Recombinant 8 (rec(8)) syndrome, also known as San Luis Valley syndrome, is a complex chromosomal disorder that is due to a parental pericentric inversion of chromosome 8 and is characterized by major congenital heart anomalies, urogenital malformations, moderate to severe intellectual deficiency and mild craniofacial dysmorphism.

Summary:
Epidemiology
The prevalence is unknown but the syndrome is rare. Rec(8) syndrome occurs typically in people with Hispanic ancestry from the Southwestern United States and is thought to be due to a single founder who emigrated from Spain to Colorado or New Mexico in the 17th or 18th century.
Clinical description
Rec(8) syndrome is characterized by major congenital heart anomalies, comprising complex conotruncal abnormalities often accompanied by patent ductus arteriosus or persistent left superior vena cava (PLSVC) or nonconotruncal anomalies including pulmonic stenosis, ventricular septal defect (VSD), patent ductus arteriosus and PLSVC; urogenital malformations such as cryptorchidism and hypoplastic scrotum in males; moderate intellectual disability; and mild craniofacial dysmorphism including abnormal hair whorl, low posterior hairline, wide face, hypertelorism, infraorbital creases, anteverted nares, thin upper lip, downturned mouth, gingival hyperplasia, abnormal tooth development, micrognathia, mal-shaped and low-set ears. Other findings include developmental delay, spasticity, leading to orthopedic complications such as scoliosis, seizures and recurring otitis media or hearing loss. Individuals with rec(8) syndrome generally present solid social and nonverbal communication skills and an overall good nature despite their intellectual disability.
Etiology
Rec(8) syndrome is a complex chromosomal disorder, rec(8)dup(8q)inv(8)(p23.1q22.1) due to a parental pericentric inversion of chromosome 8 [inv(8)(p23.1q22.1)] with presumed constant breaking points in this Hispanic population and variants in other populations.
Diagnostic methods
Diagnosis is based on clinical manifestations leading to chromosomal analysis by classical or molecular karyotyping.
Differential diagnosis
Differential diagnoses include other chromosomal anomalies involving chromosome 8, Bardet-Biedl syndrome, Williams syndrome and Noonan syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis.
Genetic counseling
Genetic counseling is recommended and needs karyotyping of the parents in order to evaluate the risk of recurrence. Segregation analysis has ascertained a 6.2% risk for a carrier parent to have a child with rec(8) syndrome with the transmission rate being higher in carrier mothers (59%) than fathers (42%).
Management and treatment
Management involves cardiac surgery in case of cardiac malformations and a multidisciplinary approach including hearing screening, evaluation of reflux and constipation and full developmental assessment with periodic follow-up. Regular neurodevelopmental screening and participation in individually adapted therapy programs are recommended. Orthopedic surgery has been shown to give suboptimal results due to the intellectual deficit impeding rehabilitation.
Prognosis
Prognosis is variable, depending on the severity of congenital heart disease. Historically, life expectancy past early childhood was very low, however with the increased quality and early treatment intervention the majority may live into adulthood. Exact life expectancy is unknown.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                             Laura PICKLER


A rare, congenital, intestinal malformation morphological anomaly characterized by an egg-like, cystic, mucus-filled mass, composed of intestinal mucosal lining and smooth muscle tissue. Commonly it presents in childhood with symptoms of recurrent urinary tract infections, gastroenteritis, obstruction, perianal sepsis and rectal bleeding. Drainage of mucus or pus from the anus is also a typical presenting sign. The majority are found in the retro-rectal space where they communicate with, or are contiguous to, the rectum.


Recurrent hepatitis C virus induced liver disease in liver transplant recipients

A rare hepatic disease characterized by recurrence of hepatitis C virus infection after liver transplantation, leading to liver injury with features resembling those observed in the non-transplant graft, and typically developing after three months post-transplantation. The clinical course is highly variable, although patients most commonly develop progressive chronic liver disease with higher viral loads and more rapid fibrosis progression than in the immunocompetent population.


A rare inflammatory optic neuropathy characterized by recurrent episodes of idiopathic inflammation of the optic nerve head with optic disc edema associated with macular exudate in a star-shaped pattern. Patients present with acute visual loss, most typically in the form of a large central scotoma. Pain is mild or absent. Bilateral involvement is frequent and usually sequential. The interval between attacks is highly variable, ranging from months to several years. Visual loss is cumulative with each attack and often severe.


Recurrent infections associated with rare immunoglobulin isotypes deficiency

Deficiencies in immunoglobulin (Ig) isotypes (including: isolated IgG subclass deficiency, IgG sublcass deficiency with IgA deficiency and kappa chain deficiency) are primary immunodeficiencies that are often asymptomatic but can be characterized by recurrent, often pyogenic, sinopulmonary infections.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Some patients may show an increased frequency of infections in their second year of life, while for others the onset of infections may be later. There are four subclasses of IgG (IgG1, IgG2, IgG3 and IgG4), the levels of which change with age. Deficiency with IgG subclass 2 is most common in children, whereas after puberty deficiency in subclass 3 is more common. Symptomatic patients experience recurrent sinopulmonary infections, particularly with Streptococcus pneumonia and Haemophilus influenza, which present as repeated ear infections, bronchitis, pneumonia, sinusitis and diarrhea. Patients may also present with meningitis, bronchiectasis and severe, recurrent otitis media, which may lead to hearing loss. Patients with kappa chain deficiency are usually asymptomatic but symptoms can include recurrent respiratory infections and diarrhea.
Etiology
The cause and mode of transmission of deficiencies in IgG subclasses is unknown. Kappa-chain deficiency is produced by mutations in the IGKC gene (2p11).
Diagnostic methods
IgG subclass deficiency, with or without IgA deficiency, should be suspected in patients suffering from recurrent or chronic infections with encapsulated bacteria. Diagnosis is based on the number of infections (more than 6 courses of antibiotics per year given for upper and lower respiratory tract infections) and a lack of functional antibodies produced in response to vaccines and, in the case of IgG subclass deficiency, measurement of IgG subclass levels. The most common subclass deficiency is in IgG2, which may be accompanied by decreased IgG4 with or without decreased IgA levels. IgG subclass deficiency may still be a possibility even when the total IgG is normal, therefore measurement of all four IgG subclasses is required for an accurate diagnosis of IgG subclass deficiency. Diagnosis of kappa chain deficiency can be confirmed with genetic testing.
Differential diagnosis
Differential diagnoses include other primary immunodeficiencies, including 22q11 microdeletion syndrome, HLA class II deficiency and ataxia telangiectasia (see these terms). In general, infections are less severe than those in patients with marked deficiencies of IgG (all subclasses), IgA and IgM (such as X-linked agammaglobulinemia and common variable immunodeficiency; see these terms).
Genetic counseling
Transmission is autosomal recessive and point mutations in one family have been described.
Management and treatment
Treatment is based on prophylactic antibiotics and/or polyvalent immunoglobulin replacement in cases with severe or recurrent infections. Asymptomatic cases do not require treatment. Treatment in children is restricted to 8-9 months over winter with attempts to stop treatment totally in the summer in order to see if the deficit has corrected itself. For kappa chain deficiency, oral poliovaccine should not be given because of the risk of paralytic disease.
Prognosis
In children these deficiencies may be transient, while in adults they seem to be permanent. However, there is no evidence at diagnosis to predict their evolution.

                            Last update:
                            September 2010

                            - Expert reviewer(s):
                            Dr Anne DURANDY  - Pr Alain FISCHER  - Pr Isabelle PELLIER


Recurrent infections due to specific granule deficiency

A rare functional neutrophil defect characterized by infantile onset of increased susceptibility to pyogenic infections, especially of the skin, ears, lung, and lymph nodes, with neutrophils lacking specific granules and exhibiting bilobed nuclei on peripheral blood smear. Bone marrow biopsy shows hypercellularity, paucity of neutrophil granulocytes, and progressive myelodysplasia. Additional manifestations may include mild to moderate developmental delay, mild facial dysmorphic features (such as dysplastic ears), and anomalies of bones, teeth, and nails.


Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome is a rare, genetic, neurodegenerative disease characterized by episodic metabolic encephalomyopathic crises (of variable frequency and severity which are frequently precipitated by an acute illness) which manifest with profound muscle weakness, ataxia, seizures, cardiac arrhythmias, rhabdomyolysis with myoglobinuria, elevated plasma creatine kinase, hypoglycemia, lactic acidosis, increased acylcarnitines and a disorientated or comatose state. Global developmental delay, intellectual disability and cortical, pyramidal and cerebellar signs develop with subsequent progressive neurodegeneration causing loss of expressive language and varying degrees of cerebral atrophy.


Recurrent Neisseria infections due to factor D deficiency is a rare, genetic, primary immunodeficiency disorder characterized by an increased susceptibility to  Neisseria  bacterial infections, resulting from complement factor D deficiency, typically manifesting as recurrent respiratory infections, recurrent meningitis and/or septicemia. Patients typically present fever, purpuric rash, arthralgia, myalgia and undetectable complement factor D plasma concentrations.


A rare respiratory disease characterized by the development of exophytic papillomas, affecting the mucosa of the upper aero-digestive tract (with a strong predilection for the larynx), caused by an infection with human papilloma virus. Symptoms at presentation vary with the age of patients and the extent of lesions and include dysphonia, chronic cough and recurrent respiratory infections.

