Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature due to pre- and postnatal growth delay, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to certain cancers.

Summary:
Epidemiology
The prevalence is unknown, but around 300 cases have been reported so far.
Clinical description
The skin is usually normal at birth but erythema develops on the cheeks at 3-6 months of age and subsequently spreads to the extremities and buttocks. The trunk and abdomen are generally spared. During the course of the disease, cutaneous atrophy with reticulated areas of hypo- and hyperpigmentation and persistent telangiectasias develop. Other cutaneous manifestations include dental anomalies, nail dystrophy and palmo-plantar hyperkeratotic lesions. The extracutaneous manifestations are clinically heterogeneous and two subforms of RTS have been defined: RTS type 1 (RTS1; see this term) characterized by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTS type 2 (RTS2; see this term) characterized by poikiloderma, congenital bone defects (frontal bossing, saddle nose and radial ray defects: thumb hypo- or aplasia or radial aplasia) and an increased risk of osteosarcoma (see this term) in childhood and cutaneous squamous cell carcinoma later in life. Gastrointestinal (chronic emesis and diarrhea), respiratory, and benign and malignant hematological manifestations (anemia, neutropenia and myelodysplasia), as well as hypogonadism and osteopenia, have been reported in some patients.
Etiology
RTS2 is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (8q24.3; detected in 60-65% of RTS patients), whereas the etiology in RTS1 remains unknown.
Diagnostic methods
Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes.
Differential diagnosis
The differential diagnosis should include other causes of childhood poikiloderma and other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, xeroderma pigmentosum, Kindler syndrome, poikiloderma with neutropenia, and dyskeratosis congenita; see these terms), and the allelic disorders, RAPADILINO syndrome (in which radial ray defects are a constant feature, poikiloderma is absent and the risk of malignancy is lower) and Baller-Gerold syndrome (which is associated with craniosynostosis; see these terms).
Genetic counseling
RTS is transmitted in an autosomal recessive manner. Genetic counseling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTS2.
Management and treatment
Management should include laser treatment for the telangiectatic lesions, annual ophthalmic examinations and a radiological survey in case of bone pain, limping or fractures (indicators of osteosarcoma). RTS patients may show increased susceptibility to the adverse effects of chemotherapy, and a higher risk of a secondary malignancy (5% risk of developing skin cancer).
Prognosis
The prognosis in RTS is variable: life expectancy is normal in the absence of cancer, whereas outcomes in patients with malignant pathologies depend on the quality and frequency of cancer screening and treatment.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Laurence OLIVIER-FAIVRE


A benign, inherited liver disorder characterized by chronic, predominantly conjugated, nonhemolytic hyperbilirubinemia with normal liver histology.

Summary:
Epidemiology
Rotor syndrome (RT) is a very rare disorder: the exact prevalence is unknown but over 50 cases have been reported in literature so far.
Clinical description
It is usually diagnosed in children or adolescents, but mild jaundice is often noted from birth. The main symptom consists of mild-to-moderate, recurrent jaundice without pruritus. Attacks of abdominal pain and low-grade fever can occur but are rare. Total serum bilirubin (mainly in the conjugated form: 50-80%) is elevated, usually between 2 and 5 mg/dl. Hematologic tests (including measurements of liver enzyme activities) and liver histology are normal. However, absolute and relative concentrations of urinary coproporphyrin I are elevated. Hemolysis is not a feature of the syndrome; however, coinheritance of hemolytic disorders, such as G-6-PD deficiency and beta thalassemia (see these terms), has been reported.
Etiology
Analysis of the retention of the cholephilic dyes indicates that RT results from a defect in hepatic storage capacity of conjugated bilirubin and other organic cholephilic anions.
Diagnostic methods
As the genetic basis remains unknown and the clinical, biochemical and histological features are non-specific, RT syndrome remains a diagnosis of exclusion. RT should be considered in all patients exhibiting predominantly conjugated hyperbilirubinemia with no concomitant change in liver enzyme activities (i.e. aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase) and in the absence of any septic condition, ultrasound anomaly of the liver or interfering drug. In this context, elevated (250 to 500% higher than controls) urinary concentrations of both total coproporphyrins and coproporphyrin I are very suggestive, but not completely specific for RT. Taken together with these findings, normal liver histology generally allows the diagnosis to be confirmed.
Differential diagnosis
The principle differential diagnosis is Dubin-Johnson syndrome (DJS; see this term). DJS and RT can be distinguished on the basis of measurements of urinary coproporphyrin excretion (total coproporphyrin excretion levels are normal in DJS) and liver histology (black-brown liver cell pigmentation is specific to DJS). If liver biopsy is not feasible or is refused, 99mTc-HIDA cholescintigraphy (revealing prominent kidney excretion in RT) or molecular analysis (detection of ABCC2 gene mutations in DJS patients) can be useful for distinguishing between RT and DJS.
Genetic counseling
RT appears to be inherited in an autosomal recessive manner, with the parents and siblings of affected individuals showing a pattern of urinary coproporphyrin excretion that is intermediate between that of RT patients and controls.
Management and treatment
As RT is a benign condition, no specific treatment is recommended or generally required. Affected individuals are advised to avoid alcohol and hepatotoxic drugs.
Prognosis
The prognosis for RT patients is good, highlighting the need for correct diagnosis to avoid unnecessary diagnostic procedures, treatment and follow-up. Unless there is a concomitant chronic liver disease, progression to liver failure, cirrhosis or hepatic fibrosis is not observed.

                            Last update:
                            January 2010

                            - Expert reviewer(s):
                            Dr Véronique BARBU  - Dr Christophe CORPECHOT


A rare demyelinating hereditary motor and sensory neuropathy characterized by prominent gait ataxia, pes cavus, tendon areflexia, distal limb weakness, tremor in the upper limbs, distal sensory loss, kyphoscoliosis, and progressive muscle atrophy. The disease becomes symptomatic in infancy or childhood, mode of inheritance is autosomal dominant.


A rare chronic encephalitis developing up to several years after congenital rubella virus infection or rubella infection in childhood, characterized by slowly progressive, wide-spread neurological symptoms, like cognitive decline, cerebellar ataxia, spasticity, and seizures, amongst others. Progredient deterioration of the neurological disease eventually leads to the death of the patient.


A rare, genetic malformation syndrome characterized by congenital anomalies (microcephaly, specific facial characteristics, and broad thumbs and halluces), short stature, intellectual disability and behavioral characteristics.

Summary:
Epidemiology
Birth prevalence is estimated at around 1/100,000 to 125,000.
Clinical description
Facial features, which become more prominent with age, include highly arched eyebrows, long eyelashes, downslanting palpebral fissures, convex nasal ridge, low hanging columella, highly arched palate and micrognathia. Talon cusps are very frequent on the permanent incisors. An unusual smile with almost complete closure of the eyes is present in most individuals. Other physical findings may include eye anomalies (nasolacrimal duct obstruction, congenital glaucoma, refractive errors), a variety of congenital heart defects (e.g. ventricular and atrial septal defect, patent ductus arteriosus), joint hypermobility, and skin anomalies (in particular keloid formation). Feeding difficulties are frequently observed in the first year, and respiratory tract infections are very common in infancy and childhood. Constipation is generally a life-long problem, and patients may become overweight during late childhood or early puberty. The children have a marked ability to establish excellent social contacts. In adulthood, sudden mood changes and obsessive-compulsive behavior may gradually become more frequent. Other than previously thought, persons with Rubinstein-Taybi syndrome under the age of 40 have no increased risk of getting malignant tumors. It is unclear whether this risk is increased in the elderly with Rubinstein-Taybi syndrome.
Etiology
Causes of Rubinstein-Taybi syndrome include: a microdeletion of chromosome 16p13.3 or chromosome 22q13.2, a variant in CREB-binding protein (CREBBP, 16p13.3) or a variant in E1A-binding protein p300 (EP300, 22q13.2). CREBBP and EP300 show a very high degree of homology and both play important roles as transcriptional coactivators; however, the exact pathogenesis of the syndrome remains uncertain. There is no significant genotype-phenotype correlation, except in the case of individuals with a EP300 mutation who on average have a higher level of functioning, less marked distal limb malformations, and a more pronounced microcephaly.
Diagnostic methods
The diagnosis is in essence based on clinical examination. A cytogenetic or molecular abnormality can be detected in about 65% of individuals.
Differential diagnosis
The syndrome can sometimes be difficult to differentiate from Saethre-Chotzen syndrome, Floating Harbor syndrome and Cornelia de Lange syndrome.
Antenatal diagnosis
If a cytogenetic or molecular abnormality is found in the affected child, reliable prenatal diagnosis is possible in future pregnancies through chorionic villus biopsy. Prenatal ultrasound only rarely allows a reliable diagnosis.
Genetic counseling
The syndrome is almost always sporadic, most cases resulting from de novo mutations. For a couple with an affected child, accumulating data suggest a recurrence risk of approximately 0.5%. If a person with Rubinstein-Taybi syndrome is able to reproduce, the recurrence risk is 50% as the transmission is autosomal dominant.
Management and treatment
All individuals should have a cardiac assessment at the time of diagnosis and should be checked for hearing loss or diminished vision (every 3 years in children and every 5 years in adults). Specialized educational programs are required, with early emphasis on psychomotor development and speech therapy. Children should be tested at regular intervals with a systematic developmental assessment starting at age 3-4 years, to ensure adequate educational support compatible with each child's potential. If surgery is required, individuals undergoing general anesthesia should be under the care of an anesthesiologist comfortable with complex airway problems and aware of the increased risk of aspiration and cardiac arrhythmia upon the use of cardioactive drugs.
Prognosis
Life expectancy does not seem to be explicitly altered.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr L.A. [Leonie] MENKE | ITHACA*

                                * European Reference Network


Ruvalcaba syndrome is an extremely rare malformation syndrome, described in less than 10 patients to date, characterized by microcephaly with characteristic facies (downslanting parpebral fissures, microstomia, beaked nose, narrow maxilla), very short stature, narrow thoracic cage with pectus carinatum, hypoplastic genitalia and skeletal anomalies (i.e. characteristic brachydactyly and osteochondritis of the spine) as well as intellectual and developmental delay.


