A rare eye tumor disease representing the most common intraocular malignancy in children. It is a life threatening neoplasia but is potentially curable and it can be hereditary or non hereditary, unilateral or bilateral.

Summary:
Epidemiology
Retonoblastoma (RB) has an incidence of approximately 1/15-20,000 in Europe.
Clinical description
RB manifests most often in young children (90% of cases <3 years old). Early clinical signs are leukocoria and strabismus. RB is most often painless and children rarely complain of visual impairment despite its rapid progression towards loss of vision in the affected eye. Other rare signs include hypopyon, vitreous hemorrhage, non rhegmatogenous retinal detachment, neovascular glaucoma and orbital cellulitis. In later stages, rarely seen in high income countries (HIC), intracranial dissemination and hematagenous metastasis, mainly to bones and bone marrow, are observed and are life-threatening. Most retinoblastomas (60%) are unilateral. Hereditary RB refers to those that arise due to a genetic predisposition (irrespective of family history); most of these patients have a bilateral disease and they are at increased risk to develop secondary tumors, mainly sarcoma but also pineoblastoma/supra-sellar tumor (both named ''trilateral retinoblastoma''), glial tumor, melanoma and carcinoma.
Etiology
RB is caused by inactivating mutations of both alleles of RB1 (13q14) with a high (90%) penetrance (RB risk) in most mutations. Some mutations have a low penetrance (asymptomatic carriers or unilateral RB). Some rare unilateral retinoblastoma cases may arise without RB1 gene mutation but with somatic NMYC amplification. Monosomy 13q14 also causes RB.
Diagnostic methods
Diagnosis is mainly clinical: Indirect ophthalmoscopy supported by fundal photography. Orbital ultrasound delineates intraocular tumor and usually shows calcification. MRI imaging is used to evaluate intra/extraocular and intracranial extension. Tumor staging (i.e. bone marrow examination, lumbar puncture and/or radionuclide bone scan) should be performed only in patients at risk of extra-ocular metastases.
Differential diagnosis
Differential diagnoses, particularly in unilateral cases, include anterior chamber or lens abnormalities especially PHPV (persistence of hyperplastic vitreous), toxocariasis, X-linked retinoschisis, uveitis, medulloepithelioma, von Hippel disease, Norrie disease, retinopathy of prematurity and Coats disease (the most difficult differential diagnosis).
Antenatal diagnosis
Prenatal and preimplantation genetic diagnoses are available in specialized centers in most HIC.
Genetic counseling
Patients with hereditary RB inherit RB1 mutation from a parent and thus the predisposition to RB is transmitted in an autosomal dominant manner. However, more than 75% of predisposed patients do not inherit the mutated RB1 from an affected parent, but might have had a de novo mutation in a parental gamete or post-zygotically. Genetic testing needs to be proposed to all patients and their families, even when retinoblastoma is unilateral.
Management and treatment
Treatment requires a multidisciplinary highly specialized approach. In HIC, conservative treatments for at least one eye are possible in most bilateral cases and increasingly used in unilateral cases. Laser treatment alone or combined with systemic chemotherapy, cryotherapy and brachytherapy are very efficient tools as well as the more recently developped local chemotherapy using intra-arterial and/or intravitreous delivery. Enucleation is still frequently used in large unilateral RB as well as in bilateral with large unilateral tumor. External beam radiotherapy is now avoided (risk of late effects, including second cancers in irradiated field).
Prognosis
Vital prognosis is excellent in HIC. Visual prognosis is dictated by tumor location and size at diagnosis (macular involvement has a poor visual prognosis). Eye preservation is possible with early diagnosis. After conservative treatment, visual prognosis depends on macular involvement. If not treated promptly, RB may rapidly metastasize and be fatal, which is still frequent in low income countries.

                            Last update:
                            July 2019

                            - Expert reviewer(s):
                            Pr François DOZ


A rare retinal vasoproliferative disease affecting preterm infants characterized initially by a delay in physiologic retinal vascular development and compromised physiologic vascularity, and subsequently by aberrant angiogenesis in the form of intravitreal neovascularization.

Summary:
Epidemiology
The incidence of Retinopathy of prematurity (ROP) is increasing as higher numbers of premature neonates survive into infancy, particularly in developing countries. Some estimates among preterm birth infants are over 30%. In some countries, ROP accounts for up to 10% of childhood blindness. Higher prevalence has been reported in South East Asia, Latin America, and subSaharan Africa. Incidence rates are similar in Caucasian and Black populations, but progression to severe forms may be more frequent in Caucasians.
Clinical description
The degree of prematurity generally correlates with the severity of the clinical manifestations, with the smallest neonates having the highest risks. In affected infants, normal retinal development is incomplete at the time of preterm birth. Subsequently, aberrant angiogenesis in the form of intravitreal neovascularization occurs leading to later cicatricial fibrosis causing partial or complete retinal detachment and possible loss of vision. Patients may also develop ametropia, anisometropia, amblyopia or strabismus. Glaucoma has also been reported in affected individuals.
Etiology
The pathophysiological mechanisms underlying ROP remain poorly understood. Associations with severe ROP include high oxygen at birth and oxygenation fluctuations during the neonatal course, low birth weight and young gestational age, and poor postnatal growth. In candidate gene studies, gene mutations associated with severe ROP have been reported, including NDP (Xp11.4-p11.3), FZD4 (11q14-q21), and LRP5 (11q13.4).
Diagnostic methods
Neonates born before 30 weeks of gestation or with a birth weight below 1,500 g should be screened for ROP, but specific guidelines may vary based on regional statistics and characteristics of affected preterm infants world-wide. Diagnosis is based on characterization of ROP severity in preterm infants usually determined by dilated fundus examination with scleral depression but increasingly more with review of photographic images. ROP is categorized into 3 zones and severity in 5 stages (stages 1 to 5, from mild disease to total retinal detachment).
Differential diagnosis
The main differential diagnostic considerations for early ROP are conditions associated with peripheral avascular retina and intravitreal neovascularization, including familial exudative vitreoretinopathy (FEVR) or incontinentia pigmenti (see these terms). For stage 5 ROP, other conditions causing leukocoria are included (e.g. retinoblastoma, persistent fetal vasculature, toxocariasis, etc.).
Management and treatment
Close work with neonatologists is recommended. All attempts are made to avoid high oxygen at birth (100% oxygen). Optimal monitoring and regulation of oxygen saturation is recommended and is chosen based on gestational age and overall health of the infant. However, the optimum saturation level is not known. Following screening of at-risk infants, monitoring is recommended based on retinal findings. Treatment options include transpupillary or sometimes transscleral laser photocoagulation of the peripheral avascular retina. For the most severe forms of ROP like zone I severe ROP and aggressive posterior ROP, intravitreal treatment with agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are being studied and considered. Visual rehabilitation is critical because of the association with myopia and refractive errors. Anisometropia should be corrected and associated amblyopia or strabismus treated. Protective eyewear and low-vision aids may be required.
Prognosis
Gestational age and birth weight are the main prognostic factors in ROP. Also associated is poor postnatal weight gain. ROP often resolves but if it develops severe characteristics, it can lead to blindness.

                            Last update:
                            July 2019

                            - Expert reviewer(s):
                            Pr Mary Elizabeth HARTNETT


A rare severe, X-linked, neurodevelopmental disorder characterized by rapid developmental regression in infancy, partial or complete loss of purposeful hand movements, loss of speech, gait abnormalities, and stereotypic hand movements, commonly associated with deceleration of head growth, severe intellectual disability, seizures, and breathing abnormalities. The disorder has a progressive clinical course and may associate various comorbidities including gastrointestinal diseases, scoliosis, and behavioral disorders.

Summary:
Epidemiology
The disorder affects approximately 1 in 10,000 live female births. The disease has been occasionally reported in males, usually with a lethal course before birth or in early infancy.
Clinical description
Classic or typical Rett syndrome (RTT) primarily affects girls and is characterized by apparently normal psychomotor development during the first 6-18 months of life followed by developmental stagnation with rapid regression in language and motor abilities, and subsequent long-term plateauing of skills. Repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures (60-80%), and acquired microcephaly. There is a wide variability in the rate of disease progression and severity. A number of males with a phenotype comparable to females with classical RTT have been described.
Etiology
Pathogenic variants in the X-linked gene methyl CpG-binding protein 2 (MECP2; Xq28) are found in more than 95% of classic RTT cases. The most common mutation involves a C to T transition at CpG dinucleotides; however, the spectrum of mutation types includes missense, nonsense, and frameshift mutations, with over 300 unique pathogenic nucleotide changes described, as well as deletions encompassing whole exons. Different phenotypes to classical RTT have been described in association within MECP2 pathogenic variants in males and females.
Diagnostic methods
The clinical diagnosis of RTT is based on consensus clinical criteria. These include one necessary criteria i.e. presence of regression plus four main criteria that are absolutely required for the diagnosis of typical RTT that include (i) partial or complete loss of acquired purposeful hand skills, (ii) partial or complete loss of acquired spoken language, (iii) gait abnormalities, (iv) stereotypic hand movements. Genetic testing identifies variants in MECP2 in 95-97% of individuals with typical RTT, but is not mandatory for RTT diagnosis.
Differential diagnosis
Differential diagnosis includes autism spectrum disorder; Angelman syndrome in which early development before 6 months is abnormal; CDKL5 deficient disorders in which early onset seizures are distinctive from RTT; FOXG1 syndrome in which congenital microcephaly and corpus callosum abnormalities are not usually found in RTT.
Antenatal diagnosis
Prenatal screening should be discussed in families with a proband having a pathogenic mutation.
Genetic counseling
As pathogenic MECP2 mutations in RTT patients are mostly de novo, the recurrence risk for future pregnancies is low, although germline mosaicism has been reported.
Management and treatment
Management is mainly symptomatic, focused on optimizing each patient's abilities through a multidisciplinary approach. Attention should be paid to scoliosis and the development of spasticity, as well as to effective communication strategies. Psychosocial support for families is essential. Pharmacological approaches aim at improving sleep disturbances, breathing disturbances, seizures, stereotypic movements and general well-being. As RTT patients have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, avoidance of a number of drugs is recommended (e.g. macrolide antibiotics).
Prognosis
The clinical picture evolves in stages over a number of years. Patients have been reported to live into middle age and beyond.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Nadia BAHI-BUISSON | EpiCARE* - Dr Andreas BRUNKLAUS | EpiCARE* - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


Reversible cerebral vasoconstriction syndrome

A rare cerebrovascular disorder characterized by severe headaches with or without focal neurological deficits or seizures, and a reversible segmental and multifocal vasoconstriction of cerebral arteries. It may occur spontaneously or be provoked by various precipitating factors, the most common being postpartum and exposure to various vasoactive substances such as illicit drugs and selective serotonin-reuptake inhibitors. The major complication is ischemic or hemorrhagic stroke.