Summary:
Epidemiology
The prevalence of recurrent respiratory papillomatosis (RRP) is estimated at about 1/70,400 in the United Kingdom. Annual incidence of the disease is about 1/23,300 in children and 1/55,500 in adults in the United States. The adult forms affect males more often than females.
Clinical description
A trimodal age distribution is characteristic, with peaks around the ages 7, 35 and 64 years. In sub-Saharan Africa the third peak does not exist. Manifestations depend on the extent and progression of the lesions and in the pediatric population include dysphonia (hoarseness and/ or breathiness), cough, wheezing, chronic dyspnea, rarely choking and syncope. The symptoms tend to be more severe in children because of the rapid growth of the lesions and can lead to potentially life-threatening airway compromise. In the adult population symptoms include dysphonia (hoarseness and/ or breathiness), chronic cough and globus. The clinical course is variable ranging from mild disease with spontaneous remission to an aggressive disease or a chronic clinical course, necessitating dozens of surgical interventions.
Etiology
RRP is caused by infection by human papillomavirus (HPV) types 6 and 11 which are considered to be ''low-risk'', or generally not associated with malignancy. RRP caused by HPV types 16, 18, 31, and 33 are considered to be premalignant lesions, not true RRP. The virus can be transmitted in utero, as a transplacental or ascending infection or during the passage through an infected birth canal. Following infection in humans, HPV is able to promote a specific immune system dysfunction, hence favoring the development of papillomatosis. It is theorized that such behavior is related to specific virus capabilities and a possible genetic predisposition.
Diagnostic methods
Laryngoscopy, followed by histologic examination and HPV genotyping is the most reliable method used to reach a definite diagnosis. Multiple non-necrotic cauliflower-like lesions can be observed on endoscopy. HPV genotyping can be performed by the detection of HPV DNA by polymerase chain reaction with consensus primers and subsequent restriction mapping or hybridization methods.
Differential diagnosis
Differential diagnosis includes asthma and bronchitis in children, and acute laryngitis, upper respiratory tract infection and other benign or malignant laryngeal tumors in all age groups.
Management and treatment
The treatment's goal is to secure airway patency (in children) or preserve the underlying laryngeal tissues (in adults), and thus, maintain an acceptable quality of voice. This is accomplished by surgical intervention with the help of either a microscope or an endoscope in order to debulk or remove the papilloma lesions. Postoperative complications include hampered voice due to scarred vocal folds. A minority of patients requires adjuvant therapy. HPV vaccination appears to be effective in reducing the intersurgical interval. Other adjuvant therapies include intralesional cidofovir and systemic bevacizumab.
Prognosis
The prognosis is often good, although it is a potentially lethal disease. Its morbidity is low in most cases, but dozens of surgical interventions are not uncommon. Malignant degeneration can rarely occur. Patients with pulmonary RRP have an increased risk of malignant transformation.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Pr F.G. [Frederik] DIKKERS | ERN CRANIO*

                                * European Reference Network


Reducing body myopathy (RBM) is a rare muscle disorder marked by progressive muscle weakness and the presence of characteristic inclusion bodies in affected muscle fibres.

Summary:
Epidemiology
The prevalence is unknown: although some sporadic cases have been described, only four families with RBM have been reported in the literature so far.
Clinical description
The age of onset, speed of progression and severity of the disease vary significantly between patients, even between affected members of the same family. Although early development is generally normal (up to 2 years of age), onset during infancy or early childhood appears to be associated with severe myopathy, hypotonia and rapidly progressive muscle weakness leading to death due to respiratory insufficiency within the first five years of life. Onset during childhood or adulthood is characterised by mainly proximal muscle weakness, a rigid spine syndrome and a slowly progressive disease course.
Etiology
Both sporadic and familial cases of RBM are caused by mutations in the gene encoding the four-and-a-half LIM domain 1 protein (FHL1; Xq27.2).
Diagnostic methods
As the clinical picture is highly variable (EMG reveals mixed myogenic patterns), diagnosis relies on recognition of the typical histopathological findings at muscle biopsy: the non-membrane-bound inclusions reduce nitro-blue tetrazolium (hence the name `reducing body myopathy') and are located in the cytoplasm, usually close to the degenerating nucleus. Electron microscopy reveals that the inclusions consist of a fine granular material and immunohistochemical analysis reveals the presence of aggresome-like proteins.
Differential diagnosis
The differential diagnosis should include other disorders with reducing bodies (e.g. acid maltase deficiency) and other congenital myopathies in familial cases (see these terms). Sarcotubular myopathy may also be considered in patients with less severe forms of the disease.
Genetic counseling
The mode of transmission remains unclear. There are no reports of male-to-male transmission in familial cases and cases of severely affected females have been reported. X-linked dominant, semi-dominant and recessive inheritance have been suggested and skewed X-inactivation has not been excluded.
Management and treatment
Management is supportive and should be multidisciplinary (involving a neurologist, orthopaedic surgeon and physical therapist).
Prognosis
The prognosis is generally severe: disease progression results in loss of ambulation, and death due to respiratory failure occurs even in patients with later-onset slowly progressive forms of the disease.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Pr Bertrand FONTAINE


Reflex epilepsy refers to epilepsies where recurrent seizures are provoked by a clearly defined extrinsic (most commonly) or intrinsic triggering stimuli such as flashing lights (photosensitive epilepsy), startling noises (startle epilepsy), urinating (micturition induced seizures), exposure to hot-water (hot water epilepsy, see these terms), eating, reading, and thinking, while being associated with an enduring abnormal predisposition to have such seizures (thereby meeting the conceptual definition of epilepsy).


Refractory anemia with excess blasts in transformation

A rare hematologic disease characterized by the presence of 20-29% blasts in the bone marrow, presence of 5-29% blasts in the peripheral blood, and/or presence of Auer rods. Patients show relatively stable peripheral blood counts for weeks or months, with specific cytogenetic and molecular genetic characteristics constituting important prognostic factors.


Refractory celiac disease is a rare intestinal disease characterized by persistent or recurrent symptoms and signs of confirmed celiac disease despite a long-term, strict, gluten-free diet, in the absence of other causes of villous atrophy or malignant complications and with or without presence of increased abnormal intraepitelial lymphocytes.


Refractory cytopenia with multilineage dysplasia

Refractory cytopenias with multilineage dysplasia (RCMD) is a frequent subtype of myelodysplastic syndrome (MDS; see this term) characterized by 1 or more cytopenias in the peripheral blood and dysplasia in 2 or more myeloid lineages.

Summary:
Epidemiology
Exact prevalence is unknown but RCMD accounts for about 30% of patients with MDS which has a prevalence estimated to be 1/25,000 to 1/33,000. The disease tends to occur in older adults with a male predominance.
Clinical description
Most patients are asymptomatic at presentation, and the disorder is detected incidentally. Some patients may have fatigue (anemia), a tendency to bleed or bruise (thrombocytopenia), or susceptibility to infections (neutropenia). Laboratory findings show one or more cytopenias.
Etiology
The etiology is not known but is thought to involve inherited susceptibility or hematopoietic stem cell damage.
Diagnostic methods
The hematological parameters used to define RCMD are as follows: less than 1% blasts in peripheral blood or less than 5% in bone marrow, multilineage dysplasia sometimes with ring sideroblasts, and no Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes).
Prognosis
Median survival of 17 to 33 months has been reported.

                            Last update:
                            February 2015


A metabolic disease characterized by anosmia, cataract, early-onset retinitis pigmentosa and possible neurological manifestations, including peripheral neuropathy and cerebellar ataxia. Other features can be deafness, ichthyosis, skeletal abnormalities, and cardiac arrhythmia. It is characterized biochemically by accumulation of phytanic acid in plasma and tissues.

Summary:
Epidemiology
About 60 cases of Refsum disease (RD) have been reported worldwide. Prevalence rates are not known but the disorder may be underdiagnosed. Prevalence has been estimated to be 1/1,000,000 in the United Kingdom. Males and females are affected equally.
Clinical description
Age of onset ranges is childhood to over 50 years of age but may be difficult to determine. Retinitis pigmentosa is often the first sign and is found in almost all patients. Onset of night blindness in childhood is common. Cataract and nystagmus may be found later on. Anosmia is a universal clinical manifestation. Symmetric mild-to-profound sensorineural hearing loss, ataxia of late onset causing an unsteady gait, and more rarely mild generalized ichthyosis may develop subsequently. Mixed motor and sensory neuropathy may also be found, causing muscular atrophy, weakness, and peripheral sensory disturbances. Autism spectrum disorder and attention deficit-hyperactivity disorder (AD-HD) are also reported. Short metacarpals and metatarsals at birth are found in about 1/3 of cases. Cardiac arrhythmia and cardiomyopathy causing heart failure are also reported.
Etiology
RD is caused by mutations in the PHYH gene (10p13) in more than 90% of cases, and mutations in the PEX7 gene (6q21-q22.2) in less than 10%. These genes are involved in lipid metabolism and protein transport. The pathogenic mechanism is related to the accumulation of phytanic acid, which is predominantly (>90%) degraded by alpha-oxidation in peroxisomes.
Diagnostic methods
The diagnosis is based on clinical manifestations including retinitis pigmentosa and variable combinations of the other features. The interval between initial signs and diagnosis may exceed 10 years. All classic disease manifestations are rarely found in a single affected person. Analysis of phytanic acid concentrations in plasma or serum shows abnormal levels generally above 200 micromol/L. Enzymatic fibroblast analysis and molecular genetic testing of the causative genes are required to confirm the diagnosis.
Differential diagnosis
Other causes of retinitis pigmentosa and sensorineural hearing loss should be considered in the differential diagnosis (Usher syndromes, types 1, 2, and 3; Alström syndrome; Kearns-Sayre syndrome; Sjögren-Larsson syndrome). Refsum disease should not be confused with infantile Refsum disease a misnomer that belongs to the Zellweger syndrome spectrum.
Antenatal diagnosis
Prenatal diagnosis can be performed if a disease-causing mutation is known in the family.
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
Phytanic acid is obtained from the diet, particularly from meat and dairy products. Dietary restriction helps to control sensory neuropathy, myopathy, ataxia and ichthyosis. In acute presentations (arrhythmia, weakness), plasmapheresis or lipapheresis may be useful. Supportive treatment includes hydrating creams, anti-arrhythmics, and cardiac medication. Bilateral cochlear implantation may be considered for severe hearing loss. Cardiac and ophthalmological monitoring is required. Rapid weight loss should be prevented (e.g. during hospital admission) because that can cause rapid increase in plasma phytanic acid levels.
Prognosis
Prognosis in the absence of treatment is generally poor. Severe cases or late diagnosis may be life-threatening. The main cause of death is arrhythmia and heart failure.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr M. [Marc] ENGELEN  - Pr C.E.M. [Carla] HOLLAK  - Dr M. [Mirjam] LANGEVELD


A rare orodental disease characterized by localized developmental anomaly of the dental tissues, with enamel and dentin hypomineralization affecting one (odontodysplasia) or several (regional odontodysplasia; ROD) teeth (deciduous and permanent, with teeth of the maxilla more frequently involved).

