, vomiting, diarrhea and potentially leading to multisystem organ failure and caused by a Staphylococcus aureus bacterial infection.

Summary:
Epidemiology
The incidence of staphylococcal TSS in the United States ranges from 1/192,000 - 1/156,000 people/year. With menstrual TSS now reduced by changes in tampon use, non-menstrual TSS represents up to 50% of staphylococcal TSS cases.
Clinical description
Staphylococcal TSS is seen most commonly in otherwise healthy adult women. However non-menstrual staphylococcal TSS can also be observed in men and children. Onset is sudden and includes high fever (> 38.9°C), nausea, diarrhea, vomiting, myalgia, abdominal pain and sore throat. Unlike streptococcal TSS (see this term), a generalized rash is seen in most cases of staphylococcal TSS, occurring within the first 2 days of symptom onset and affecting both the mucosa and the skin. Later during convalescence, skin peeling also occurs. More serious manifestations include confusion, shock, renal and myocardial dysfunction and acute respiratory distress syndrome (ARDS; see this term). ARDS is the most common cause of death seen in staphylococcal TSS.
Etiology
Staphylococcal TSS is due to an infection with Staphylococcus aureus, that releases toxins and causes a massive immune reaction involving mainly cytokines and chemokines. This reaction is related to the activation of T cells by the production of superantigens that circumvent the normal pathway of antigen presentation. It was originally often associated with high absorbency tampon use, but also intravaginal devices (i.e. barrier contraceptive, menstrual cup) and infections following surgical procedures. Currently, many cases of Staphylococcal TSS are complications of suppurative infections or upper airways colonization.
Diagnostic methods
Diagnosis of staphylococcal TSS is suspected when rash followed by skin peeling, shock and involvement of at least three other organs are clinically observed. Laboratory analysis, where staphylococcal superantigens (such as toxic shock syndrome toxin 1) are identified in urine or serum, can aid in confirming diagnosis. Blood cultures are rarely positive for staphylococci.
Differential diagnosis
Differential diagnoses include streptococcal TSS, Rocky Mountain spotted fever, leptospirosis, dengue fever, typhoid fever (see these terms), peritonitis, pneumonia, pelvic inflammatory disease, pericarditis and acute myocardial infarction, meningococcemia, viral/ drug/allergic rash and septic shock.
Management and treatment
The onset of staphylococcal TSS is sudden and requires immediate medical treatment in an intensive care unit. Treatment of staphylococcal TSS involves antibiotics (clindamycin) along with supportive therapy (fluid resuscitation, inotropes and vassopressors) and intravenous immunoglobins (IVIGs) that block superantigens. Corticosteroids and recombinant activated protein C (derotrecogin-alpha) can also be helpful in some cases. Dialysis may be necessary for those with renal dysfunction and oxygen supplementation along with mechanical ventilation is required for patients with ARDS. Vancomycin and linezolid can be used in penicillin-allergic patients or when the strain is resistant to the methicillin. Women should refrain from using intravaginal devices, unless necessary, in order to minimize the risk of menstrual related staphylococcal TSS.
Prognosis
The prognosis is usually good. Staphylococcal TSS has a mortality rate of only 1-6%.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                             Claude-Alexandre GUSTAVE  - Pr Gerard LINA  - Dr Anne TRISTAN


A rare ophthalmic disorder that is usually characterized by a progressive loss of central vision associated with irregular macular and perimacular yellow-white fundus flecks, and a so-called ''beaten bronze'' atrophic central macular lesion.

Summary:
Epidemiology
The prevalence is estimated at 1/8,000 - 1/10,000. Both sexes are equally affected.
Clinical description
The disease typically presents within the first two decades of life, even though symptoms can also appear during adulthood and as late as the seventh decade. Although disease progression and severity varies widely, Stargardt disease (STGD1) is usually characterized by a progressive loss of central vision causing blurry vision and, occasionally, an increasing difficulty to adapt in the dark. Peripheral vision is usually normal. Most affected individuals also have impaired color vision. Photophobia may be present.
Etiology
The disorder has been linked to mutations in the ABCA4 gene, which encodes an adenosine triphosphate (ATP)-binding cassette transporter (ABCR) expressed specifically in the cones and rods of the retina. Defects in ABCR function cause the accumulation of all-trans-retinal and its cytotoxic derivatives, mainly lipofuscin pigments (e.g., diretinoid-pyridinium-ethanolamine) in photoreceptors and retinal pigment epithelial (RPE) cells, ultimately causing RPE cell death and the subsequent loss of photoreceptors. Mutations in ABCA4 have been linked to a spectrum of phenotypes ranging from STGD1 to cone rod dystrophy and severe early-onset retinal dystrophy.
Diagnostic methods
The clinical diagnosis is based on ophthalmological examinations consisting of visual acuity and visual field testing, ophthalmoscopy, electroretinography (ERG), fluorescein angiography (FA), fundus autofluorescence (FAF), and optical coherence tomography (OCT), revealing macular anomalies (progressive atrophy often in a 'beaten bronze pattern') and yellow-white fishtail flecks that may present only in the central macula but may also extend beyond the vascular arcades. These flecks are hyper autofluorescent on FAF images. Fluorescein angiography reveals the characteristic dark choroid (''silence choroidien'') in aproximately 85% of the patients. Diagnosis can be confirmed by genetic testing of the ABCA4 gene.
Differential diagnosis
Differential diagnosis includes multifocal pattern dystrophy simulating STGD1 and retinal and/ or macular dystrophies such as central areolar choroidal dystrophy (CACD), achromatopsia, cone dystrophy (CD) and cone rod dystrophy (CRD). In addition, two autosomal dominant types of macular dystrophy exist that resemble STGD1: STGD3 caused by mutations in the ELOVL4 gene and STGD4 associated with mutations in PROM1.
Antenatal diagnosis
Prenatal diagnosis is technically possible by means of genetic testing of the ABCA4 gene, but is not used in clinical practice.
Genetic counseling
The disorder is transmitted in an autosomal recessive or an autosomal dominant mode of inheritance. Genetic counseling should be offered to at-risk couples informing them that there is 25% or 50% risk, respectively, of transmitting the disease to offspring.
Management and treatment
Preventive measures for slowing down the progression of the disease include avoidance of overexposure to visible light with sunglasses and no intake of vitamin A supplements. Regular ophthalmologic evaluations are recommended. Currently, various treatment options are being developed. Different oral medical treatments that prevent the accumulation of lipofuscin in Stargardt disease are being tested in phase II/III clinical trials. These medical treatments inhibit the visual cycle by blocking the action of certain enzymes in the retina (RPE65/RBP4/LRAT/RDH5), replace vitamin A with a deuterated form of vitamin A (ALK001) or aid in the removal of lipofuscine by breaking down the lipofuscin (Soraprazan).
Prognosis
Due to the high clinical variability, prognosis depends on certain parameters (notably age of onset and electroretinographic findings) that may help the clinician provide the patient with an indication of the course of the disease. STGD1 may progress rapidly over a few months or gradually over several years leading to a severe decrease in visual acuity. Typically, peripheral vision is not affected, although certain patients may progress to a cone-rod phenotype that does affect the peripheral retinal function.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Patty DHOOGE  - Pr C.B. [Carel] HOYNG


Startle epilepsy is a rare neurologic disease characterized by frequent and spontaneous epileptic seizures (frequently with symmetrical or asymmetrical tonic features) triggered by a normal startle in response to a sudden and unexpected somatosensory (most frequently auditory) stimulus. Falls are common and can be traumatic. In most cases, the disease is associated with spastic hemi-, di-, or tetraplegia and intellectual disability.


STAT1-related autoimmune enteropathy and endocrinopathy-susceptibility to chronic infections syndrome

An extremely rare, autosomal dominant immunological disorder characterized by variable enteropathy, endocrine disorders (e.g. type 1 diabetes mellitus, hypothyroidism), immune dysregulation with pulmonary and blood-borne bacterial infections, and fungal infections (chronic mucocutaneous candidiasis) developing in infancy. Other manifestations include short stature, eczema, hepatosplenomegaly, delayed puberty, and osteoporosis/osteopenia.


STAT3-related early-onset multisystem autoimmune disease

A rare, genetic, lymphoproliferative syndrome characterized by early onset recurrent infections, lymphadenopathy with hepatosplenomegaly and variable autoimmune disorders, including hemolytic anemia, thrombocytopenia, neutropenia, enteropathy, type I diabetes, scleroderma, arthritis, atopic dermatitis, and inflammatory lung disease. Patients commonly have failure to thrive. Variable immunologic findings include decreased regulatory T-cells, hypogammaglobulinemia, and reduction in memory B cells.


Steatocystoma multiplex-natal teeth syndrome

A rare malformation syndrome characterized by generalized multiple steatocystomas and natal teeth.

Summary:
Epidemiology
It has been described a five-generation Chinese family with at least 21 affected patients.
Genetic counseling
The same condition has been reported in one additional sporadic case. Autosomal dominant inheritance has been suggested.

                            Last update:
                            September 2009


A rare genetic bone disease characterized by short stature, bilateral congenital hip dislocation, radial head dislocation, carpal coalition, scoliosis, pes cavus, and atlantoaxial subluxation. Dysmorphic facial features include broad forehead, broad nasal bridge, hypertelorism, and mild midface hypoplasia. Association with bilateral sensorineural hearing loss has also been described.