Revesz syndrome is a rare severe phenotypic variant of dyskeratosis congenita (DC; see this term) with an onset in early childhood, characterized by features of DC (e.g. skin hyper/hypopigmentation, nail dystrophy, oral leukoplakia, high risk of bone marrow failure (BMF) and cancer, developmental delay sparse and fine hair) in conjunction with bilateral exudative retinopathy, and intracranial calcifications.


A rare, systemic disease characterized by persistent vomiting with confusion, lethargy, disorientation, hyperreflexia, hyperventilation, and tachycardia, with rapid progression to seizures, non-inflammatory encephalopathy, coma and death. It typically develops between 12 hours and 3 weeks after recovery from a viral illness, such as upper respiratory tract infection or gastroenteritis. Hepatomegaly, acute hepatic steatosis, fatty liver degeneration and multiple laboratory abnormalities are associated.


Reynolds syndrome (RS) is an autoimmune disorder characterized by the association of primary biliary cirrhosis (PBC) with limited cutaneous systemic sclerosis (lcSSc) (see these terms).

Summary:
Epidemiology
The prevalence of systemic sclerosis (SSc) in PBC patients is 5-15%. Conversely, the prevalence of PBC in SSc patients is about 2%. Females are more affected.
Clinical description
Onset occurs between 30-65 years. RS associates the features of PBC (fatigue, pruritus due to cholestasis, hepatomegaly) with most features of lcSSC (cutaneous calcifications, digital ulcers, facial telangiectasias, calcinosis, Raynaud's phenomenon, esophageal involvement and sclerodactyly). In 50% of cases, symptoms of scleroderma occur prior to those of PBC. About 25-50 % of newly diagnosed RS patients have hyperpigmentation of skin, and jaundice at a later stage. Inflammatory arthropathies are observed in approximately 40% of patients with PBC. In some, RS is associated with other autoimmune diseases such as Sjögren's syndrome, autoimmune hemolytic anemia and (in one case) with thymoma (see these terms). An overlap syndrome between nodular regenerative hyperplasia of the liver (see this term), PBC, and lcSSc may exist.
Etiology
The pathological mechanism of RS has not yet been established, but it is assumed to be an auto-immune disorder. A heterozygous missense mutation in LBR exon 9 was identified in a Caucasian woman with RS. The mutation was predicted to induce a change in Lamin B receptor tertiary structure. Mutations in LBR may either have a direct pathogenic effect or constitute a predisposing factor in conjunction with other genetic and environmental factors.
Diagnostic methods
Diagnosis of RS relies on the clinical findings for lcSSc and, for PBC, on the biochemical evidence of cholestasis which is based on marked elevation of serum alkaline phosphatase, gamma-glutamyl transpeptidase enzymes and IgM concentrations, a positive test for serum mitochondrial antibody, histologic evidence of non suppurative destructive cholangitis and destruction of interlobular bile ducts. An elevated serum bilirubin is a poor prognostic sign. Specific autoantibodies associated with both facets of the disease (antimitochondrial antibodies for PBC and anticentromere/antitopoisomerase for SSc), and suggestive microscopical abnormalities in the skin and liver have been found in patients affected with RS. Furthermore, a higher prevalence of clonal populations of CD8+ TCRBV3+ T cells has been found in RS.
Differential diagnosis
The association with primary sclerosing cholangitis and SSc is extremely rare. Cholestasis in SSc patients may also reflect liver congestion due to right-sided heart failure in cases with severe pulmonary hypertension. Medications (antibiotics, anabolic steroids, birth control pills, chlorpromazine, cimetidine, estradiol) may cause cholestasis similar to that of PBC.
Genetic counseling
RS occurs sporadically, but rare familial cases with an unknown inheritance pattern have been observed.
Management and treatment
There is no cure for RS and management is mainly supportive. It includes physiotherapeutic assistance and treatment of PBC with ursodeoxycholic acid so as to normalize the cholestatic parameters. Potential hepatotoxic drugs such as bosentan monohydrate or methotrexate can be used to treat some SSc manifestations, if transaminases are < 3 fold the upper limit of normal and remains < 3 fold the upper limit of normal over time.
Prognosis
Nodular regenerative hyperplasia of the liver is a rare complication in those with SSc. Patients usually have a good prognosis, particularly when UDCA treatment is started in the early stages. RS prognosis depends on PBC's severity, but also depends on SSc evolution, as lcSSc has a higher risk of pulmonary arterial hypertension. The regular evaluation of liver function tests is useful for monitoring disease progression. Advanced age, hyperbilirubinemia, low serum albumin and cirrhotic liver biopsy indicate a worse prognosis. Survival of patients with RS seems to be better than that of patients with PBC alone.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Pr Eric HACHULLA


RFT1-CDG is a form of congenital disorders of N-linked glycosylation characterized by poorly coordinated suck resulting in difficulty feeding and failure to thrive; myoclonic jerks with hypotonia and brisk reflexes progressing to a seizure disorder; roving eyes; developmental delay; poor to absent visual contact; and sensorineural hearing loss. Additional features that may be observed include coagulation factor abnormalities, inverted nipples and microcephaly. The disease is caused by mutations in the gene RFT1 (3p21.1).


A rare constitutional hemolytic anemia due to a red cell membrane anomaly characterized by lack or severe reduction of Rh blood group antigens, resulting in increased osmotic fragility of red blood cells and chronic hemolytic anemia of varying severity with stomatocytosis and spherocytosis. Two types of the syndrome arising from independent genetic mechanisms have been distinguished: the regulator type is caused by defects of the Rh associated glycoprotein (encoded by the RHAG gene), while the amorph type is due to mutations at the RH locus itself.


Rhabdoid tumor (RT) is an aggressive pediatric soft tissue sarcoma that arises in the kidney, the liver, the peripheral nerves and all miscellaneous soft-parts throughout the body. RT involving the central nervous system (CNS) is called atypical teratoid rhabdoid tumor (ATRT; see this term).

Summary:
Epidemiology
The United Kingdom registry estimated that the age-standardized annual incidence of extra-CNS RT is about 1/2,000,000 children, which might be underestimated. Altogether, in infants less than one year, RT may account for 20% of renal cancers, and 15% of soft-part tumors. In the same age range, ATRT may be the most frequent malignant tumor of the posterior fossa.
Clinical description
RT usually occurs in infancy or childhood (mostly affecting patients < 2 years, with a median of 20 months).In most cases, the first symptoms are linked to the compressive effects of a bulky tumor (such as respiratory distress, abdomen mass, peripheral nerve palsy). Subcutaneous nodular metastases are specifically seen in patients with neonatal tumors. Exceptional cases can occur in adolescents and adults. RT arises in the kidney, liver, peripheral nerve and miscellaneous soft parts. Hypercalcemia may be seen at diagnosis (<1/3 of cases). RT affecting the CNS is called ATRT and constitutes about half of all RTs.
Etiology
90% of RT cases have biallelic inactivation of  SMARCB1 (22q11.23), a tumor suppressor gene encoding a member of SWI/SNF chromatin remodeling complex which broadly regulates the expression of the genome. Rare cases are associated with a biallelic mutation of SMARCA4 (19p13.3) (encoding another SWI/SNF chromatin-remodeling complex member).
Diagnostic methods
Once a tumor is evidenced by imaging scans (magnetic resonance and computed tomography), the diagnosis relies on tumor biopsy. The tumor is composed of a diffuse proliferation of rounded or polygonal cells with eccentric nuclei, prominent nucleoli and glassy eosinophilic cytoplasm containing hyaline-like inclusion bodies, arranged in sheets and nests (rhabdoid cells). Tumor cells are usually positive to glypican-3 (50% of cases), vimentin, epithelial markers (keratins, epithelial membrane antigen) and mesenchymal markers (smooth muscle actin, muscle-specific actin, S100 protein). Diagnosis is confirmed by loss of nuclear staining of SMARCB1 (or SMARCA4, exceptionally) protein by immunohistochemistry.
Differential diagnosis
Differential diagnosis includes all undifferentiated sarcomas, peripheral primitive neuroectodermal tumor in children, epithelioid sarcoma (especially the proximal type) in older patients, extraskeletal myxoid chondrosarcoma, and undifferentiated chordomas (see these terms) in cases with clivus involvement.
Genetic counseling
In 25% of cases, RT is associated with a germline mutation of  SMARCB1. Rarely, germline mutations are inherited from asymptomatic parents, either because of gonadal mosaicism or incomplete penetrant mutations (familial RT; see this term). Adult carriers may develop multiple schwannomas or meningiomas (see these terms).
Management and treatment
No standard care exists for RT although several prospective trials are now running throughout the world. Treatment includes resection of the tumor mass (as complete as possible), multimodal aggressive chemotherapy and radiotherapy whenever feasible. However, the young age of patients may limit use of radiotherapy.
Prognosis
The survival rate is low with a 5 year survival rate of 20%. Prognostic factors include metastases, young age at diagnosis (< 2years), and incomplete resection.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Franck BOURDEAUT


Rhabdomyosarcoma of the cervix uteri is a rare, highly malignant soft tissue sarcoma located in the uterine cervix and arising from primitive mesenchymal cells displaying skeletal muscle differentiation. It most often presents with abnormal vaginal discharge or dysfunctional uterine bleeding, abdominal pain and/or a cervical mass protruding into the vagina. Association with DICER1 syndrome has been reported.