Summary:
Epidemiology
The prevalence is unknown but around 180 cases have been reported in the literature so far.
Clinical description
The defects involve both primary and permanent dentitions in the majority of the cases. The teeth of individuals with ROD are usually hypoplastic, small and atypically shaped with surface pits and grooves and a yellowish or brownish discoloration. Early loss of primary teeth is described. The condition usually affects the maxilla more than the mandible and is generally unilateral. Other common features include eruption failure or delay, and facial swellings (cellulitis), abscesses or fistulae in the absence of caries. Radiographic examination reveals a lack of contrast between enamel and dentin, with very thin (ghost-like) layers. Both dentin and enamel are hypomineralized. The pulp looks large and pulp stones or denticles can be seen. Histological features include mixed areas of cellular, amorphous and interglobular dentin. The enamel is hypoplastic, and hypocalcified areas and invaginations from the enamel surface into the dentin layer have been observed and may result in bacterial contamination of the pulp, leading to pulpitis or necrosis. The bone itself is not affected.
Etiology
The underlying cause of ROD is still a matter of debate but various etiological factors have been suggested such as local circulatory disorders, viral infections, local trauma, pharmacotherapy during pregnancy, facial asymmetry or a combination of these factors. Some familial cases may also point towards a genetic etiology.
Diagnostic methods
Diagnosis should be suspected on the basis of the clinical aspect of the teeth, or upon presentation with failure of eruption, or pulpitis or necrosis in absence of caries. The diagnosis may be confirmed by radiography revealing the typical ''ghost-like'' appearance of the teeth and the presence of enamel and dentin with similar radiodensities.
Differential diagnosis
The differential diagnosis includes dentinogenesis imperfecta, dentin dysplasia and amelogenesis imperfecta.
Management and treatment
Management is mainly conservative and includes treatment of the pulpitis and necrosis when necessary, with the aim of trying to maintain the affected teeth as long as possible to permit normal jaw development. If extraction is required, the extracted teeth should be replaced with removable appliances to maintain aesthetic appearance and function, and to avoid overeruption of opposing teeth and preserve the normal vertical dimension. Some patients benefit from autotransplants. Prosthesis and implants can be considered when craniofacial development is complete.
Prognosis
The prognosis for patients is good, especially when the condition is diagnosed and managed during the early stages. Life-long treatment is expected.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN | ERN CRANIO*

                                * European Reference Network


A rare, primary bone dysplasia characterized by mild short stature, rhizomelic shortening of the arms and legs, bowing of long bones with widened and irregular metaphyses, thoracolumbar kyphosis, and metacarpal shortening. A marked improvement of the radiologic skeletal features is typical. Pelger-Huet anomaly (i.e. dumbbell shape bilobed nuclei of neutrophils) is a characteristic hematological feature of this disease.


Reis-Bücklers corneal dystrophy (RBCD), also known as granular corneal dystrophy type III, is a rare form of superficial corneal dystrophy characterized by bilateral symmetrical reticular opacities in the superficial central cornea, with progressive visual impairment.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known.
Clinical description
Lesions develop at about 4 to 5 years of age. The opacities assume an irregular ring-shaped pattern of discrete spots and lines that focally elevate the corneal epithelium. RBCD remains asymptomatic until epithelial erosions precipitate acute episodes of ocular hyperemia, pain, and photophobia. Visual acuity eventually becomes reduced during the second and third decades of life following a progressive superficial haze and development of an irregular corneal surface. Compared to other variants of granular corneal dystrophy, RBCD involves earlier onset of symptoms and a higher frequency of recurrent erosions.
Etiology
Reis-Bücklers corneal dystrophy is caused by a specific mutation in the TGFBI gene (5q31).
Diagnostic methods
The superficial corneal stroma contains deposits of mutated transforming growth factor beta-induced protein that are indistinguishable from those of other forms of granular corneal dystrophies.
Differential diagnosis
RBCD is clinically similar to Thiel-Behnke corneal dystrophy (TBCD, see this term), but generally has a more severe course. Tissue examination or molecular genetic analysis can be used to differentiate RBCD and TBCD.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
In advanced cases of RBCD, a superficial keratectomy, phototherapeutic keratectomy (PTK) or lamellar keratoplasty (LKP) may improve vision, but a penetrating keratoplasty (PK) is rarely necessary because the pathologic changes only involve the superficial cornea.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare ependymal tumor characterized by the presence of a RELA fusion gene. This supratentorial grade II or III ependymoma most often occurs in children and young adults. Histopathological features are variable, but a distinctive vascular pattern of branching capillaries or clear-cell change are common. Patients may present with focal neurological deficits, seizures, or features of raised intracranial pressure. Prognosis is worse than in other supratentorial ependymomas.


Relapsing fever is an infection caused by bacteria of the genus Borrelia, excluding those responsible for Lyme disease (see this term) belonging to the Borrelia burgdorferi complex.

Summary:
Epidemiology
Louse-borne relapsing fever is a world-wide disease but occurs mainly in localized regions of developing countries. Tick-borne relapsing fever occurs in Africa, the Mediterranean region, Asia and America. Only a few imported cases are seen in Northern European countries.
Clinical description
The disease is characterized by cyclic fever (alternating periods of sudden fever followed by remission) associated with a general state of ill health with other rare complications (cardiac, neurologic or ocular manifestations and hemorrhage).
Etiology
The disease may be epidemic and transmitted by lice or endemic and transmitted by soft-bodied ticks (Ornithodoros and Argas).
Diagnostic methods
Diagnosis revolves around direct examination of stained blood smears and on PCR analysis of blood samples.
Differential diagnosis
The principle differential diagnosis is malaria.
Management and treatment
Antibiotic treatment (cycline) is effective. Prevention revolves around eradication of the host vector.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Muriel CORNET  - Dr Elisabeth FERQUEL


A rare, clinically heterogeneous, multisystemic inflammatory disease characterized by inflammation of the cartilage and proteoglycan rich structures leading to cartilage damage along with joint, ocular and cardiovascular involvement.

Summary:
Epidemiology
The prevalence and annual incidence of Relapsing polychondritis (RP) are not known. The estimated incidence is 1/285,000. The sex ratio appears to be equal and all ethnic groups seem to be affected (with more cases reported among Caucasians).
Clinical description
Onset is generally sudden and most commonly occurs in the 5th decade of life (age 40 to 55). Cases with early and late onset do occur. RP follows a flaring and remitting course. Clinical manifestations vary from intermittent auricular and nasal chondritis, to occasional organ or life-threatening complications. Unilateral or bilateral external ear inflammation with pain, tenderness, swelling, erythema, and discoloration, limited to the cartilaginous portion of the pinna with characteristic sparing of the lobule, is one of the hallmark features of RP (90-95% of patients). Auricular collapse or inflammation of vestibular structures can lead to conductive or sensorineural hearing loss. Other associated complications include nausea, vomiting, tinnitus, vertigo and ataxia. Nasal chondritis with sudden pain and tenderness is found at some stage of the disease in more than 50% of patients. Nasal cartilage may be severely damaged resulting in saddle nose deformity. Some patients develop potentially serious laryngotracheal involvement with hoarseness, aphonia, stridor and wheezing, dyspnea, or even airway collapse. Joint pain lasting weeks or months is found in most patients (>70%) and is often the presenting feature (30%). Cardiovascular manifestations (25-50%) include large vessel vasculitis, aneurysmal involvement, and aortic or mitral valve disease. Ocular manifestations reported are proptosis, conjunctivitis, ulcerative keratitis, episcleritis/scleritis, uveitis, and periorbital edema. Cutaneous manifestations that may precede chondritis include aphthosis, nodules, purpura, and papules. Neurological manifestations are due to vasculitis of central or peripheral nervous system. Renal involvement is rare. MAGIC syndrome represents a subset of patients with RP who also have mouth and genital ulcers, which are features of Behçet disease.
Etiology
The exact etiopathogenesis of RP is not known but it is thought to be an immune-mediated disease. A complex cytokine network is thought to be involved in the recruitment of infiltrating cells in RP lesions.
Diagnostic methods
There is no single blood or imaging test that can be used to diagnose this condition. The diagnosis is generally based upon the detection of a combination of clinical presentations. According to the most accepted and widely used diagnostic criteria, three of the following six features are required to make a diagnosis of RP: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage.
Differential diagnosis
Differential diagnoses include granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, Behçet disease, and leprosy.
Management and treatment
Treatment is primarily symptomatic and no standard therapeutic protocol has been established due to the rarity of the disease. In less severe cases, non-steroidal anti-inflammatory drugs, dapsone, and colchicine may be used. In severe cases with organic involvement, systemic corticosteroids (oral prednisolone or rarely intravenous methylprednisolone) are required. Methotrexate, azathioprine, cyclosporine and chlorambucil may constitute an alternative. Use of biological agents like anti TNFs, tocilizumab, anakinra, rituximab and abatacept has been reported with various efficacy in case reports and small case series. A relapsing polychondritis disease activity index (RPDAI) and damage index (RPDAM) has been validated for assessing disease activity and damage respectively.
Prognosis
Prognosis is generally good in the majority of cases, but the disease may occasionally follow a severe, life-threatening course, with respiratory complications (tracheal collapse and infections) as the primary cause of mortality. Cardiovascular involvement may also lead to a fatal outcome.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Aman SHARMA


REN-related autosomal dominant tubulointerstitial kidney disease

A rare autosomal dominant tubulointerstitial kidney disease (ADTKD) of childhood due to REN mutations and characterized by early onset hypoproliferative anemia, hyperuricemia, gout, and slowly progressive tubulointerstitial kidney disease.