A rare genetic multi-system disorder characterized by a wide range of muscle-related manifestations (muscle weakness, myotonia, early onset cataracts (before age 50) and systemic manifestations (cerebral, endocrine, cardiac, gastrointestinal tract, uterus, skin and immunologic involvement) that vary depending on the age of onset. The very wide clinical spectrum ranges from lethal presentations in infancy to mild, late-onset disease.

Summary:
Epidemiology
It is the most frequent adult muscular dystrophy and has an estimated prevalence ranging from 1/215,000 in Taiwan to 1/5,500 in Croatia. It appears to be more prevalent in the Saguenay-Lac-St-Jean region-Quebec, Canada (1/600), suggesting a founder effect. The disease occurs worldwide.
Clinical description
The age of onset is highly variable, from prenatal to adulthood. The clinical manifestations also cover a wide range and may differ within and between affected families. Five forms are currently recognized: congenital, early childhood, juvenile, adult-onset and late-onset. Congenital disease (15% of cases) is the most severe form and includes severe generalized weakness at birth with respiratory distress, hypotonia, and feeding difficulty. Patients subsequently develop delayed cognitive and motor milestones intellectual disability, and autism spectrum disorder. The course may be fatal in congenital cases (30-40%). In childhood onset cases (with the age of onset between 1 and 10 years of age), the main clinical manifestations involve muscle weakness (including both proximal and distal muscle group, facial weakness, respiratory and gastrointestinal complications such as respiratory distress, aspiration, dysphagia, constipation and speech disturbances), myotonia, sleep breathing disorders, recurrent infections, cognitive impairment, psychiatric disorders (phobia, depression, anxiety, attention deficit-hyperactivity). The juvenile form with the age of onset between 11 and 20 years of age, is characterized by scholar and behavioral problems and is often under recognized. The classic adult form (75% of cases), which develops between 20 and 40 years of age, is characterized by progressive distal muscle weakness, pain, myotonia and multiorgan involvement (irritable bowel disease, conduction and other cardiac disorders, cataracts, ophthalmoplegia, diabetes mellitus, hypogonadism, hypotestosteronism, and thyroid dysfunction). Intellectual deficit is also present in adult cases. Balding may occur in affected males and females and infertility may be present. Late-onset disease after 40 years of age involves mild myotonia and weakness, daytime sleepiness, and cataracts. A higher cancer risk has been reported in affected patients.
Etiology
The disease is due to abnormal CTG expansion in the non-translating region of the DMPKgene (19q13.3). Disease severity generally correlates with the number of DNA repeats. More than 2000 CTG repeats may be found. The expansion is unstable, which may explain the clinical variability.
Diagnostic methods
Diagnosis is suspected on the characteristic clinical manifestations and a consistent family history, and confirmed by molecular genetic testing of the causative gene expansion. Muscle biopsy is not anymore necessary for the diagnosis and is has been replaced by genetic testing, which represents the gold standard.
Differential diagnosis
There are several overlapping features with myotonic dystrophy type 2; however, the diseases are distinct genetically and have different courses and management requirements.
Antenatal diagnosis
Early-onset cases may be identified prenatally with polyhydramnios and reduced fetal movements.
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counselling should be provided to affected families. Whilst there is a 50% risk of disease transmission from an affected parent to their offspring, the disease shows variable penetrance.
Management and treatment
No specific targeted treatment is currently available. Management primarily includes monitoring for complications and supportive care (assistive devices, hormone therapy, pain medication).
Prognosis
Some cases are severe and may have an impact on life expectancy, particularly early-onset cases caused by massive gene expansions. The prognosis in adult-onset cases is mainly dependent on the severity of cardiac manifestations. Causes of death include respiratory failure, cardiovascular disease, arrhythmia, and neoplasms.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Giovanni MEOLA


Sterile multifocal osteomyelitis with periostitis and pustulosis is a rare, severe, genetic autoinflammatory syndrome characterized by usually neonatal onset of generalized neutrophilic cutaneous pustulosis and severe, recurrent, multifocal, aseptic osteomyelitis with marked periostitis, typically affecting distal ribs, long bones and vertebral bodies. High levels of acute-phase reactants (with no fever associated) and onychosis are frequently observed additional features.


A rare idiopathic congenital thoracic malformation characterized by a sternal fusion defect, that can be complete or partial (either superior or inferior), that is usually asymptomatic in the neonatal period (apart from a paradoxical midline thoracic bulging) but that can lead to dyspnea, cough, frequent respiratory infections and increased risk of trauma-related injury to the heart, lungs and major vessels if left untreated.


Steroid dehydrogenase deficiency-dental anomalies syndrome

A rare metabolic liver disease characterized by progressive liver disease and early cirrhosis due to accumulation of toxic cholesterol metabolites, which are detectable in bile, plasma, and urine, in association with dental abnormalities such as general hypomineralization and enamel hypoplasia, as well as occurrence of supernumerary teeth. There have been no further descriptions in the literature since 1996.


Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare, acquired, neurological disease characterized by encephalopathy associated with elevated antithyroid antibodies, in the absence of other causes. Clinical presentation varies from minor cognitive impairment to status epilepticus and coma, and frequently includes seizures, confusion, speech disorder, memory impairment, ataxia and psychiatric manifestations.


A limited form of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum characterized by destruction and detachment of the skin epithelium, involving less than 10% of the body surface area, and mucous membranes. Onset usually occurs 4-28 days after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides, allopurinol, nevirapine, and oxicams (non-steroidal anti-inflammatory drugs), but many other medications have also been implicated. The disease is not induced by medication in 15% of cases. Histology is characterized by an epidermal necrolysis. Multiple disabling long-term sequelae (especially cutaneous, ocular and psychological) are frequent.


Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome

An intermediate form of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum characterized by destruction and detachment of the skin epithelium, involving between 10 to 29% of the body surface area, and mucous membranes. Onset usually occurs 4-28 days after administration of the causal medication and is most frequently associated with anticonvulsants, antibacterial sulfonamides, allopurinol, nevirapine, and oxicams (non-steroidal anti-inflammatory drugs), but many other medications have also been implicated. The disease is not induced by medication in 15% of cases. Histology is characterized by an epidermal necrolysis. Multiple disabling long-term sequelae (especially cutaneous, ocular and psychological) are frequent.


Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum

A rare toxic dermatosis with clinical and histological features characterized by the destruction and detachment of the skin epithelium and mucous membranes.

Summary:
Epidemiology
On average, the annual incidence is 1/319,000 in Europe; however, it varies worldwide with a higher incidence observed in Asian populations and in the US. Females are more often affected than males.
Clinical description
Onset may occur at any age, but the risk increases after 40 years. Three subforms have been described according to the percentage of the body surface area affected: Stevens-Johnson syndrome (<10%), toxic epidermal necrolysis (≥ 30%; TEN) and an intermediate form, Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome (10-29%). The initial manifestations are nonspecific: a seemingly banal rash, fever, and a burning sensation involving the eyes, mouth and genitalia. The rash rapidly progresses to become vesicular and bullous on the face and body. The cutaneous vesicles aggregate and rupture under mild friction, revealing denuded red skin with seeping and pain. Mucous membrane lesions are present in 85 to 95% of patients with involvement, in order of frequency, of the oropharynx, eyes, genitalia and anus. Lesions are painful and lead to hypersalivation, feeding problems, photophobia, and burns following urination. High fever is a constant feature. Visceral manifestations are also frequent with hematological, respiratory and digestive involvement.
Etiology
In 85% of cases, the disorder is triggered by a clearly identifiable drug allergy. A dozen high risk drugs have been identified: allopurinol, anti-infective sulphonamide agents, carbamazepine, phenobarbital, phenytoin, lamotrigine, nevirapine, and oxicam-derived nonsteroidal anti-inflammatory drugs. Genetic predisposition is described in some populations. In the other 15% of cases, the disease is associated with infections (in particular, Mycoplasma pneumoniae) or lupus erythematosus (TEN-like lupus). The remaining cases are classed as idiopathic and should be confirmed by skin biopsy.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by skin biopsy which will reveal full-thickness epidermal necrosis and the absence of antibody deposits by direct immunofluorescence. Medication history will find a suspect drug in 85% of cases. Allergology work-up may help assessing the culprit in case of multiple suspects, and to find alternatives. Assessing possible genetic predisposition may help identifying the culprit drug in predisposed populations (e.g. Chinese Hans for carbamazepine and allopurinol).
Differential diagnosis
The differential diagnosis should include chicken pox during the early stages of the disease, staphylococcal epidermolysis, staphylococcal scalded skin syndrome, generalized bullous fixed drug eruption and, more rarely, severe graft versus host disease, and autoimmune bullous diseases (excluded by examination of skin biopsies). The more limited forms of TEN are still often misdiagnosed as erythema multiforme major.
Genetic counseling
HLA predisposition should be screened before prescription of carbamazepine (and other aromatic anti-epileptics) and allopurinol in Chinese Hans population; and before prescription of abacavir in all populations.
Management and treatment
Patients should be admitted (according to the severity) to a dermatology or an intensive care or burns unit as soon as the diagnosis is suspected. The causative drug, together with any related compounds should be contraindicated for the patient and their close relatives (in case a genetic predisposition). No disease-modifying drugs have been shown to be efficient in the treatment of this disease. The benefits of general corticotherapy, cyclosporine or anti-TNF administration are still under evaluation. High-dose intravenous immunoglobulins appear to be of limited efficacy. Intensive supportive care is essential: a heated environment, analgesia, daily dressing changes, prevention of infections, and symptomatic intensive care measures (especially hydration, nutrition, analgesics, ocular care).
Prognosis
Reepithelialization is usually rapid (2-3 weeks). However, the prognosis for patients with extensive forms is poor (20-25% mortality). Sequelae are reported in over 80% of surviving patients with ocular sequelae being the most problematic as they tend to be severe and progressive. Other sequelae (cutaneous, genital, buccal/dental or bronchial problems) are generally easier to detect and treat.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Pr Saskia ORO | ERN-Skin*

                                * European Reference Network


A rare group of genetic connective tissue disorders characterized by ophthalmic, auditory, orofacial and articular manifestations. The two main clinical forms are clinically distinguished by the vitreous phenotype; stickler type 1 by a vestigial vitreous gel in the immediate retrolental space, bordered by a distinct folded membrane, and Stickler type 2 by sparse and irregularly thickened bundles of ﬁbers throughout the vitreous cavity.