A rare, multisystemic inherited metabolic diseases characterized clinically, by a variable spectrum of severity, primarily comprised of psychomotor delay, myopathy and liver dysfunction. Most patients present in infancy, but the onset can be already in utero or in adult age. Hypermethioninemia is frequent, but often absent in infancy. Creatine kinase is elevated in most patients.

Summary:
Epidemiology
Approximately 15 cases of S-adenosylhomocysteine hydrolase (SAHH) deficiency have been described to date.
Clinical description
Disease onset is typically in infancy, but may occur in utero or in adult age. In infancy, the clinical picture is typically comprised of developmental delay and hypotonia due to myopathy with markedly increased creatine kinase (CK) plasma levels, and more variably with cerebral hypomyelination, coagulation abnormalities and hepatopathy. Microcephaly, strabismus and behavioral changes are frequent. Severe cases may present in utero with fetal hydrops, congenital brain anomalies (pontine and cerebellar hypoplasia, hypoplastic corpus callosum), synthetic liver failure, respiratory insufficiency due to severe muscle weakness and death in early infancy. Specific biochemical findings include markedly increased plasma S-adenosylhomocysteine (AdoHyc) and S-adenosylmethionine (AdoMet) in combination with normal or near normal total homocysteine (tHcy) and hypermethioninemia which is not always present, particularly not in early infancy. Whilst the disease is typically severe with poor developmental outcomes, the phenotype can vary from mild to asymptomatic (one report). The milder phenotype includes later disease onset and milder weakness and developmental delay. Hepatocellular carcinoma was reported in one patient and was possibly present in another.
Etiology
The disease is due to mutations in the gene encoding S-adenosylhomocysteine hydrolase, AHCY (20q11.22), an enzyme involved in methionine metabolism.
Diagnostic methods
Diagnosis should be suspected in patients with any combination of the clinical symptoms and in all patients with unexplained hypermethioninemia. Marked elevations of AdoMet and AdoHcy, in combination with normal or near normal tHcy are characteristic for the disease, thus plasma AdoMet and AdoHcy should be measured where there is clinical suspicion for the disease. Since these biochemical assays are poorly available, gene analysis could be a better choice. The latter , as well as enzyme assay of AdoHcy hydrolase, serves also for confirmation of the diagnosis.
Differential diagnosis
Based on the multiorgan clinical presentation, SAHH deficiency has a very wide differential diagnosis, with chronic myopathies, muscular dystrophies, floppy infant syndrome and group of isolated persistent hypermethioninemias being the most important.
Antenatal diagnosis
Prenatal testing is possible if a genetic mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers of the disease, the risk of transmission to offspring is 25%. There is variable disease severity between different families. Intrafamilial variability is also possible.
Management and treatment
Whilst there is little evidence to support specific treatment strategies, the current consensus is on a methionine-restricted diet (with methionine-free amino acid mixture supplementation), which can decrease and sometimes even normalize plasma AdoMet and AdoHcy. Subsequent close clinical and biochemical monitoring seem mandatory. Phosphatidylcholine, creatine and cysteine supplementation may be beneficial. Liver transplantation has resulted in clinical and biochemical improvement in a single case.
Prognosis
Prognosis depends on the severity of the disease and ranges from death during the neonatal period to survival into adulthood and possibly normal life span. Functional outcomes in surviving patients are frequently severe, with the most common impact on neurodevelopment and mobility. Long term follow-up is missing in most patients and accurate and precise prognosis is not possible. Whilst dietary management is promising in some cases, it is not effective in all (improving metabolic parameters but not functional outcomes). Evidence on liver graft is limited.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Ivo BARIC


A rare autosomal recessive disorder of the lysine catabolism characterized by elevated levels of lysine in the cerebrospinal fluid and blood with variable degrees of saccharopinuria. Some patients present with neurological symptoms such as seizures, spastic diplegia, mild psychomotor delay, intellectual deficit, and behavioral difficulties. However, current findings suggest no causal association between isolated hyperlysinemia and neurological symptoms.


Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome is a rare, genetic, neural tube defect malformation syndrome characterized by sacral agenesis and abnormal vertebral body ossification with normal vertebral arches associated with notochord canal persistence on ultrasonography. Additional findings include bilateral clubfoot, oligohydramnios, single umbilical artery and, in some, increased nuchal translucency.


A syndrome characterized by unilateral or bilateral coronal synostosis, facial asymmetry, ptosis, strabismus and small ears with prominent superior and/or inferior crus, among other less common manifestations.

Summary:
Epidemiology
Saethre-Chotzen syndrome (SCS) prevalence ranges from 1/25,000 to 1/50,000 livebirths.
Clinical description
SCS has a variable spectrum of manifestations. Classic SCS presents at birth with synostosis of coronal (less commonly in conjunction with sagittal, metopic or lambdoid) sutures resulting in abnormal skull shape, facial asymmetry, low frontal hairline, ptosis, strabismus, tear duct stenosis and small ears with prominent crus. Brachydactyly, broad toes, partial cutaneous syndactyly of digits 2 and 3 of the hand, duplicated distal phalanx of the hallux are also often present. Intelligence is normal in most, but mild to severe developmental delay has been reported, primarily in cases with a large genomic deletion. Some may experience conductive and/or sensorineural hearing loss. Less common manifestations include short stature, hypertelorism, cleft palate, bifid uvula, maxillary hypoplasia, lacrimal duct stenosis, parietal foramina, vertebral anomalies, radioulnar synostosis, obstructive sleep apnea and congenital heart malformations. Mild phenotypes include patients with ptosis or blepharophimosis with or without craniosynostosis. Elevated intracranial pressure (ICP) associated with severe cases of synostosis may lead to headaches, visual loss, seizures and death if untreated.
Etiology
SCS is due to point mutations or deletions involving (or removing completely) the TWIST1 gene (7p21), which encodes a basic helix-loop-helix (bHLH) transcription factor responsible for cell lineage determination and differentiation. Loss of function mutations in this gene lead to the induction of premature cranial suture fusion. Gene deletions cause more severe phenotypes, usually associated with significant neurocognitive delays.
Diagnostic methods
Diagnosis is based mainly on the presence of characteristic clinical findings. CT of the head and radiographs are useful in characterizing abnormalities of the skull, spine and limbs. Molecular genetic testing can identify a TWIST1 mutation or deletion, confirming diagnosis.
Differential diagnosis
Although several features (such as 2-3 syndactyly of the hand) are unique to SCS, differential diagnoses include other syndromic forms of craniosynostosis such as Muenke, Baller-Gerold, Pfeiffer, and Crouzon syndromes as well as isolated unilateral coronal synostosis. Robinow-Sorauf syndrome is now considered within the spectrum of SCS, typically with milder features. Mutations in FGFR3, FGFR2, TCF12, RECQL4, and EFNB1 have been reported to cause synostosis conditions that phenotypically overlap with SCS. This is not surprising, as there is evidence that FGFR and TWIST1 may be integrated into overlapping pathways, including in osteoblast differentiation. In addition, TWIST1 mutations have been noted in some cases of isolated single-suture craniosynostosis, including sagittal and unicoronal cases.
Antenatal diagnosis
Prenatal testing for a TWIST1 mutation is rare, but it can be performed in families with a known mutation or when an ultrasound shows craniosynostosis of unknown etiology.
Genetic counseling
SCS is inherited as an autosomal dominant trait. Genetic counseling is valuable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Treatment of SCS requires management by a multidisciplinary craniofacial team with follow-up until young adulthood. In general, patients must undergo cranioplasty in the first year of life to increase the intracranial volume and restore a more normal head shape. Recurrent increased ICP may necessitate further surgical expansion procedures. In childhood, orthodontic care and/or midfacial surgery may be necessary for treatment of airway obstruction and malocclusion. In those with cleft palate, surgical closure can be performed in the context of other malformations, with evaluation for velopharyngeal insufficiency and speech therapy offered as necessary. Routine evaluations of facial growth, hearing loss and psychomotor development are needed, as well as regular ophthalmologic examinations to monitor strabismus, amblyopia or chronic papilledema (that indicates increased ICP). Early intervention programs should be offered to children with developmental delay. Augmentation of hearing and supportive interventions related to deafness should be pursued when indicated.
Prognosis
In most cases, when treated and monitored from an early age, the prognosis is excellent. Developmental prognosis is worse for patients with a TWIST1 deletion, compared to those with point mutations.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Matthew BLESSING  - Dr Michael CUNNINGHAM


A rare bone disease characterized by secondary hyperparathyroidism in patients with chronic renal failure, caused by improper treatment in the early stages of the disease with retention of phosphorus, vitamin D deficiency, and disturbed calcium-phosphorus metabolism, which result in increased parathyroid hormone levels. Patients present with short stature, severe changes of the skull and jaws as well as other skeletal deformities, dental anomalies, ''brown tumors'' in the mouth, hearing loss, and neuropsychiatric disorders.


Saldino-Mainzer syndrome is characterised by the association of renal disease, retinal pigmentary dystrophy, cerebellar ataxia and skeletal dysplasia.

Summary:
Epidemiology
Around 10 cases have been described in the literature so far.
Clinical description
Mild to moderate short stature has also been reported. Radiologic studies reveal shortened phalanges with cone-shaped epiphysis. Femoral epiphyseal and metaphyseal anomalies are common.
Genetic counseling
The syndrome is transmitted as an autosomal recessive trait.

                            Last update:
                            July 2008


Salivary gland type cancer of the breast describes a group of uncommon neoplasms, usually seen in the salivary glands but occurring in the breast, with a variable clinicopathologic spectrum and divided into those with myoepithelial differentiation and those without. This group includes mammary adenoid cystic carcinoma, adenoid cystic carcinoma (see this term), mucoepidermoid carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma and oncocytic carcinoma.


A rare autosomal recessive lysosomal disease characterized by accumulation of GM2 gangliosides in the nervous system due to hexosaminidase A and hexosaminidase B deficiency as a consequence of biallelic pathogenic variants in the HEXB gene.