Rhabdomyosarcoma of the corpus uteri is an extremely rare, highly malignant soft tissue sarcoma located in the uterine body and arising from primitive mesenchymal cells displaying variable degrees of skeletal muscle differentiation. It most often presents with abnormal vaginal discharge or dysfunctional uterine bleeding, abdominal pain and lower abdominal mass. Association with DICER1 syndrome has been reported.


A malignant soft tissue tumor which develops from cells of striated muscle. It is the most common form of tumor found in children and adolescents.

Summary:
Epidemiology
The annual incidence is 1/170,000. In children younger than 15 years, the annual incidence is estimated at 1/244,000.
Clinical description
The median age of diagnosis is 5 years. Rhabdomyosarcoma can develop anywhere in the body, including in sites where striated muscle does not normally occur. The most frequent locations are: the head and neck (40%), including tumors of the orbit and para-meningeal tumors, the genitourinary tract (20%) including tumors in the bladder and/or prostate, in the uterus and vagina, para-testicular tumors, and tumors in the limbs (20%) and trunk (10%). Rhabdomyosarcoma has a high risk of local relapse, a high risk of local extension to lymph nodes and a lower risk of metastases. There are two main histological subtypes of rhabdomyosarcoma: embryonic (80% of cases) and alveolar (15-20% of cases). Clinically there is little difference between the two types. The alveolar form occurs more readily in the limbs, nearly never in the orbits and more frequently affects the lymph nodes.
Etiology
The cause of rhabdomyosarcoma is unknown, but a translocation t(2;13) is very often associated with the alveolar type.
Diagnostic methods
Diagnosis is based on positive muscular markers and immunohistochemistry. The evidence of a translocation t(2;13) leads to diagnosis of alveolar forms.
Differential diagnosis
Differential diagnoses include small round cell tumors (lymphoma, neuroblastoma, Ewing sarcoma; see these terms). It is possible to distinguish between tumors using immunohistochemistry. Some rhabdomyosarcomas are associated with a genetic predisposition to cancer as part of Li-Fraumeni syndrome or neurofibromatosis type 1 (see these terms).
Management and treatment
Treatment should be managed by a multidisciplinary team, expert in the treatment of childhood cancers. Initial surgery should only be considered if it can be completed, and completed without significant consequences. Chemotherapy is indicated in all other cases from diagnosis. Local treatment is carried out by secondary surgery, often complemented by radiotherapy. Alveolar forms require more intensive treatment than embryonic forms. The objective of current protocols is to avoid radiotherapy, if possible, in order to reduce long term sequelae.
Prognosis
Survival depends on the location of the tumor. In localized forms the survival rate is greater than 80% for tumors of the orbit, bladder, vagina and paratesticular region. The survival rate is in the order of 60-70% for other localized tumors. For patients with metastases at diagnosis the survival rate is lower, and adolescents and patients with osteo-medullar metastases have a survival rate of less than 20%.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Odile OBERLIN


Rheumatic fever (RF) is a multisystem inflammatory disease occurring as a post-infectious, nonsuppurative sequela of untreated streptococcus pyogenes (Group A streptococcus [GAS]) pharyngitis, and mainly occurs in individuals aged 5 to 15 years. The most common presenting signs are fever, migratory polyarthritis and carditis.

Summary:
Epidemiology
The incidence of RF in industrialized countries, due to sporadic outbreaks, is typically less than 1/20, 000 individuals. In the developing world, the annual incidence is at least 100 times higher with some reports of > 1/200 individuals in select subpopulations, such as Australian Aboriginals. RF remains a major cause of acquired cardiac morbidity and mortality among people under 50 years of age.
Clinical description
RF usually initially occurs between 5 and 15 years of age, and involves the heart, large joints and skin and is a delayed sequela of untreated GAS pharyngitis. The major diagnostic criteria include migratory polyarthritis (46-66% of cases), most commonly in the knee, ankle, elbow and wrists; carditis (53-68% clinical and additional ''subclinical'' diagnosed by echocardiogram), which is typically inflammation of the mitral (90%) or aortic valve (10%) in isolation, but any combination of all 4 valves have been reported; Sydenham chorea (8-15%); erythema marginatum (1-11%); and subcutaneous nodules on the flexor surfaces (1-8%). Minor criteria include fever (35-75% of cases), arthralgia (35-56%), first degree heart block (prolonged PR interval) (20-29%) and elevated inflammatory markers (53-91%). There is not always a prior clinically apparent GAS infection.
Etiology
There are proposed associations with certain HLA types (most frequently HLA-DR7), but numerous types have been implicated and are not always consistent among different populations. Immunological cross-reactivity is believed to occur through molecular mimicry and has been attributed to the M-protein in the GAS cell membrane. Tumor necrosis factor α and mannose-binding lectin may also be upregulated in individuals with increased RF susceptibility.
Diagnostic methods
The revised Jones criteria require the presence of two major or one major and two minor criteria, as well as evidence of a prior GAS infection. Diagnostic tests include an antistreptolysin O (ASO) titer, erythrocyte sedimentation rate (ESR) or C reactive protein (CRP), electrocardiogram to detect first degree heart block, and echocardiogram to diagnose valvulitis.
Differential diagnosis
The differential diagnosis includes other causes of febrile polyarthritis in children: juvenile idiopathic arthritis, Lyme disease, mixed connective tissue disease, reactive arthritis, sickle cell anemia, systemic lupus erythematosus (see these terms), and septic arthritis.
Management and treatment
Treatment of RF includes: 1) treatment of pharyngitis to eradicate GAS, with penicillin as first line therapy, 2) anti-inflammatory treatment, usually aspirin in the acute phase, although the use of corticosteroids is sometimes suggested, especially with severe carditis, and 3) secondary antibiotic prophylaxis to prevent recurrence of RF, usually with benzathine penicillin every 3 to 4 weeks.
Prognosis
Prognosis is generally good after initial episode of RF and all of the symptoms usually resolve completely with the exception of cardiac valve damage, which can progress over time, especially with subsequent episodes of RF, and require chronic medical management for heart failure and eventual surgical valve replacement.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Dr Michael SECKELER


Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis

A rare form of polyarticular juvenile idiopathic arthritis characterized by childhood-onset chronic arthritis of unknown cause involving five or more joints at disease onset and absence of rheumatoid factor IgM.

Summary:
Epidemiology
Rheumatoid factor-negative juvenile polyarthritis represents around 15-20% of cases of juvenile idiopathic arthritis (JIA). Prevalence has been estimated at between 1 and 13 in 22,200 children, with an annual incidence of 1-26 in 700,000 children. Females are affected more often than males, with a female/male ratio of 3:1.
Clinical description
Rheumatoid factor negative juvenile polyarthritis is clinically heterogeneous with two patient groups distinguished by age of onset and distribution of arthritis. The early onset form typically appears between 2 and 6 years of age with asymmetrical pattern of joint involvement, possible eye inflammation (asymptomatic chronic anterior uveitis), and presence of anti-nuclear antibody. This form resembles oligoarticular juvenile idiopathic arthritis. The second group has a later onset around 10 years of age with often symmetrical distribution and distal joint involvement (commonly small joints of the hands, wrist and knees). Patients may be ANA positive or negative. This form closely resembles rheumatoid polyarthritis.
Etiology
The etiology remains unknown but auto-immunity plays a role.
Diagnostic methods
Rheumatoid factor-negative polyarthritis is defined as the presence of arthritis affecting five or more joints at disease onset. Exclusion criteria are the presence of systemic arthritis or psoriasis in the patient, or a family history of psoriasis in one of the parents or a first-degree relative, HLA B27-positivity in males with onset of arthritis after 6 years of age, and detection of rheumatoid factor IgM in two test samples taken three months apart. Other exclusion criteria include: the presence of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient, or a family history of one of these conditions in a parent or first-degree relative. It is important to note that these diagnostic criteria were established in 2001 (International League of Associations for Rheumatology, Edmonton) and are currently under revision.
Differential diagnosis
The differential diagnosis should include other forms of polyarthritis (associated with inflammatory or haemato-oncologic diseases).
Management and treatment
Patients should be managed by a multidisciplinary team, incorporating expertise in pediatric rheumatology, physiotherapy, psychology and infantile orthopedic care. Treatment is based on the association nonsteroidal anti-inflammatory agents (NSAIDS), and disease-modifying antirheumatic drugs; methotrexate is used as first-line treatment and then in case of inefficacy or intolerance. Biologics such as anti-tumor necrosis factor (TNF)-alpha, tocilizumab (anti IL6 receptor) and abatacept (targeting T lymphocyte activation) could be prescribed. Rehabilitation is necessary in case of limited joint motion. Corticotherapy is used at low doses and as rarely as possible. Intraarticular injection of delayed-action corticoids (triamcinolone hexacetonide) may be recommended in case of localized persistent arthritis.
Prognosis
The prognosis is difficult to determine due to the heterogeneity of the condition; but the new therapeutic strategies (initial aggressive and combined therapy) seem able to improve the prognosis and the percentage of remission mainly under treatment.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Chantal DESLANDRE


Rheumatoid factor-positive polyarticular juvenile idiopathic arthritis

A rare form of juvenile idiopathic arthritis characterized by distal and symmetrical polyarthritis (more than 5 joints) with presence of rheumatoid factor and possible evolution towards the appearance of erosions and joint destruction.