Summary:
Epidemiology
Prevalence at birth has been estimated at around 1/7,500 to 1/9,000.
Clinical description
Ocular manifestations include a high risk of retinal detachment, congenital abnormalities of vitreous development, congenital myopia and congenital cataract. Retinal paravascular lattice degeneration may develop in adulthood. Orofacial features include Pierre Robin sequence (PRS), cleft palate and midfacial hypoplasia. In addition, congenital high-frequency sensorineural deficit is common and variable conductive hearing loss may also occur. Musculoskeletal problems include spinal abnormalities, hypermobility, epiphyseal dysplasia and premature osteoarthritis. Two other forms are characterized by the ocular-only (autosomal dominant rhegmatogenous retinal detachment) or systemic-only (Stickler syndrome type 3) manifestations.
Etiology
Stickler syndrome is an inherited connective tissue disorder most commonly caused by mutations in the genes encoding collagen types II (COL2A1, 12q13.11), IX (COL9A1, 6q13; COL9A2, 1p34.2; COL9A3, 20q13.33), and XI (COL11A1, 1p21.1), but rarer non-collagen gene variants have been reported.
Diagnostic methods
Diagnosis is made on the basis of clinical and ophthalmic examination and confirmed by molecular genetic analysis. Vitreous phenotyping is helpful in segregating sub-types as many of the other shared clinical features are similar.
Differential diagnosis
Differential diagnoses includes spondyloepiphyseal dysplasia congenita, spondyloperipheral dysplasia, Kniest dysplasia, Wagner syndrome, Knobloch syndrome, multiple epiphyseal dysplasia, metatropic dysplasia, Marfan syndrome and Marshall syndrome.
Antenatal diagnosis
Prenatal diagnosis may be possible. First trimester prenatal diagnosis based on the analysis of linked markers may be possible. In second trimester, ultrasound may be helpful in detecting features such as micrognathia or cleft palate, but their absence does not exclude the diagnosis.
Genetic counseling
The pattern of inheritance for Stickler syndrome type 1 and 2 is autosomal dominant; the risk of disease transmission to offspring is 50%. Autosomal recessive inheritance is rarely observed but should be considered if there is a history of consanguinity. However, there is wide variation in clinical expression of the disease. The disease is highly penetrant but with wide variability in its extraocular phenotype. Affected family members in the high risk sub-groups should be offered prophylactic treatment to reduce the risk of retinal detachment and be offered genetic counselling.
Management and treatment
Management should be multidisciplinary and as clinical expression is very variable, treatment needs to be adapted to each case. Patients with PRS or cleft palate will require referral to a specialist multidisciplinary cleft team for assessment and management. This may also include speech therapy for patients with sub-clinical or soft palate cleft. Any refractive error should be corrected and prophylactic retinopexy discussed for the high risk variants. For type 1 Stickler syndrome, retinopexy substantially reduces the risk of giant retinal tear detachment. Patients should be warned of the signs and symptoms of retinal detachment and have rapid access to specialist vitreoretinal expertise in the event of such a development. Cataract is common and the surgical management, particularly in the pediatric sub-group requires specialist care. All affected patients should be referred for specialist audiology assessment if this has not already been undertaken by the cleft team. Patients may be unaware of sub-clinical hearing loss, particularly if present from birth. Although intellect is normal, pre-verbal children may need additional educational support with respect to their auditory and visual impairment. Specialist rheumatology and orthopedic management may be required for the associated arthropathy.
Prognosis
Prognosis of the disease is generally good. There is no direct reduction on life expectancy. The quality of life will differ depending on clinical expression, age of diagnosis and degree (if any) of associated visual loss, deafness, speech impairment and arthropathy.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Martin SNEAD  - Dr Aijing WANG


A rare neurological disorder comprising fluctuating trunk and limb stiffness, painful muscle spasms, task-specific phobia related to walking, an exaggerated startle response, and often ankylosing deformities such as fixed lumbar hyperlordosis.

Summary:
Epidemiology
The prevalence is estimated at about 1/1,000,000. Approximately 2/3 of patients are female.
Clinical description
The most common form of stiff person spectrum disorders (SPSD) is classic stiff person syndrome (SPS). Age of onset peaks around 45 and symptoms develop over months or years. Progressive muscle stiffness renders the trunk and hips immobile, and the gait becomes stiff and awkward. Superimposed painful spontaneous or reflex-induced muscle spasms may cause serious falls. A specific fear of crossing open spaces (pseudo-agoraphobia) may induce freezing of gait, sudden spasms, and falls. Focal neurological signs are absent. Clinical variants of SPSD include the stiff limb syndrome (SLS) where symptoms affect only one limb, and progressive encephalomyelitis with rigidity and myoclonus (PERM) where stiffness and myoclonic spasms are associated with focal neurological signs. Many patients with SPSD have insulin-dependent diabetes mellitus (30%), autoimmune thyroiditis (10%), atrophic gastritis with pernicious anemia (5%), and some have tumors of the breast, lung, colon or thymus.
Etiology
The presence of antibodies against glutamic acid decarboxylase (GAD-Abs; ~70-80%), glycine receptors (GlyR-Abs; ~10-20%), amphiphysin (~5%) and other, rarer antibodies (e.g. DPPX) in most of cases suggests an autoimmune pathogenesis. The exact immunopathophysiology (idiopathic vs. paraneoplastic; T-cell mediated vs. antibody mediated) varies amongst the different antibody subgroups. In particular for GAD-antibody associated autoimmunity there seems to be a certain genetic predisposition with an association of certain HLA haplotypes (DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype and DRB1*04:01 allele), and genetic variants in genes relevant for immune regulation as risk factors.
Diagnostic methods
Diagnosis essentially relies on clinical examination, and is substantiated by detection of associated antibodies in serum and cerebrospinal fluid (CSF), and by characteristic electromyographic abnormalities. Scans of the spinal cord can help to exclude mechanical causes such as a cyst or disc compression of the spinal cord.
Differential diagnosis
Differential diagnosis includes an atypical manifestation of a spinal cord disease (e.g. multiple sclerosis; tumors), axial dystonia, tetanus, neuromyotonia, acquired hyperekplexia (startle disease), and functional movement disorders.
Management and treatment
Benzodiazepines and baclofen are standard drugs for symptomatic treatment. Immunomodulating therapies (corticosteroids, intravenous immunoglobulin, plasmapheresis, rituximab, cyclophosphamide, autologous hematopoietic stem cell transplantation) have been proposed with variable results. Treatments help to control symptoms in the majority of patients affected by SPSD. PERM is a potentially lethal variant and requires early and consequent immunotherapy. GlyR-antibody mediated disease is often associated with thymomas, which need to be removed. In amphiphysin antibodies-associated SPSD or other paraneoplastic forms, the treatment of the underlying malignancy is of paramount importance.
Prognosis
The prognosis varies widely and depends greatly on the immunological and clinical subtype. While there are monophasic forms (e.g. GlyR-antibody related PERM) in which patients may make a good recovery with adequate treatment, the most common GAD-antibody related form is chronic. Many patients lose their ability to walk independently, and stiffness spreads, leading to an overall decline in the functional status and quality of life. In paraneoplastic SPSD, the prognosis is mainly determined by the underlying malignancy.

                            Last update:
                            August 2023

                            - Expert reviewer(s):
                            Pr Bettina BALINT


Stiff skin syndrome is a rare, slowly progressive cutaneous disease characterized by rock-hard skin bound firmly to the underlying tissues (mainly on the shoulders, lower back, buttocks and thighs), mild hypertrichosis and hyperpigmentation overlying the affected areas of skin, as well as limited joint mobility (mainly of large joints) with flexion contractures. Cutaneous nodules, affecting mostly distal interphalangeal joints, as well as extracutaneous manifestations, including diffuse entrapment neuropathy, scoliosis, a tiptoe gait and a narrow thorax, may be associated. Restrictive pulmonary changes, muscle weakness, short stature and growth delay have also been reported. No vascular hyperreactivity, immunologic abnormalities nor visceral, muscular or bone involvement has been described.


Stimmler syndrome is characterised by the association of microcephaly, low birth weight and severe intellectual deficit with dwarfism, small teeth and diabetes mellitus. Two cases have been described. Biochemical tests reveal the presence of high levels of alanine in the urine and elevated alanine, pyruvate and lactate levels in the blood.