Summary:
Epidemiology
The prevalence of the disease is 1/380,000 live births.
Clinical description
The clinical picture is almost identical to that of Tay-Sachs disease: three forms have been described according to age of onset. The infantile form begins at 3-6 months of age for the early infantile (< 12 months) and 12-24 months for the late infantile. The earliest signs are an incessant startle response to noise, and a progressive loss of vision. Psychomotor regression appears during the second semester of life with hypotonia, amaurosis, rapidly pharmacoresistant epilepsy and progressive macrocephaly. A cherry-red macular spot is nearly always present and is strongly evocative even if not specific. Light visceromegaly or cardiomyopathy may be present in infantile Sandhoff disease, contrary to infantile Tay-Sachs disease. Muscular weakness progresses and leads to paralysis. The disorder degenerates into a state of decerebration and is fatal during childhood. Onset of the juvenile form is at 2-10 years of age, with progressive cerebellar ataxia, dystonia, behavioral disorders, and cognitive regression. Death occurs during the second decade. The adult form begins around the age of 10 or later, and is often not diagnosed until adulthood. The onset is insidious with a progressive course. Two initial clinical presentations are described: i) proximal lower limbs weakness with amyotrophy due to a motor neuropathy (mimicking progressive spinal amyotrophy; first complaint: difficulty to climb stairs) that eventually extends to upper limbs and distal parts of the limbs; ii) generalized cerebellar ataxia (more rarely dystonia). In the course of the disease the motor neuropathy almost always occurs, other motor symptoms may occur (dysarthria, swallowing disorder). Cognition is usually preserved.
Etiology
The causative gene HEXB encodes the beta subunit of hexosaminidase A and hexosaminidase B and is located on chromosome 5 (5q13.3).
Diagnostic methods
Hexosaminidase A and hexosaminidase B enzymatic activities on blood leukocytes is always very low compared to normal values (around 0% for severe infantile form, around 10-15% for adult form). Diagnosis should be confirmed by HEXB gene sequencing. The diagnosis may be firstly suggested by pathogenic variants findings from a panel of genes, or exome or genome sequencing, and should be confirmed by hexosaminidase A and hexosaminidase B enzymatic activities measurement. Abnormal oligosaccharides urinary excretion may be detected in Sandhoff disease.
Differential diagnosis
GM2 gangliosidosis, AB variant (GM2A gene variant), may perfectly mimic Sandhoff or Tay-Sachs diseases, but with normal hexosaminidase A and B enzymatic activities. In adults the differential diagnoses include proximal spinal muscular atrophy and autosomal recessive diseases causing cerebellar ataxia (e.g. Niemann Pick disease type C).
Antenatal diagnosis
Prenatal diagnosis is available: a complete study of hexosaminidases A and B activities, and HEXB gene sequencing for the propositus and both parents is requested before prenatal diagnosis may be done for the fetus.
Genetic counseling
Transmission is autosomal recessive; at-risk couples (both parents are carriers of a pathogenic variant) have a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is no specific and efficient treatment for Sandhoff disease. Treatment is symptomatic.
Prognosis
For the pediatric forms: the severity is correlated to age of onset, with a more rapid regression in the early infantile form leading to death around 2-4 years of age, whereas death occurs in the second decade in the juvenile form. All patients will have pharmacoresistant epilepsy in the advanced stages of the disease. For the adult form: the disease is usually very slow progressive and may last decades. Patients are progressively disabled, may lose the ability to walk and have difficulties for upper limbs utilization, speech, swallowing, and may more rarely have cognitive symptoms.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Dr Bénédicte HERON | MetabERN* - Dr Yann NADJAR

                                * European Reference Network


Sandifer syndrome is a paroxysmal dystonic movement disorder occurring in association with gastro-oesophageal reflux, and, in some cases, hiatal hernia.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Onset usually occurs during infancy or early childhood. The dystonic movements are characterised by abnormal posturing of the head and neck (torticollis) and severe arching of the spine. Episodes usually last for between 1-3 minutes and can occur up to 10 times a day, although they are usually associated with the ingestion of food. Vomiting, poor feeding, anaemia, epigastric discomfort, haematemesis and abnormal eye movements have also been reported. Reflux oesophagitis is common.
Etiology
The dystonic movements are clearly associated with gastro-oesophageal reflux but the pathophysiological mechanism is not clearly understood. Several studies have indicated that the dystonic posturing is a pathological reflex triggered in response to abdominal pain caused by gastroesophageal reflux and oesophagitis. Although conflicting results have been obtained, some authors have suggested that the dystonic posture provides relief from abdominal pain.
Diagnostic methods
Sandifer syndrome is diagnosed on the basis of the association of gastro-oesophageal reflux with the characteristic movement disorder. Neurological examination is usually normal.
Differential diagnosis
However, in the absence of clear indications of gastro-oesophageal reflux, misdiagnosis as infantile spasms, epilepsy or paroxysmal dystonia is common.
Management and treatment
Early diagnosis of the syndrome is essential, as effective treatment of the gastro-oesophageal reflux (by pharmacological therapy or surgical intervention) leads to resolution of the movement disorder.
Prognosis
The prognosis for patients is good.

                            Last update:
                            March 2007


Sanjad-Sakati syndrome (SSS), also known as hypoparathyroidism - intellectual disability-dysmorphism, is a rare multiple congenital anomaly syndrome, mainly occurring in the Middle East and the Arabian Gulf countries, characterized by intrauterine growth restriction at birth, microcephaly, congenital hypoparathyroidism (that can cause hypocalcemic tetany or seizures in infancy), severe growth retardation, typical facial features (long narrow face, deep-set eyes, beaked nose, floppy and large ears, long philtrum, thin lips and micrognathia), and mild to moderate intellectual deficiency. Ocular findings (i.e. nanophthalmos, retinal vascular tortuosity and corneal opacification/clouding) and superior mesenteric artery syndrome have also been reported. Although SSS shares the same locus with the autosomal recessive form of Kenny-Caffey syndrome (see this term), the latter differs from SSS by its normal intelligence and skeletal features.


A rare, pyogenic autoinflammatory disease, characterized by the association of neutrophilic cutaneous involvement and chronic nonbacterial osteomyelitis.

Summary:
Epidemiology
Although its incidence and prevalence are probably underestimated, SAPHO syndrome (acronym for Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) is considered to be a rare disorder.
Clinical description
The age of onset ranges from adolescence to late adulthood, with a median age between 30 and 40 years. SAPHO syndrome encompasses a wide spectrum of anomalies characterized by variable combinations of osteoarticular and cutaneous manifestations of varying degrees of severity. The onset of bone and joint pain, stiffness and swelling is most often insidious. In adults, inflammation occurs mainly in the anterior chest wall but also in the spine, less frequently in the mandible and the iliac bones ; in children it shows a comparable distribution as chronic nonbacterial osteomyelitis (CNO/CRMO) (e.g. long bones, clavicle, spine). When synovitis occurs, it manifests most of the times in the sacro-iliac joint, hips or knees, or the sternoclavicular joints. Depending on severity of symptoms, a limited range of motion may be observed. Dermatological involvement includes severe acne, palmoplantar pustulosis, and pustular psoriasis. Skin manifestations often begin 1-2 years before osseous changes but may appear simultaneously or more than 20 years later. Patients may also suffer from abdominal pain, diarrhea, anal fissures or abscesses, suggesting the possible association with an inflammatory bowel disease (IBD). Most authors regard CNO/CRMO as the pediatric form of SAPHO syndrome. In fact, the frequent occurrence of dermatological disorders or IBD pleads for the inclusion of these two entities in the same spectrum.
Etiology
The etiology is unknown. SAPHO syndrome seems to have a multifactorial origin with genetic, environmental, immunologic, and infectious components. Slow-growing bacteria, such as Propionibacterium acnes, could act as a triggering factor.
Diagnostic methods
Diagnosis, suspected upon clinical examination, must be confirmed with imaging procedures (X-rays, CT, MRI) showing a combination of osteolysis and osteosclerosis with secondary hyperostosis, bone marrow edema, endosteal-periosteal inflammation, perifocal myositis, and adjacent arthritis. Bone biopsy often reveals an infiltrate of neutrophils in early stages, progressively replaced by mononuclear cells and associated with sclerosis in later stages. A bacteriological study is sometimes positive for Propionibacterium acnes. Synovial fluid culture is usually negative.
Differential diagnosis
Differential diagnosis includes infectious osteomyelitis or arthritis, Langerhans cell histiocytosis, and bone tumors such as Ewing sarcoma, osteoblastoma, and osteoid osteoma. Hypophosphatasia may mimic the bone phenotype of SAPHO syndrome.
Genetic counseling
Most cases are sporadic. Some familial cases have been reported.
Management and treatment
Treatment is mainly symptomatic and is based on non-steroidal anti-inflammatory drugs, sometimes replaced by corticosteroids (e.g. prednisone). In resistant cases, disease-modifying antirheumatic drugs (e.g. methotrexate) can also be used. Intravenous biphosphonates (pamidronate, zoledronate) can alleviate bone pain. More recently, TNF-inhibitors showed encouraging results in controlling both osteoarticular and cutaneous manifestations. The osteoarticular features may also be treated by sulfasalazine. Acne may be treated with systemic antibiotics, like doxycycline. Palmoplantar pustulosis or pustular psoriasis usually responds well to either topic corticosteroids or PUVA therapy. Physiotherapy is recommended.
Prognosis
The disease usually has a chronic evolution, with alternating periods of remission and relapse, sometimes with the appearance of new osteosclerotic lesions. Spontaneous resolution can occur. Complications include impairment of bone and joint function, vascular compression, chronic pain syndrome, and progression towards classical spondyloarthritis.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Hermann GIRSCHICK


A rare parasitic disease characterized by infection with sarcocystis species with humans as definitive (intestinal sarcocystosis) or aberrant intermediate (muscular sarcocystosis with development of sarcocysts in myocytes of skeletal, cardiac, and smooth muscle) host. Enteric infection is often mild or asymptomatic but may cause symptomatic enteritis with nausea, abdominal pain, diarrhea, and vomiting. Symptoms of muscular sarcocystosis include fever, fatigue, headache, cough, myalgia, and arthralgia, among others, with the possibility of a long-lasting, waxing and waning course.