Summary:
Epidemiology
The disorder occurs worldwide with regional variation in occurrence; prevalence in juvenile populations ranges from 1/10,000-350,000, and incidence ranges between 1/140,000-1,000,000. The disorder is less frequent in Asian populations. Females are predominantly affect with a female-to-male ratio of 8-9:1.
Clinical description
The disease is considered as the childhood onset of seropositive adult rheumatoid arthritis; it represents about 10% of all cases of JIA. Patients are frequently diagnosed in late childhood/adolescence, typically between the 10-12 years of age. As with adult rheumatoid arthritis (RA), patients have a chronic symmetric, erosive polyarticular arthritis. To have polyarticular RF-positive disease, the ILAR classification requires the involvement of 5 or more joints. Also, by definition, patients must have two positive tests for IgM rheumatoid factor (RF). Although anti-cyclic-citrullinated peptide (anti-CCP) antibody status is not part of the ILAR criteria, children with childhood-onset RA also commonly have anti-CCP antibodies.
Etiology
Rheumatoid factor-positive polyarthritis is an autoimmune inflammatory disease associated with enhanced lymphocyte activity and production of proinflammatory cytokines (IL1, IL6 and TNF alpha).
Diagnostic methods
The international diagnostic criteria rely on the clinical, biological and radiological (joint erosion) features of the disease. Rheumatoid factor-positive polyarthritis is defined as the presence of arthritis affecting five or more joints at disease onset and by detection of rheumatoid factor in two tests carried out in the first six months of the disease course. Exclusion criteria are the presence of systemic arthritis or psoriasis in the patient, or a family history of psoriasis in one of the parents or first-degree relative, and HLA B27-positivity in males with onset of arthritis after 6 years of age. Other exclusion criteria include: the presence of ankylosing spondylarthritis, enthesitis and arthritis, sacroiliitis with an inflammatory enteropathy or acute anterior uveitis in the patient, or a family history of one of these conditions in a parent or first-degree relative.
Differential diagnosis
The differential diagnosis should include other polyarticular diseases: connective tissue disorders (lupus, dermatomyositis) and hematological diseases (notably, acute leukemia).
Management and treatment
Patients should be managed by a multidisciplinary team, incorporating expertise in pediatric rheumatology, physiotherapy, psychology and infantile orthopedic care. Treatment is based on the association of nonsteroidal anti-inflammatory agents (NSAIDS), disease-modifying antirheumatic drugs (DMARDs) and rehabilitation. Methotrexate is used as first-line treatment and then in case of inefficacy or intolerance , biologics (anti-tumor necrosis factor (TNF)-alpha, tocilizumab (anti-IL6 receptor) or abatacept (targeting T lymphocyte activation) could be prescribed. Corticotherapy, at low doses, can be used while waiting for the effectiveness of DMARDs. Rehabilitation will be associated if necessary to avoid joint limitation or amyotrophy. Intra-articular injection of delayed-action corticoids (triamcinolone hexacetonide) may be recommended in case of persistent localized arthritis.
Prognosis
Remission is rare during adulthood (10% of cases). In the vast majority of cases, the disease remains progressive and requires follow-up treatment. The risk of cartilage and bone damage has been significantly reduced with the use of rapid and more aggressive therapeutic strategies.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Chantal DESLANDRE


A rare, primary bone dysplasia characterized by rhizomelic limb shortening, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata) and coronal cleft vertebrae associated with profound postnatal growth deficiency, early-onset cataracts, severe intellectual disability and seizures.

Summary:
Epidemiology
Rhizomelic chondrodysplasia punctata (RCDP) prevalence is estimated to be lower than 1/100,000. The disorder is pan ethnic.
Clinical description
Presentation is at birth with severe joint contractures; cataracts may be present or appear in the first few months of life. Respiratory distress and feeding difficulties are commonly observed after birth. Whilst birth parameters (weight, length, and head circumference) are in the lower range from normal, profound postnatal growth retardation ensues. Rhizomelic limb shortening is typically greater in the humerus than the femur. Other skeletal abnormalities include punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata) and coronal cleft vertebrae. Intellectual disability is severe, and the majority of children develop seizures.
Etiology
The disease is caused by defective plasmalogen biosynthesis and impaired peroxisome function. The majority of patients have variants in the PEX7 gene (6q21-q22.2, RDCP type 1) encoding the peroxisomal targeting signal 2 receptor which plays an important role in peroxisomal protein import. Biallelic variants in the GNPAT gene (1q42) encoding dihydroxyacetone phosphate acyltransferase cause RDCP type 2, variants in the AGPS gene (2q31) encoding peroxisomal alkyldihydroxyacetonephosphate synthase cause RDCP type 3, and variants in the PEX5 gene (12p13.31) encoding the peroxisomal targeting signal 1 receptor cause RDCP type 5.
Diagnostic methods
Diagnosis is suspected on clinical and radiologic findings and confirmed by either biochemical or molecular testing. Sub-typing requires molecular testing.
Differential diagnosis
The principle differential diagnosis is Zellweger syndrome. It also includes Warfarin embryopathy, fatty acyl-CoA reductase 1 deficiency, and Chondrodysplasia punctata, tibia-metacarpal type.
Antenatal diagnosis
Prenatal diagnosis is feasible for at risk pregnancies where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disease is transmitted in an autosomal recessive manner. Genetic counseling should be proposed to at risk couples (where both parents are unaffected carriers of the disease) informing them that the risk of having and affected child is 25% for each pregnancy.
Management and treatment
Management is supportive. Cataract extraction may restore some vision. Physical therapy is recommended to improve contractures; orthopedic procedures may improve function in some individuals. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with milder forms of RCDP. Gastrostomy tube may be considered for poor weight gain, feeding intolerance, aspiration, and gastroesophageal reflux. Anti-seizure medications may be considered for seizures particularly where seizures are progressive, continuous and apparently painful, or significantly interfering with a child's interaction with the environment.
Prognosis
RCDP has a severe prognosis with death generally occurring during the first decade of life, mainly due to respiratory complications; a proportion may die in the neonatal period. Greater than 90% of individuals with RCDP survive the first year of life, and about 75% live to school age. Those with less severe plasmalogen deficiency, had improved survivability compared with those with very low classical plasmalogen levels.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Karen HEATH


Rhizomelic dysplasia, Patterson-Lowry type is a rare primary bone dysplasia characterized by short stature, severe rhizomelic shortening of the upper limbs associated with specific malformations of humeri (including marked widening and flattening of proximal metaphyses, medial flattening of the proximal epiphyses, and lateral bowing with medial cortical thickening of the proximal diaphyses), marked coxa vara with dysplastic femoral heads and brachimetacarpalia.


Rhizomelic syndrome, Urbach type is a rare primary bone dysplasia characterized by upper limbs rhizomelia and other skeletal anomalies (e.g. short stature, dislocated hips, digitalization of the thumb with bifid distal phalanx), craniofacial features (e.g. microcephaly, large anterior fontanelle, fine and sparse scalp hair, depressed nasal bridge, high arched palate, micrognathia, short neck), congenital heart defects (e.g. pulmonary stenosis), delayed psychomotor development and mild flexion contractures of elbows. Radiologic evaluation may reveal flared epiphyses, platyspondyly and/or digital anomalies.


A rare cerebellar malformation characterized by congenital complete or partial fusion of the cerebellar hemispheres, dentate nuclei, and middle cerebellar peduncles, and complete or partial absence of the vermis. It may occur as an isolated anomaly or with other malformations of the brain.

Summary:
Epidemiology
More than 150 cases of rhombencephalosynapsis (RES) have been reported in the literature, 24% of which are reported as an isolated malformation. The prevalence remains unknown.
Clinical description
Onset is variable as rhombencephalosynapsis (RES) may be detected in the antenatal period or manifest later in childhood. Brain MRI typically reveals an underdeveloped or absent cerebellar vermis associated with a midline fusion of cerebellar hemispheres. Classically, patients with RES present with motor developmental delay, ataxia, and abnormal movements (e.g. diminished movement at birth, head rolling, oculomotor abnormalities, a characteristic ''figure-of-eight'' head shaking). The range of cognitive outcome is very large, from profound intellectual disability to normal IQ. Clinical presentation may vary from a mild phenotype of truncal ataxia with preserved cognition, to a severe form associating cerebral palsy, congenital hydrocephalus and intellectual impairment. Most RES patients without obvious associated malformation and/or obstructive hydrocephaly and/or chromosomal anomaly seem to have preserved intellectual abilities. Attention-deficit/hyperactivity disorder (ADHD) is frequently observed. Other associated brain malformations include aqueductal stenosis, mesencephalosynapsis, holoprosencephaly, corpus callosum dysgenesis, microlissencephaly, pontocerebellar hypoplasia.
Etiology
The genetic etiology of RES remains unknown and no teratogenic effect has been confirmed. Most cases are sporadic, with no chromosomal anomaly. The recurrence risk for a couple is extremely low. Syndromal genetic associations like de novo mutations in MN1 (MN1 C-terminal truncation syndrome; MCTT) or pontocerebellar hypoplasia with RES and microlissencephaly (homozygous variant in EXOSC3) are very rare.
Diagnostic methods
Diagnosis is confirmed by brain MRI which shows characteristic dysgenesis or agenesis of the cerebellar vermis, a midline fusion of the cerebellar hemispheres, dentate nuclei and in some cases the superior cerebellar peduncles, as well as variable supratentorial anomalies including absent septum pellicidum, dysplastic corpus callosum, aqueductal stenosis associated with hydrocephalus, dilated third and lateral ventricles, and a keyhole-shaped fourth ventricle. Malformation severity ranges from partial to complete rhombencephalosynapsis and includes an atypical form characterized by absent posterior vermis and residual anterior vermis.
Differential diagnosis
RES sometimes occurs as part of a syndrome such as VACTERL association or the recently described MCTT syndrome. The most common syndrome related to RES is Gomez-Lopez-Hernandez syndrome (GLHS). Differential diagnosis includes other disorders with brain/cerebellar malformations such as holoprosencephaly, Dandy-Walker syndrome and Joubert syndrome.
Antenatal diagnosis
Antenatal diagnosis is possible after 21 weeks of gestation, when cerebellar structures are well defined. Ultrasound may reveal enlarged cerebral ventricles, a common indication for fetal MRI which may in turn show typical findings of RES. Follow-up fetal MRI should be considered in uncertain cases. In case of prenatal diagnosis, the prognosis will be defined by the search for associated cerebral or extra-cerebral malformations, chromosomal abnormalities (CGH array) or a pathogenic variant in the MN1 gene.
Genetic counseling
RES cases happen sporadically and are not inherited from parents.
Management and treatment
Management is symptomatic and may include surgical treatment of spasticity (e.g. hamstring release), or hydrocephalus. Neuropsychological assessment should be provided for cases involving intellectual and behavioral impairment.
Prognosis
Most RES patients without obvious associated malformation and/or obstructive hydrocephaly and/or chromosomal anomaly seem to have preserved intellectual abilities, which is a crucial point for couples' decision following prenatal diagnosis. Nevertheless, ADHD is frequent. Syndromic cases of RES have a poor prognosis except Gomez-Lopez-Hernandez syndrome.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr Sylvie ODENT | ITHACA*

                                * European Reference Network


A rare genetic, syndromic retinal disorder characterized by the association of retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia.