STING-associated vasculopathy with onset in infancy (SAVI) is a rare, genetic autoinflammatory disorder, type I interferonopathy due to constitutive STING (STimulator of INterferon Genes) activation, characterized by neonatal or infantile onset systemic inflammation and small vessel vasculopathy resulting in severe skin, pulmonary and joint lesions. Patients present with intermittent low-grade fever, recurrent cough and failure to thrive, in association with progressive interstitial lung disease, polyarthritis and violaceous scaling lesions on fingers, toes, nose, cheeks, and ears (which are exacerbated by cold exposure) that often progress to chronic acral ulceration, necrosis and autoamputation.


Stormorken-Sjaastad-Langslet syndrome is characterized by thrombocytopathy, asplenia, miosis, muscle fatigue, migraine, dyslexia, and ichthyosis. It has been described in six members of one family. It is transmitted as an autosomal dominant trait.


Straddling and/or overriding mitral valve

A rare, congenital, non-syndromic heart malformation characterized by an abnormal attachment of the mitral chordae to both ventricles. Straddling mitral valve is usually associated with conotruncal anomalies, most commonly double outlet right ventricle or transposition of the great arteries. Overriding mitral valve is characterized by a mitral annulus committed to the two ventricular chambers, where the mitral valve is shared between the ventricles. Straddling and overriding mitral valve can occur together or in isolation.


Straddling or overriding tricuspid valve is a rare, congenital, tricuspid valve malformation characterized by the tricuspid valve that overrides the ventricular septum and communicates with both ventricles, as part of the tension apparatus of the valve crosses the ventricular septal defect and is attached in the left ventricle. The anomaly occurs with other congenital heart defects (transposition of great vessels, left ventricle outflow tract obstruction, double outlet right ventricle, hypoplastic right ventricle), which determine the main clinical manifestation.


Streptobacillary rat-bite fever (RBF) is a systemic zoonosis caused by the aerobic Gram-negative bacterium Streptobacillus moniliformis and is transmitted to humans through the bites and scratches of infected rats.

Summary:
Epidemiology
The disease is found worldwide, but the exact incidence is unknown.
Clinical description
High fever (up to 40 °C) is the first sign of infection (2-7 days after the bite) and is closely followed by chills, headache, nausea and vomiting. RBF is also associated with a morbilliform or purpuric rash of the extremities (in particular on the palms and the soles) and occasionally hemorrhagic vesicles on the hands and feet that may desquamate. Migratory polyarthralgia of the joints may also occur, generally leading to restricted movement. The bite typically heals quickly. In rare cases, complications are reported including endocarditis, pericarditis, myocarditis, diarrhea and degenerative changes in organs such as the kidneys and liver.
Etiology
The disease is generally contracted by the bites of infected rats and less often by other S. moniliformis hosts (gerbils, squirrels etc.>/i>). It can also be transmitted via ingestion of rat excrement through contaminated water, milk or food, in which case the contracted disease is called Haverhill fever. Streptobacillus moniliformis is predominantly present in the pharynx of the rats, but is also found in blood cultures and on arthritic or skin exudates.
Diagnostic methods
Diagnosis is based on characteristic growth, fatty acid profiles obtained by gas-liquid chromatography, blood antibody tests (agglutinating antibodies appearing from the 10th day) and to a lesser extent, on molecular detection of the germ.
Differential diagnosis
The differential diagnosis includes spirillary RBF (Sudoku; see this term) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever, malaria, typhoid fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthemas, secondary syphilis, Epstein-Barr virus and coxsackieviruses).
Management and treatment
Management requires a prophylactic (avoiding direct or indirect contact with host animals) and therapeutic approach (local treatment and antimicrobial therapy). The most effective antibiotic treatment is penicillin G administration in non-allergic patients and tetracycline and streptomycin in penicillin-allergic patients.
Prognosis
Prognosis is excellent if the disease is treated. If left untreated, RBF carries a mortality rate of 13% due to complications.

                            Last update:
                            August 2009

                            - Expert reviewer(s):
                            Dr François TREMOLIERES


Streptococcal toxic-shock syndrome (streptococcal TSS) is an acute disease mediated by the production of superantigenic toxins characterized by the sudden onset of fever and other febrile symptoms, pain, multisystem organ involvement and potentially leading to coma, shock and death due to a Streptococcus pyogenes infection.

Summary:
Epidemiology
The annual incidence is estimated to range between 1/300,000 - 1/1,000,000.
Clinical description
Streptococcal TSS usually presents with a sudden onset of pain, often mimicking peritonitis or located in the extremities in previously healthy adults. General flu-like symptoms such as high fever, myalgia, nausea, diarrhea and vomiting are signs of streptococcal TSS and most patients develop hypotension soon after hospital admission. Signs of soft tissue infection can also be present manifesting with localized erythema and swelling which can lead to necrotizing fasciitis in some cases. A diffuse scarlatina-like erythema occurs in about 10% of cases. Other serious manifestations include confusion, shock, renal dysfunction, acute respiratory distress syndrome (ARDS; see this term) and coma. In some cases streptococcal TSS can be associated with acute adrenal insufficiency (see this term).
Etiology
Streptococcal TSS is caused by an infection with Streptococcus pyogenes, also known as group A streptococcus (GAS), and is usually associated with skin infections, child birth, and surgeries. Infection occurs at a site of trauma or can follow viral infections (influenza or varicella). Streptococcal TSS is the result of toxins released by the bacteria that cause a massive immune reaction involving mainly cytokines and chemokines. This reaction is related to the activation of T cells by the production of superantigens that circumvent the normal pathway of antigen presentation. Group C and G Streptococcus are also rarely associated.
Diagnostic methods
Clinical symptoms along with laboratory analysis are the basis for diagnosis of streptococcal TSS. Patients with fever, multisystem organ failure and shock are tested for GAS in their blood or a normally sterile site (e.g. cerebrospinal, pleural or peritoneal fluid) and those who test positive are given a diagnosis of streptococcal TSS. Bacteremia is present in most patients with streptococcal TSS (approximately 60%) which is not the case in staphylococcal TSS (see this term) where it is seen in approximately 5% of cases.
Differential diagnosis
Differential diagnoses include staphylococcal TSS, septic shock, typhoid fever, Rocky Mountain spotted fever, leptospirosis (see these terms), peritonitis, pneumonia, pelvic inflammatory disease, pericarditis, acute myocardial infarction, meningococcemia, viral/ drug/ allergic rash.
Management and treatment
The onset of streptococcal TSS is sudden and requires immediate medical treatment in an intensive care setting. Treatment involves antibiotics (beta-lactam antibiotics and clindamycin) along with supportive therapy (fluid resuscitation, inotropes and vassopressors) and intravenous immunoglobins that block superantigens. Corticosteroids and recombinant activated protein C (derotrecogin-alpha) can also be helpful in some cases. Dialysis may be necessary for those with renal dysfunction and oxygen supplementation along with mechanical ventilation is required for patients with ARDS. Suspected necrotizing fasciitis may require debridement.
Prognosis
The prognosis varies, with streptococcal TSS having a mortality rate of 30-80% in adults and 5-8% in children.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                             Claude-Alexandre GUSTAVE  - Pr Gerard LINA  - Dr Anne TRISTAN


Striate palmoplantar keratoderma is an isolated, focal, hereditary palmoplantar keratoderma characterized by linear hyperkeratosis along the flexor aspect of the fingers and on palms, as well as focal hyperkeratosis of the plantar skin. Patients present with painful thickening of the skin on palms and soles, with occasional fissuring, blistering and hyperhidrosis. Rarely, hyperkeratosis on other areas may be seen (knees, dorsal aspects of the digits). Histopatologically, widened intercellular spaces between keratinocytes are observed.


The stromal corneal dystrophies refer to a group of rare genetically determined corneal dystrophies (CDs) characterized by lesions affecting the corneal stroma, and variable effects on vision depending on the type of dystrophy.

Summary:
Epidemiology
Prevalence of this group of corneal dystrophies is unknown, but all are rare.
Clinical description
Age of onset is variable. Eleven subtypes of stromal corneal dystrophy have been identified: Pre-Descemet CD, Type I and Type II lattice CD, Type I and type II granular CD, Macular CD, Schnyder CD, Congenital stromal CD, Fleck CD, Posterior amorphous CD and Central cloudy dystrophy of François (see these terms).
Etiology
Like most corneal dystrophies, stromal forms are mostly genetically determined and mutations in the following genes have been identified as causing stromal lesions: TGFBI (5q31), CHST6 (16q22), UBIAD1 (1p36.22), DCN (12q23), and  PIKFYVE (2q34).
Genetic counseling
An autosomal dominant pattern of inheritance has been reported for all subtypes, with the exception of macular CD which is transmitted as an autosomal recessive trait.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia. Facial dysmorphism is reported in some cases and may include narrow or sloped forehead, hypertelorism, microphthalmia, dysplastic, edematous deep-set eyes, short palpebral fissures, large or low set ears, broad nasal root, anteverted or broad nasal tip, long philtrum, micrognathia, thin upper vermillion, large mouth and skin tag on the cheek. Motor delay and intellectual disability have been reported. Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present. Rarely, cases without intestinal atresia, microcephaly or developmental delay can be found. Severe lethal cases have also been reported.


A parasitosis caused by the intestinal nematode Strongyloides stercoralis (round worm).