A rare multisystemic, autoinflammatory disorder of unknown etiology characterized by the formation of immune, non-caseating granulomas in any organ(s), leading to variable clinical symptoms and severity. Clinical presentation is typically with persistent dry cough, eye or skin manifestations, peripheral lymph nodes, fatigue, weight loss, fever or night sweats, and Löfgren syndrome.

Summary:
Epidemiology
Sarcoidosis is a ubiquitous disease with incidence varying according to age, sex, race and geographic origin. The highest rates are reported in Northern Europe and in African-American individuals, the lowest rates in Asia. In Europe, incidence ranges between 1/625 to 500,000 inhabitants. There is a slight predominance in females.
Clinical description
Presentation, severity and evolution of sarcoidosis is highly variable. Diagnosis typically occurs in the fourth and fifth decade of life with a second peak of incidence occurring in women older than 50 years of age, but presentation may occur anywhere between childhood and elderly age. The disease is classed as either acute, resolving within 2 years, or chronic, persisting for 3-5 years or longer. The lung and the lymphatic system are predominantly affected, but virtually every organ may be involved. Other severe manifestations result from cardiac, neurological, ocular, kidney or laryngeal localizations. In most cases, sarcoidosis is revealed by persistent dry cough, eye or skin manifestations, peripheral lymph nodes, fatigue, weight loss, fever or night sweats, and Löfgren syndrome (an acute form characterized by fever, bilateral ankle arthritis and/or erythema nodosum and bilateral hilar lymphadenopathy). Abnormal metabolism of vitamin D3 within granulomatous lesions and hypercalcemia are possible. Chest radiography is abnormal in about 90% of cases and shows lymphadenopathy and/or pulmonary infiltrates (without or with fibrosis), defining sarcoidosis stages from I to IV. African-Americans present a more severe disease, and in Scandinavian countries, about one third of cases have Löfgren syndrome.
Etiology
The etiology remains unknown. The prevailing hypothesis is that various, unidentified antigens of either infectious or environmental origin could trigger an exaggerated immune reaction in genetically susceptible hosts.
Diagnostic methods
Diagnosis relies on compatible clinical and radiographic manifestations, biopsy showing non-caseating granulomas and exclusion of all other causes of granulomatous disease. Some situations do not require biopsy such as Lofgren's syndrome or the presence of typical asymptomatic bilateral mediastino-hilar adenopathies. Biopsies from easily accessible areas (skin, peripheral lymphadenopathies, conjunctival nodules) should be considered. However, bronchoscopy with bronchial and transbronchial biopsies has a good diagnostic performance. Endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) provide a high yield in case of mediastino-hilar lymphadenopathies.
Differential diagnosis
Differential diagnosis includes infections, chronic beryllium disease, common variable immunodeficiency, hypersensitivity pneumonitis, granulomatous polyangiitis, Crohn disease, sarcoid-like reactions (cancer or lymphomas), as well as drug-induced granulomatosis.
Genetic counseling
Sarcoidosis results from a complex interaction of multiple genes and thus does not require genetic counseling.
Management and treatment
Depending on the evolution and severity of sarcoidosis, patients may not require systemic therapy. Therapy is considered where there is a possibility of severe complications (i.e. functional organ failure) or to reduce persistent symptoms of discomfort that impact on quality of life. Discomfort may be due to fibrosis, para-sarcoidosis syndrome or comorbidities as well as active disease. Treatment is principally with systemic corticosteroids, and generally maintained for 12 months; however, the duration and minimal efficient dose should be adapted to each patient. Patients with repeated relapses may require long-term, low-dose corticosteroid therapy. Other treatments including immunosuppressive drugs (methotrexate, azathioprine, or leflunomide) and aminoquinolins may be useful in case of unsatisfactory response to corticosteroids, poor tolerance or as sparing agents. In some strictly selected cases refractory to standard therapy, specific anti-TNF-alpha agents (infliximab or adalimumab) may offer improvement. Some patients benefit from topical corticosteroids.
Prognosis
In at least half of cases, sarcoidosis resolves spontaneously within 2 years. Remission is less likely where diseases persists for five years after presentation. Mortality is estimated at 6-8% and typically due to organ failure (typically respiratory or cardiac). The extent of pulmonary fibrosis and pulmonary hypertension are predictive of mortality.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Alain CALENDER  - Dr Florence JENY  - Pr Hilario NUNES


A rare inborn error of metabolism characterized by increased concentrations of sarcosine in plasma and urine due to sarcosine dehydrogenase deficiency. The condition is considered benign and not associated with any specific clinical phenotype. Mode of inheritance is autosomal recessive.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by moderate to severe developmental delay/intellectual disability with absent or limited speech development, various behavioral problems (including autistic features, hyperactivity, or aggressiveness), and craniofacial anomalies such as long face, high and prominent forehead, bulbous nose with low-hanging columella, thin vermillion of the upper lip, palatal (cleft palate, high-arched palate, and bifid uvula) and dental (abnormal upper incisors) abnormalities, and micrognathia. Hypotonia and feeding difficulties are frequent. Other supportive findings may include skeletal anomalies with low bone density and abnormal brain imaging.


Satoyoshi syndrome is a rare, multisystemic autoimmune disease mainly characterized by intermittent painful muscle spasms, alopecia (totalis or universalis in most cases) and long-lasting diarrhea that could lead to malnutrition, growth retardation, and amenorrhea. Secondary bone deformities and various endocrine anomalies may also be associated. Antinuclear antibodies are reported in many cases.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by microcephaly, developmental delay and intellectual disability, postnatal growth retardation, dysmorphic craniofacial features (including sloping forehead, beaked nose, large and protruding ears, micrognathia, high-arched palate, and craniosynostosis), immunologic abnormalities with transient hypogammaglobulinemia in infancy and defective chemotaxis leading to recurrent infections, as well as autoimmune/autoinflammatory phenomena. Skeletal anomalies and hypogonadism have also been reported.


Scalp defects-postaxial polydactyly syndrome

A rare syndrome with limb malformations as a major feature characterized by congenital scalp defects and postaxial polydactyly type A. There is a wide variability of expression, with some patients showing only one of the typical manifestations. There have been no further descriptions in the literature since 1985.


SCALP syndrome is a rare skin disease characterized by the association of sebaceous nevus and aplasia cutis congenita (usually on the scalp and face) in conjunction with limbal dermoid of the eye, a giant congenital melanocytic nevus and variable central nervous system abnormalities, including seizures, hydrocephalus, neurocutaneous melanosis, arachnoid cysts, and diffuse unilateral hemisphere enlargement.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by aplasia cutis congenita of the scalp, breast anomalies ranging from hypothelia or athelia to amastia, and anomalies of the external ears. Variable clinical characteristics include nail and dental anomalies, syndactyly and camptodactyly of fingers and/or toes, sparse or absent secondary sexual hair, renal malformations, and facial dysmorphism. Cases with severe hypotonia and developmental delay have been reported.


A rare, genetic motor neuron disease characterized by predominantly motor axonal peripheral neuropathy manifesting with progressive scapuloperoneal muscular atrophy and weakness, laryngeal palsy, congenital absence of muscles, and, in some, skeletal abnormalities.

Summary:
Epidemiology
The precise prevalence of Scapuloperoneal spinal muscular atrophy (SPSMA) is not available. To date, more than 30 affected individuals have been described worldwide. Males are more severely affected than females.
Clinical description
Onset is usually congenital or occurs in infancy or early childhood. Clinical hallmarks of SPSMA are muscular atrophy of the shoulders, peroneal and small hand muscles resulting in distal weakness, predominantly of the lower limbs, and pectoral muscle wasting and weakness. Patients present difficulty walking on heels, winged scapulae, and diminished or absent deep tendon reflexes. Other common features reported include vocal cord paralysis, scoliosis, and/or arthrogryposis. Skeletal abnormalities have been described in some patients, including congenital hip dysplasia, short limbs/limb length discrepancy, bilateral congenital clubfoot, metatarsal dysplasia, spondylometaphyseal dysplasia, platyspondyly, metatropic dysplasia, and/or mild short stature. Mildly diminished vibration sense may also be associated. The disease has slow clinical progression and variable pattern of expression, ranging from severe neonatal onset to mild symptoms referred only in adulthood.
Etiology
The causative gene of SPSMA is TRPV4 (12q23-q24.1), which encodes for a calcium, nonselective cation channel thought to be involved in the regulation of systemic osmotic pressure and mechanosensitivity. De novo mutations have also been reported in the literature.
Diagnostic methods
Diagnosis is based on clinical manifestations, family history and biopsy findings which reveal severe muscle fiber-type grouping and atrophy, extensive fatty replacement, increased endomysial fibrosis, marked variability of fiber size, fiber splitting, and many fibers with multiple internal nuclei. Pathological changes are particularly severe in the gastrocnemius muscle. Atrophy of both type 1 and type 2 fibers can be observed with ATPase staining. Electroradiography shows reduced compound motor action potentials (cMAPS) but normal sensory action potentials and nerve conduction velocity. Brain and spinal cord sections reveal normal numbers of motor neurons in the motor complex and spinal cord. Genetic testing which reveals a pathogenic mutation confirms diagnosis.
Differential diagnosis
The differential diagnosis includes Charcot-Marie-Tooth disease type 2C, congenital distal spinal muscular atrophy, neurogenic scapuloperoneal syndrome Kaeser type, and facioscapulohumeral dystrophy.
Antenatal diagnosis
Prenatal diagnosis is possible if a pathogenic variant has been previously identified in the family.
Genetic counseling
SPSMA has an autosomal dominant pattern of inheritance. Genetic counseling can inform parents of the 50% risk of transmitting the mutation responsible for the disease to their children. Early diagnosis is crucial to prevent the more severe congenital form, as disease tends to be more progressive and severe in succeeding generations.
Management and treatment
There is no effective treatment to date.
Prognosis
The prognosis is not so poor, even if the problems of ambulation predispose to falls, to the development of arthrosic problems, which together with the dysmorphic aspects and the distal weakness contribute to get worse the motor problems. Generally the respiratory muscles are not involved.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Carmelo RODOLICO


A rare multiple congenital anomalies syndrome characterized by variable skeletal abnormalities (including craniostenosis, pectus carinatum, short sternum, joint hyperextensibility, and anbnormal vertebrae), cutis laxa with excessive skin folds around the cheek, chin and neck, ambiguous genitalia with a micropenis and perineal hypospadia, an umbilical hernia, intellectual disability, premature aged appearance, and cardiac enlargement involving either the ventricles or atria. Facial dysmorphism is variable and can include multiple hair whorls, ptsosis, high and broad nasal root, low set ears and small chin. Enamel hypocalcification, abnormal modelling of tubular bones, and reduced cutis laxa may become apparent later on.