Summary:
Epidemiology
To date, approximately 35 families have been reported in the medical and scientific literature.
Clinical description
For patients with mutations in the promoter or prosegment of the REN gene, disease onset typically occurs from the first year of life, with presentation of hypoproliferative anemia and elevated serum creatinine. The anemia resolves as the child enters adolescence. Dysfunction of the renin-angiotensin system puts children at risk of volume depletion and acute kidney injury (particularly after febrile illness). Acute kidney injury typically resolves with appropriate treatment; however, baseline chronic kidney disease (CKD) may be noted. Individuals also suffer from hyperuricemia and may develop gout in their teenage years. Other occasional features include polyuria, mild hypotension and mild hyperkalemia. Kidney function slowly worsens over time with progression to end-stage kidney disease (ESKD) between 40-70 years of age. Patients with mutations in the segment of the REN gene encoding mature renin present with gout in the late teens and early twenties as well as early CKD which worsens over time and eventually requires renal replacement therapy.
Etiology
The disease is due to heterozygous missense mutations in the REN gene (1q32) and results in reduced renin biosynthesis and secretion, and intracellular accumulation of abnormal protein. These changes lead to accelerated apoptosis, nephron dropout, interstitial fibrosis, and progressive loss of kidney function.
Diagnostic methods
The diagnosis is suspected on clinical and laboratory findings including hypoproliferative anemia and hyperuricemia, decreased fractional excretion of uric acid, and evidence of slowly progressive, chronic tubulointerstitial kidney disease. A family history compatible with ADTKD may assist in diagnosis. Renal ultrasound shows normal or small-sized kidneys with no signs of cyst formation. Plasma renin levels are low. Genetic diagnosis through a multi-gene panel or whole exome sequencing provides a good option for differentiating from similar conditions.
Differential diagnosis
Renal manifestations are similar to that of nephronophthisis; however, nephronophthisis is often associated with other symptoms. For individuals with mutations in the segment encoding the mature part of the REN gene, patients present very similarly to ADTKD-UMOD.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known mutation through molecular genetic testing.
Genetic counseling
The pattern of inheritance is autosomal dominant. The risk of inheriting the pathogenic variant is 50% in siblings and offspring of affected individuals. Penetrance is 100%, although the rate of progression of ESKD is variable. Cascade testing should be performed within families, as family members may have been misdiagnosed. Children of a parent with a REN mutation in the promoter or prosegment should have a basic metabolic panel within the first week of life, with genetic testing also performed.
Management and treatment
Children at risk should be referred to a pediatric nephrologist as early management is likely beneficial. Erythropoiesis-stimulating agents and fludrocortisone can be used for the treatment of anemia and symptomatic hypotension, respectively. Alkali supplementation can also correct metabolic acidosis but may not be as effective or as palatable as fludrocortisone. It is important to normalize serum bicarbonate to maximize growth. Fludrocortisone can potentially aggravate interstitial fibrosis and should not be used in those with declining kidney function, hypertension, hyperkalemia, or edema. Gout is typically prevented with allopurinol or febuxostat and prevention therapy is life-long; treatment with a low sodium diet and nonsteroidal anti-inflammatory drugs is contraindicated. Progression of kidney disease should be monitored by a nephrologist. As kidney disease progresses, renal replacement therapy may be required. Kidney transplantation without prior dialysis is the treatment of choice for kidney failure.
Prognosis
The prognosis is good with suitable, timely treatment. The disorder does not reoccur in transplanted kidneys.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Pr Anthony BLEYER  - Pr Stanislav KMOCH  - Dr Martina ZIVNA


A form of renal agenesis characterized by complete absence of kidney development, absent ureters and subsequent absence of fetal renal function resulting in Potter sequence with pulmonary hypoplasia related to oligohydramnios, which is fatal shortly after birth.


A form of renal agenesis characterized by the complete absence of development of one kidney accompanied by an absent ureter.


A rare, congenital renal tract malformation characterized by the complete absence of development of one or both kidneys (unilateral or bilateral renal agenesis respectively), accompanied by absent ureter(s).

Summary:
Epidemiology
The birth prevalence of unilateral renal agenesis (RA) is estimated at around 1/2,000. Fetal prevalence of bilateral renal agenesis in Europe has been estimated at 1/8,500.
Clinical description
Most patients with unilateral RA are asymptomatic early in life if the other kidney is fully functional in which case the condition is commonly detected as an incidental finding later in life. However, hypertension, proteinuria and renal failure may develop in the long run (20-50% of cases at the age of 30). Unilateral RA is occasionally associated with additional urogenital tract anomalies on the same side (e.g. seminal vesicle hypoplasia and absence of the vas deferens), cardiac anomalies (such as atrial or ventricular septal defects) and/or gastrointestinal anomalies (such as anal atresia). Bilateral RA is characterized by complete absence of kidney development, absent ureters and subsequent absence of fetal renal function resulting in Potter sequence with pulmonary hypoplasia related to oligohydramnios, which left untreated is fatal shortly after birth.
Etiology
Renal agenesis results from a developmental failure of the ureteric bud and the metanephric mesenchyme. Unilateral renal agenesis can be caused by mutations in many genes, such as RET (10q11.2), BMP4 (14q22-q23), FRAS1 (4q21.21), FREM1 (9p22.3), or UPK3A (22q13.31). A few cases of bilateral renal agenesis have been found to be caused by mutations in the RET, FGF20 (8p22) or ITGA8 (10p13) genes. Maternal diabetes mellitus or use of specific drugs during pregnancy may also cause renal agenesis.
Diagnostic methods
Diagnosis is based on ultrasonography, showing an empty renal fossa and no ectopic kidney. Additional radiological examinations like MRI (magnetic resonance imaging) and/or DMSA (dimercaptosuccinic acid) scintigraphy may confirm the diagnosis. The contra-lateral kidney may be compensatory hypertrophied.
Differential diagnosis
Differential diagnoses of an empty renal fossa include kidney ectopia and involution of multi-cystic dysplastic kidneys (MCDK).
Antenatal diagnosis
Prenatal diagnosis may be made by prenatal ultrasonography.
Genetic counseling
In familial cases, unilateral RA is typically inherited in an autosomal dominant manner with incomplete penetrance. Bilateral RA is inherited autosomal recessively.
Management and treatment
Clinical management of unilateral renal agenesis with fully functioning contra-lateral kidney included routine evaluations of blood-pressure and screening for proteinuria as individuals with RA have an elevated risk of chronic kidney disease.
Prognosis
The prognosis of RA with fully functioning contra-lateral kidney is generally good. Without intensive care, bilateral RA is fatal shortly after birth.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Stefan KOHL | ERKNet*

                                * European Reference Network


Renal caliceal diverticuli-deafness syndrome

A rare, syndromic, developmental defect during embryogenesis characterized by urinary tract and kidney anomalies, such as renal pelviocaliceal attenuation with multiple tiny caliceal diverticula, associated with sensorineural hearing loss. There have been no further descriptions in the literature since 1981.


A genetic condition characterized by optic nerve dysplasia and renal hypodysplasia.

Summary:
Epidemiology
Prevalence and prevalence at birth are not known. 177 mutation-positive cases (90 different families) have been reported. The number of mutation-negative individuals with clinical findings of Renal coloboma syndrome (RCS) is not known. There is no ethnic predilection.
Clinical description
RCS is characterized primarily by ocular signs (77%) and renal manifestations (92%). Eye anomalies consist of a wide and sometimes excavated dysplastic optic disc with emergence of the retinal vessels from the disc periphery, frequently called optic nerve coloboma or ''morning glory'' anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, reduced corneal diameter, optic nerve cyst, microphthalmia, foveal hypoplasia and pigmentary macular dysplasia. Nystagmus and myopia have also been reported. Consequences include decreased visual acuity, blindness, and retinal detachment. Renal malformations and/or insufficiency are frequently the presenting feature and consist of small and abnormally formed kidneys known as renal hypodysplasia. Histologically, kidneys exhibit fewer than normal enlarged glomeruli (oligomeganephronia). Other renal findings include multicystic dysplastic kidney and horseshoe kidney. Consequences include hypertension, proteinuria, vesicoureteral reflux, and renal insufficiency that frequently progresses to end-stage renal disease (ESRD). ESRD may present prenatally with severely hypoplastic or dysplastic kidneys and oligohydramnios resulting in fetal loss due to Potter sequence. Patients can progress to stage 5 chronic kidney disease at any age. High frequency (HF) hearing loss is reported in 7% of patients.
Etiology
Mutations in thePAX2gene (10q24) have been identified in about 1/2 of patients with renal hypodysplasia and abnormalities of the optic nerve. PAX2 mutations have been identified in about 9% of unselected individuals presenting with renal hypoplasia. The genetic basis of the remaining cases is not known.
Diagnostic methods
Formal diagnostic criteria have not been established. However, the disorder should be suspected in patients who have the classical findings of optic nerve dysplasia or coloboma and renal hypodysplasia. Oligomeganephronia is a common histologic finding in renal hypodysplasia but it is not pathognomonic for RCS.
Differential diagnosis
The differential diagnosis includes conditions where colobomas and renal anomalies have been identified such as CHARGE syndrome and Joubert syndrome with oculorenal defect (see these terms). However these disorders generally have other characteristic findings not found in RCS.
Antenatal diagnosis
Prenatal diagnosis or pre-implantation genetic testing is possible if a clearly pathogenic PAX2 mutation has been identified in a family.
Genetic counseling
RCS is inherited in an autosomal dominant pattern, though this is complicated by de novo cases, variable expression, incomplete clinical penetrance, and maternal and paternal gonosomal mosaicism.
Management and treatment
Management involves care for the renal and ophthalmologic manifestations. Patient evaluation should include renal function testing, renal ultrasound, urinalysis (proteinuria), blood pressure measurements and evaluation for vesicouretal reflux if clinically indicated. Long-term follow-up by a nephrologist and ophthalmologist are recommended. Low vision experts may also be called upon if needed. Audiologic evaluation for HF hearing loss is indicated as it may affect verbal communication.
Prognosis
Prognosis depends primarily on appropriate specialized treatment. Renal failure can occur at any age requiring dialysis and renal transplantation. Formal longitudinal studies of visual prognosis have not been carried out. However, decreased visual acuity over time has been reported.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                             Matthew BOWER  - Pr Lisa SCHIMMENTI