Summary:
Epidemiology
It affects between 30 and 60 millions people worldwide and is endemic to sub-tropical zones including Africa, the West Indies, Central and South America, the Indian Ocean region, South East Asia.
Clinical description
Acute infection is characterized by cutaneous manifestations such as serpiginous urticarial rash, cough, dyspnea, gastrointestinal symptoms (including pain and soft stools) and allergic manifestations; however over half of infected individuals remain asymptomatic. Strongyloides hyperinfection syndrome (SHS) may occur in patients with underlying illness such as HTLV1 infection or those undergoing corticosteroids or immunosuppressive treatment and often results in sepsis, shock, and acute respiratory distress syndrome. Respiratory, gastrointestinal, cutaneous, and neurologic symptoms are observed at variable frequencies, but the hallmark of SHS is the severity of organ failure requiring ICU admission.
Etiology
The female nematodes, which measure 2.5 mm in length, live in the small intestine of humans. Eggs laid in the small intestine hatch to release larvae that are normally excreted in the feces. On damp ground, these larvae reach their infectious stage directly or after a phase of sexual reproduction. In this infectious form they can penetrate the skin directly. Evolution towards the infectious stage may also take place within the digestive system, explaining the long duration of parasitosis (more than 30 years) observed in some cases.
Diagnostic methods
Diagnosis is made by serological test, agar plate culture or stool examination, the latter of which has low sensitivity and requires a minimum of three samples.
Differential diagnosis
Differential diagnosis may include ancylostomiasis and other causes of gastritis, enteritis, bronchitis, and dysentery.
Management and treatment
Access to clean water, footwear, and sanitation is fundamental to preventing new cases of strongyloidiasis. The treatment of choice is ivermectin. Disseminated infections may require intensive care.
Prognosis
Lifelong infection is possible if left untreated. Most patients remain asymptomatic even with chronic disease, but prognosis depends on development of complications. Disseminated infection is fatal in 60-70% of cases.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Luc PARIS


STT3A-CDG is a form of congenital disorders of N-linked glycosylation characterized by developmental delay, intellectual disability, failure to thrive, hypotonia and seizures. STT3A-CDG is caused by mutations in the gene STT3A (11q23.3).


STT3B-CDG is a form of congenital disorders of N-linked glycosylation characterized by intrauterine growth retardation, microcephaly, failure to thrive, developmental delay, intellectual disability, hypotonia, seizures, optic nerve atrophy and respiratory difficulties. Genital abnormalities (micropenis, hypoplastic scrotum, undescended testes) have also been reported. STT3B-CDG is caused by mutations in the gene STT3B (3p24.1).


A rare congenital neurocutaneous syndrome defined by a facial capillary malformation or port-wine birthmark (PWB) associated with cerebral and ocular ipsilateral vascular malformations in most of the cases resulting in variable ocular and neurological complications.

Summary:
Epidemiology
The birth prevalence in Europe is estimated at around 1/20,000 to 1/50,000.
Clinical description
The facial port-wine birthmark is present at birth and covers the forehead and/or the upper eyelid (at risk zone). Glaucoma is the most common ocular complication, affecting 30 to 60% of patients with a risk of early visual impairment. Epilepsy is often the first neurological manifestation. Around 80% of patients develop seizures at a median age of 6 months. First seizures are usually focal motor. Drug resistant seizures are reported in up to 50% of patients and status epilepticus is commonly seen. Fever induced seizures are frequently reported. A pattern of seizure clustering followed by prolonged period of seizure freedom occurs in 40% of cases. The natural history is highly variable but typically marked by seizures in early childhood, stroke-like events, progressive hemiparesis and developmental impairment, glaucoma and visual field defects. Later manifestations include headaches, academic difficulties, behavioral and psychiatric disorders. An increased risk of growth hormone deficiency is reported.
Etiology
The syndrome is caused by a somatic mosaic mutation in GNAQ (9q21) that codes for the protein guanine nucleotide-binding protein G(q) subunit alpha which is critical to the intracellular signaling of a large group of G protein coupled receptors important to vascular development and function. Mutations in GNAQ can also result in an isolated PWB phenotype. The phenotypic presentation is thought to be determined by the developmental time point at which the somatic mutation occurs.
Diagnostic methods
Diagnosis is suspected at birth in newborns presenting facial PWB in the at risk zone. The risk of cerebral involvement in such situation ranges between 15 and 40%. Diagnosis can be confirmed by a contrast-enhanced cerebral magnetic resonance imaging showing direct (angioma) and indirect (enlargement of choroid plexus unilaterally) radiological signs of the leptomeningeal angioma. A computer tomography scan can help diagnosis showing localized calcifications and atrophy, although they might develop later during the course of the disease. Electroencephalogram (EEG) recording can show decreased amplitude of the EEG signal on the side of brain involvement.
Differential diagnosis
The main diagnostic concern is to separate infants with an isolated facial PWB from those with Sturge-Weber syndrome (SWS) brain involvement. Differential diagnosis includes PIK3CA-related overgrowth syndromes, especially megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome.
Antenatal diagnosis
Prenatal ultrasounds are usually normal.
Genetic counseling
The disease is sporadic and due to somatic mutations.
Management and treatment
A multidisciplinary approach is needed from onset to monitor disease progression in the skin, eye, and brain. Laser treatment is proposed in infancy to reduce the PWS. Regular ocular monitoring is recommended throughout life. Eye drops are used to lower intraocular pressure but surgical interventions may be required. Parental education for early seizure recognition and individualized emergency plans including the use of rescue benzodiazepine therapy is recommended. Low-dose aspirin might be useful to prevent the stroke-like episodes and possibly seizures but the risk-benefit ratio of such approach is not well established. Antiseizure medications are used to treat epilepsy. Patients with focal drug-resistant seizures should be considered early for pre-surgical evaluation at a reference center. Neuropsychological assessments and rehabilitation are needed and physiotherapy is required for functional deficits.
Prognosis
The prognosis of SWS is highly variable. Early seizure onset, drug-resistant seizures and bilateral intracranial involvement have been associated with poor cognitive outcomes.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Katarzyna KOTULSKA-JOZWIAK | EpiCARE* - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


A rare genetic neurological disorder characterized by a phenotypic spectrum comprising severe intellectual disability, developmental delay, and, in the majority of cases, early-onset epilepsy. The most frequent seizure type are epileptic spasms, but a broad spectrum of seizure types has been reported. Motor disturbances include ataxia, hypotonia, dystonia, tremor, spasticity, and dyskinesia. Some patients may also present with autism/autistic-like features. Older patients have been reported to show signs of parkinsonism, including tremor, bradykinesia, and antecollis.


Stüve-Wiedemann syndrome (SWS) is a rare autosomal recessive congenital primary skeletal dysplasia, characterized by small stature, bowing of the long bones, camptodactyly, hyperthermic episodes, respiratory distress/apneic episodes and feeding difficulties that usually lead to early mortality.

Summary:
Epidemiology
SWS is a rare syndrome with few cases reported to date, but the disease is relatively common in the United Arab Emirates, apparently due to a high number of consanguineous unions, with a reported prevalence of approximately 0,5/10,000 births.
Clinical description
SWS is characterized by short stature, bowing of extremities that affect the lower limbs more than the upper limbs, camptodactyly, respiratory distress/apneic spells and hyperthermic episodes frequently associated with feeding/swallowing difficulties. Other clinical findings are mask-like face, pursed mouth, hypoplastic midface, osteopenia, congenital contractures and muscular hypotonia. The condition is fatal in most cases as a result of respiratory distress or hyperthermia. However, survival beyond one year have been reported in few cases, and patients develop severe spinal deformities, along with streaky osteoporosis and spontaneous fractures, bowing of the lower limbs (with prominent joints) and dysautonomia (including temperature instability, absent corneal and patellar reflexes, and smooth tongue). Motor development is generally delayed but no intellectual deficit has been reported.
Etiology
SWS is due to missense or nonsense mutations in the leukemia inhibitory factor receptor (LIFR) gene (5p13.1). These null mutations lead to modifications in the stability of the LIFR transcripts, inhibiting synthesis of the LIFR protein and resulting in alterations in the JAK/STAT3 signaling pathway. In some patients diagnosed for SWS, LIFR mutations were not identified, suggesting that other genes may be involved in the disease.
Diagnostic methods
The diagnosis of SWS is mainly postnatal, based on clinical and radiological findings. Radiographic examination reveals bowed long bones with cortical thickening and rarefaction, wide metaphysis with decreased density and blurred margins, and abnormal trabecular pattern. Other features include flared iliac wings, hypoplasia of the lower ilia. Genetic molecular testing for LIFR mutation may be useful to confirm SWS diagnosis.
Differential diagnosis
Differential diagnosis includes Crisponi syndrome (cold-induced sweating syndrome) and other skeletal dysplasias, such as Ehlers-Danlos syndrome type IX, Campomelic dysplasia and autosomal dominant Larsen syndrome (see these terms).
Antenatal diagnosis
In some cases, ultrasound examination may be useful to predict the presence of SWS before birth. Prenatal symptoms can sometimes be seen in the late second- or third trimester and include oligohydramnios, intrauterine growth restriction despite normal Doppler findings about the umbilical artery, camptodactyly, bowing of the lower bones affecting the tibia more than the femur, and micromelia.
Genetic counseling
SWS is a congenital condition inherited as an autosomal recessive disorder.
Management and treatment
To date, SWS management is only symptomatic and should include prevention of lung aspirations and chocking while eating (intubation, nasogastric tube feeding and/or gastrostomy often required during the first year of life), physiotherapy and/or surgery for bone malformations, eyes protection from damage to prevent visual loss, and osteopenia or osteoporosis treatment. Predisposition to hyperthermia necessitates caution during procedures requiring anesthesia.
Prognosis
SWS is a life-threatening disease which is usually fatal during the neonatal period, due to respiratory distress or hyperthermic episode. However, more patients are surviving for longer (into and, in some cases, beyond adolescence), if diagnosed and monitored appropriately.