Scarring in glaucoma filtration surgical procedures

A rare ophthalmic condition characterized by formation of excessive scar tissue between the conjunctiva/Tenon capsule and the sclera at the surgical site following glaucoma filtration surgery. Scarring can occur months or years after surgery, resulting in treatment failure with poor postoperative control of intraocular pressure and, potentially, loss of vision.


A rare mycosis caused by Scedosporium species, characterized by disparate disease pictures including pneumonia, skin and soft tissue infection, mycetoma, and disseminated infection. Central nervous system infection has also been reported. Infections with this ubiquitous mold can occur in a range of contexts like solid organ transplantation, chemotherapy, chronic lung disease, but also in immunocompetent hosts and near drowning.


Scheie syndrome is the mildest form of mucopolysaccharidosis type 1 (MPS1; see this term), a rare lysosomal storage disease, characterized by skeletal deformities and a delay in motor development.

Summary:
Epidemiology
Prevalence is estimated at 1/500,000.
Clinical description
Symptoms commonly occur after the age of 5 years but are so mild that diagnosis is often not considered until adulthood. Patients are of almost normal height and do not show intellectual deficiency. Corneal opacification occurs progressively and diffusely, usually after the age of four years. Glaucoma is more frequent than in Hurler syndrome (see this term). Patients present with mild coarsening of the facial features, including a large mouth with thick lips. Patients may present with nasal secretion, neurosensorial hearing loss, stiff joints, mild skeletal changes and carpal tunnel syndrome. Aortic valve disease may be present. Compression of the cervical spinal cord, caused by glycosaminoglycan infiltration of the dura, may lead to spastic paresis if not corrected by neurosurgical intervention.
Etiology
Scheie syndrome is caused by mutations in the IDUA gene (4p16.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate.
Diagnostic methods
Early diagnosis is difficult because the first clinical signs are not specific, but is very important to allow early treatment. Diagnosis is based on detection of increased urinary secretion of heparan and dermatan sulfate through the 1,9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.
Differential diagnosis
Differential diagnoses include the more severe forms of mucopolysaccharidosis type 1, Hurler-Scheie syndrome and Hurler syndrome, and mucopolysaccharidosis type VI and mucopolysaccharidosis type II (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended.
Management and treatment
Management should be carried out by a multidisciplinary team and should include physiotherapy to maintain range of movement. The enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. Given through weekly infusions it leads to improvement of lung function and joint mobility. Enzyme replacement therapy (ERT) should be started at diagnosis and may be beneficial in patients awaiting hematopoietic stem cell transplantation (HSCT). Early treatment slows the progression of the disease.
Prognosis
Life expectancy for patients with Scheie syndrome may only be slightly affected.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Michael BECK


Schilbach-Rott syndrome (SRS) is an autosomal dominant dysmorphic disorder that is characterized by dysmorphic facies with hypotelorism, blepharophimosis, and cleft palate, and the frequent occurrence of hypospadias in males.

Summary:
Epidemiology
SRS has been described in 18 individuals to date. Its prevalence is unknown.
Clinical description
Features of SRS include a typical facial gestalt characterized by hypotelorism, blepharophimosis, facial asymmetry, small posteriorly angulated ears, a long prominent nose, a small mouth and an array of cleft palate abnormalities. Cutaneous syndactyly of the fingers and toes is a recurrent manifestation. Affected individuals often have a short stature and may present with a mild intellectual disability or learning difficulties. Hypospadias is frequently reported in males with SRS.
Etiology
Etiology is unknown.
Genetic counseling
Transmission is autosomal dominant with variable expressivity.

                            Last update:
                            January 2014


Schilder's disease is a progressive demyelinating disorder of the central nervous system.

Summary:
Epidemiology
Less than 20 sporadic cases (predominantly males) have been reported so far.
Clinical description
The onset is usually in childhood (age 5-14 years). The disease often occurs shortly after an infectious illness and may manifest with headache, malaise and fever. Variable neurological abnormalities progressively develop and include personality changes, poor attention, dementia, aphasia, headache, vomiting, tremor, seizures, balance instability, incontinence, muscle weakness. Deafness, paralysis of eye movements, nystagmus, optic neuritis and optic atrophy are common. Malnutrition and cachexia are reported in the later chronic stages of illness. Schilder's disease is considered as a variant or borderline form of multiple sclerosis.
Etiology
Pathologically, it is characterized by bilateral widespread demyelination of the brain hemispheres with varying degrees of axonal injury. Etiology remains unclear.
Diagnostic methods
Diagnosis is based on sequential neuroimaging (consistent with subacute or chronic myelinoclastic diffuse sclerosis) and electroencephalographic studies.
Differential diagnosis
Differential diagnosis includes a wide range of neurodegenerative disorders such as multiple sclerosis, acute disseminated encephalomyelitis, subacute sclerosing panencephalitis, progressive rubella panencephalitis, brucellosis, metachromatic leukoencephalopathy, Churg-Strauss disease, Wegener granulomatosis (see these terms). Schilder's disease often mimics intracranial neoplasm or abscess.
Management and treatment
Management is mainly symptomatic and supportive (physiotherapy, occupational therapy, nutritional support in the later stages). Corticosteroids have been shown effective in some patients. Additional treatments include beta-interferon and/or immunosuppressive drugs.
Prognosis
Prognosis of Schilder's disease is variable. The clinical course is usually progressive, but significant improvement and remissions have also been described. Survival has been reported to be less than ten years after the onset. Patients with a good response to corticosteroids and those with smaller lesions may have a better prognosis.

                            Last update:
                            July 2009

                            - Expert reviewer(s):
                            Pr Bertrand FONTAINE


A rare a multisystem disorder characterized by spondyloepiphyseal dysplasia and disproportionate short stature, facial dysmorphism, T-cell immunodeficiency, and progressive, proteinuric steroid-resistant nephropathy.

Summary:
Epidemiology
The prevalence is unknown. Data from large pediatric registries suggest that it accounts for ~1% of steroid resistant nephrotic syndrome.
Clinical description
The main clinical features are spondyloepiphyseal dysplasia, growth retardation both pre- and post-natal, defective cellular immunity and episodic lymphopenia with increased susceptibility to life-threatening infections, and a progressive steroid-resistant nephrotic syndrome that leads to end-stage renal failure. Almost all patients have T-cell deficiency with a normal CD4/CD8 ratio. Hyperpigmented macules, thin hair and dysmorphic facial features (a triangular-shaped face, microdontia, broad depressed nasal bridge, narrow nasal ridge and a broad nasal tip) are common. Neurologic manifestations include atherosclerosis and cerebrovascular disease, which manifest as migraine-like headaches, cerebral ischemia, cardiac dysfunction and cognitive deficiency. Additional features may include hypothyroidism, enteropathy, normocytic or microcytic anemia and thrombocytopenia.
Etiology
The disorder is caused by biallelic pathogenic variants in the SMARCAL1 gene (2q35) which encodes the chromatin remodeling protein, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1.
Diagnostic methods
Diagnosis is based on careful clinical, biochemical and radiologic evaluation typically demonstrating osteopenia, ovoid and flattened vertebral bodies, and hypoplastic femoral heads and acetabular roofs. Some patients with progressive proteinuria might be diagnosed incidentally through multigenic mutational screening (next generation sequencing/whole exome sequencing).
Differential diagnosis
Cartilage-hair hypoplasia is the main differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variants) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Therapy is largely limited to the prophylaxis and management of the various disease manifestations, such as dialysis and renal transplantation, supplementation of hematopoietic growth factors for neutropenia, orthopedic surgery as required, preventive antiviral therapies and vaccinations, anticoagulation, immunosuppressive therapy for those with autoimmune manifestations, and thyroid hormone supplementation.
Prognosis
Life expectancy is limited to childhood or early adolescence in most patients, due to stroke, infections, bone marrow failure, and renal failure. Survival into adulthood has been reported for patients with milder late-onset forms of the disease and successful management of the renal manifestations.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*

                                * European Reference Network


Schinzel-Giedion syndrome (SGS) is an ectodermal dysplasia syndrome chiefly characterized by a distinctive facial dysmorphism, hydronephrosis, severe developmental delay, typical skeletal malformations, and genital and cardiac anomalies.