A form of renal dysplasia (RD), a renal tract malformation, characterized by abnormal or incomplete development of both kidneys. Bilateral RD can be segmental, and of variable severity, with renal aplasia corresponding to extreme RD. Patients may be asymptomatic if the residual kidney function is sufficient. In cases of severe bilateral RD, the risk of renal failure in childhood is high.


A form of renal dysplasia (RD) characterized by abnormal or incomplete development of one kidney. Unilateral RD can be segmental, and of variable severity, with renal aplasia corresponding to extreme RD. Patients may be asymptomatic if the contralateral kidney is functional. Even in cases of severe unilateral RD, i.e. renal aplasia, the risk of renal failure in childhood is minimal; however, patients may develop hypertension, proteinuria and renal failure as adults.


A rare renal malformation in which the kidney(s) are present but their development is abnormal, leading to malformation of histologic architecture of the kidney and presence of embryological tissue such as mesenchymal collarettes or other forms of undifferentiated and metaplastic tissues. Renal dysplasia can be unilateral or bilateral, segmental, and of variable severity.

Summary:
Epidemiology
Prevalence and incidence are not known due to the highly variable presentation and asymptomatic unilateral cases. In Europe, the prevalence at birth is estimated 1 / 2,300. Renal aplasia/hypoplasia/dysplasia are the most frequent underlying pathology in children requiring renal replacement therapy (13.5%).
Clinical description
Renal dysplasia is usually asymptomatic, but an abnormal kidney sonographic appearance may be detected during routine antenatal ultrasonography (US), US for urinary tract infections (in children) or renal disease (in children and adults). The severity of dysplasia is variable with renal aplasia at the extreme end. In cases of unilateral renal aplasia, consequences are similar to having a solitary functioning kidney, potentially resulting in hypertension and proteinuria, and possible kidney failure in adulthood. In cases of bilateral renal dysplasia, chronic kidney disease and kidney failure can occur during childhood. Bilateral renal dysplasia may limit kidney function to such an extent that oligohydramnios occurs during pregnancy, which is associated with the Potter sequence. In such cases, neonates may die shortly after birth due to respiratory failure; those with residual renal function may develop complications of chronic kidney disease: failure to thrive, growth retardation, anemia, hypertension, proteinuria and kidney failure.
Etiology
The etiology of renal dysplasia is multi-factorial. Generally, it may occur as an isolated condition or as a component of numerous rare syndromes, either secondary due to antenatal urine obstruction or due to primary maldevelopment of nephrogenic tissues. Isolated renal dysplasia has been reported in families with mutations in HNF1B (17q12). Incomplete penetrance and variable expressivity are very common in CAKUT (congenital anomalies of kidney and urinary tract); thus, genes involved in multi-organ syndromes ( such as EYA1, GATA3, GREBI1L, PAX2, PBX1, SALL1, FRAS1, FREM2, and GRIP1) may possibly lead to an isolated renal phenotype (dysplasia/hypoplasia/agenesis). Other forms of renal dysplasia may be caused by embryotoxic drugs such as angiotensin converting enzyme inhibitors or prenatal programming triggers such as hypoxia or diabetes mellitus.
Diagnostic methods
Diagnosis is based on ultrasonography, showing an abnormal appearing kidney with absent or poor corticomedullary differentiation with or without cysts and increased echogenicity. Kidneys may be of normal size or small. Renography shows decreased renal uptake of DMSA-tracer. Histology shows disorganized primitive ducts surrounded by mesenchymal stroma. Genetic analysis may identify variants in one of the previously mentioned genes in a minority of cases.
Differential diagnosis
Differential diagnoses of an abnormally differentiated kidney on ultrasound include renal hypoplasia, polycystic kidney disease, vascular insults, and renal post-infectious damage. Renal dysplasia may occur as part of recognized syndromes such as Kallmann, Bardet-Biedl, Beckwith-Wiedemann, diGeorge, Fraser, and renal coloboma syndromes as well as HNF1B-related autosomal dominant tubulointerstitial kidney disease.
Antenatal diagnosis
Antenatal diagnosis is possible from midway through gestation. The condition is dynamic and can evolve during pregnancy and after birth; therefore, repeated assessments are necessary.
Genetic counseling
Families may benefit from genetic counseling in case of renal dysplasia as part of a multi-organ syndrome, in familial cases or in bilateral cases with chronic kidney disease. The recurrence risk in families may be elevated, but data remain scarce.
Management and treatment
Regular evaluation of the remaining kidney function is recommended. Due to an increased risk of hypertension and/or proteinuria, a long-term follow-up is recommended. In severe cases, kidney replacement therapy may be needed.
Prognosis
Infants with pulmonary hypoplasia show substantial mortality in the neonatal period. Survivors may develop chronic renal failure in childhood. In unilateral renal dysplasia, the risk of kidney failure in childhood is minimal but patients may develop hypertension, proteinuria and kidney failure as adults.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Stefan KOHL | ERKNet*

                                * European Reference Network


A form of renal hypoplasia characterized by bilateral small kidneys with a deficit in the number of nephrons present. The condition is typically asymptomatic but may be associated with hypertension, and some excretory functional limitations, as well as eventual chronic renal failure.


A form of renal hypoplasia characterized by unilateral small kidneys with a deficit in the number of nephrons present. The condition is typically asymptomatic with minimal risk of renal failure in childhood


A congenital renal malformation characterized by abnormally small kidney(s) (kidney volume below two standard deviations of that of age-matched normal individuals or a combined kidney volume of less than half of what is normal for the patient's age) with normal corticomedullary differentiation and reduced number of nephrons.

Summary:
Epidemiology
Isolated renal hypoplasia is considered rare and, given the difficulty to distinguish it from renal dysplasia that may also result in small kidneys, its prevalence and incidence are unknown. Both renal dysplasia and renal hypoplasia account for a significant proportion of chronic kidney disease in children and of inborn causes of chronic kidney disease in adults.
Clinical description
Isolated, unilateral renal hypoplasia is usually asymptomatic. It may be detected in a prenatal ultrasound screening, after a urinary tract infection in children, or with hypertension, proteinuria (generally symptoms of chronic kidney disease) in children and adults. Disease severity depends on the degree of reduction in the number of nephrons, the involvement of the other kidney, and whether other congenital anomalies of the kidney and urinary tract (CAKUT) are present. The disease may lead to glomerular hyperfiltration associated with hypertension, proteinuria and, in the long term, with chronic kidney failure.
Etiology
The occurrence of renal hypoplasia may be caused by mutations in kidney developmental genes (HNF1B, PAX2, PBX1) and/or multiple environmental factors such as intrauterine growth restriction, maternal diseases (diabetes, hypertension), maternal drug intake (inhibitors of the renin-angiotensin system or non-steroidal anti-inflammatory drugs (NSAIDs)) and intoxication (smoking and alcohol). Variants in multiple additional genes or genomic alterations have been linked to kidney hypoplasia or dysplasia but their specific role for hypoplasia is not clearly understood (EYA1, GATA3, GREB1L, SALL1, large copy number variations). Premature birth (before the 36th week) is also a risk factor due to incomplete nephrogenesis. Generally, kidney hypoplasia is seen as a defect in nephron endowment.
Diagnostic methods
The clinical diagnosis is typically based on ultrasonography. On fetal or postnatal ultrasound, renal hypoplasia is defined as a kidney volume of below two standard deviations or a combined kidney volume of less than half of age-related normal kidney volume. Corticomedullary differentiation typically is normal. Postnatal renography with technetium-99m-labeled dimercaptosuccinic acid shows smooth kidney outline.
Differential diagnosis
Differential diagnoses include all forms of kidney dysplasia. Although the definite differentiation can only be made on histological grounds, in clinical practice ultrasonography is used to distinguish normal appearing small kidneys (hypoplasia) from abnormal appearing small kidneys with disturbed corticomedullary differentiation and/or increased echogenicity, and/or cysts. Oligomeganephronia represents a severe variant of hypoplasia in which nephron number is reduced by 80% and nephrons are markedly hypertrophied
Antenatal diagnosis
Antenatal ultrasonographic screening is becoming routine and allows detection of renal hypoplasia from midway through gestation.
Genetic counseling
Most cases are sporadic. Familial cases have been observed with an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity and thus the recurrence risk of is up to 50% in such cases.
Management and treatment
Management largely depends on the degree of chronic kidney disease and whether or not there are additional CAKUT. Therefore, assessment of renal function (blood pressure, estimate of the glomerular filtration rate and proteinuria) should be obtained to evaluate the function of the remaining nephrons. Due to an increased risk of hypertension and/or proteinuria, individuals with renal hypoplasia deserve long-term follow-up. In extreme cases, kidney replacement therapy may be needed.
Prognosis
The risk of end stage chronic kidney disease in childhood is low but kidney failure may occur in severe cases.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Stefan KOHL | ERKNet*

                                * European Reference Network


Renal medullary carcinoma is a rare, aggressive subtype of renal cell carcinoma characterized by a large, white or tan, firm, infiltrative tumor with microabscess-like foci centered in the renal medulla, typically presenting with hematuria, abdominal/flank pain, weight loss and fever. It is associated with sickle cell trait and disease and metastasis to the bones and lungs is common at time of diagnosis.