A rare, genetic motor neuron disease characterized by a peripheral and cranial neuropathy, neuronal loss in anterior horns and atrophy of spinal sensory tracts, causing muscle weakness, sensory loss, diaphragmatic paralysis and respiratory insufficiency, and multiple cranial nerve deficits such as sensorineural hearing loss, bulbar symptoms, and loss of vision due to optic atrophy. Depending on the transporter affected, Riboflavin transporter deficiency 2 (RFVT2) and Riboflavin transporter deficiency 3 (RFVT3) are distinguished.

Summary:
Epidemiology
Riboflavin transporter deficiency (RTD) has been reported in more than 100 genetically diagnosed cases to date.
Clinical description
Onset may occur from early infancy until adulthood, with a more severe presentation at a younger age. The most frequent presenting symptoms are cranial neuropathy, sensory ataxia, muscle weakness and respiratory insufficiency due to diaphragmatic paralysis. The cranial neuropathy leads to sensorineural hearing loss, loss of vision due to optic atrophy, dysarthria, dysphagia, feeding problems, facial weakness and eye movement impairments. Peripheral neuropathy in combination with anterior horn cell dysfunction and atrophy of the sensory tracts in the spinal cord causes muscle weakness with atrophy and (sensory) ataxia. Diaphragmatic paralysis in combination with general muscle weakness may rapidly lead to respiratory insufficiency, especially in infants and young children. Often, feeding through a nasogastric tube or gastrostomy device and artificial ventilation and tracheotomy are required. Sensory ataxia and optic atrophy seem more prevalent in RFVT2 than RFVT3 deficient patients.
Etiology
Pathogenic biallelic mutations in the genes SLC52A2 and SLC52A3 that encode riboflavin transporter 2 and 3 cause RTD2 and RTD3, respectively. Riboflavin (Vitamin B2) is a water-soluble vitamin that is essential for normal metabolism. The loss of function of the riboflavin transporter results in cellular flavin deficiency in different tissues. As flavins play an important role in mitochondrial function, mitochondrial dysfunction might act as a pathomechanism contributing to neurodegeneration in RTD.
Diagnostic methods
Diagnosis is only possible through mutational analysis of all genes coding for riboflavin transporters. Biochemical tests can show abnormalities such as abnormal (MADD-like) plasma acylcarnitine profiles, abnormal urine organic acids and decreased plasma flavin levels; however, approximately 50% of patients have normal results. Magnetic resonance imaging (MRI) is normal in the large majority of RTD patients. Electrophysiological testing (EMG) can show findings consistent with a sensorimotor axonal neuropathy with signs of anterior horn cell dysfunction, but normal results can also be observed.
Differential diagnosis
Differential diagnosis include neuromuscular diseases, in particular congenital or mitochondrial myopath and rapidly progressive neuropathies.
Antenatal diagnosis
Prenatal diagnosis is possible if family mutations in the SLC52A2 or SLC52A3 genes are known.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Riboflavin supplementations is lifesaving and daily administration of a high dose oral riboflavin supplementation should be started immediately upon suspicion of RTD; treatment is lifelong. In cases with early onset, assisted ventilation, tracheostomy, and maintenance of nutrition via gastrostomy may be required. Regular clinical evaluation is required and includes neurological examination as well as evaluation of hearing and vision, respiratory function and skeletal deformities like scoliosis. Depending on the symptoms, physical and speech therapy should be initiated. Cochlear implants have proven highly successful for hearing loss in RTD.
Prognosis
If untreated, RTD is progressive and often fatal, with respiratory insufficiency as the main cause of death. However, severity and rate of progression vary between patients. When treated with high doses of riboflavin, the majority of patients show improvement over time and early treatment may even result in full recovery and normal development. In contrast, patients with irreversible damage may show stabilization but no improvement of symptoms. No deaths have been reported in riboflavin-treated patients.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr A.M. [Annet] BOSCH  - Dr Eva HOYTEMA VAN KONIJNENBURG  - Dr B. [Bregje] JAEGER


Ribose-5-P isomerase deficiency is an extremely rare, hereditary, disorder of pentose phosphate metabolism characterized by progressive leukoencephalopathy and a highly increased ribitol and D-arabitol levels in the brain and body fluids. Clinical presentation includes psychomotor delay, epilepsy, and childhood-onset slow neurological regression with ataxia, spasticity, optic atrophy and sensorimotor neuropathy.


Richards-Rundle syndrome is an extremely rare neurodegenerative disorder characterized by progressive spinocerebellar ataxia, sensorineural hearing loss, and hypergonadotropic hypogonadism associated with additional neurological manifestations (such as peripheral muscle wasting, nystagmus, intellectual disability or dementia) and ketoaciduria.


Richieri Costa-da Silva syndrome is a rare, genetic, myotonic syndrome characterized by childhood onset of progressive and severe myotonia (with generalized muscular hypertrophy and progressive impairment of gait), short stature, skeletal abnormalities (including pectus carinatum, short, wedge-shaped thoracolumbar vertebrae, kyphoscoliosis, genu valgum, irregular femoral epiphyses), and mild to moderate intellectual deficiency. No facial dysmorphism nor joint limitation is associated. There have been no further descriptions in the literature since 1984.


Richieri Costa-Pereira syndrome is characterized by short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies (including hypoplastic thumbs), and clubfoot. It has been described in 14 Brazilian families and in one unrelated French patient. Prominent low set ears and a highly arched palate were also observed. Transmission is autosomal recessive.


A rare disorder due to poisoning characterized by acute onset of potentially life-threatening illness following ingestion, inhalation, or injection of ricin, a lectin present in the seeds of Ricinus communis, the castor oil plant. Clinical presentation depends on the route of administration, inhalation being the most toxic route, followed by oral ingestion. Presenting signs and symptoms include nausea, vomiting, diarrhea, hematemesis, and melena (upon ingestion), cough, wheezing, dyspnea, sore throat, and congestion (upon inhalation), and erythema, induration, blisters, capillary leak syndrome, and localized necrosis (upon injection). The condition can progress to seizures, shock, organ failure, pulmonary edema, and respiratory failure.


A rare, acquired, self-limiting, infectious disease due to the mite-borne bacteria Rickettsia akari characterized by an asymptomatic, 0.5 to 2 cm in diameter papulovesicle that typically ulcerates and forms an eschar, followed by a generalized papulovesicular rash associating variable constitutional symptoms, such as localized lymphadenopathy, fever, malaise, and headaches. Additonal symptoms may include diaphoresis, myalgia and, less frequently, rhinorrhea, pharyngitis, nausea, vomiting, splenomegaly, conjunctival hyperemia, and abdominal pain. Systemic symptoms resolve within 6-10 days.


A rare, genetic, primary immunodeficiency disorder characterized by increased radiosensitivity(R), mild immunodeficiency (ID), dysmorphic features (D), and learning difficulties (LE).


Rieger's anomaly is a congenital ocular defect caused by anterior segment dysgenesis and is characterized by severe anterior chamber deformity with prominent strands and marked atrophy of the iris stroma, with hole or pseudo-hole formation and corectopia. The term covers the association of these iris and pupil anomalies with the features of Axenfelds anomaly (see this term).


Rift Valley fever (RVF), caused by the Rift Valley fever virus (RVFV), is an arbovirus characterized by a usually self-limiting febrile illness but that in some cases can also manifest with thrombosis, vision loss, hemorrhages and/or neurological symptoms.


Right inferior vena cava connecting to left-sided atrium

A rare vascular anomaly characterized by a congenital anomalous connection between the inferior vena cava and the left atrium. Clinical manifestations depend on the presence and nature of additional cardiac defects and include cyanosis, dyspnea, failure to thrive, clubbing of fingers and toes, and potentially heart failure.


A rare heterotaxia characterized by complex congenital heart malformations and abnormal lateralization of other thoracic and abdominal organs due to embryonic disruption of the left-right axis development. Cardiac defects include dextrocardia or mesocardia, common atrioventricular valve associated with complete atrioventricular septal defect or common atrium, transposition or malposition of the great arteries, and total anomalous pulmonary venous drainage, among others. Cardiac arrhythmias are frequently observed. Typical abnormalities of other organs are bilateral trilobed lungs, midline liver, and asplenia. Patients present in the newborn period with severe cardiac failure and cyanosis. Prognosis is poor.


Right superior vena cava connecting to left-sided atrium

A rare, congenital vascular malformation of the major vessels characterized by the right SVC passing medially and dorsally to the aortic root and draining into the left atrium. Patients usually present a right-to-left systemic venous blood shunt which may manifest with arterial hypoxemia, cyanosis, exercise dyspnea, clubbing of the fingers, palpitations, murmurs and/or potentially fatal brain abscess. Association with other cardiac anomalies has been reported.


Rigid spine syndrome (RSS) is a slowly progressive childhood-onset congenital muscular dystrophy (see this term) characterized by contractures of the spinal extensor muscles associated with abnormal posture (limitation of neck and trunk flexure), progressive scoliosis of the spine, early marked cervico-axial muscle weakness with relatively preserved strength and function of the extremities and progressive respiratory insufficiency.


RIN2 syndrome, formerly known as macrocephaly, alopecia, cutis laxa and scoliosis (MACS) syndrome, is a very rare inherited connective tissue disorder characterized by macrocephaly, sparse scalp hair, soft-redundant and hyperextensible skin, joint hypermobility, and scoliosis. Patients have progressive facial coarsening with downslanted palpebral fissures, upper eyelid fullness/infraorbital folds, thick/everted vermillion, gingival overgrowth and abnormal position of the teeth. Rarer manifestations such as abnormal high-pitched voice, bronchiectasis, hypergonadotropic hypergonadism and brachydactyly (see this term) have also been reported.


Ring chromosome 1 syndrome is an autosomal anomaly characterized by variable clinical features, most commonly including significant intrauterine and postnatal growth failure, developmental delay, intellectual disability, microcephaly, and dysmorphic facial features. Some less frequent clinical features are dysgenesis of corpus callosum, atrial septal defect, rocker bottom feet and clinodactyly.