Summary:
Epidemiology
The birth prevalence of SGS is not known. More than 50 cases have been reported worldwide to date.
Clinical description
At birth, SGS is quite easily characterized by the distinctive facial dysmorphism with a prominent forehead, midface retraction resembling a broadened ''figure-of-eight'' in marked cases, and a short upturned nose, as well as visceral abnormalities and hypertrichosis. Hydronephrosis is present in nearly all affected cases (91%). Cardiac abnormalities, including septal defects, valvular dysplasias, hypoplastic ventricles and patent ductus arteriosus are common (43%), as are other genitourinary abnormalities (76%), such as cryptorchidism, micropenis, hypospadias, hypoplastic uterus, hypoplastic labia minora and majora, deep labial sulcus, and anteriorly displaced anus. Neonates frequently present with short limbs and the following limb malformations: valgus or varus foot deformity, mesomelic brachymelia with hypoplastic and hyperconvex nails and single palmar creases of the hands. Affected neonates suffer from hypotonia and typically present with respiratory failure, with all having a severe developmental delay accompanied by seizures (often refractory), and visual and hearing impairment. Additionally, a higher than normal prevalence for neuroepithelial tumors (17%) in SGS patients has been reported.
Etiology
SGS is caused by de novo mutations in the SETBP1 gene (18q21.1), probably resulting in a gain-of-function or dominant-negative effect.
Diagnostic methods
Diagnosis is based on clinical findings (including the distinctive facial dysmorphism), the presence of hydronephrosis on ultrasound, and radiographic findings of multiple typical skeletal malformations including sclerotic skull base, wide occipital synchondrosis, increased cortical thickness/density and broad ribs. Under 12 months of age, skull radiographs reveal a gap between the 2 parts of the occipital bone and dense pyramids are also common. Genetic testing for SETBP1 is possible.
Differential diagnosis
Other conditions with the distinctive midface retraction that could be considered in the differential diagnosis include fetal hydantoin, fetal warfarin syndromes, Zellweger syndrome, mucopolysaccharidosis, gangliosidosis, and rhizomelic chondrodysplasia punctata, as well as congenital hypothyroidism (see these terms).
Antenatal diagnosis
Hydronephrosis is detectable on prenatal ultrasound between the 18th-37th week of pregnancy, in about 40% of affected cases. Genetic testing is possible.
Genetic counseling
SGS is an autosomal dominant disorder. Practically all cases occur sporadically, identification of the proband should be undertaken along with genetic counseling for parents.
Management and treatment
Management is supportive and consists of palliative care. The chief complications are respiratory failure, feeding intolerance, refractory seizures and frequent and recurrent infections such as pneumonia.
Prognosis
Prognosis is severe, with most affected patients not surviving infancy due to the progressive neurodegeneration, increased risk of tumors, recurrent infections and respiratory failure, although survival until adolescence has been reported.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Pr Albert SCHINZEL


Schisis association describes the combination of two or more of the following anomalies: neural tube defects (e.g. anencephaly, encephalocele, spina bifida cystica), cleft lip/palate, omphalocele and congenital diaphragmatic hernia (see these terms). These anomalies are associated at a higher frequency than would be expected with random combination rates.


A rare parasitic disease characterized by infection with trematodes of the genus Schistosoma. Humans become infected when larvae (cercariae) in infested freshwater penetrate the skin, potentially causing cercarial dermatitis. After a few weeks, eggs laid by the adult female worms living in blood vessels become trapped in body tissues, causing progressive organ damage due to inflammation, granuloma formation, and fibrosis. Acute schistosomiasis presents with fever, cough, headache, and urticaria, while chronic manifestations depend on the localization of the eggs and typically include abdominal pain, diarrhea, hepatosplenomegaly, blood in stool or urine, and dysuria, among others.


A rare developmental defect during embryogenesis characterized by the presence of linear clefts containing cerebrospinal fluid lined by abnormal grey matter that extend from the lateral ventricles to the pial surface of the cortex. Schizencephaly can involve one or both cerebral hemispheres and may lead to a variety of neurological symptoms such as epilepsy, motor deficits, and psychomotor retardation.

Summary:
Epidemiology
The birth prevalence is estimated at 1/64,935 in the USA and 1/69,444 in the UK.
Clinical description
Patients have varying clinical features including epilepsy (50-60% of cases), motor impairment, microcephaly and cognitive and learning disability. The severity of the clinical manifestations depends upon the extent of clefting and on whether other cerebral malformations are present. When a cleft affects one hemisphere alone (unilateral clefts), patients can have a hemiparesis but they may have little or no intellectual disability. Patients with bilateral clefts have a more severe phenotype that may be characterized by severe developmental impairment with spastic quadriplegia and severe intellectual disability. Schizencephaly is often associated with septo-optic dysplasia
Etiology
The disorder usually results from an acquired defect of the cerebral mantle and often becomes apparent only in the second half of pregnancy. Schizencephaly has been linked to a young maternal age and to conditions secondary to vascular disruption such as maternal drug administration (e.g. warfarin), amniocentesis, and infections (cytomegalovirus). Mutations in the COL4A1 gene encoding the major type IV alpha collagen chain of basement membranes have been found responsible of some schizencephaly cases. Other genetic factors have been suggested to play a role in its pathogenesis, such as EMX2, SHH, and SIX3 that could act as susceptibility factors.
Diagnostic methods
Postnatally, the diagnosis is made by computed tomography (CT) and/or magnetic resonance imaging (MRI) showing unilateral or bilateral clefting of the brain. There are different classification systems for schizencephaly but a frequently used one refers to clefts as either closed-lip (type I) when the tissue surrounding the clefts are closely opposed, and open-lip (type II) when the tissue is widely separated by cerebrospinal fluid. Cerebral malformations found in association with schizencephaly on neuroimaging studies include optic nerve hypoplasia, enlarged cerebral ventricles, absence of corpus callosum or septum pellucidum, cerebellar hypoplasia, or calcifications. Genetic testing will confirm mutations in the genes associated with susceptibility to the condition but these are rare.
Differential diagnosis
Differential diagnosis includes porencephaly.
Antenatal diagnosis
Prenatal diagnosis can made after 20 weeks of pregnancy by ultrasound examination or on in utero MRI, which demonstrates clefting and abnormalities of the cerebral mantle. The diagnosis may be confirmed post-natally by MRI, which may give additional information about the presence of septo-optic dysplasia and other abnormalities.
Genetic counseling
Most cases are sporadic but some familial cases have also been observed with inheritance reported to be either autosomal recessive or autosomal dominant with variable penetrance. Genetic counseling should be proposed to at risk couples informing them that there is either 25% risk of transmitting the disease to offspring in the case of an autosomal recessive inheritance or 50% risk for an autosomal dominant inheritance.
Management and treatment
Treatment consists on administration of anti-epileptic drugs in order to prevent seizures. In drug resistant cases (1/3rd of cases), surgery (e.g. resection of either the schizencephalic cleft alone or the cleft and surrounding epileptogenic tissue, temporal or frontotemporal lobectomy) can be performed. A regular neurologic evaluation is necessary. Physical and occupational therapy are essential.
Prognosis
The prognosis is variable and depends on the degree of clefting and the association with other cerebral malformations. Individuals with schizencephaly can have features of a hemiparesis only but the clinical picture can extend to profound neurological impairment with spastic quadriplegia leading to immobility and to severe learning disability and epilepsy.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Pr Paul GRIFFITHS


Schneckenbecken dysplasia (or chondrodysplasia with snail-like pelvis) is a prenatally lethal spondylodysplastic dysplasia.

Summary:
Epidemiology
Less than 20 cases have been reported in the literature so far.
Clinical description
The typical radiographic finding is the snail-like configuration of the hypoplastic iliac bone. Additional features include flattened hypoplastic vertebral bodies, short ribs, short and wide fibulae, short and broad long bones with a dumbbell-like appearance, and precocious ossification of the tarsus.
Etiology
This syndrome is caused by loss-of-function mutations of the SLC35D1 gene (1p32-p31)
Genetic counseling
Schneckenbecken dysplasia is transmitted in an autosomal recessive manner.

                            Last update:
                            September 2009


Schnitzler syndrome is a rare, underdiagnosed disorder in adults characterized by recurrent febrile rash, bone and/or joint pain, enlarged lymph nodes, fatigue, a monoclonal IgM component, leukocytosis and systemic inflammatory response.

Summary:
Epidemiology
Prevalence is unknown and about 150 cases have been reported, primarily in Europe.
Clinical description
There is a slight male predominance and mean age of disease onset is 51 years. Time to diagnosis often exceeds 5 years. The first clinical sign is usually a mildly or non-pruritic skin rash. Elementary lesions are rose or red macules or slightly elevated plaques, which resolve within 24 hours. Lesions can occur on every body part, though involvement of face and extremities is rare. The frequency and duration of flares are variable. Almost all patients develop intermittent fever and body temperature can rise above 40°C. Fever is usually well tolerated and chills are rare. About 80% of patients experience bone and/or joint pain. Bone involvement is common, and 30 to 40% of patients show bone lesions on imaging studies. IgM levels can remain stable or progressively increase at a rate of about 0.5 to 1 g/L/year. Other signs include elevated erythrocyte sedimentation rate (ESR), inflammatory anemia sometimes with thrombocytosis (up to 50 % of cases), palpable lymph nodes (45%), and hepatic or splenic enlargement (30%). The monoclonal IgM component is a defining feature of the disease. Inflammatory AA amyloidosis may be a serious complication. The disease follows a chronic course.
Etiology
Etiology remains unclear but the syndrome is probably an acquired auto-inflammatory disorder. It shares many features with genetically determined auto-inflammatory diseases.
Diagnostic methods
Diagnosis is based on a combination of clinical, laboratory and radiological findings and on exclusion of another cause. Histopathological skin findings are noteworthy showing a neutrophilic infiltrate of the dermis, without vasculitis and without significant edema, characteristic of neutrophilic urticarial dermatosis. An immediate and marked response to anakinra treatment is supportive of the diagnosis. The initial work-up should include an examination of bone marrow, immunoelectrophoresis of serum and urinary proteins, and determination of immunoglobulin subtypes. The two latter examinations can then be used for follow-up on a biannual basis. Lymph nodes should be biopsied when they are enlarged.
Differential diagnosis
Differential diagnosis includes adult-onset Still's disease, hypocomplementic urticarial vasculitis, cryoglobulinemia, hyper IgD syndrome, and acquired C1 inhibitor deficiency (see these terms).
Management and treatment
Some treatments provide only incomplete and/or transient improvement or control of symptoms (steroids, non-steroidal anti-inflammatory drugs, colchicine, dapsone, peflacine, phototherapy) while others are mostly ineffective (anti-histamines, rituximab, intravenous immunoglobulins, TNF-blocking agents, immunosuppressive drugs). In contrast, the IL-1 receptor antagonist anakinra relieves all symptoms within hours after the first injection. Injection-site reactions are frequent with anakinra and sometimes severe, and can be a real concern. The neutrophil count must be monitored.
Prognosis
The overall prognosis depends on the development of lymphoproliferative complications such as lymphoma, IgM myeloma or Waldenström's disease (see these terms). Although these complications have only been reported in about 20% of cases, their incidence may be higher since they generally develop more than 10 to 20 years after the first signs of the syndrome.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr Dan LIPSKER


Schnyder corneal dystrophy (SCD) is a rare form of stromal corneal dystrophy (see this term) characterized by corneal clouding or crystals within the corneal stroma, and a progressive decrease in visual acuity.