                            Last update:
                            March 2016

                            - Expert reviewer(s):
                            Pr Cheryl JORCYK  - Dr Dawn MIKELONIS  - Pr Julia OXFORD  -  Ken TAWARA


A form of cutaneous lupus erythematosus (CLE) that can present either as a non-scarring, annular photo-distributed dermatosis or psoriasiform plaques. This disorder is associated with anti-Ro/SSA antibodies and can be drug-induced.


Subacute inflammatory demyelinating polyneuropathy (SIDP) is a subacute progressive symmetric sensorial and/or motor disorder characterized by muscular weakness with impaired sensation, absent or diminished tendon reflexes and elevated cerebrospinal fluid (CSF) proteins. SIDP is an intermediate form between Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP; see these terms).

Summary:
Clinical description
The time to maximum severity (nadir) and the subsequent course of SIDP differentiate it from GBS and CIDP. Onset can occur at any age but is more common between the 4th and 5th decades. When onset is in childhood, SIDP is rather considered as CIDP. Males are predominantly affected. Patients present a 4 to 8 week history of progression of monophasic demyelinating neuropathy (DN) associated with the occurrence of a symmetric progressive weakness in both proximal and distal muscles with impaired sensation and absent/diminished tendon reflexes. Neuropathy is symmetric and can be either sensorimotor or pure motor in nature. Rarely, cranial nerve dysfunction and respiratory failure may occur.
Etiology
SIDP, like CIDP, could be due to an immune reaction, resulting in segmental demyelination which may induce a concomitant axonal loss.
Diagnostic methods
Diagnosis is based on clinical and electrophysiological findings. CSF analysis and histological findings can provide additional supportive data but are not mandatory. Four diagnostic criteria allow definite diagnosis: progressive motor and/or sensory dysfunction consistent with neuropathy in more than one limb with time to nadir between 4 to 8 weeks, electrophysiological evidence of demyelination at least in 2 nerves (EMG and nerve conduction study), no other etiology of neuropathy and no relapse on adequate follow-up (in the absence of this last criterion, a probable SIDP is diagnosed). In addition, supportive criteria include raised CSF proteins and segmental and multifocal demyelination in nerve biopsy (in clinically suspected SIDP cases in which electrophysiological proof of demyelination is absent). Cytoalbuminologic dissociation in CSF is characteristic, pointing to nerve root involvement. Occasionally, CSF studies reveal mild lymphocytic pleocytosis and elevated gamma globulins. SIDP presents mostly the same clinical manifestations as CIDP with 3 exceptions: a higher rate of history of infection (about 40% of cases), no relapsing course and a higher rate of recovery to normal.
Differential diagnosis
Differential diagnosis includes GBS and rarely some other acquired polyneuropathies (monoclonal gammopathy (see this term), infections, or systemic inflammatory or immune-mediated diseases, toxic neuropathies, neuropathy due to nutritional deficiency).
Management and treatment
Most patients respond to steroid therapy (prednisone). A few cases may also require intravenous immunoglobulins (IVIg) and/or plasmapheresis.
Prognosis
The earlier treatment begins in the course of the disease, the higher the rate of recovery to normal (70%) and 30% of patients have partial recovery; some of these cases may progress to CIDP. Rare cases of spontaneous remission have also been reported.

                            Last update:
                            December 2010

                            - Expert reviewer(s):
                            Pr Jean-Michel VALLAT


A rare infectious disease characterized by slowly progressive brain disorder caused by a mutant measles virus, typically affecting children and young adults. The condition leads to cognitive decline, myoclonus, vision loss, and eventually a vegetative state.

Summary:
Epidemiology
The global burden of subacute sclerosing leukoencephalitis (SSPE) is greater in countries with high measles incidence. According to the WHO, there is one case of SSPE every 9,090 to 25,000 measles cases, increasing to one SSPE case every 5,555 measles cases in early childhood. Higher incidences are reported in resource-constrained countries such as India, Pakistan, Papua New Guinea, and Turkey. In high-income countries, fewer cases are seen due to vaccination efforts, though outbreaks can still lead to new SSPE cases. Additionally, the risk of SSPE is twice as high in males.
Clinical description
In children, SSPE starts with cognitive decline, poor school performance, forgetfulness, behavioral changes, and gait abnormalities. Verbal output diminishes, progressing to akinesia and mutism. Patients develop pyramidal signs, periodic myoclonus, and eventually enter a vegetative state with autonomic instability. Ophthalmological symptoms, such as chorioretinitis and vision loss, may precede neurological signs. SSPE is almost always lethal. Diagnosis is supported by characteristic electroencephalogram (EEG) findings and elevated measles antibody titers in the cerebrospinal fluid.
Etiology
SSPE results from mutant measles virus entry during acute infection. Mutations in the virus genome, particularly in the M and F genes, enable viral persistence and transneuronal spread. The virus enters the brain via infected monocytes, endothelial cells, or the olfactory bulb. Hyperfusogenic properties due to changes in the F protein and defective M protein facilitate viral survival and spread, with genetic susceptibility influencing disease development.
Diagnostic methods
EEG reveals characteristic periodic discharges, while neuroimaging shows periventricular white matter abnormalities and significant cerebral atrophy in advanced stages. Diagnosis is confirmed by elevated measles antibody titers in cerebrospinal fluid.
Differential diagnosis
The differential diagnosis of SSPE includes autoimmune encephalopathies, vitamin B12 deficiency, herpes simplex encephalitis, neurosyphilis, and progressive multifocal leukoencephalopathy in HIV patients. Misdiagnosis can involve psychiatric disorders, autoimmune encephalitis, eclampsia, brain tumors, and acute disseminated encephalomyelitis, potentially leading to incorrect treatments.
Management and treatment
Universal measles vaccination has significantly reduced the incidence of SSPE. However, treatment remains challenging, with no proven effective therapies currently available. Although various drugs, such as isoprinosine, interferon-alpha, and ribavirin, are used to manage SSPE, there is a lack of randomized clinical trials to support their efficacy. About 6% of patients may experience extended spontaneous remission. Future treatments might involve fusion inhibitor peptides, but universal measles vaccination remains the only proven preventive measure.
Prognosis
SSPE is almost always lethal, typically within 1-3 years, with ~60% of patients surviving less than 2 years. Survival rates vary, with some cases experiencing prolonged remission of up to 18 years. In cases of fulminant SSPE, death occurs rapidly, often within 6 months.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Pr Ravindra Kumar GARG


Subaortic course of innominate vein is a rare congential anomaly of the great veins characterized by an anomalous course of the left brachiocephalic vein, passing from left to right below the aortic arch and entering the superior vena cava below the orifice of the azygos vein. Patients are frequently asymptomatic and diagnosed incidentally on imaging studies. Other cardiac malformations may be associated.


Subaortic stenosis-short stature syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the association of short stature and progressive discrete subaortic stenosis. Additional variable manifestations include upturned nose, voice and vocal cord abnormalities, obstructive lung disease, inguinal hernia, kyphoscoliosis and, occasionally, epicanthus, strabismus, microphthalmos and widely spaced teeth. There have been no further descriptions in the literature since 1984.


A rare, acquired, chronic neutrophilic dermatosis characterized by sterile superficial pustules, typically involving the flexural sites of the trunk and proximal extremities.

Summary:
Epidemiology
Approximately 200 cases have been reported worldwide. The disease occurs more frequently in adults (40-60 years of age with a male to female ratio of 4:1).
Clinical description
Superficial flaccid grouped pustular lesions, which spread in an annular or gyrate pattern, arise within a few hours and resolve over a few days. Pruritus and irritation occur occasionally. The lesions characteristically evolve to fine scales with crusting and, in rare cases, mild hyperpigmentation. The disease may be associated with IgA monoclonal gammopathy, multiple myeloma or pyoderma gangrenosum. Less frequently associated conditions include rheumatoid arthritis, lupus erythematosus, hyperthyroidism and hypothyroidism, polycythemia rubra vera, SAPHO syndrome.
Etiology
The etiology remains unknown.
Diagnostic methods
Diagnosis is confirmed by skin biopsy demonstrating a sterile subcorneal pustule filled with neutrophils, an absence of acantholysis, and negative results from immunofluorescence studies.
Differential diagnosis
Differential diagnosis includes the subcorneal-type of IgA pemphigus, pemphigus foliaceus, dermatitis herpetiformis, pustular psoriasis, generalized pustulosis, generalized exanthematous pustulosis and bacterial impetigo.
Management and treatment
Management aims at preventing the complications. A dramatic response to dapsone has been reported but not all patients respond to this drug. In cases refractory to dapsone, other possible treatments (in combination with dapsone or not) include sulfapyridine, oral corticosteroids, tetracycline with niacinamide, retinoids, colchicine, phototherapy, and TNF-alpha inhibitors.
Prognosis
There is no impact on life expectancy for this disease. Dapsone is the drug of choice in most patients; lesions may resolve within weeks of treatment but maintenance doses may be needed to prevent relapses. In addition, addressing the underlying associated conditions has helped to achieve clinical response when done in conjunction with above treatments.