An autosomal anomaly characterized by variable clinical features, depending on the size and precise location of deleted chromosome segments. Most patients present with developmental delay, intellectual disability, growth retardation, microcephaly, clinodactyly, and dysmorphic features. Congenital heart disease and genitourinary anomalies were reported in some cases.


A rare autosomal anomaly characterized by variable clinical features, including early growth retardation and short stature, microcephaly, developmental delay, some degree of intellectual disability, facial dysmorphism and café-au-lait spots. In some cases, congenital heart disease and endocrine abnormalities have been reported.


Ring chromosome 12 syndrome is a rare chromosomal anomaly syndrome with a highly variable phenotype principally characterized by postnatal growth retardation, variable degrees of developmental delay and intellectual disability, microcephaly and facial dysmorphism (incl. epicanthal folds, low-set, cupped ears, prominent nose with flat nasal bridge, high arched palate, micrognathia). Skeletal abnormalities (e.g. pectus excavatum, clinodactyly), congenital heart malformations, cryptorchidism, café-au-lait spots and epilepsy have also been reported.


A rare chromosomal anomaly of chromosome 13 characterized by a widely variable phenotype (ranging from mild to severe) principally characterized by intrauterine growth retardation, developmental delay, short stature, moderate to severe intellectual deficit, microcephaly, facial dysmorphism (i.e. upslanting palpebral fissures, hypertelorism, abnormal ears, broad nasal bridge, high arched palate, micrognathia, small mouth, and thin lips), hands and feet anomalies, and genital abnormalities. Additional features reported include behavioral problems, hearing and speech disorders, congenital heart defects, cerebral malformations, and anal atresia.


A rare chromosomal anomalie characterized by intellectual deficit, retinal and skin pigmentation disorders, seizures, and dysmorphic features, including flat occiput, epicanthal folds, downward slanting eyes, flat nasal bridge, upturned nostrils, short neck, and large low set ears.


A rare chromosomal anomaly syndrome, with a highly variable phenotype, characterized by pre- and/or postnatal growth retardation, variable intellectual disability, short stature, dysmorphic features (microcephaly, triangular facies, frontal bossing, hypertelorism, ear anomaly, broad nasal bridge, highly arched palate, micrognathism), hand and feet anomalies (e.g. brachydactyly, clinodactyly, syndactyly), and multiple hyperpigmented and/or hypopigmented spots. Severe phenotypes present with cardiac abnormalities and/or renal malformations. Other reported features include hypotonia, speech delay, talipes equinovarus, and genital anomalies (cryptorchidism and hypospadias).


A rare chromosomal anomaly syndrome, resulting from the partial deletion of chromosome 16, characterized by pre- and postnatal growth delay, severe developmental delay, intellectual disability, speech delay, and craniofacial dysmorphism (e.g. microcephaly, hypertelorism, downslanted palpebral fissures, ptosis, telecantus, low set and dysmorphic ears, broad flat nasal bridge, down-turned mouth corners, high palate, retrognathia). Patients may also present congenital cataract, mild synophrys, hypotonia, and poor social contact. Congenital heart anomalies (e.g. ventricular septal defect, patent ductus arteriosus) have also been reported.


A rare chromosomal anomaly characterized by highly variable manifestations, ranging from a severe phenotype which presents with lissencephaly and severe intellectual disability to a milder phenotype that includes short stature, microcephaly, intellectual disability, seizures (that may be pharmacoresistant), café-au-lait spots, retinal flecks and minor facial dysmorphism, depending on the presence or absence of the Miller-Dieker critical region.


A rare autosomal anomaly characterized by variable clinical features, most commonly including hypotonia, neonatal feeding and respiratory difficulties, microcephaly, global developmental delay and intellectual disability, growth hormone deficiency, hypothyroidism, hearing loss, aural atresia, dysmorphic facial features and behavioral characteristics.


Ring chromosome 19 syndrome is a rare chromosomal anomaly syndrome with a highly variable phenotype that may range from normal to patients with profound intellectual disability, developmental delay, learning disability (esp. speech) and mild dysmorphism (incl. micro/macrocephaly, prominent forehead, low-set and posteriorly rotated ears, hypertelorism, high nasal bridge, prominent philtrum, retro/micrognathia). Mild hypotonia and autistic-like mannerisms (e.g. hand opening and closing, head banging) may also be associated. Other anomalies, such as cutis laxa, hearing loss, syndactyly, digital hypoplasia, and talipes equinovarus, have also been reported.


Ring chromosome 2 syndrome is a rare chromosomal anomaly syndrome with highly variable phenotype principally characterized by intrauterine growth retardation, failure to thrive, developmental delay, hypotonia, mild dysmorphic features (incl. microcephaly, short forehead, upslanting palpebral fissures, hypertelorism, epicanthal folds, wide nasal bridge, broad nasal tip, long philtrum, thin upper lip, micrognathia, short neck), skeletal anomalies (e.g. kyphosis, brachydactyly, clinodactyly, talipes equinovarus) and dermatological features (i.e. café-au-lait spots). Patients may also present ventriculoseptal defects and genital abnormalities (e.g. genital hypoplasia, phimosis, cryptorchidism).


A rare chromosomal disorder, characterized by childhood onset drug resistant epilepsy with typical electroencephalographic findings (EEG), mild to severe intellectual disability and behavioral problems.

Summary:
Epidemiology
The overall birth prevalence of ring chromosomes is 1/30-60,000 and ring 20 (r20) is one of the most common and is probably underdiagnosed.
Clinical description
Initial psychomotor development is usually unaffected. Age of seizure onset varies between 1-24 years (frequently 4-10 years) and are typically recurrent focal motor seizures during sleep or whilst awake with alteration of consciousness, staring, automatisms, ictal visual, affective behavior and periods of intense fear. Seizures can progress to generalized tonic or tonic-clonic seizures. Non-convulsive status epilepticus (NCSE) is common, recognizable by an altered state of vigilance, staring, reduced motor activity and speech. R20 syndrome is considered a developmental epileptic encephalopathy since epilepsy onset is followed by an early cognitive-behavioral decline which seems to be focused on frontal lobe dysfunction. Language and learning disabilities, attention problems, aggressive and obsessive behavior, and apathy are frequently reported. The electroencephalogram (EEG) shows frontal spikes within runs of bilateral slow high voltage activity. Age-related patterns of sleep deterioration, ranging from normal to destructured non-rapid eye movement/rapid eye movement, is also typical. There are no distinct dysmorphisms although microcephaly, strabismus, micrognathia, down-slanting palpebral fissures, ear abnormalities and poor somatic growth can be present. Associated brain, cardiac and renal malformations are rare.
Etiology
A ring chromosome is an aberrant chromosome whose ends have fused together. Ring chromosomes are unstable: during mitosis, the ring may be lost or duplicated. Patients carrying a ring chromosome often have mosaic karyotypes with normal cells, cells with a ring chromosome, cells with monosomy and/or cells with reorganized/duplicated rings. Some patients with r20 lose the terminal part of 20q. The epileptogenic mechanism remains unknown. Currently there is no evidence to support a correlation between the level of mosaicism and the severity of the phenotype, although non-mosaic cases present with the most severe symptoms/comorbidities.
Diagnostic methods
Diagnosis is suspected in patients with childhood onset recurrent seizures with a cognitive deterioration, behavioral changes and typical EEG findings. As mosaicism is frequent, r20 chromosome should be confirmed by karyotyping with at least 100 metaphases on blood lymphocytes. Diagnosis may be missed using other genetic techniques including aCGH.
Differential diagnosis
Differential diagnosis includes primarily Lennox Gastaut syndrome. Moreover, frontal lobe epilepsy, continuous spike and wave during slow wave sleep and NCSE of other etiologies should be considered.
Genetic counseling
R20 mosaicism could be sporadic or inherited: parent-to child transmission has been reported in a few exceptional families. Genetic counseling is recommended.
Management and treatment
Seizures associated with r20 are often refractory to medications and there is no specific treatment regimen for the disorder. A more favorable outcome has been reported with the combination of valproate and lamotrigine. Ketogenic diet can be helpful, with better results if introduced at seizure onset. Resective brain surgery is not a therapeutic option. Mild improvement with vagus nerve stimulation is reported.
Prognosis
Prognosis is generally poor since epilepsy is drug resistant, remaining into adulthood. Cognitive performance can remain locked at the time of epilepsy onset or worsen over time.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Valentina DE GIORGIS | EpiCARE* - Pr Rima NABBOUT | EpiCARE* -  Allison WATSON | EpiCARE*

                                * European Reference Network


Ring chromosome 21 syndrome is an autosomal anomaly characterized by variable clinical features, most commonly including growth retardation, developmental delay, intellectual disability, epilepsy, microcephaly, short stature, dysmorphic features, hypogammaglobulinemia, thrombocytopenia and unspecific skeletal anomalies (hemivertebrae, clinodactyly, syndactyly). In rare cases, it has been described in phenotypically normal individuals.


A rare autosomal anomaly characterized by variable clinical features, most commonly including global developmental delay, hypotonia, growth retardation with microcephaly, intellectual disability with severe speech delay, seizures or abnormal EEG, autistic spectrum disorder and other behavioral characteristics.


Ring chromosome 3 syndrome is a rare chromosomal anomaly syndrome with a highly variable phenotype principally characterized by pre- and postnatal growth retardation, short stature, developmental delay, mild to severe intellectual disability, microcephaly and mild dysmorphic features (incl. triangular face, dysplastic ears, upslanting palpebral fissures, epicanthic folds, broad nasal bridge, full nasal tip, long philtrum, downturned corners of the mouth, and micro/retrognathia). Additional manifestations reported include hypotonia, mild articular limitation, hearing loss, digital anomalies (i.e. clinodacytyly, brachydactyly), café-au-lait patches and hypospadias.


Autosomal anomaly characterized by variable clinical features, most commonly including significant intrauterine and postnatal growth retardation, developmental delay, intellectual disability, microcephaly, and dysmorphic facial features. Some less frequent features are cleft lip and/or cleft palate, congenital cardiovascular, gastrointestinal and genitourinary system anomalies.