Summary:
Epidemiology
The prevalence of this form of corneal dystrophy is not known.
Clinical description
Lesions usually develop early in life and are mostly bilateral, but one eye may become affected prior to the other. Some patients complain of glare, which increases with age. Visual acuity gradually decreases. Associated systemic disorders have been commonly reported (hypercholesterolemia, arcus lipoides and genu valgum). Over time, small white opacities develop in the corneal stroma along with a diffuse haze. In about 50% of patients, crystals are not observed clinically.
Etiology
SCD is caused by various mutations in the UBIAD1 gene (1p36.22).
Diagnostic methods
Typically, a ring-shaped yellow-white opacity composed of innumerable fine needle-shaped crystals forms in Bowman layer and the adjacent anterior stroma of the central cornea. The crystals usually remain in the anterior third of the cornea. The corneal epithelium and endothelium as well as Descemet membrane are spared.
Differential diagnosis
SCD should be differentiated from other lipid keratopathies and particular from lecithin cholesterol acyltransferase disease (LCAT deficiency, see this term).
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
The superficial pathologic corneal tissue needs to be excised.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare genetic syndromic intellectual disability characterized by mild to moderate intellectual disability, developmental delay (with speech and language development more severely affected). Association with infantile hypotonia, seizures, cryptorchidism in males and congenital abnormalities, including cardiac, cerebral or ocular defects, may be observed.

Summary:
Epidemiology
The prevalence of Schuurs-Hoeijmakers syndrome (also called PACS1-related syndrome) is estimated at <1/1,000,000 birth. To date approximately 60 individuals were reported in the literature, however the disease is most likely under-reported.
Clinical description
The disease is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Feeding difficulty is common, with many of the children requiring gastrostomy tube to maintain appropriate caloric intake. Common facial features include full, arched eyebrows, hypertelorism, down-slanting palpebral fissures, long eyelashes, ptosis, low-set, simple ears, bulbous nasal tip, flat philtrum, wide mouth with downturned corners and thin upper lip and diastema of the teeth. Other common features include short stature and/or low weight, hypotonia, constipation, seizures, autism, behavioral issues, congenital heart anomalies, genitourinary abnormalities, renal issues, and ocular anomalies.
Etiology
Almost all individuals with PACS1-related syndrome have a c.607C>T (NM_018026.3) mutation in the PACS1 gene, within a region thought to be important for the function of the protein. The expression of the PACS1 gene is significant both during embryonic development and after birth. Pathogenic variations in PACS1 lead probably to a dominant-negative mechanism responsible for disrupting protein trafficking in the golgi apparatus.
Diagnostic methods
The diagnosis of PACS1 syndrome is established by molecular genetic testing. All individuals reported to date have the disorder as the result of a de novo pathogenic variant.
Differential diagnosis
The differential diagnosis includes Winter-Baraitser syndrome and Kabuki syndrome.
Antenatal diagnosis
Once a pathogenic variant has been identified in a family, detection of PACS1 syndrome can be done by amniocentesis and exome sequencing for malformative syndrome screening during pregnancy.
Genetic counseling
Transmission of PACS1 syndrome is autosomal dominant with full penetrance (50% risk of transmission at each pregnancy); however, in most situations, the pathogenic variants arise de novo and thus the risk of sibling recurrence is low. Detection of PACS1-related syndrome should be discussed with the parents of an affected individual during subsequent pregnancies.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow‐up by a clinical geneticist, paediatrician, ophthalmologist, psychologist/psychiatrist, speech therapist, physiotherapist and ophthalmologist will have a major impact on the quality of life and learning at school. Developmental assessments are needed to tailor medical services to each individual's needs. Other specialists can be needed, like a cardiologist, gastroenterologist, nephrologist, otolaryngologists or stomatologist.
Prognosis
Autonomy may be limited and affected individuals will sometimes require life-long support from caregivers. There is little data on adults, so it is not currently possible to provide information on the long-term future of PACS1-related syndrome patients.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr David GENEVIEVE | ITHACA*

                                * European Reference Network


A rare, genetic neuromuscular disease characterized by permanent myotonia, mask-like facies (with blepharospasm, narrow palpebral fissures, small mouth with pursed lips and puckered chin) , and chondrodysplasia (variably manifesting with short stature, pectus carinatum, kyphoscoliosis, bowing of long bones, epiphyseal, metaphyseal, and hip dysplasia).

Summary:
Epidemiology
Approximately, 130 cases have been described in the literature to date.
Clinical description
Presentation is typically by 1 year to 2 years of age, but may occur earlier, with myotonia, maske-like facies, short stature, non-progressive muscle weakness, muscle hypertrophy, progressive restriction of range of motion and paucity of subcutaneous tissue. Facial features consist of blepharospasm, progressive blepharophimosis, pursed lips and a puckered chin. Micrognathia, low-set ears with folded helices and dystopia canthorum have also been reported. The myotonia is characterized by continuous muscle activity recorded on electroneuromyography. Limited joint mobility leads to an unsteady gait. Joint stiffness is progressive, reaching its peak during adolescence The severity of chondrodysplasia is variable and may consist of flattening of the vertebral bodies, hip dysplasia, metaphyseal widening, slender diaphyses, kypho-scoliosis, multiple joint contractures and bowing of long bones. Rarely, myopia, inguinal and umbilical hernias and micro-orchidism have been reported.
Etiology
Loss of function mutations in HSPG2 (1p36) are causative. HSPG2  encodes perlecan, a major component of the cellular matrix that plays an important role in maintaining cartilaginous tissue integrity and regulating muscle excitability. The exact pathogenesis is unknown.
Diagnostic methods
Diagnosis is established by demonstration of both myotonia via electromyography and chondrodysplasia via radiographs. Genetic testing may confirm diagnosis.
Differential diagnosis
Schwartz-Jampel syndrome (SJS) is non-allelic with Stuve-Wiedemann syndrome, a severe skeletal dysplasia that is typically fatal during the neonatal period and was formerly described as SJS type 2. Other differential diagnosis should include Freeman Sheldon and Marden Walker syndrome and, in cases with minimal skeletal abnormalities, myotonic disorders ( including myotonia congenita, myotonia permamens, and myotonic dystrophy).
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to affected families, informing them that the risk of disease transmission is 25% where both parents are unaffected carriers.
Management and treatment
The management of patients with SJS is primarily supportive and best offered by a team comprising a neurologist, a geneticist, a physical therapist, an orthopedic surgeon, an ophthalmologist and a psychologist. Medical treatment with muscle relaxants and antiepileptic drugs, such as carbamazepine, phenytoin, or procainamide, aimed to alleviate myotonia has limited usage, although early initiation of treatment may limit the extent of disability. Physical therapy is important to prevent contracture formation and fixed skeletal deformity. Botulinum toxin A injections for blepharospasm has been reported with limited and variable results Rarely, surgical intervention is considered for blepharospasm including orbicularis oculi myectomy or levator aponeurosis resection improve functional and cosmetic outcome. Malignant hyperthermia is a potentially lethal complication of anesthesia.
Prognosis
Progressively worsening blepharospasm is an important morbidity that can interfere with vision. The disease appears to stabilize after adolescence and does not affect life span.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Bertrand FONTAINE


Schöpf-Schulz-Passarge syndrome (SSPS) is a rare autosomal recessive ectodermal dysplasia characterized by multiple eyelid apocrine hidrocystomas, palmoplantar keratoderma, hypotrichosis, hypodontia and nail dystrophy.

Summary:
Epidemiology
More than 25 cases with SSPS have been described so far.
Clinical description
SSPS refers to a discrete phenotype of ectodermal dysplasia with a relatively benign course and late diagnosis, often established in adulthood. The onset of symptoms occurs in childhood and early adolescence, but they consist of relatively unspecific features, including various degrees of hypodontia, hypotrichosis, palmoplantar keratoderma and nail dystrophy. Telangiectatic rosacea is a further relatively common feature. Multiple eyelid apocrine hidrocystomas commonly appear in (late) adulthood. Palmoplantar keratoderma with histologic features of eccrine syringofibroadenoma is observed in nearly half of cases and occasionally develops a malignant potential. Other adnexal tumors described include basal cell carcinoma, eccrine poroma, benign acanthoma and follicular infundibulum tumor. Some patients have been described to have a bird-like facies. Within the WNT10A mutational spectrum, odonto-onycho-dermal dysplasia and SSPS are regarded as discrete entities, while an increasing number of patients are described with incomplete phenotypes of the odonto-onychial, tricho-odonto and tricho-odonto-onychial types.
Etiology
SSPS is due to homozygous or compound heterozygous mutations in WNT10A. Incomplete/localized disease expression in heterozygous carriers and multiple instances of consanguinity occasionally lead to a pseudodominant transmission.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Marco CASTORI


Scimitar syndrome is characterized by a combination of cardiopulmonary anomalies including partial anomalous pulmonary venous return connection of the right lung to the inferior caval vein leading to the creation of a left-to-right shunt.