A rare, syndromic renal disease characterized by the entrapment of left renal vein (LRV) between the superior mesenteric artery (SMA) and the abdominal aorta, resulting in increased luminal pressure, renal hilar varices, hematuria and, at the microscopic level, rupture of thin-walled veins into the collecting system in renal fornices.

Summary:
Epidemiology
The exact prevalence is not known. Most cases have been reported from the Far-East. Women are more commonly affected than men.
Clinical description
Patients with renal nutcracker syndrome (NCS) are usually asthenic, tall and thin. Many patients remain asymptomatic and are incidentally discovered during radiological imaging for other causes. Symptomatic cases present mostly in second/third decade of life with urological or gynecological symptoms. Urological manifestations include left loibdominal pain, left-sided macroscopic or microscopic hematuria (on endoscopy, varicocele, or lower limb varices. Gynecological symptoms resemble pelvic congestion syndrome and include symptoms of dysmenorrhea, dyspareunia, post-coital ache, lower abdominal pain, dysuria, pelvic/vulvar/gluteal/gonadal or thigh varices, and emotional disturbances. Three types of renal nutcracker syndrome have been defined, according to the site of LRV compression: anterior nutcracker syndrome, posterior nutcracker syndrome and combined nutcracker syndrome.
Etiology
Normally SMA separates from the abdominal aorta (AA) at a 90-degree angle. The LRV lies anterior to the aorta in the fork between the SMA and AA. In anterior NCS, the SMA arises from the aorta at an acute angle, compressing the LRV causing left renal venous hypertension. In posterior NCS, the LRV courses posterior to the AA and is compressed between the aorta and the vertebral column. In combined NCS, the anterior branch of the duplicated LRV is compressed between the aorta and the SMA, while the posterior is sandwiched between the aorta and the vertebral column.
Diagnostic methods
Diagnosis should be suspected upon presentation with left-sided loin pain and hematuria. Diagnostic tests include urine analysis, ultrasound scan, color Doppler scan, CT or MR angiography, and left renal vein phlebography and manometry. Doppler sonography is usually the first imaging tool, which can detect collateral veins around LRV, whose presence sustains venous hypertension and are a radiological criterion for NCS. The ''gold standard'' for diagnosis remain phlebography, intravascular pressure measurement and intravascular ultrasound through which the venous pressure gradient between LRV and inferior vena cava and the renal vein diameter can be measured. Patients usually show an LRV/inferior vena cava pressure gradient >1 mmHg. Computed tomography venography and magnetic resonance venography are noninvasive evaluation tools which provide good definition of LRV compression and grade of involvement of other organs.
Differential diagnosis
Compression of LRV leading to loin pain and hematuria can be seen in pancreatic neoplasms, paraortic lymphoadenopathy, retroperitoneal masses, overarching testicular artery, lordosis, reduced retroperitoneal and mesenteric fat or too much fibrolymphatic tissue between SMA and AA.
Management and treatment
Surveillance is appropriate in pubertal patients, who may undergo spontaneous remission with physical development and weight gain, and in patients with insignificant symptoms and microscopic hematuria, or intermittent painless gross hematuria with a normal hemogram. Open surgery procedures with good outcomes include vascular transpositions and renal auto transplantation. Extra-vascular stenting can be performed through open or laparoscopic surgery. Intravascular stenting is a treatment option in which a self-expanding metallic stent is deployed in the stenotic region of the LRV.
Prognosis
As this is a benign condition, overall prognosis is excellent. In highly symptomatic patients, with severe pain, frank/recurrent hematuria requiring blood transfusion, active intervention needs to be considered. Prognosis following intervention is excellent.

                            Last update:
                            March 2019

                            - Expert reviewer(s):
                            Dr Max Christoph LIEBAU | ERKNet*

                                * European Reference Network


A form of pseudohypoaldosteronism type 1 characterized by mild mineralocorticoid resistance that is restricted to the kidneys and that usually improves in early childhood. Typical presentation is in the neonatal period with weight loss, failure to thrive, vomiting and dehydration in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels.


Renal tubular dysgenesis due to twin-twin transfusion

A rare acquired form of renal tubular dysgenesis that develops in donor fetuses due to the shunting of blood flow to the kidney of the recipient and characterized by absent or poorly developed proximal tubules, persistent oligohydramnios and consequently the Potter sequence (facial dysmorphism with large and flat low-set ears, lung hypoplasia, arthrogryposis and limb positioning defects).


A rare disorder of the fetus characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence (facial dysmorphism with large and flat, low-set ears, lung hypoplasia, arthrogryposis and limb positioning defects), and skull ossification defects.

Summary:
Epidemiology
The incidence of renal tubular dysgenesis is unknown.
Clinical description
The clinical picture is of early onset oligohydramnios, skull ossification defects and neonatal pulmonary and renal failure.
Etiology
Non-syndromic renal tubular dysgenesis can be acquired during fetal development due to drugs taken by the mother (such as in utero exposure to ACE inhibitors) or in the context of twin-twin transfusion syndrome (TTTS). The genetic form is due to biallelic pathogenic variations in genes encoding either angiotensinogen (AGT; 1q42.2), renin (REN; 1q32.1), angiotensin converting enzyme (ACE ; 17q23.3) or angiotensin 2 receptor type 1(AGTR1; Xq23). Other disorders that can feature renal tubular dysgenesis include severe fetal cardiopathy, congenital hemochromatosis, and severe fetal renal artery stenosis.
Diagnostic methods
The diagnosis is based on renal histology with or without proximal tubule labeling, and molecular genetics.
Differential diagnosis
The differential diagnosis includes secondary forms of renal tubular dysgenesis and leakage of amniotic fluid.
Antenatal diagnosis
Diagnosis may be suspected on routine prenatal ultrasound by presentation of oligohydramnios in the presence of a normal kidney scan. In families with an antecedence, genetic prenatal diagnosis is possible where the pathogenic variations have been previously identified.
Genetic counseling
For the genetic form, 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
Management is typically expectant. Severe pulmonary hypoplasia is not treatable. Few cases with less severe respiratory disease were treated with peritoneal dialysis, followed by renal transplantation when the weight was sufficient. In cases due to twin-to-twin transfusion, fetoscopic laser photocoagulation, amnioreduction or delivery be suggested.
Prognosis
The prognosis is extremely severe in the majority of cases.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Dr Laurence HEIDET | ERKNet*

                                * European Reference Network


Renal tubulopathy-encephalopathy-liver failure syndrome

Renal tubulopathy - encephalopathy - liver failure describes a spectrum of phenotypes with manifestations similar but milder than those seen in GRACILE syndrome (see this term) and that can be associated with encephalopathy and psychiatric disorders.

Summary:
Epidemiology
The prevalence is unknown. Several cases have been described in Turkey, Spain, New Zealand and Australia.
Clinical description
Disease presentation is variable. Most of the characteristics of GRACILE syndrome are present (fetal growth restriction, proximal tubulopathy and hepatopathy, as well as lactic acidosis) but they are often less severe. Signs of disturbances in iron metabolism have been described, such as increased serum ferritin levels, but it is unclear whether severe liver iron overload is present. Most infants die during the neonatal period. In those who survive, encephalopathy and psychiatric disorders have been described.
Etiology
This disease is due to different mutations in the BCS1L gene (2q35) encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain.
Genetic counseling
Renal tubulopathy - encephalopathy - liver failure is inherited autosomal recessively and genetic counseling is possible.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Pr Vineta FELLMAN


Renal-hepatic-pancreatic dysplasia is a rare, genetic, developmental defect during embryogenesis syndrome characterized by the triad of pancreatic fibrosis (and cysts, with a reduction of parenchymal tissue), renal dysplasia (with peripheral cortical cysts, primitive collecting ducts, glomerular cysts and metaplastic cartilage) and hepatic dysgenesis (enlarged portal areas containing numerous elongated binary profiles with a tendancy to perilobular fibrosis). Situs abnormalities, skeletal anomalies and anencephaly have also been associated. Patients that survive the neonatal period present renal insufficiency, chronic jaundice and insulin-dependent diabetes.


Renin-angiotensin-aldosterone system (RAAS)-blocker induced angioedema (RAE) is a type of acquired angioedema (AAE, see this term) characterized by acute edema in subcutaneous tissues, viscera and/or the upper airway.