Ring chromosome 5 syndrome is a rare chromosomal anomaly syndrome, with high phenotypic variability, principally characterized by a neonatal mewing cry, severe developmental delay and intellectual disability, short stature, hypotonia, dysmorphic features (incl. microcephaly, facial asymmetry, hypertelorism, epicanthal folds, abnormal ears, micro/retrognathia), congenital cardiac anomalies (such as atrial and ventricular septal defect, tricuspid insufficiency, hypoplastic aorta) and skeletal abnormalities (e.g. hypoplastic thumbs, anomalous ulna/radius, dysplastic metacarpals and phalanges).


Ring chromosome 6 syndrome is a rare chromosomal anomaly syndrome with highly variable phenotype principally characterized by prenatal/postnatal growth failure, intellectual disability, developmental delay, craniofacial dysmorphism (incl. microcephaly, microphthalmia, epicanthus, low-set and malformed ears, broad and flat nasal bridge, full lips, micrognathia), central nervous system anomalies (e.g. hydrocephalus, cortical atrophy, ventriculomegaly), short neck, and delayed bone age. Cardiac defects, limb anomalies, hip joint malformations, and seizures have also been reported.


Ring chromosome 7 syndrome is a rare chromosomal anomaly syndrome, with highly variable phenotype, principally characterized by growth failure, short stature, intellectual disability, dermatological abnormalities (nevus flammeus, dark pigmented nevi, café-au-lait spots), microcephaly and facial dysmorphism (incl. facial asymmetry, small ears, abnormal palpebral fissures, ptosis, epicanthic folds, hyper/hypotelorism). Additional reported features include convulsions, cleft lip and palate, clinodactyly, kyphoscoliosis and genital anomalies (i.e. cryptorchidism, hypospadias, micropenis).


A rare chromosomal anomaly comprising variable parts of chromosome 8. The phenotype of mosaic or non-mosaic supernumerary r(8)/mar(8) ranges from almost normal to variable degrees of minor abnormalities, and growth and mental retardation overlapping with the well-known mosaic trisomy 8 syndrome.


A rare autosomal anomaly characterized by variable clinical features, most commonly including developmental delay, some degree of intellectual disability, facial dysmorphism, microcephaly, congenital heart anomalies, and variable genital, limb and skeletal anomalies.


A rare chromosome Y structural anomaly, with a highly variable phenotype, mostly characterized by short stature, partial to total gonadal failure, sexual infantilism, genital anomalies (e.g. ambiguous genitalia, hypospadias, cryptorchidism), and azoospermia or oligozoospermia. Additional reported features include speech delay, obesity, and acanthosis nigricans. Gender dysphoria and comorbid bipolar disorder have also been observed.


Ring dermoid of cornea is characterised by annular limbal dermoids (growths with a skin-like structure) with corneal and conjunctival extension. Less than 30 cases have been described. Transmission is autosomal dominant and mutations in the PITX2 gene have been suggested as a potential cause of the condition.


Rippling muscle disease with myasthenia gravis is a rare, acquired, neuromuscular disease characterized by CAV3 mutation-negative rippling muscle disease in association with acetylcholine receptor antibody-mediated myasthenia gravis. Patients typically present exercise-induced, electrically-silent muscle rippling with myalgia, in combination with generalized myasthenia gravis symptoms (ptosis, diplopia, neck weakness, dysphagia and dyspnea).


Rippling muscle disease is a rare, genetic, neuromuscular disorder characterized by muscle hyperirritability triggered by stretch, percussion or movement. Patients present wave-like, electrically-silent muscle contractions (rippling), muscle mounding, painful muscle stiffness and muscle hypertrophy, usually with elevated serum creatine kinase.


RNF13-related severe early-onset epileptic encephalopathy

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly, infantile-onset epileptic encephalopathy, and profound developmental delay. Additional reported features include cortical visual impairment, sensorineural hearing loss, increased muscle tone, limb contractures, scoliosis, and dysmorphic features like midface hypoplasia, narrow forehead, short nose, narrowed nasal bridge, and small chin. Brain imaging may show thin corpus callosum and delayed myelination.


Roberts syndrome (RBS) is characterized by pre- and postnatal growth retardation, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit. SC phocomelia is a milder form of RBS.

Summary:
Epidemiology
The prevalence and incidence are not known. Less than 150 cases have been described in the literature.
Clinical description
Upper limbs are more frequently and severely affected than lower limbs. The defect is mostly mesomelic with the radius being the most affected in the upper limbs, and the fibula in the lower limbs. The most severe defects result in phocomelia. Aplastic or hypoplastic thumbs, oligodactyly, clinodactyly or syndactyly can also occur. Craniofacial anomalies include microcephaly (more severe in males than in females), hypoplastic nasal alae, malar hypoplasia, hypertelorism, micrognathia, capillary hemangioma, exophthalmos, downslanting palpebral fissures, dysplastic or small ears, cloudy cornea or cataracts, and cleft lip and palate. There is a correlation between the degree of limb and facial malformations. Other malformations such as congenital heart defects, cystic kidney and large genitalia (enlarged phallus or clitoris), may occur. Severe intellectual deficit is observed in patients surviving the newborn period.
Etiology
The disease is caused by mutations in the ESCO2 gene (8p21.1), which encodes a protein belonging to the Eco1/Ctf7 family of acetyltransferases, involved in the establishment of sister chromatid cohesion during S phase. ESCO2 mutations lead to delayed cell division, increased cell death and impaired cell proliferation. The loss of progenitor cells during embryogenesis is likely responsible for the developmental defects observed in RBS.
Diagnostic methods
The diagnosis is based on clinical features and karyotyping (with a characteristic ``railroad track'' appearance of chromosomes due to repulsion of heterochromatic regions and premature centromere separation). Direct sequencing of the ESCO2 gene can confirm the diagnosis.
Differential diagnosis
Differential diagnoses include thalidomide embryopathy, and the Baller-Gerold, Cornelia de Lange and TAR syndromes (see these terms).
Antenatal diagnosis
When a previous child in the family is diagnosed with RBS and carries ESCO2 mutations, prenatal diagnosis can be performed through DNA analysis of chorionic villus samples. Otherwise, RBS may be suspected by observation of characteristic RBS anomalies at ultrasonography and can be confirmed by karyotyping.
Genetic counseling
The mode of transmission is autosomal recessive.
Management and treatment
Management includes surgical correction of facial malformations, surgical and/or orthopedic treatment of limb defects and management of the cognitive disabilities.
Prognosis
Prognosis is relatively unfavorable. High mortality in the newborn period or early childhood is due to cardiac or renal malformations.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Pr Sylvie MANOUVRIER-HANU


Robin sequence-oligodactyly syndrome is a rare, genetic, developmental defect during embryogenesis syndrome characterized by Robin sequence (i.e. severe micrognathia, retroglossia and U-shaped cleft of the posterior palate) associated with pre- and postaxial oligodactyly. Facial features can include a narrow face and narrow lower dental arch. Clinodactyly, absent phalanx, metacarpal fusions, and hypoplastic carpals have also been reported. There have been no further descriptions in the literature since 1986.


Robinow syndrome (RS) is a rare genetic syndrome characterized by limb shortening and abnormalities of the head, face and external genitalia.

Summary:
Epidemiology
Exact prevalence is unknown. About 200 cases have been reported to date. Cases have been reported primarily from the USA, Arab countries, Turkey, Czech Republic and Slovakia, the Indian subcontinent, and Brazil. Prevalence in other geographic areas is unknown. There is an equal male-to-female ratio.
Clinical description
Two forms of the syndrome with different patterns of inheritance and variable frequency of clinical signs have been described: a milder autosomal dominant form (autosomal dominant Robinow syndrome, see this term) and a more severe autosomal recessive form (autosomal recessive Robinow syndrome, see this term). The syndrome has a wide clinical spectrum. Clinical signs such as short stature, characteristic facial features (hypertelorism, midface hypoplasia, large nasal bridge, short upturned nose, and anteverted nares), mesomelic limb shortening, as well as brachydactyly, clinodactyly, gingival hyperplasia, and genital hypoplasia are generally common to both forms. Vertebral segmentation defects are common but more severe in the recessive form: hemivertebrae and scoliosis are more common (75% of cases). Rib fusions appear to be present almost exclusively in the autosomal recessive form. Umbilical hernia and supernumerary teeth appear to be present exclusively in patients with the dominant form. Associated conditions include frequent ear infections, hearing loss, developmental and respiratory disorders, hypotonia, eating difficulties and esophageal reflux.
Etiology
Autosomal recessive Robinow syndrome is caused by mutations in the ROR2 gene (9q22). Mutations in the WNT5A gene (3p14.3) have been reported in some patients (< 10%) with autosomal dominant Robinow syndrome.
Diagnostic methods
Diagnosis is based on the clinical picture and the characteristic fetal face appearance of patients. Radiological examination is however necessary to confirm the presence of skeletal malformations.
Differential diagnosis
The main differential diagnosis is RS with a different pattern of inheritance. Syndromes that commonly involve dysmorphic facial features similar to RS, particularly hypertelorism, along with genital hypoplasia such as Aarskog-Scott syndrome and Opitz G syndrome (see these terms) should also be considered. Chromosome abnormalities have occasionally been reported in patients with a Robinow-like phenotype. Similar costovertebral segmentation defects can be found in autosomal recessive spondylocostal dysostosis (ARSD) (see this term).
Antenatal diagnosis
Prenatal diagnosis may be performed by fetal ultrasound from the 19th week of pregnancy but the severity of the syndrome is difficult to ascertain. Genetic testing may be performed to confirm the diagnosis in AR cases.
Genetic counseling
Transmission is autosomal dominant or recessive. Genetic counseling is recommended. Parents of AD cases should be clinically evaluated to exclude a milder manifestation of the syndrome prior to genetic counseling.
Management and treatment
Management of the skeletal deformities includes bracing or surgical correction. Growth hormone has been administered to increase the growth rate in children with the syndrome. In patients with wide palpebral fissures, the need for surgical intervention should be evaluated.
Prognosis
Prognosis of Robinow syndrome is generally good but the severity of heart disorders may affect life expectancy.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Juliana MAZZEU


A rare, acquired, life-threatening, infectious disease due to the tick-borne bacteria Rickettsia rickettsii characterized by an acute onset of fever, malaise, and severe headache, variably accompanied by myalgia, anorexia, nausea, vomiting, abdominal pain, and photophobia, associating (2-5 days after fever onset) a typically erythematous, blanching or non-blanching, maculopapluar rash with petechiae, starting on the wrists and ankles and progressing centrifugally to the palms and soles and centripetally to the arms, legs and trunk. Additonal variable features may include conjunctivitis, mucosal ulcers, post-inflammatory hyperpigmentation, jaundice, pneumonia, hepatomegaly, renal failure, meningismus, amnesia, optic disc edema, and ocular arterial occlusion.