Summary:
Epidemiology
The prevalence is estimated at between 1/100,000 and 1/33,333 live births. Females seem to be more frequently affected than males.
Clinical description
In the majority of cases, the disease manifests in the first months of life. In the neonatal period, the disease presents with congestive cardiac failure, most commonly due to pulmonary hypertension and respiratory distress. The right lung is most frequently involved. Variable degrees of hypoplasia and malformations of the pulmonary arteries are found in the affected lung, as well as arterial supply from the aorta, which can also arise above or below the diaphragm. The heart itself is usually right-sided. Rarely, the disease may manifest with a small shunt, a cardiac murmur, and recurrent respiratory infections in children and adults. About one-fourth of affected patients have associated congenital heart disease (aortic coarctation, tetralogy of Fallot, patent arterial duct or ventricular septal defect; see these terms). Other reported associated anomalies include bronchogenic cysts, horseshoe lung, accessory diaphragm and hernias.
Etiology
The etiology is not completely understood. In several patients with total anomalous pulmonary venous return, the gene locus has been mapped to chromosome 4q12.
Diagnostic methods
The diagnosis is based on clinical presentation and transthoracic or transesophageal echocardiography, angiography, computed tomography and magnetic resonance angiography. The characteristic feature on chest radiographs, giving the condition its name, is a lesion in the shape of a scimitar (a type of curved Turkish sword).
Differential diagnosis
Scimitarsyndrome must be differentiated from pseudoscimitar syndrome (abnormal descending vein draining into the left atrium) and from Kartagener syndrome (see this term).
Antenatal diagnosis
Prenatal diagnosis is feasible by fetal echocardiography. Rarely, Scimitar syndrome is diagnosed incidentally in older children and adults who undergo chest radiography for diverse reasons.
Management and treatment
Management depends on the hemodynamic state. No therapy is required if the amount of blood flowing to the inferior caval vein is small. In case of significant left-to-right shunt and pulmonary hypertension, surgical correction is warranted, and can include repair of the anomalous venous return, ligation of collateral arteries, and right pneumonectomy.
Prognosis
When diagnosed in infancy, the syndrome is associated with significant mortality due to severe respiratory insufficiency, cardiac failure, and pulmonary infections.

                            Last update:
                            May 2009

                            - Expert reviewer(s):
                            Pr Robert ANDERSON


A rare acquired skin disease characterized by excessive mucin deposition and thickened collagen bundles in the dermis, resulting in woody, non-pitting induration of the skin of the neck, spreading to the shoulders and upper trunk, but sparing hands and feet. According to the association with preceding or underlying conditions, three types can be distinguished: type 1 usually follows a febrile infection, type 2 is associated with paraproteinemia, and type 3 occurs in patients with diabetes mellitus. Especially in types 2 and 3, extracutaneous involvement may be present. Other potentially associated conditions include a variety of endocrinopathies, systemic diseases, and neoplasms.


Scleroderma is a rare autoimmune connective tissue disorder characterized by abnormal hardening of the skin and, sometimes, other organs. It is classified into two main forms: localized scleroderma and systemic sclerosis (SSc), the latter comprising three subsets; diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc) and limited SSc (lSSc).

Summary:
Epidemiology
The prevalence is estimated at around 1-9/100,000 for localized scleroderma, and 1/6,500 adults for systemic sclerosis. Women are predominantly affected (F/M sex ratio around 4:1).
Clinical description
Localized scleroderma is the cutaneous form of scleroderma characterized by fibrosis of the skin causing cutaneous plaques (morphea) or strips (linear scleroderma). Systemic sclerosis (SSc) is a generalized disorder characterized by fibrosis and vascular obliteration in the skin and organs, particularly, lungs, heart, and digestive tract.
Etiology
The exact cause of scleroderma is unknown. The disease originates from an autoimmune reaction which leads to localized overproduction of collagen. In some cases, the condition is associated with exposure to chemicals. Other suggested causes include genetic and infectious mechanisms.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                            Pr Eric HACHULLA


Scleromyxedema without monoclonal gammopathy is a form of atypical lichen myxedematosus (see this term), characterized by a generalized sclerodermoid infiltration of skin studded with multiple, firm papules of 1-3 mm in diameter involving face (leonine appearance), trunk, and limbs, without monoclonal gammopathy. The involvement of the face can be missing and pruritus may be prominent.


A rare lichen myxedematosus characterized by a progressive, generalized, papular, sclerodermoid cutaneous eruption usually occurring in association with monoclonal gammopathy, but in the absence of thyroid disease. Histological hallmark is the triad of dermal mucin deposition, fibroblast proliferation, and fibrosis. Patients present with relatively sudden onset of numerous closely spaced, waxy, firm papules and plaques predominantly involving the head, neck, trunk, and dorsal aspects of the extremities, on the background of thickened, edematous, erythematous skin with sclerodermoid appearance. Systemic involvement with cardiovascular, gastrointestinal, pulmonary, musculoskeletal, renal, or nervous system complications is common.


Sclerosteosis is a very rare serious sclerosing hyperostosis syndrome characterized clinically by variable syndactyly and progressive skeletal overgrowth (particularly of the skull), resulting in distinctive facial features (mandibular overgrowth, frontal bossing, midfacial hypoplasia), cranial nerve entrapment causing facial palsy and deafness, and potentially lethal elevation of intracranial pressure.


Scorpion envenomation is a rare intoxication caused by a scorpion sting which typically manifests with localized pain, edema, erythema, and paresthesias at the site of the sting and, when severe, progresses to produce systemic symptoms of variable severity that include respiratory difficulties, abnormal systemic blood pressure, cardiac arrhythmia, and a combination of parasympathetic (i.e. excessive salivation and lacrimation, diaphoresis, miosis, frequent urination, diarrhea, vomiting, priapism) and sympathetic (e.g. hyperthermia, hyperglycemia, mydriasis) manifestations. Neurological manifestations may also be associated, such as abnormal eye movements, blurred vision, agitation and restlessness, as well as muscle fasciculations and spasms. Signs and symptoms are highly variable and in most severe cases may lead to cardiogenic shock and pulmonary edema.


Scott syndrome is an extremely rare congenital hemorrhagic disorder characterized by hemorrhagic episodes due to impaired platelet coagulant activity.


Scrub typhus is a rare dust mite-borne infectious disease caused by the Orientia tsutsugamushi bacterium and characterized clinically by an eruptive fever which is potentially serious.

Summary:
Epidemiology
Precise prevalence and incidence rates of scrub typhus are not known. An estimated 1 billion people worldwide are at risk for scrub typhus, and an estimated 1 million cases occur each year. The disease is widespread in rural South and South-East Asia and the Western Pacific (Korea to Australia) as well as from Japan to India and Pakistan. In these regions its annual incidence is approximately 1/4,000. Scrub typhus occurs preferentially in spring and autumn in rural areas and has frequently been reported in individuals who traveled to endemic regions.
Clinical description
After a silent incubation period of 10 days or more, onset is sudden with constant high fever, headache, obtundation, cough, myalgia and nausea. A pale macular rash is common and an inoculation eschar at the site of the mite bite is found in many cases, often with painful satellite lymph nodes. Splenomegaly is observed in 1/3 of cases. Most cases are mild, but pneumonitis, meningoencephalitis, multiorgan failure, bleeding and even death may occur, especially in untreated patients. Relapses after recovery may occur but are usually less severe than the inaugural episode.
Etiology
Scrub typhus is caused by Orientia tsutsugamushi, an obligate intracellular Gram-negative rod bacteria belonging to the genus Orentia, which is transmitted to humans by the bites of larval thrombiculid mites (chiggers).
Diagnostic methods
Diagnosis is based on clinical signs (fever, headache, eschar at the bite site, rash) in an endemic rural zone. Non-specific laboratory test results include increased transaminase levels, thrombocytopenia, leucopenia and CD4/CD8 lymphocyte ratio inversion. A definitive diagnosis can be made by culture of O. tsutsugamushi in a shell vial or molecular biology analysis of sampling (skin, lymph nodes, EDTA blood) using PCR amplification. The organisms stain poorly with the Gimenez method but easily with Giemsa staining. Immunohistochemistry of skin lesions may reveal an O. tsutsugamushi infection. Later serological confirmation is possible by indirect immunofluorescence.
Differential diagnosis
Differential diagnosis includes typhoid fever, leptospirosis, malaria, and dengue (see these terms), as well as HIV seroconversion and rickettsial diseases (see this term).
Management and treatment
Treatment usually involves drug therapy with doxycycline and chloramphenicol. Doxycycline is administered for a short time (3-7 days) in adults (200 mg/day) and children (2.2 mg/kg, twice daily). All patients with a suspected infection should be treated. Patients with poor response to doxycycline and chloramphenicol, as well as pregnant women, can be treated with rifampicin (600-900 mg/day) or azithromycin (500 mg on the first day, then 250 mg/day).
Prognosis
The disease course may be severe. However, the mortality rate depends on the geographic areas and varies from 3% in Taiwan up to 30% in Northern Japan. The exact reasons for the variable mortality in these regions are not known, but it is likely that different serotypes may account for the varying manifestations of the disease.

                            Last update:
                            March 2013

                            - Expert reviewer(s):
                            Dr Senaka RAJAPAKSE


Sebocystomatosis is characterized by multiple (100 to 2000) asymptomatic dermal cysts that usually occur on the sternal region, upper back, axillae and proximal parts of the extremities.

Summary:
Epidemiology
At least 30 cases from unrelated families (over three to five generations) and several sporadic cases have been reported.
Clinical description
Sebocystomatosis usually manifests during the first or second decade of life and affects both sexes, with some studies indicating that the prevalence is higher in males.
Etiology
Sebocystomatosis is caused by mutations in the keratin-17 gene (KRT17, 17q12-q21).
Genetic counseling
An autosomal dominant pattern of inheritance has been suggested.

                            Last update:
                            September 2009


Seborrhea-like dermatitis with psoriasiform elements

A rare, genetic, epidermal disorder characterized by a chronic, diffuse, fine, scaly erythematous rash on the face (predominantly the chin, nasolabial folds, eyebrows), around the earlobes and over the scalp, associated with hyperkeratosis over elbows, knees, palms, soles and metacarpophalangeal joints, in the absence of associated rheumatological or neurological disorders. Cold weather, emotional stress and strenuous physical activity may exacerbate symptoms.