Summary:
Clinical description
Like other forms of AAE it has a later onset than HAE (see this term) and occurs generally in adults.
Etiology
The main causative RAAS-blockers are the angiotensin-converting enzyme inhibitors (ACEIs) which increase levels of bradykinin leading to increased vascular permeability and vasodilation. Angioedema develops in 0.1%-0.5% of patients taking these drugs. Angioedema develops more often at an early phase of treatment, but may also occur with long-term treatment. The same side effect appears more rarely with angiotensin II receptor antagonists (ARAIIs) and direct renin inhibitors (DRIs). Co-administration of ACEI and an antidiabetic agent, dipeptidylptidase-4 (DPP-4) inhibitor, significantly increases the risk of angioedema. This reaction imposes the immediate cessation of these drugs.
Management and treatment
The orphan drug icatibant or C1-INH concentrate can be effective for acute attack treatment.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Laurence BOUILLET


Renpenning syndrome is an X-linked intellectual disability syndrome (XLMR, see this term) characterized by intellectual deficiency, microcephaly, leanness and mild short stature.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The main clinical manifestations of Renpenning syndrome are usually moderate intellectual deficiency, leanness, microcephaly and short stature (relative to familial target measurements) and sometimes small testes (testicular volumes below 15 ml), that are noticed at puberty. Manifestations are expressed only in males, and female carriers show normal facial features, growth development and intelligence. Small head and brain sizes are noted at birth. Characteristic craniofacial features include long triangular faces with upslanting palpebral fissures, half-depilated eyebrows, large ridged or bulbous nose with overhanging columella, short philtrum, and cupped and laterally protruding ears. Patients are thin and show failure to thrive. Delayed motor and language development is noticed in children from an early age. Moderate to severe intellectual deficiency is seen in two thirds of cases. Muscular atrophy is also observed affecting mostly the spine and back muscles resulting in fall of head, upper back curve loss and an appearance of scapula alata. Metacarpophalangeal ankylosis of the thumb and muscular atrophy of the intrinsic muscles of the hand can occur in some cases. Although uncommon, cardiac malformations (atrial septal defect), cleft palate, ocular colobomas and imperforate anus have been noted in a few patients. Phenotypic variants grouped under Renpenning syndrome include Golabi-Ito-Hall syndrome, Hamel cerebro-palato-cardiac syndrome (see these terms), Porteous syndrome, Sutherland-Haan syndrome, MRX55 and three other XLMR families. Hamel cerebro-palato-cardiac syndrome usually has the most severe manifestations.
Etiology
Renpenning syndrome is an X-linked condition caused by mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene, encoding a nuclear protein that regulates pre-mRNA splicing and transcription. Six of the seven mutations discovered in the PQBP1 gene result in a truncated protein whereas a missense mutation that does not affect the length of the mutated protein is seen in Golabi-Ito-Hall syndrome.
Diagnostic methods
Diagnosis is based on inheritance of clinical manifestations of Renpenning syndrome. It is often difficult if there is only one male with intellectual deficiency in a family, but it must be suggested even in sporadic cases. Brain magnetic resonance imaging (MRI) shows no obvious gyral reduction, which contrasts with frank microcephaly. PQBP1 gene screening for a mutation can confirm diagnosis.
Differential diagnosis
Fragile X syndrome is a differential diagnosis but microcephaly is not a feature. Other causes of microcephaly such as fetal CMV infection, fetal alcohol syndrome, maternal phenylketonuria, autosomal recessive microcephalies and Smith-Lemli-Opitz syndrome (see this term) should be considered.
Antenatal diagnosis
If a mutation is identified, prenatal diagnosis may be proposed to parents for further pregnancies. In sporadic cases, germinal mosaicism should be ruled out on prenatal setting.
Genetic counseling
Renpenning syndrome follows an X-linked recessive pattern of inheritance. Genetic testing is possible to identify carrier females and to inform them of the risk of passing on the gene to their offspring.
Management and treatment
Management for Renpenning syndrome involves early education and intervention by trained therapists and treatment of any associated symptoms (cardiac defect, hypospadias, conductive deafness, strabismus). Children need to attend special education courses at school due to learning disabilities.
Prognosis
There is no cure for Renpenning syndrome but in most cases there is no decrease in life expectancy.

                            Last update:
                            June 2012

                            - Expert reviewer(s):
                            Pr Vincent DES PORTES


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, hypotonia, seizures, and autism spectrum disorder. Variable associated features include ophthalmologic anomalies, congenital heart defects, genitourinary defects, and craniofacial dysmorphism (including frontal bossing, epicanthal folds, low-set, posteriorly rotated ears, anteverted nares, and micrognathia). Brain imaging may show thinning of the corpus callosum, white matter abnormalities, ventriculomegaly, and a small cerebellar vermis.


Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha

A rare primary congenital hypothyroidism characterized by a markedly reduced T4/T3 ratio, normal levels of thyroid-stimulating hormone, and a highly variable clinical phenotype, which most commonly includes decreased metabolic rate, bradycardia, chronic constipation, neurodevelopmental delay, and delayed bone age and skeletal abnormalities. Dysmorphic craniofacial features, such as macrocephaly, broad face, flat nose, large tongue, and thick lips, have also been reported. Some patients may show only minimal signs and symptoms.


Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta

A rare genetic hyperthyroidism characterized by elevated levels of circulating free thyroid hormones, normal or elevated thyroid-stimulating hormone, decreased peripheral tissue responses to iodothyronine action, and a highly variable clinical phenotype which most commonly includes goiter, resting tachycardia, osteoporosis, short stature, and attention deficit disorder. Some patients may be entirely asymptomatic.


Resistance to thyrotropin-releasing hormone syndrome

Resistance to thyrotropin-releasing hormone (TRH) syndrome is a type of central congenital hypothyroidism (see this term) characterized by low levels of thyroid hormones due to insufficient release of thyroid-stimulating hormone (TSH) caused by pituitary resistance to TRH. It may or may not be observed from birth.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.
Etiology
Resistance to TRH is caused by mutations in the TRH receptor gene (TRHR; 8q23).

                            Last update:
                            August 2010

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


Respiratory bronchiolitis-interstitial lung disease syndrome

Respiratory bronchiolitis - interstitial lung disease is a mild inflammatory pulmonary disorder developed by cigarette smokers and characterized by shortness of breath and cough, pulmonary function abnormalities of mixed restrictive and obstructive lung disease and high resolution CT scanning showing centrilobular micronodules, ground glass opacities and peribronchiolar thickening.


A congenital genodermatosis with skin/mucosae involvement, characterized by very tight and thin skin with erosions and scaling, associated to a typical facial dysmorphism, arthrogryposis multiplex, fetal akinesia or hypokinesia deformation sequence (FADS) and pulmonary hypoplasia without neurological abnormalities.

Summary:
Epidemiology
To date, approximately 80 children with restrictive dermopathy (RD) have been described in the world literature.
Clinical description
RD is a congenital disorder and newborns are usually born prematurely (due to premature rupture of membranes with delivery at about 30-32 weeks of gestation). They present at birth with a very typical and recognizable clinical phenotype including tight, thin, rigid and translucent skin with epidermal hyperkeratosis and shedding, erosions and scaling at flexure sites, protruding nipples. Skeletal defects include: bone mineralization defects, large fontanelles, thin dysplastic clavicles, narrow chest, overtubulated long bones, generalized arthrogryposis with rocker-bottom feet. Facial dysmorphism is also characteristic and includes telecanthus, short, down-slanting palpebral fissures, sparse/absent eyelashes and eyebrows, a small and pinched nose, posteriorly rotated low-set ears, retromicrognathism and a small mouth fixed in the ''O'' position with expressionless facies. Additional features may include congenital anonychia, neonatal teeth, ectropion, choanal atresia, patent ductus arteriosus, interatrial septal defects, kyphoscoliosis, camptodactyly, hypospadias (males), ureteral duplication, adrenal hypoplasia. Intrauterine growth retardation (IUGR) with polyhydramnios, and decreased fetal movements are almost always reported. Pulmonary hypoplasia most often leads to respiratory insufficiency and death. Neither structural central nervous system nor visceral defects occur in RD.
Etiology
RD can be caused by heterozygous, de novo mutations of the LMNA gene (primary Laminopathy) or, much more frequently, by homozygous or compound heterozygous null mutations of the ZMPSTE24 gene (secondary Laminopathy). Defects in ZMPSTE24 impair the processing of Prelamin A into mature Lamin A, causing the massive intranuclear accumulation of wild type Prelamin A which exerts sytemic toxic effects and leads to the development of RD.
Diagnostic methods
The diagnosis is based upon physical examination at birth and skin histology (flat dermis with paucity/hypoplasia of appendages, abnormally dense collagen bundles parallel to the dermo-epidermic basal lamina and almost total depletion of elastic fibers), cerebral imagery, blood analysis. Molecular genetic testing for mutations confirms the diagnosis and allows genetic counselling.
Differential diagnosis
Yunis-varon syndrome, Neu-laxova syndrome, Pena-Shokeir syndrome, cerebrooculofacioskeletal syndrome, Paraná hard-skin syndrome, aplasia cutis congenita, lethal multiple pterygium syndrome.
Antenatal diagnosis
Earliest manifestations are only apparent in the late second trimester/early third trimester and include intrauterine growth retardation, decreased fetal movements, eventual joint contractures, and mouth fixed in an 'O' position. However, these signs are too nonspecific to suggest the diagnosis prenatally in cases with no family history.
Genetic counseling
The ZMPSTE24 mutations are inherited recessively, leading to the possibility of genetic counseling and prenatal diagnosis for further pregnancies if the molecular bases of the disease are identified (25% risk of having an affected child for two mutation carriers). The rare dominant mutations in the LMNA gene are de novo and the risk of recurrence of the disorder is very low (eventual germinal mosaicism).
Management and treatment
Corticosteroids are administered for fetal lung maturation. Gavage feeding may be necessary. Supportive treatment consists of mechanical ventilation, broad-spectrum antibiotics, parenteral nutrition, and intravenous analgesia.
Prognosis
The affected babies who are liveborn often die within the first week of life.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                             Annachiara DE SANDRE-GIOVANNOLI


Reticular dysgenesis is the most severe form of severe combined immunodeficiency (SCID; see this term) and is characterized by bilateral sensorineural deafness and a lack of innate and adaptive immune functions leading to fatal septicemia within days after birth if not treated.