A rare, genetic immuno-osseous dysplasia associated with pre- and post-natal growth retardation, retinopathy, microcephaly, intellectual disability and dysmorphic features.

Summary:
Epidemiology
To date less than 20 cases have been reported worldwide in the scientific and medical literature.
Clinical description
Roifman syndrome is characterized by pre- and post-natal growth retardation, hypotonia, borderline to moderate intellectual disability, retinal dystrophy, spondyloepiphyseal dysplasia (epiphyseal dysplasia, epiphyses ossification delay, vertebral changes) and skeletal anomalies (brachydactyly, fifth finger clinodactyly), as well as humoral immunodeficiency, characterized by inability to generate specific antibodies and low circulating B-cells, suggestive of a partial block of B-cell proliferation and maturation. Craniofacial dysmorphism typically includes microcephaly, narrow palpebral fissures, prominent and long eyelashes, a narrow, tubular, upturned nose with hypoplastic alae nasi, long philtrum and thin upper lip. Eczema and mild limitation in hip flexion may be observed. One instance of hypogonadotrophic-hypogonadism and one instance of myocardial noncompaction were reported.
Etiology
Roifman syndrome is caused by bi-allelic mutations of RNU4ATAC (2q14.2), a gene encoding a small nuclear RNA involved in minor (U12) splicing. At least one mutation locates in the stem II region of RNU4ATAC. Mutations in the same gene also cause Taybi-Linder syndrome, a more severe disorder in which there are many overlapping features.
Diagnostic methods
Diagnosis is suggested based on the clinical, immune and radiological phenotype and confirmed by RNU4ATAC sequencing.
Differential diagnosis
Other syndromes that combine immunodeficiency and skeletal aberrations may be considered and include cartilage hair hypoplasia, primary bone dysplasias with micromelia, severe combined immunodeficiency due to adenosine deaminase deficiency, and Schimke immune-osseous dysplasia.
Antenatal diagnosis
There have been no reports of prenatal diagnosis to date.
Genetic counseling
Roifman syndrome is transmitted as an autosomal recessive trait. Genetic counseling should be offered to at risk families (where each parent is an unaffected carrier) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is supportive only. Particular attention should be given to susceptibility to infections, growth and psychomotor development. Medical care and management should be provided according to recurrent infections and intellectual disability.
Prognosis
Prognosis appears to be good with no reported limitation of life expectancy. Infections can be severe and recurrent (pneumonia, septicemia, recurrent herpes reactivation, etc.).

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr Patrick EDERY | ITHACA*

                                * European Reference Network


Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome

A rare genetic epilepsy syndrome characterized by infantile or childhood onset of focal motor seizures remitting with age, as well as childhood onset of exercise-induced dystonia which often persists into adulthood. Additional reported features include nystagmus and postural tremor of the hands.


Rolandic epilepsy-speech dyspraxia syndrome is a rare, genetic epilepsy characterized by speech disorder (including a range of symptoms from dysarthria, speech dyspraxia, receptive and expressive language delay/regression and acquired aphasia to subtle impairments of conversational speech) and epilepsy (mostly focal and secondary generalized childhood-onset seizures, sometimes with aura). Mild to severe intellectual disability may also be observed.


A form of familial long QT syndrome (LQTS) characterized by syncopal episodes and electrocardiographic abnormalities (QT prolongation, T-wave abnormalities and torsade de pointes (TdP) ventricular tachycardia).

Summary:
Epidemiology
The prevalence of Romano-Ward syndrome (RWS) is estimated at 1/2,500.
Clinical description
Cardiac events occur from infancy through middle age but may manifest as early as the intrauterine stage with possibility of still birth. Most patients develop the symptoms during exercise or in response to stress or emotional disturbances and symptoms rarely occur at rest or during sleep. The syncopal episodes are due to TdP, a polymorphic ventricular tachycardia. TdP often degenerates to ventricular fibrillation and causes cardiac arrest or sudden death. In some patients, cardiac arrest may be the first manifestation of the disease. The electrocardiogram typically shows a prolongation of ventricular repolarization (QTc > 460 ms) and biphasic or notched T-waves in the precordial leads. Beat-to-beat alternation of the T wave (in polarity or amplitude) may be present at rest, but most commonly appears during emotional or physical stress and may precede TdP. The heart rate at rest or during exercise may be slower than normal.
Etiology
RWS may result from mutations in genes either encoding subunits of cardiac ion channels or proteins interacting with cardiac ion channels. To date pathogenic mutations have been identified in numerous genes, the most frequently observed causative genes are KCNQ1, KCNH2, SCN5A. The genes CALM1, CALM2 and TRDN have also undisputable evidence as LQTS-causative genes, while the remaining genes have moderate to limited evidence for LQTS causation.
Diagnostic methods
Diagnosis is based on typical electrocardiographic findings, clinical manifestations and family history. Genetic diagnosis should always be performed in patients with a clinically suspected diagnosis. It should also be performed on affected family members with normal/borderline QT intervals to identify those at risk of sudden death.
Differential diagnosis
Typical cases are so characteristic that they do not require differential diagnosis. For borderline cases, the following conditions should be considered: catecholaminergic polymorphic ventricular tachycardia (CPVT), Jervell and Lange-Nielsen syndrome and other forms of LQTS, as well as vasovagal syncope, ventricular tachycardia, drug-induced LQTS and epilepsy.
Antenatal diagnosis
Prenatal testing may be available for families in which the disease-causing mutation is known.
Genetic counseling
The pattern of inheritance is autosomal dominant and genetic counseling is recommended for affected families. There is a 50% risk of transmitting the pathogenic variant from an affected individual to their offspring. Autosomal recessive transmission has been described in very few cases of RWS, and in some with  TRDN mutations only.
Management and treatment
Beta-adrenergic blockers represent the first choice therapy in symptomatic patients. Whenever syncopal episodes recur despite full-dose beta-blocking therapy, left cardiac sympathetic denervation (LCSD) should be considered and implemented whenever possible. Cardiac pacing is only rarely indicated (e.g. in infants or young children with 2:1 atrioventricular block). Implantable cardioverter defibrillators (ICDs) are always indicated after cardiac arrest, or when requested by the patient, and whenever syncope recurs despite beta-blockade and LCSD. Prophylactic use of beta blockers is indicated in asymptomatic children and adults under age 40 years with LQTS (LQT1, LQT2 or LQT3). LQTS and its variants are leading causes of sudden cardiac death in young, otherwise healthy, subjects and contribute significantly to sudden infant death syndrome (SIDS). As very effective therapies exist, early diagnosis (neonatal ECG screening) is of crucial importance and permits preventive management.
Prognosis
The prognosis is severe for infants with arrhythmic events in the first year of life and for those with mutations in the Calmodulin genes.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Peter SCHWARTZ


Rombo syndrome is characterized by vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, peripheral vasodilation with cyanosis and basal cell carcinomas.

Summary:
Epidemiology
It has been described in four generations of one family and in two additional sporadic cases.
Clinical description
The skin lesions become visible between 7 and 10 years of age and are most pronounced on the face. Basal cell carcinomas are frequent and develop at around 35 years of age.
Etiology
The etiology remains unknown.

                            Last update:
                            September 2009


A rare non-Langerhans cell histiocytosis characterized by infiltration of lymph nodes or extranodal tissues by non-malignant histiocytes displaying emperipolesis, a non-destructive phagocytosis of lymphocytes or erythrocytes. Most typical presentation is as a massive cervical lymphadenopathy in adolescents and young adults. Most frequent sites of extranodal disease are skin, soft tissue, bones, paranasal sinuses, orbit, salivary glands, and central nervous system. Symptoms are related to mass effect in the affected organs.


Rosette-forming glioneuronal tumor is a rare mixed neuronal-glial tumor characterized by the presence of uniform, rosette- (or pseudorosette-) forming neurocytes with an astrocytic component, together creating a biphasic pattern. It can present with signs of raised intracranial pressure (headache, vomiting, papilledema), hydrocephalus, seizures, ataxia and visual disturbances, or can be diagnosed incidentally in asymptomatic patients. The tumor usually arises in the midline, involving the fourth ventricle or the cerebellum.


Rothmund-Thomson syndrome type 1 is a subform of Rothmund-Thomson syndrome (RTS; see this term) presenting with a characteristic facial rash (poikiloderma) and frequently associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, and rapidly progressive bilateral juvenile cataracts. In contrast to RTS2 (see this term), patients with RTS1 do not appear to have an increased risk of developing cancer.

Summary:
Epidemiology
Around 300 cases of RTS have been reported in the literature so far, with RTS1 accounting for around one-third of cases.
Etiology
RTS is transmitted in an autosomal recessive manner and although mutations in the RECQL4 gene have been found in patients with the RTS2 subform (see this term), the etiology of RTS1 remains unknown.

                            Last update:
                            February 2010


Rothmund-Thomson syndrome type 2 is a subform of Rothmund-Thomson syndrome (RTS; see this term) presenting with a characteristic facial rash (poikiloderma) and frequently associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, congenital bone defects and an increased risk of osteosarcoma in childhood and squamous cell carcinoma later in life.

Summary:
Epidemiology
Around 300 cases of RTS have been reported in the literature so far, with RTS2 accounting for around two-thirds of the cases.
Clinical description
The skeletal abnormalities may be overt (such as frontal bossing, saddle nose and congenital radial ray defects), and/or subtle anomalies visible only by radiographic analysis.
Etiology
RTS is transmitted as an autosomal recessive trait and RTS2 is caused by homozygous or compound heterozygous mutations in the RECQL4 gene (8q24.3), whereas the etiology of RTS1 (see this term) remains unknown.

                            Last update:
                            February 2010