                            Last update:
                            July 2024

                            - Expert reviewer(s):
                            Dr Sung Kyung CHO  - Dr Victoria WERTH


A rare, non-syndromic cerebral malformation due to abnormal neuronal migration characterized by variable clinical manifestation depending on the location, size and thickness of subcortical bands. Clinical presentation ranges from mild cognitive deficit to developmental delay with severe intellectual disability, seizures and behavioral problems.


A rare cytotoxic cutaneous alpha-beta T-cell lymphoma characterized by solitary or multiple erythematous subcutaneous nodules and plaques that can be localized to the lower extremities or generalized. It has been recognized as a distinct subset of peripheral T-cell lymphomas originating and presenting primarily in the subcutaneous fat tissue and often associated with hemophagocytic lymphohistiocytosis.

Summary:
Epidemiology
The exact incidence is unknown but estimated around 1/10,000,000 individuals per year in Europe. A slight female preponderance has been reported. Median age of diagnosis is around 40 years old, but cases are reported from 1 to 90 years old.
Clinical description
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is characterized by solitary or multiple erythematous subcutaneous nodules and plaques (proliferation of T lymphocytes and macrophages in the subcutaneous fat lobule), which appear in crops and are localized to the lower extremities or may be more generalized. Systemic manifestations include fever, chills, malaise, weight loss, hepatosplenomegaly, mucosal ulcers, and serosal effusions. SPTCL may be accompanied by hemophagocytic syndrome (characterized by the proliferation of histiocytes and phagocytosis of blood elements, hepatosplenomegaly, and coagulopathy and reported in approximately 30-40% of cases), which may be fatal.
Etiology
The etiology is not completely understood. An infectious trigger events has been described in some pediatric cases. Recently, germline homozygous mutation of HAVCR2 has been associated with SPTCL in 32 to 85% of patients.
Diagnostic methods
Repeated biopsies may be required to establish the diagnosis. Pathology is characterized by CD8+ T cells expressing alpha-beta T cell antigen receptors (TCRs) and infiltrating subcutaneous adipose tissue, rimming adipocytes in a lace-like pattern, and adipocyte necrosis. The immunophenotype of the lymphoma is CD8+, CD56-, CD30-, granzymeB+, TiA-1, betaF1+. Molecular clonality assay should exclude gamma-delta T cell lymphoma which has a more aggressive course and is considered as a distinct entity.
Differential diagnosis
The differential diagnosis includes other lymphomas as well as atypical lobular panniculitis and cytophagic histiocytic panniculitis. Lupus panniculitis can be excluded by the frequent MxA staining on lymphocytes, macrophages and on clusters of CD123+CD303+ PDC, and by the presence of lymphoid follicles and B cells.
Genetic counseling
Transmission of HAVCR2-associated risk is autosomal recessive with incomplete penetrance. 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 a child with heterozygous HAVCR2 variant at each pregnancy.
Management and treatment
SPTCL may be rapidly fatal or indolent. Most patients respond to immunosuppressive drugs (ciclosporin A, corticosteroids, hydroxychloroquine or methotrexate). Systemic chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) is an available option in severe case or when associated with hemophagocytic lymphohistiocytosis. Allogeneic hematopoietic stem cell transplantation has been proposed in severe cases and is a curative treatment option, especially in HAVCR2-variant cases.
Prognosis
SPTCL is a life-threatening disease with a good prognosis in most cases. 2-years overall survival is estimated around 90% and complete remission around 80% with immunosuppressive drugs.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Pr David MICHONNEAU


A rare low-grade astrocytoma characterized by a benign, slowly growing lesion typically arising in the wall of the lateral ventricles, composed of large ganglioid astrocytes. The tumor corresponds to WHO grade I and typically occurs during the first two decades of life in patients with tuberous sclerosis complex. Most patients present with worsening of epilepsy or symptoms of increased intracranial pressure.


Subependymoma is a rare and slow growing type of ependymoma (see this term), often presenting in middle-aged adults, found more commonly in men than in women, usually located in the fourth and lateral ventricles and manifesting with variable symptoms including headache, nausea, and loss of balance. In some cases it can be asymptomatic. It is usually associated with a better prognosis than other forms of ependymoma.


Subepithelial mucinous corneal dystrophy (SMCD) is a very rare form of superficial corneal dystrophy characterized by frequent recurrent corneal erosions in the first decade of life, with progressive loss of vision.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is unknown. The condition has only been reported in one single family.
Clinical description
Painful episodes of recurrent corneal erosions occur in the first decade of life but decrease during adolescence. Later in life, patients are reported to develop subepithelial opacities and a corneal haze. SMCD eventually progresses over time leading to corneal opacities and loss of vision.
Etiology
The etiology is unknown but is thought to be genetic. The gene related to SMCD has not been mapped to a particular chromosomal locus.
Diagnostic methods
A striking morphologic feature of corneal tissue in this form of corneal dystrophy is the presence of subepithelial mucinous material revealed by special stains.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
SMCD can be treated medically with the aim of healing the epithelial defect and protecting the loosely adherent epithelium. A topical antibiotic, cycloplegic and pressure patch are valuable. A lubricating ointment is useful at night. Hypertonic saline and bandage contact lens therapy may also be beneficial.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare form of cleft palate characterized by congenital muscular diastasis of the soft palate along the midline with an intact oral and nasal mucosal lining. It is diagnosed by the triad of a bifid uvula, a translucent zone in the soft palate, and a bony notch in the posterior edge of the hard palate, all of which may vary in severity. Velopharyngeal insufficiency in the absence of this triad is classified as occult submucosal cleft palate. Patients may be asymptomatic or present with early feeding problems with fluid reflux through the nose, speech problems, recurrent otitis media with effusions, and hearing loss.


Succinic semialdehyde dehydrogenase deficiency

A rare neurometabolic disorder of gamma-aminobutyric acid (GABA) metabolism with a nonspecific clinical presentation (ranging from mild to severe) with the most frequent symptoms being cognitive impairment with prominent deficit in expressive language, hypotonia, ataxia, epilepsy, and behavioral dysregulation.

Summary:
Epidemiology
Approximately 450 cases have been reported in the literature to date.
Clinical description
The mean age of onset is 11 months. Contrary to what is seen in many metabolic encephalopathies, patients do not present with hypoglycemia, hyper-ammonemia, or intermittent lethargy. Infants usually present with a slowly progressive or static encephalopathy manifesting with hypotonia, hyporeflexia, ataxia and delayed acquisition of motor and language developmental milestones in the first two years of life. Seizures occur in more than half of all affected individuals and are usually generalized tonic-clonic or atypical absence. Intellectual disability, psychiatric manifestations (i.e. attention deficit hyperactivity disorder and aggression in early childhood, obsessive-compulsive disorder and anxiety in adolescence and adulthood) and sleep disturbances are commonly observed. Hyperkinetic behavior, self-injurious behaviors and hallucinations are reported in half of all cases. A more fulminating, early-onset presentation occurs in up to 10% of patients and is characterized by extrapyramidal signs and sometimes a progressive disease course.
Etiology
SSADH deficiency is due to mutations in the ALDH5A1 gene (6p22), encoding mitochondrial succinate-semialdehyde dehydrogenase, a protein involved in amino-acid degradation. A deficiency of SSADH enzyme activity impairs degradation of GABA, the brain's major inhibitory neurotransmitter, and thereby results in elevated concentrations of a putative toxic metabolite, gamma-hydroxybutyric acid (GHB), which is detectable in physiological fluids including blood, urine, and cerebrospinal fluid.
Diagnostic methods
The key laboratory diagnostic test suggestive of SSADH deficiency is urine organic acid analysis with results of elevated GHB. Findings from plasma analysis include elevated GHB and lymphocytes will display low SSADH enzymatic activity. In cerebrospinal fluid analysis, GHB and GABA will be elevated. Cranial magnetic resonance imaging shows increased bilateral and usually symmetrical T2-weighted signal involving the globus pallidi, as well as the cerebellar dentate nuclei and subthalamic nuclei. Electroencephalogram findings include mainly generalized background slowing and spike discharges. Molecular genetic testing revealing a mutation in the ALDH5A1 gene confirms diagnosis.
Differential diagnosis
The main differential diagnoses include gamma-aminobutyric acid transaminase deficiency and homocarnosinosis (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
SSADH deficiency is inherited in an autosomal recessive fashion. Genetic counseling is recommended.
Management and treatment
As there is no treatment currently available to effectively address the underlying disorder, long-term management of the phenotype focuses on pharmacologically controlling the most debilitating manifestations (typically seizures and neurobehavioral disorders). Carbamazepine and lamotrigine are effective in controlling seizures. Anxiety, aggressiveness, inattention, and hallucinations may be treated with benzodiazepines, methylphenidate, thioridazine, risperidone or fluoxetine. Physical and occupational therapy, sensory integration, and/or speech therapy may be beneficial in some cases.
Prognosis
The prognosis varies. Although most patients live until adulthood, neuropsychiatric symptoms can be disabling, decreasing quality of life. Early mortality, including sudden unexpected death in epilepsy patients (SUDEP), has been reported.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Dr Mahsa PARVIZ  - Dr Phillip PEARL


Succinyl-CoA:3-oxoacid CoA transferase deficiency

A rare, genetic disorder in ketone body utilization characterized by severe, potentially fatal intermittent episodes of ketoacidosis.