Summary:
Epidemiology
Reticular dysgenesis accounts for less than 2% of all SCID cases. The annual incidence has been estimated at 1/3,000,000-1/5,000,000. Both males and females are affected, and consanguinity has been noted in several families.
Clinical description
The disease presents earlier than other forms of SCID, at birth or early in the neonatal period, with signs of sepsis, failure to thrive, diarrhea, fever, recurrent infections including upper respiratory tract infections, oral candidiasis, perianal infections and abscesses, and bilateral sensorineural deafness. Despite recurrent infections, no significant lymphoid or tonsillar tissue is evident. Hemoglobin levels are usually within reference ranges at birth, but patients may develop anemia secondary to sepsis and chronic illness.
Etiology
Reticular dysgenesis is characterized by profound neutropenia and T and natural killer (NK) cell lymphocytopenia, and is caused by mutations in the AK2 gene (1p34). The resulting deficiency in adenylate kinase 2 causes increased apoptosis of myeloid and lymphoid precursors. However, patients without this mutation have been observed implying an alternative cause. An imbalance of growth factor independent-1 transcription repressor (Gfi-1) and/or Gfi-1b has been proposed.
Diagnostic methods
Diagnosis is based on evidence of sensorineural deafness in combination with evidence of a marked reduction of T and NK cell counts when compared to age-matched healthy controls. Materno-fetal engraftment is usually present.
Differential diagnosis
Differential diagnosis includes all other forms of SCID.
Antenatal diagnosis
Prenatal diagnosis can be performed in families where there is a family history and where the genetic mutation has been identified.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
The only curative treatment for this disease is allogenic hematopoietic stem cell transplantation.
Prognosis
Without treatment, patients die from septicemia within days after birth.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Reticular dystrophy of the retinal pigment epithelium

A rare, patterned dystrophy of the retinal pigment epithelium, of progressive course, characterized by the presence of a bilateral hyperpigmented reticular pattern resembling a fishnet with knots, resulting in a slowly progressive loss of vision that often only becomes apparent in old age. This disorder is sometimes associated with scleral staphyloma, choroidal neovascularization, convergent strabismus, spherophakia with myopia and luxated lenses, and partial atrophy of the iris.


A rare, genetic, hyperpigmentation of the skin disease characterized by childhood to adulthood-onset of reticulate, slightly depressed, sharply demarcated, brown, macular skin lesions without hypopigmentation, affecting the dorsa of the hands and feet, and, occasionally, progressing to involve limbs, neck, forehead and/or trunk. Interrupted dermatoglyphics and palmoplantar pits may be additionally observed. Histologically, hyperpigmented lesions show slightly elongated and thinned rete ridges, mild hyperkeratosis without parakeratosis and absence of incontinentia pigmenti.


A rare vascular tumor characterized by a slowly growing lesion with predominant involvement of the skin and subcutaneous tissue of the distal extremities. Distinctive arborizing blood vessels lined by endothelial cells with characteristic hobnail morphology are a typical feature. Local recurrences are frequent unless wide local excision is performed, while metastasis is rare.


Retinal cavernous hemangioma is a rare, benign, usually unilateral retinal vascular hamartoma that in most cases is asymptomatic but in some patients may present with blurred vision or floaters and that is characterized by the presence of grape-like vacuoles.


Retinal degeneration-nanophthalmos-glaucoma syndrome is characterized by progressive pigmentary retinal degeneration (with nyctalopia and visual field restriction), cystic macular degeneration and angle closure glaucoma. It has been described in seven members of one family. Patients also have hyperopia and nanophthalmos. The mode of transmission is autosomal recessive.


Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies is a rare, genetic, retinal dystrophy disorder characterized by decreased central retinal sensitivity associated with hyper-reflectivity of ganglion cells and nerve fiber layer with loss of optic nerve fibers manifesting with photophobia, optic disc pallor and progressive loss of central vision with preservation of peripheral visual field.


Retinal dystrophy-optic nerve edema-splenomegaly-anhidrosis-migraine headache syndrome

A rare presumably genetic disorder characterized by idiopathic massive splenomegaly with pancytopenia and childhood-onset chronic optic nerve edema with slowly progressive vision loss. Additional reported features include anhidrosis, urticaria and headaches.


Retinal ischemic syndrome-digestive tract small vessel hyalinosis-diffuse cerebral calcifications syndrome

A rare systemic disease characterized by progressive hyalinosis involving capillaries, arterioles and small veins of the digestive tract, kidneys, and retina, associated with idiopathic cerebral calcifications, manifesting with severe diarrhea (with rectal bleeding and malabsorption), nephropathy (with renal failure and systemic hypertension), chorioretinal scarring, and subarachnoid hemorrhage. Poikiloderma and premature greying of the hair may be additionally observed.


Retinal macular dystrophy type 2 is a rare, genetic macular dystrophy disorder characterized by slowly progressive ''bull's eye'' maculopathy associated, in most cases, with mild decrease in visual acuity and central scotomata. Usually, only the central retina is involved, however some cases of more widespread rod and cone anomalies have been reported. Rare additional features include empty sella turcica, impaired olfaction, renal infections, hematuria and recurrent miscarriages.


Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

A rare genetic cerebral small vessel disease characterized by progressive loss of visual acuity due to retinal vasculopathy, in combination with more variable neurological signs and symptoms including stroke, cognitive decline, migraine-like headaches, and seizures, among others, typically beginning in middle age. Psychiatric features such as depression and anxiety may also occur. Systemic vascular involvement with Raynaud phenomenon, micronodular liver cirrhosis, and glomerular kidney dysfunction is present in a subset of patients.


Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay with mild intellectual disability, short stature, facial dysmorphism (such as sparse hair, high forehead, deep-set eyes, short and upslanting palpebral fissures, short nose, anteverted nares, wide nasal base with broad nasal tip and broad columella, long philtrum, thin upper lip, and low-set, posteriorly rotated ears), and variable onset of sensorineural hearing loss and retinitis pigmentosa. Additional features are other ocular anomalies, abnormalities of the fingers, hypothyroidism, and signs of premature aging. Brain imaging shows cerebellar atrophy and dysmyelination.


Retinitis pigmentosa-intellectual disability-deafness-hypogonadism syndrome

A rare syndromic retinitis pigmentosa characterized by pigmentary retinopathy, diabetes mellitus with hyperinsulinism, acanthosis nigricans, secondary cataracts, neurogenic deafness, short stature mild hypogonadism in males and polycystic ovaries with oligomenorrhea in females. Inheritance is thought to be autosomal recessive. It can be distinguished from Alstrom syndrome (see this term) by the presence of intellectual disability and the absence of renal insufficiency. There have been no further descriptions in the literature since 1993.


Retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome

A rare, genetic, syndromic rod-cone dystrophy disorder characterized by psychomotor developmental delay from early childhood, intellectual disability, short stature, mild facial dysmorphism (e.g. upslanted palpebral fissures, hypoplastic alae nasi, malar hypoplasia, attached earlobes), excessive dental spacing and malocclusion, juvenile cataract and ophthalmologic findings of atypical retinitis pigmentosa (i.e. salt-and-pepper retinopathy, attenuated retinal arterioles, generalized rod-cone dysfunction, mottled macula, peripapillary sparing of retinal pigment epithelium).


Retinitis pigmentosa (RP) is an inherited retinal dystrophy leading to progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades.

Summary:
Epidemiology
Prevalence of RP is reported to be 1/3,000 to 1/5,000. No ethnic specificities have been reported although founder effects are possible.
Clinical description
Retinitis pigmentosa is slowly progressive but relentless. There is however broad variability in age of onset, rate of progression and secondary clinical manifestations. Affected individuals generally first develop night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and over time loss of central vision, usually at late stages, often around midlife. Central visual acuity loss may occur at any age as a result of cystoid macular edema or photoreceptor loss. Posterior subcapsular cataracts are common and severity is age dependent. Reduced color vision may also be found. Fundus examination reveals bone spicule pigment deposits, attenuated retinal vessels, retinal atrophy and waxy optic nerve pallor. Severity is partly correlated with the pattern of inheritance with X-linked cases having the most severe course, autosomal recessive and single occurrence cases having intermediate severity, and autosomal dominant the most favorable course.
Etiology
More than 3,000 mutations in over 57 different genes or loci are currently known to cause non-syndromic RP.
Diagnostic methods
The diagnosis of RP is based on peripheral visual field loss, pigment deposits in fundus, loss of photoreceptors at the optical coherence tomography (OCT) scan of the retina and decreased or abolished responses as measured by electroretinography (ERG). Molecular genetic testing using single-gene testing, an RP multi-gene panel or exome sequencing allows for genetic subtype classification.
Differential diagnosis
Besides non syndromic forms, there are syndromic forms of RP of which the most frequent are Usher syndrome (RP and deafness) and BardetBiedl syndrome (RP and metabolic impairment). RP is to be distinguished from macular dystrophies (peripheral visual field is normal) and Leber congenital amaurosis (congenital retinal dystrophy) (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible by DNA analysis following amniocentesis or chorionic villus sampling.
Genetic counseling
RP may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP mutations generally only affect men. Genetic counseling should be provided to affected individuals and their families once the mode of inheritance has been determined through family history or molecular testing. Identical mutations may however produce different clinical manifestations. In X-linked familial cases, carrier testing for female relatives can be performed.
Management and treatment
Treatment is primarily aimed at slowing progression of the disease. Vitamin A palmitate and lutein-DHA may be provided as protecting antioxydants. Oral acetazolamide or topical dorzolamide are used to reduce cystoid macular edema. Lens extraction is required when cataracts reduce visual acuity. Sunglasses with short wavelength filtering improve visual performance and optical aids are recommended. Rehabilitation for reading and moving can be proposed in end-stage patients.
Prognosis
Except for mild cases or sectorial RP, most cases progress to legal blindness (visual acuity < 1/20 and visual field < 5 degrees).

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Pr Christian HAMEL


A progressive form of familial flecked retinopathy characterized by white punctata throughout the fundus (but sparing the macula in the early stages). Patients present with nightblindness in childhood and may also experience a loss of visual acuity. Significant loss of vision is reported in the 5th and 6th decades of life.