Summary:
Epidemiology
Over 30 cases have been reported to date.
Clinical description
Neonatal onset occurs in half of patients, presenting with a first ketoacidotic attack 2-4 days after birth. Patients with later onset present with an initial episode of ketoacidosis between 6-20 months of age. Initial episodes are often severe, and further episodes may be triggered by metabolic stress, infection or extended periods of fasting. Symptoms include tachypnea, vomiting, lethargy, hypotonia, and, in severe cases, coma. Episode intensity and frequency is variable and severe attacks are potentially fatal. Patients are generally healthy and develop normally between episodes, but infants may present with failure to thrive and poor feeding prior to diagnosis. Cardiomegaly has developed in two cases and may lead to congestive heart failure.
Etiology
This disease is caused by mutations in the OXCT1 gene (5p13) that encodes the mitochondrial enzyme, succinyl-CoA:3-oxoacid CoA transferase, essential for ketone body metabolism in all extrahepatic tissue. Over 30 different mutations to OXCT1 have been identified, all leading to the accumulation of ketone bodies and ketoacidosis during periods of catabolic stress. Partial loss-of-function mutations have been identified that also lead to severe ketoacidosis, but without permanent ketosis.
Diagnostic methods
Permanent ketosis or persistent ketouria are pathognomic features; however, some mild cases may not present with these signs. Patients display metabolic acidosis during crises and both serum and urinalysis reveal high levels of ketones, pH levels between 6.8 and 7.12, and HCO3 levels between 3-8 mmol/L may be observed. There is no characteristic organic acid or acylcarnitine profile. The ratio of free fatty acids to total ketone bodies becomes less than 0.3 during a short fast and this may lead one to suspect the disease. Enzyme activity assays using fibroblasts, lymphocytes or platelets reveal a lack, or great reduction, of functional succinyl-CoA:3-oxoacid CoA transferase.
Differential diagnosis
Differential diagnoses include physiological ketosis (e.g. ketoacidosis due to significant catabolism due to rotavirus infection) and ketoacidosis due to beta-ketothiolase deficiency or monocarboxylate transporter 1 deficiency.
Antenatal diagnosis
Prenatal diagnosis by enzyme activity assays is possible using cultured amniocytes.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling should be offered to affected families. There is a 25% risk of disease transmission to offspring where both parents are unaffected carriers.
Management and treatment
Ketoacidotic crises must be treated immediately with intravenous fluid therapy including enough glucose, even when patients show normo- or hyper-glycemia, to suppress ketogenesis. Treatment of metabolic acidosis using sodium bicarbonate is controversial. Minimal usage of sodium bicarbonate is recommended. Patients must avoid prolonged fasting. A fat-rich diet which induces ketogenesis should be avoided. Protein restriction may be not necessary, because the effect of prevention of ketoacidosis is not proven. Home monitoring of urinary ketones helps parents to follow the patient's condition. Carbohydrate-rich food or drink should immediately be provided if ketone levels are higher than usual. If patients become weak or vomit, intravenous glucose infusions should be considered. There is no recommended medication for the chronic phase. The use of oral sodium bicarbonate and L-carnitine have been reported in the literature, but the effect of prevention of ketoacidosis attack is not proven. Affected females should be closely monitored during pregnancy and delivery.
Prognosis
Risk of premature death is highest during the neonatal and infantile period due to severe episodes of ketoacidosis. However, the frequency and severity of ketoacidosis decreases after 10 years of age; thus, beyond this period, life expectancy maybe as good as in the general population. Normal growth and development is expected when proper treatment and diet are followed.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Toshiyuki FUKAO  - Dr Hideki MATSUMOTO


Sudden infant death-dysgenesis of the testes syndrome

Sudden infant death with dysgenesis of the testes (SIDDT) syndrome is a lethal condition in infants with dysgenesis of testes.

Summary:
Epidemiology
SIDDT syndrome has been described in 21 infants from nine separate sibships among the Old Order Amish.
Clinical description
Infants with SIDDT syndrome appear normal at birth except that they are often recognized by the unusual staccato sound of their cry. Within the first months of life, they develop signs of viscera-autonomic nerve dysfunction including bradycardia, hypothermia, severe gastroesophageal reflux, laryngospasm, bronchospasm, and abnormal cardiorespiratory patterns during sleep. XY males have testicular dysgenesis and ambiguous genitalia. Female sexual development is normal.
Etiology
SIDDT syndrome is caused by homozygous mutation in the testis-specific protein Y-like-1 gene, TSPYL1 on chromosome 6 (6q22.1-q22.31).
Genetic counseling
The syndrome follows an autosomal recessive pattern of inheritance.
Prognosis
Prognosis is very poor: infants die before 12 months of age of sudden cardiorespiratory arrest.

                            Last update:
                            December 2010


A rare otorhinolaryngologic condition characterized by sudden hearing loss of at least 30 decibels across three contiguous frequencies, within 72 hours or less, due to acute damage to the cochlear hair cells, resulting from acoustic trauma or mechanical trauma during surgery, or occurring without any known cause. The hearing loss may affect one or both ears. Typical concomitant symptoms are aural fullness, tinnitus, and vertigo. Patients may fully recover or remain with hearing loss of variable intensity.


Sugarman brachydactyly is a rare, genetic, congenital limb malformation characterized by brachydactyly of fingers, with major proximal phalangeal shortening and immobile proximal interphalangeal joints, as well as dorsally and proximally placed, non-articulating great toes (with or without angulation). Radiographic findings of hands include bilateral double first metacarpals and biphalangeal fifth fingers. There have been no further descriptions in the literature since 1982.


A rare primary headache disorder characterized by unilateral trigeminal pain that occurs in association with ipsilateral cranial autonomic symptoms (conjunctival injection and tearing).

Summary:
Epidemiology
The prevalence is estimated at approximately 1 in 15,000. It is slightly more predominant in males (male-to-female ratio of 1.5:1), with a mean age of onset of around 50 years. A few cases of SUNCT/SUNA syndrome have been reported in children.
Clinical description
The disease manifests with strictly unilateral pain attacks of moderate-to-severe or very severe intensity. The pain is described as throbbing, sharp or stabbing. It usually involves the ophthalmic division of the trigeminal nerve and, less commonly, may involve any part of the head. In the majority of cases, the pain attacks are triggered by cutaneous stimuli (and not by alcohol or nitroglycerin). Spontaneous attacks have also been described. The typical SUNCT/SUNA patient may have 50 to 100 short attacks a day, lasting for 1 to 5 minutes. The attacks predominate during the daytime. Prominent, ipsilateral conjunctival injection and lacrimation regularly accompany the attacks. Nasal stuffiness and rhinorrhea are frequent.
Etiology
Etiopathology remains unclear. Trauma, arteriovenous malformations and pituitary adenomas may have a causative role.
Diagnostic methods
The diagnosis is made after a careful history with attention to the features of the disorder as set out in the International Classification of Headache Disorders, 3rd Edition, careful physical examination and relevant investigations. Particular features of note are the relative brevity of lateralised attacks, their triggerability and the absence of a refractory period to stimulation.
Differential diagnosis
Trigeminal neuralgia is the major differential diagnosis. It is very important to differentiate SUNCT/SUNA syndrome from other trigeminal autonomic cephalgias such as cluster headache and paroxysmal hemicrania, as each of these syndromes have a highly selective response to treatment.
Management and treatment
There is no cure for SUNCT/SUNA syndrome. Patients may benefit from administration of lamotrigine, topiramate, gabapentin or carbamazepine. Oxygen, anaesthetic blockades, and sumatriptan or indomethacin therapies, known to be effective in other trigeminal autonomic cephalgias, have little or no effect in SUNCT syndrome. In severe cases, surgical techniques, such as microvascular trigeminal nerve root decompression, have been considered.
Prognosis
The prognosis is guarded in that most patients will continue to have attacks over many years.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Peter GOADSBY


The superficial corneal dystrophies refer to a group of rare genetically determined corneal dystrophies (CDs) characterized by lesions affecting the corneal epithelium and its basement membrane and the superficial corneal stroma, and variable effects on vision depending on the type of dystrophy.

Summary:
Epidemiology
Prevalence of this group of corneal dystrophies is unknown, but all are rare and found mainly in populations carrying the responsible mutated genes.
Clinical description
Age of onset is variable, between early childhood and the second decade of life. Eight subtypes of superficial corneal dystrophy have been identified: Grayson-Willbrandt CD, Epithelial recurrent erosion dystrophy, Subepithelial mucinous CD, Meesmann CD, Lisch epithelial CD, Gelatinous drop-like CD, Reis-Bücklers CD, and Thiel-Behnke CD (see these terms).
Etiology
Genetic heterogeneity has been reported but all superficial corneal dystrophies appear to be genetically determined, and are usually inherited as Mendelian traits. Mutations in four genes:KRT3 (12q13.13), KRT12 (17q11-q12), TGFBI (5q31), and TACSTD2 (1p32), are currently known to cause inherited diseases that are apparently limited to the superficial cornea.
Genetic counseling
Transmission is autosomal dominant, autosomal recessive, or X-linked recessive depending on the condition.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH