A lethal skeletal osteochondrodysplasia characterized by severe generalized osteosclerosis.

Summary:
Epidemiology
The disease is very rare and only five cases (four males and one female) have been reported in the literature so far.
Clinical description
Pyknoachondrogenesis may be detected prenatally due to the extreme shortening of the limbs and hydrops fetalis, or is recognized at birth. The main clinical manifestations include a large head, palpebral edema, a flat nose, low-set ears, a short neck, a short and wide trunk, a prominent abdomen, and severe micromelic dwarfism.
Etiology
Etiology remains unknown. Familial occurrence of affected sibs of both sexes points to an autosomal recessive pattern of inheritance but parental consanguinity has not been reported.
Diagnostic methods
Diagnosis is based on clinical findings and typical radiographic features. X-rays show marked sclerosis of the facial bones and extremities, and poor ossification elsewhere.
Differential diagnosis
Achondrogenesis (see this term) is the main differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis of pyknoachondrogenesis may be made by ultrasound.
Prognosis
Pyknoachondrogenesis has a lethal outcome, either prenatally or during the early neonatal period.

                            Last update:
                            November 2008


A rare bone dysplasia characterized by long bones with wide and expanded metaphyses, thin cortical bone and bone fragility. The metaphyseal widening and undermodeling extends well into the diaphysis and causes in the distal femur the typical ''Erlenmeyer flask'' or ''paddle'' appearance. Bone undermodeling is also seen in the tubular bones of the hands where there is lack of diaphyseal constriction. Common clinical features include genua valga, big clavicles and dental anomalies. Mild hyperostosis of the skull and mild platyspondyly can also be observed on radiographs.

Summary:
Epidemiology
To date, less than 30 cases have been reported in the literature.
Clinical description
The disorder is usually not apparent at birth. Genua valga in childhood is a frequently presenting symptom. Dental anomalies are common and may include malocclusion, caries, delayed eruption or prolonged retention of teeth. Prominent clavicles are a characteristic feature that can help in making the diagnosis. Joint pain, muscle weakness and mild scoliosis are occasionally seen. Height is usually in the higher range of normal. Mild sclerosis of the skull base may be present but this does not result in cranial nerve palsy. There is an increased bone fragility but fracturing is usually not a significant problem. The diagnosis can be made incidentally by radiography performed for a fracture.
Etiology
Pyle disease is an autosomal recessive disorder caused by biallelic loss-of-function mutations in the SFRP4 gene, located on chromosome locus 7p14.1. SFRP4 codes for secreted frizzled-related protein 4, a soluble Wnt inhibitor that plays a role in bone remodeling by differential inhibition of the canonical and non-canonical Wnt signaling in cortical and trabecular bone.
Diagnostic methods
The diagnosis is suspected based on clinical presentation and radiographic evaluation and can be confirmed by genetic analysis of the SFRP4 gene.
Differential diagnosis
Pyle disease should be differentiated from other skeletal dysplasias with osteosclerosis and/or bone undermodeling. The ''Erlenmeyer flask'' deformity (usually to a lesser degree) can also be observed in metaphyseal dysplasia, Braun-Tinschert type; craniometaphyseal dysplasia; frontometaphyseal dysplasia; Gaucher disease; and some forms of dysosteosclerosis (CSF1R-related) or osteopetrosis. Prominent clavicles, dental anomalies and bone undermodeling are also features of metaphyseal dysplasia-maxillary hypoplasia-brachydactyly syndrome (RUNX2-related).
Antenatal diagnosis
Antenatal diagnosis is possible in case the biallelic pathogenic variants in SFRP4 have been identified in an affected relative.
Genetic counseling
Inheritance 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
Affected individuals may be asymptomatic. Genu valgum and/or fractures may require orthopedic intervention. Dental and orthodontic care may be necessary when dental anomalies are present. There is no specific or curative treatment available to date.
Prognosis
Life expectancy is normal.

                            Last update:
                            February 2024

                            - Expert reviewer(s):
                            Pr Geert MORTIER


A rare inflammatory neutrophilic dermatosis characterized by painful cutaneous ulcerations with a violaceous and undermined border affecting the lower extremities; however, any hair-bearing area can be affected.

Summary:
Epidemiology
The worldwide incidence of pyoderma gangrenosum (PG) is estimated to be between 3-10 cases per million people with an increased incidence in women. The exact prevalence of PG is unknown but has been estimated to be approximately 1 in 17,000 adults. It tends to affect middle-aged individuals (40-60 years).
Clinical description
Clinically, onset occurs with pustules, nodules, or ulcers on the lower extremity with a violaceous, undermined border. Ulcers are primarily sterile but may be complicated by secondary microbial colonization. They can rapidly progress and turn into very painful ulcers of variable depth and size. Other presentations are rarer and include peristomal, pustular, bullous, and vegetative/superficial granulomatous PG as well as extracutaneous manifestations (most commonly pulmonary). The clinical course is unpredictable; it can be mild or severe, chronic, or relapsing with significant morbidity; some patients might heal spontaneously.
Etiology
The etiology has not yet been clearly determined.
Diagnostic methods
Diagnosis of PG is based on clinical presentation, exclusion of other causes of ulceration, and can be supported by histopathology showing neutrophilic infiltrate (though this is not specific and may be evident only in acute cases). Tissue culture is often necessary to rule out superinfection. Diagnosis may be assisted with use of existing clinical frameworks, including PARACELSUS score, Delphi criteria, and Mayo Clinic criteria.
Differential diagnosis
PG can occur spontaneously or in association with other autoimmune conditions, including most commonly inflammatory bowel disease (IBD), rheumatologic conditions, hematologic disorders, or in association with autoinflammatory syndromes including PAPA (pyogenic arthritis, PG, and acne), PASH (PG, acne, and suppurative hidradenitis), PAPASH (pyogenic arthritis, acne, PG, and suppurative hidradenitis), PAC (PG, acne, and ulcerative colitis), PsAPASH (psoriatic arthritis, PG, acne and suppurative hidradenitis), PAMI (PSTPIP1-associated myeloid related proteinemia syndrome), and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis). The most common differential diagnoses in clinical practice are chronic venous ulcers, calciphylaxis, and factitial ulcers. Other entities include vasculitic/vasculopathic ulcers, metastatic Crohn's disease, hidradenitis suppurativa, other neutrophilic dermatoses (e.g., Sweet's Syndrome), infectious (e.g. Leishmaniasis, Buruli ulcer, Lues maligna), Marjolin and neoplastic ulcers.
Management and treatment
Treatment of PG remains challenging and there is currently no FDA-approved medication for its treatment. Prednisolone is approved in Europe by the EMA and adalimumab is approved in Japan by the Pharmaceutical and Medical Devices Agency. In addition to pharmacological interventions, wound and pain management are also necessary. Globally, the cornerstone of treatment remains systemic corticosteroids and cyclosporine, with a step-up to biologics as second line therapies in addition to wound care and pain management.
Prognosis
Despite recent advances in therapy, the prognosis of PG remains unpredictable. Recurrence rates have been reported in up to 30% of patients. Patients carry an increased mortality rate, three times higher than that of the general population, which may be due to associated conditions rather than PG itself though this remains to be elucidated.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                             Sarah BECKER  - Dr Alex ORTEGA-LOAYZA


Pyomyositis (PM) is a rare primary bacterial infection of the skeletal muscle, usually resulting from hematogenous spread or due to muscle injury, and characterized by pain and tenderness in the affected muscle, fever and abscess formation.

Summary:
Epidemiology
Prevalence is unknown. PM is commonly found in the tropics and is endemic to Eastern Uganda where 400-900 cases are reported annually. Cases in temperate regions such as the U.S. are now increasing in frequency.
Clinical description
PM occurs in all ages with a male predominance. In tropical regions, it usually presents in otherwise healthy, athletic individuals and affects mainly children (aged 2-5) and young adults, while in temperate regions most patients are immunocompromised (due to malnutrition, chemotherapy, diabetes mellitus, HIV infection) or suffer from chronic renal failure or rheumatoid arthritis. Muscles most commonly involved include the serratus anterior, pectoralis major, biceps, the abdominal and spinal muscles, glutei, iliopsoas, quadriceps and gastrocnemius. There are 3 phases seen in disease development. The invasive stage lasts 1-10 days with manifestations of localized muscle ache/pain and swelling (with a lack of warmth or erythema), along with a low grade fever. Symptoms of appendicitis can be reported in those with iliopsoas pyomyositis. The purulent or suppurative stage follows 2-3 weeks after symptom onset with a progressive febrile illness and a soft tissue mass that is tender and painful when touched. If left untreated, the third stage involves sepsis that can lead to bacteremia, septicemia, metastatic abscess, acute renal failure, septic shock and death.
Etiology
The exact etiology is unknown but muscle trauma or vigorous exercise may facilitate hematogenous access of bacteria to the skeletal muscles (usually resistant to these types of infections). Fibronectin binding receptors on muscle cells have been proposed as a possible entry point for bacteria. In most cases the causative organism is Staphylococcus aureus (SA) (up to 90% of tropical cases, 70% of temperate cases) but infections with various other species (ex. Streptococci) have been reported. Methicillin-resistant SA (MRSA) is increasing in frequency as the infectious agent seen in non-tropical PM.
Diagnostic methods
PM is often hard to diagnose. Aspiration of pus from the muscle is usually possible at the purulent stage and can determine a diagnosis. If an abscess is absent, a culture and a muscle biopsy with special staining can equally identify the bacteria responsible and eliminate other possibilities. Diagnostic imaging is useful for diagnosing and treating PM.
Differential diagnosis
Differential diagnoses include parasitic and viral myositis, leptospirosis, polymyositis, trichinellosis (see these terms), osteomyelitis, cellulitis, necrotizing fasciitis, clostridial myonecrosis, septic arthritis, deep vein thrombosis and muscle contusions, hematomas, ruptures or strains.
Management and treatment
Early diagnosis and prompt treatment with antibiotics is essential. Due to the increased occurrence of MRSA, vancomycin, teicoplanin, tigecycline, daptomycin, linezolid, or daptomycin are the antibiotics of choice. Treatment with tetracycline or trimethoprim-sulfamethoxisole may be sufficient in some cases. Antibiotics are taken for 3-4 weeks, or longer, in cases of multiple muscle involvement, poorly drained infections, when initiation of treatment is delayed or when due to mycobacteria or Bartonella. If an abscess forms, treatment involves incision, debridement and muscle drainage or in some cases guided aspiration followed by antibiotic therapy. Muscle drainage is required in 40-70% of cases and repeated drainage in 10% of cases. Treatment should continue until a patient is fever-free for 7-10 days, wound is clean and leukocyte count is back to normal.
Prognosis
The prognosis is good when diagnosed and treated properly and there is very little residual deformity of the muscles, if any. When PM is left untreated, the mortality rate is 0.5 - 2%.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Grigorios MITSIONIS  - Dr Sotiris PLAKOUTSIS


Pyramidal molars-abnormal upper lip syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by a variable combination of dental, cutaneous, ocular, and bone abnormalities, including pyramidal and fused molar roots, taurodontism, an abnormal upper lip without a cupid's bow and thickened and wide philtrum, juvenile glaucoma, syndactyly, and clinodactyly. There have been no further descriptions in the literature since 1973.


A very rare neonatal epileptic encephalopathy disorder characterized clinically by onset of severe seizures within hours of birth that are not responsive to anticonvulsants, but are responsive to treatment with pyridoxal phosphate.


A rare neurometabolic disease characterized by recurrent intractable seizures in the prenatal, neonatal and postnatal period that are resistant to anti-epileptic drugs (AEDs) but that are responsive to pharmacological dosages of pyridoxine (vitamin B6).

Summary:
Epidemiology
The prevalence of Pyridoxine-dependent epilepsy (PDE) has been estimated to range from 1/20,000 to 1/783,000 live births. More than 200 cases have been reported in the literature to date.
Clinical description
Onset is classically fetal/neonatal but a later onset (>2 months) has also been reported. Patients present with epileptic encephalopathy manifesting with intractable seizures along with irritability, crying, poor feeding, gastrointestinal symptoms (emesis, abdominal distention), sleeplessness, facial grimacing and abnormal eye movements. Although prolonged seizures and recurrent episodes of status epilepticus are most common, recurrent self-limiting partial, generalized or atonic seizures, myoclonic events and infantile spasms can also occur. Intellectual disability/developmental delay ranges from mild to severe (particularly affecting the expressive language domain). With treatment, most patients achieve complete seizure control, but 75-80% have some degree of intellectual disability. Atypical features include seizures that initially respond to AEDs and later become intractable, seizures initially unresponsive to pyridoxine but that respond several months later and prolonged seizure-free intervals after the discontinuation of pyridoxine treatment.
Etiology
PDE is caused by mutations in the ALDH7A1 gene (5q31) that encodes alpha-aminoadipic semialdehyde dehydrogenase (antiquitin), a multifunctional enzyme which, among other functions, is involved in the catabolism of cerebral lysine.
Diagnostic methods
Diagnosis is suspected in patients with early onset epilepsy with a poor response to AEDs. Laboratory testing reveals elevated urinary and plasma concentrations of alpha-aminoadipic semialdehyde and sometimes elevated pipecolic acid in the plasma and cerebrospinal fluid. Electroencephalography findings are non-specific but thinning of the corpus callosum, particularly of the isthmus, is always seen on brain MRI. Molecular genetic testing, identifying homozygous or compound heterozygous ALDH7A1 mutations, confirms diagnosis.
Differential diagnosis
Differential diagnoses include other causes of neonatal epileptic encephalopathy such as inborn errors of metabolism (e.g. glucose transporter type I deficiency, 4-hydroxybutyric aciduria and molybdenum cofactor deficiency), single gene defects and fetal or neonatal brain injury. Pyridoxal phosphate-responsive seizures, hyperprolinemia type 2 and infantile hypophosphatasia (see these terms) should also be excluded.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation in order to start prophylactic prenatal/postnatal treatment.
Genetic counseling
PDE is inherited in an autosomal recessive manner. Genetic counseling is possible in families with a known mutation.
Management and treatment
Standard treatment involves lifelong oral pyridoxine supplementation (15-30mg/kg/day, divided into 3 doses in infants; up to 200mg/day in neonates and 500mg/day in adults) to control seizures, as well as regular clinical follow-up. Initial interruption of status epilepticus requires up to five 100mg doses of pyridoxine administered intravenously while closely monitoring patients for signs of cardio-respiratory arrest. Dietary lysine restriction is also recommended as an adjunct to pyridoxine therapy. In at-risk pregnancies, mothers may take supplemental pyridoxine (100mg/day) during the last half of gestation and newborns should received prophylactic pyridoxine until diagnostic tests are finalized.
Prognosis
Prognosis is variable and depends, in part, on genotype, associated abnormalities in brain development, and response to pyridoxine treatment. A delay in diagnosis and initiation of treatment generally confers a poorer prognosis associated with more significant neurodevelopmental disabilities.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Sidney GOSPE


Pyruvate carboxylase deficiency, benign type

Benign pyruvate carboxylase (PC) deficiency (Type C) is a rare, very mild form of PC deficiency characterized by episodic metabolic acidosis and normal or mildly delayed neurological development.

Summary:
Epidemiology
Benign PC deficiency is a very rare form of PC deficiency and has been described in fewer than 10 patients to date. No ethnic predilection has been reported.
Clinical description
Onset typically occurs during the first year of life with episodic metabolic acidosis associated with lactic acidemia and occasionally with ketoacidosis during metabolic stress. Neurological development is normal or mildly impaired. Other signs include dystonia, episodic ataxia, dysarthria, transitory hemiparesis and seizures.
Etiology
Type C PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).
Diagnostic methods
Blood lactic acid levels are usually between 2 and 5 mmol/l. The abnormal biochemical parameters found in severe forms of PC deficiency are absent in patients with Type C, although lysine, proline and alanine may be elevated, while citrulline is normal. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.
Genetic counseling
Pyruvate carboxylase deficiency is inherited in an autosomal recessive manner.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Darryl DE VIVO  - Dr Dong WANG


Pyruvate carboxylase deficiency, infantile type

Infantile pyruvate carboxylase (PC) deficiency (Type A) is a rare, severe form of PC deficiency characterized by infantile-onset, mild to moderate lactic acidemia, and a generally severe course.

Summary:
Epidemiology
The specific prevalence of type A pyruvate carboxylase deficiency is not known but it has been reported most often in Native Americans from North American Algonquian-speaking groups including the Mi'kmaq, Cree, and Ojibwa tribes. In these groups, the carrier frequency may be as high as 1/10.
Clinical description
Patients with Type A PC deficiency usually first present with symptoms at the age of two to five months, often after normal early development. Clinical manifestations include mild to moderate metabolic acidosis with acute vomiting and tachypnea, failure to thrive, apathy, delayed intellectual and motor development, hypotonia, pyramidal dysfunction, ataxia, nystagmus and seizures. Renal tubular acidosis has also been reported.
Etiology
PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).
Diagnostic methods
Biochemical testing shows hypoglycemia and ketosis, increased alanine and proline levels, but normal citrulline and lysine levels, along with a normal lactate-to-pyruvate ratio despite acidemia, and normal hydroxybutyrate/acetoacetate (H/A) ratio in plasma. Blood lactic acid levels are usually between 2 and 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.
Genetic counseling
PC deficiency is inherited in an autosomal recessive manner.
Prognosis
Most affected patients die in infancy or in early childhood. Surviving children require special care and schooling.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Darryl DE VIVO  - Dr Dong WANG


Pyruvate carboxylase deficiency, severe neonatal type

Severe neonatal pyruvate carboxylase (PC) deficiency (Type B) is a rare, extremely severe form of PC deficiency characterized by severe, early-onset metabolic acidosis, and a generally fatal outcome in early infancy.

Summary:
Epidemiology
The exact prevalence of Type B pyruvate carboxylase deficiency is not known. The disorder has been reported to be more common in populations of Arab descent (Algerian, Egyptian, and Saudi Arabian). Higher incidence is also reported in France, Germany and the United Kingdom.
Clinical description
Patients develop clinical manifestations during the first 72 hours of life with severe truncal hypotonia and tachypnea. Subsequent clinical signs include anorexia, failure to thrive, hepatomegaly, myoclonic or generalized tonic-clonic seizures, stupor, pyramidal dysfunction, abnormal movements (high-amplitude tremor and dyskinesia), abnormal limb and ocular movements and severe impairment of mental and motor development. Renal tubular acidosis has been reported.
Etiology
PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).
Diagnostic methods
The biochemical hallmarks of Type B pyruvate carboxylase deficiency include elevated lactate/pyruvate (L/P) ratio, ketoacidosis with low hydroxybutyrate/acetoacetate (H/A) ratio in plasma, hypoglycemia, increased citrulline, proline, lysine and alanine levels, low glutamine, hyperammonemia and hypernatremia. Blood lactic acid levels are usually above 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.
Genetic counseling
Pyruvate carboxylase deficiency is inherited in an autosomal recessive manner.
Prognosis
The prognosis is very poor with almost all affected infants dying within the first three months of life.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Darryl DE VIVO  - Dr Dong WANG


Pyruvate carboxylase (PC) deficiency is a rare neurometabolic disorder characterized by metabolic acidosis, failure to thrive, developmental delay, and recurrent seizures at an early age in severely affected patients.

Summary:
Epidemiology
The overall prevalence of PC deficiency is not known and annual incidence has been reported to be 1/250,000 births. The disorder affects males and females equally.
Clinical description
Three clinical presentations of PC deficiency, probably constituting a continuum, have been described: infantile PC deficiency (type A); severe neonatal PC deficiency (type B); and intermittent/benign PC deficiency (type C). The only common feature is metabolic acidosis. Type A is characterized by infantile onset, generally with a severe course. Type B has a very severe course with a fatal outcome in early infancy, and Type C involves only episodic metabolic acidosis.
Etiology
PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5), involved in the conversion of pyruvate to oxaloacetate, an intermediate in the citric acid cycle and gluconeogenesis. Pyruvate carboxylase also participates in a wide range of other metabolic processes. Most cases are familial but some de novo mutations have been reported. Genotype-phenotype correlations have not been clearly established but missense mutations appear to be associated with infantile PC deficiency (Type A), while truncating mutations are more common in patients with the severe neonatal form (Type B).
Diagnostic methods
PC deficiency may be suspected in patients with the non-specific clinical signs of the condition. Diagnosis is based on detection of characteristic laboratory test abnormalities in amino acid, organic acid, glucose, and ammonia serum concentrations. A PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.
Differential diagnosis
Several inborn errors of metabolism have certain features similar to those of PC deficiency. Similar disorders to consider in the differential diagnosis include biotinidase deficiency, holocarboxylase synthase deficiency, pyruvate dehydrogenase deficiency, as well as respiratory chain disorders, tricarboxylic acid cycle disorder, and gluconeogenic defects.
Antenatal diagnosis
Prenatal testing for pregnancies at increased risk is possible and requires identification of both disease-causing alleles in an affected family member.
Genetic counseling
PC deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families, particularly regarding the risk of recurrence in subsequent pregnancies.
Management and treatment
The aim of treatment is to provide alternative energy sources and to correct acute metabolic acidosis. Other management and treatment options depend on the type of PC deficiency. Current symptomatic and supportive treatments are generally ineffective.
Prognosis
Type A patients usually die in infancy or early childhood. Type B most commonly has a fatal outcome within the first three months of life. Type C is mostly a benign form of the disorder with little or no effect on life-expectancy.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Darryl DE VIVO  - Dr Dong WANG


Pyruvate dehydrogenase deficiency (PDHD) is a rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders. Six subtypes related to the affected subunit of the PDH complex have been recognized with significant clinical overlap: PDHD due to E1-alpha, E1-beta, E2 and E3 deficiency, PDHD due to E3-binding protein deficiency, and PDH phosphatase deficiency (see these terms).

Summary:
Epidemiology
Exact prevalence is unknown but hundreds of cases have been reported.
Clinical description
PDHD may affect fetal development, with poor fetal weight gain and low birth weight being noted. Characteristic facial dysmorphism has only been described in some patients (narrow head, frontal bossing, wide nasal bridge, long philtrum and flared nostrils). Structural brain lesions are commonly observed, especially in females. Other patients develop symptoms soon after birth. Some have a primarily metabolic-type picture (potentially fatal lactic acidosis, occasionally with hyperammonemia, poor feeding, lethargy, tachypnea) and few neurological signs, while others have mainly neurological signs (developmental delay, growth retardation, poor acquisition or loss of motor milestones, hypotonia, seizures, ataxia and dystonia). Symptoms may occur in periods of stress or illness in the less severe, later-onset cases. Many patients have the characteristic clinical presentation, disease course and neuropathological changes of Leigh syndrome (see this term).
Etiology
PDHD is caused by a deficiency of one of the components of the PDH complex. The most common cause are mutations in the PDHA1 gene (Xp22.1), which encodes the E1-alpha subunit. Mutations in the genes for the other subunits have been described, but are far less frequent: E1-beta and E2 subunits (PDHB, DLAT); E3 binding protein (PDHX gene); and E3 and PDH phosphatase (DLD andPDP1).
Diagnostic methods
PDHD should be considered in cases of early-onset neurological disease and unexplained lactic acidosis, particularly if there are structural cerebral abnormalities. In many cases, lactate concentration in cerebrospinal fluid (CSF) is disproportionately increased compared to blood lactate. Definitive diagnosis is made by demonstrating abnormal enzyme function and immunochemical demonstration of a specific subunit deficiency.
Differential diagnosis
Differential diagnosis includes other causes of primary lactic acidosis (pyruvate carboxylase deficiency, defects of gluconeogenesis and a wide range of mitochondrial diseases). In patients presenting as Leigh syndrome, the differential diagnosis includes various forms of Complex I deficiency (see this term), cytochrome oxidase deficiency due to mutation in the SURF1 gene and a number of mitochondrial DNA mutations.
Antenatal diagnosis
Due to the severity of PDHD, prenatal diagnosis is requested in affected families (chorionic villi or amniocyte testing).
Genetic counseling
Most cases are due to mutations in the PDHA1 gene and are thus inherited as an X-linked dominant trait. As patients almost always have severe symptoms and greatly reduced life expectancy, most new cases are sporadic. Inheritance of all other forms of PDHD is autosomal recessive.
Management and treatment
Treatment is generally aimed at stimulating the PDH complex or providing an alternative energy source for the brain. Cofactor supplementation with thiamine, carnitine, and lipoic acid has been recommended. A very small number of patients with mutations in the PDHA1 gene are thiamine-responsive. A ketogenic diet may be indicated especially for those presenting with a dystonic disorder. Dichloroacetate has been used but significant side effects, such as peripheral neuropathy, may limit effectiveness. No treatment has an effect on preventing prenatal development of structural central nervous system anomalies.
Prognosis
Prognosis is variable but is generally poor (in terms of impact on development and life expectancy).

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


Pyruvate dehydrogenase E1-alpha deficiency

A disorder that is the most frequent form of pyruvate dehydrogenase deficiency (PDHD) characterized by variable lactic acidosis, impaired psychomotor development, hypotonia and neurological dysfunction.

Summary:
Epidemiology
Prevalence is unknown. Over 200 patients have been reported and while there are approximately equal numbers of males and females, male patients are generally more severely affected.
Clinical description
Patients present with a range of classic signs and symptoms of PDHD, including lactic acidosis, poor feeding, lethargy, tachypnea, developmental delay, growth retardation, poor acquisition or loss of motor milestones, hypotonia, seizures, ataxia and dystonia. Structural brain lesions including cortical atrophy, dilated ventricles, and incomplete corpus callosum, absence of the medullary pyramids and ectopia of the olivary nuclei are commonly observed, especially in female patients heterozygous for the disease-causing mutations that result in complete deficiency of E1-alpha subunit protein in cells expressing the gene mutation.
Etiology
The disease is caused by deficiency of the E1-alpha subunit of the PDH complex related to mutations in the PDHA1 gene (Xp22.1).
Genetic counseling
The pattern of inheritance is X-linked.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


Pyruvate dehydrogenase E1-beta deficiency is an extremely rare form of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by severe lactic acidosis, developmental delay and hypotonia.

Summary:
Epidemiology
Prevalence is unknown. About 8 cases have been reported to date.
Clinical description
Patients presented with lactic acidosis and hypotonia at birth and were often from consanguineous families. There are no specific clinical features that distinguish this condition from pyruvate dehydrogenase E1-alpha deficiency.
Etiology
The disorder is caused by mutations in the gene coding for the E1-beta subunit of the PDH complex (PDHB; 3p21.1-p14.2).
Genetic counseling
The pattern of inheritance is autosomal recessive.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


A very rare form of pyruvate dehydrogenase deficiency (PDHD) characterized by variable lactic acidosis and neurological dysfunction, mainly appearing during childhood.

Summary:
Epidemiology
Prevalence is unknown. Only 4 cases have been reported to date.
Clinical description
Patients with E2 deficiency generally present later in childhood with movement disorders and lesions in the globus pallidus similar to those found in patients with pantothenate kinase-associated neurodegeneration (see this term). Other signs include general hypotonia and delayed psychomotor development. Lactate concentration may be normal in both blood and cerebrospinal fluid.
Etiology
The condition is caused by mutations in the DLATgene (11q23.1) encoding the dihydrolipoamide acetyl transferase E2 subunit of the PDH complex. Parental consanguinity is commonly reported.
Genetic counseling
The pattern of inheritance is autosomal recessive.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


Pyruvate dehydrogenase E3 deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by either early-onset lactic acidosis and delayed development, later-onset neurological dysfunction or liver disease.

Summary:
Epidemiology
Prevalence is unknown. About 20 cases have been reported to date.
Clinical description
The majority of patients have presented with neonatal lactic acidosis or with lactic acidosis, delayed development and hypotonia during infancy. A few patients have presented later in childhood with ataxia and dystonia with normal cognitive development. A separate group of patients, essentially all of Ashkenazi Jewish origin and many homozygous for a common G229C missense mutation, present with episodic vomiting, abdominal pain, encephalopathy and liver cell dysfunction. In some patients, there is evidence of branched chain alpha-ketoacid dehydrogenase deficiency, with elevated concentrations of the branched chain amino acids and their metabolites. However, clinical manifestations in most cases appear to be related to the pyruvate dehydrogenase deficiency.
Etiology
The disorder is caused by mutations in the DLD gene (7q31-q32).
Genetic counseling
The pattern of inheritance is autosomal recessive.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


Pyruvate dehydrogenase E3-binding protein deficiency is a rare mild form of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by variable lactic acidosis and neurological dysfunction.

Summary:
Epidemiology
Prevalence is unknown. About 20 cases have been reported to date. The disorder is more frequent than PDHD E2 deficiency but less frequent than E1-alpha deficiency (see these terms).
Clinical description
Patients usually present with neonatal lactic acidosis or with delayed development and hypotonia during infancy. In contrast to other forms of pyruvate dehydrogenase deficiency, patients with E3 binding protein deficiency often survive well into childhood or adult life as there is some assembly of the pyruvate dehydrogenase complex even with complete deficiency of this protein. Thinning or agenesis of the corpus callosum is a common finding on MRI imaging of the brain.
Etiology
PDHD E3 binding protein deficiency is caused by a mutation in the PDHX gene (11p13) encoding the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex.
Genetic counseling
The pattern of inheritance is autosomal recessive.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


Pyruvate dehydrogenase phosphatase deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD, see this term) characterized by lactic acidemia in the neonatal period.

Summary:
Epidemiology
Prevalence is unknown but this form of PDHD appears to be very rare, with only three patients reported.
Clinical description
All three patients presented in the newborn period with lactic acidosis and hypotonia. Two siblings from one family have had a prolonged course on a ketogenic diet, surviving into teenage years with exercise intolerance and mild developmental delay. The third patient died at age 6 months.
Etiology
The disorder is caused by mutations in the PDP1 gene (8q22.1) encoding pyruvate dehyrogenase phosphatase isoform 1, an enzyme which regulates the activity of the pyruvate dehydrogenase complex.
Genetic counseling
The pattern of inheritance is autosomal recessive.

                            Last update:
                            August 2012

                            - Expert reviewer(s):
                            Dr Garry BROWN


Q fever, caused by Coxiella burnetii, is a bacterial zoonosis with a wide clinical spectrum that can be life-threatening and, in some cases, can become chronic.

Summary:
Epidemiology
In recent years in Europe, there has been an increase in the number of reported cases. In the Netherlands in particular, between 2007 and 2010 there were more than 4,000 cases reported.
Clinical description
Q fever affects all ages, but is mostly reported in those aged 30-70 years. The incubation period is 2-3 weeks. Approximately 60% of cases are asymptomatic. The most common symptoms of acute Q fever are high fever, severe headache, myalgia, chills, and cough. It may also be associated with pneumonia or hepatitis. Pneumopathy is mostly moderate but pleural effusion or acute respiratory distress may occur. Symptoms may last 10-90 days. Rarely, patients may have neurological (ex. meningitis), cardiac (pericarditis, myocarditis) or dermatological manifestations (maculopapular eruption, erythema nodosum). Children often suffer from gastrointestinal manifestations and skin rash (in up to 50% of diagnosed children). The infection may evolve to a chronic form (<5% of cases) in persons with a predisposition (ex. heart valve or vascular defect), months or years after initial infection. Chronic manifestations include endocarditis, vascular infections and osteomyelitis, or less commonly, fever with hepatitis evolving to hepatic fibrosis or cirrhosis. During pregnancy, a primary infection may cause spontaneous abortion, prematurity, low birth weight, fetus infection or recurrent miscarriages. Chronic Q fever after delivery may be associated with cardiac involvement.
Etiology
Coxiella burnetii, is an intracellular gram-negative bacterium now classified in the gamma group of Proteobacteria. Most infections are due to inhalation of aerosols or dust contaminated with dried birth fluids or excreta from infected animals. Less frequent routes of infection include ingesting contaminated milk, tick bite, or fomite transmission. Person-to-person and mother-to-fetus transmission has been reported.
Diagnostic methods
Diagnosis of acute Q fever is confirmed by serologic evidence of a fourfold increase in phase II immunoglobulin (Ig) G via an immunofluorescent assay test between paired sera taken 3-6 weeks apart. PCR testing on blood or serum may be useful in the first 2 weeks of symptom onset and before antibiotic administration. A single high serum phase II IgG titer in the convalescent stage may be considered as evidence of probable infection. Confirmation of chronic Q fever is based on an increasing phase 1 IgG titer (typically ≥1:1024) and an identifiable nidus of infection (e.g., endocarditis, vascular infection, osteomyelitis, chronic hepatitis). Liver enzyme levels are commonly increased.
Differential diagnosis
Differential diagnosis includes any disease with fever and other constitutional symptoms such as Brucellosis (see this term) and influenza.
Management and treatment
Prophylactic strategies are based on vaccination (in Australia) and appropriate hygiene measures. Adherence to standard precautions during care of patients prevents transmission. Symptomatic patients with acute Q fever should be treated for 2 weeks with doxycycline. A pregnancy test should be performed before commencing treatment in women of child-bearing age. Children aged younger than 8 with mild illness, pregnant women, and patients allergic to doxycycline can be treated with trimethoprim-sulfamethoxazole. Chronic Q fever is treated with a combination of doxycycline and hydroxychloroquine for a minimum of 18 months.
Prognosis
Acute Q fever is often a mild or self-limiting illness with a low risk for death. Untreated chronic Q fever endocarditis or vascular infection is often fatal. In treated patients with chronic Q fever endocarditis, the 10-year mortality rate is 19%.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Dr Alicia ANDERSON


A rare, genetic, syndromic intellectual disability disorder characterized by non-progressive, congenital, marked, central hypotonia, severe psychomotor delay and intellectual disability, chronic constipation, distended abdomen, abnormal dermatoglyphics, delayed and dysharmonic skeletal maturation, and preponderance of type 2 larger-sized muscle fibers. Additional features include narrow and high-arched palate, prominent nasal root, long philtrum, and open mouth with drooling, as well as variably present cryptorchidism, hypertelorism, and tapered fingers. Seizures and/or an abnormal electroencephalograph may also be assoicated. There have been no further descriptions in the literature since 1994.


QRICH1-related intellectual disability-chondrodysplasia syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by the association of developmental delay and mild chondrodysplasia with short stature and abnormal growth plate morphology. Dysmorphic facial features are variable and may include hypertelorism, upslanting palpebral fissures, broad nose with broad nasal tip, and low-set, cup-shaped ears, among others. Autism spectrum disorder and neurologic abnormalities have also been reported.


QRSL1-related combined oxidative phosphorylation defect

A rare mitochondrial disease characterized by prenatal or early infantile onset of severe cardiomyopathy, failure to thrive and global developmental delay, sensorineural hearing loss, and severe lactic acidosis. Hepatic involvement and adrenal insufficiency, as well as encephalopathy and anomalies of deep gray matter structures on brain MRI have also been reported.


A rare congenital aortic malformation characterized by an aortic valve with four cusps instead of the usual three. The cusps can be equal-sized or vary in size. The malformation is an isolated finding in the majority of cases but may also be associated with other cardiac anomalies. The most common complication is aortic regurgitation. Aortic stenosis is infrequently observed. Patients usually become symptomatic in the fifth to sixth decade of life and may present with palpitations, chest pain, dyspnea, fatigue, pedal edema, and syncope. In severe cases, congestive heart failure can be the presenting symptom.


A rare platelet granule disorder characterized by moderate to severe bleeding after trauma, surgery or obstetric interventions, frequent ecchymoses, mucocutaneous bleeding and muscle and joint bleeds.


A rare chronic inflammatory cicatricial alopecia of the scalp occurring in middle-aged adults and characterized by the development of alopecic patches with slowly centrifugal spread predominantly in the vertex and occipital area of the scalp, associated with perifollicular erythema, follicular pustules and hemorrhagic crusts.


Rabies is a viral zoonosis leading to a fatal encephalopathy if not treated.

Summary:
Epidemiology
Epidemiology depends on the control level of the pathogen and its animal vectors, so the rabies is much more prevalent in the developing world than in developed countries. The WHO estimates that around 50,000 persons die each year from rabies.
Clinical description
Rabies evolution follows a three steps path. After a contact (bite) with an infected animal, incubation lasts 20 to 90 days while patients remain asymptomatic. This duration varies with the quantity and the location of the inoculum. It can extend to several years in rare cases. The second phase, the prodromal period, lasts 2 to 10 days and is characterized by paresthesia or pain at the inoculation site. Other nonspecific symptoms may occur, including malaise, anorexia, headaches, fever, chills, pharyngitis, nausea, emesis, diarrhea, anxiety, agitation, insomnia and depression. The third phase is the most distinctive one, named the acute neurologic period. It is associated to clear central nervous system (CNS) involvement, its duration is 2 to 7 days and it can be of two kinds: the furious rabies or the paralytic rabies. In the first case, patients show agitation, hyperactivity, restlessness, trashing, biting, confusion or hallucinations. Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. After hours or days these signs appear by bouts - during less than 5 minutes - alternating with calm phases of lucidity. Seizures may occur. The terminal evolution of this phase is cardiorespiratory arrest or paralysis. In the second case, also named apathetic rabies, paralysis develops from the outset with fever, headache and nuchal rigidity. In both cases, the terminal evolution, if untreated, is coma and death.
Etiology
Rabies is caused by infection of a virus of the Lyssavirus genus. Infection occurs in a large majority through the bite of a rabid dog and more generally through contact of broken skin or mucous membrane with infected saliva, CNS tissue or aerosolized secretions from infected animals. Lyssavirus are neurotropic viruses that escape immune system invading peripheral nerve ending. Incubation duration depends on the time needed to invade the CNS.
Diagnostic methods
Diagnosis is based on clinical examination, early signs being paresthesia or pain at the inoculum site, and firmly relies on PCR detection of viral RNA in the saliva, the cerebrospinal fluid (CSF) or in a nuchal skin biopsy, on blood or CSF serological findings.
Differential diagnosis
Tetanus is the main differential diagnosis which also includes other types of encephalomyelitis and neuropaludism.
Management and treatment
Standardized vaccination procedures are established for pre- or post-exposure situations. In case of exposition, rapid washing, antisepsis and vaccine administration could be associated to a serotherapy protocol consisting of immunoglobulins injection at the inoculum site. Each infection has to be declared.
Prognosis
If not treated, rabies is always fatal. Treatment has to be administrated during the incubation period to be efficient.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Hervé BOURHY


A rare syndrome that belongs to the group of extreme insulin-resistance syndromes (which also includes leprechaunism, the lipodystrophies, and the type A and B insulin resistance syndromes).

Summary:
Epidemiology
It is an extremely rare disorder of unknown prevalence.
Clinical description
Early onset is marked by intrauterine and postnatal growth retardation, hypotrophy of muscle and adipose tissues, acanthosis nigricans (a skin lesion associated with extreme insulin resistance), dental dysplasia, abnormal hair and nails, hirsutism, and acromegaloid facies. A hypertrophic pineal gland has been reported in some cases.
Etiology
As in leprechaunism (of which Rabson-Mendenhall syndrome may represent a less severe form); the condition is caused by anomalies in both alleles of the insulin-receptor gene (INSR;19p13.3-p13.2).
Diagnostic methods
Biologically, infants display fasting hypoglycemia, postprandial hyperglycemia and hyperinsulinemia, which progress to permanent hyperglycemia and recurrent diabetic ketoacidosis.
Differential diagnosis
Differential diagnoses include early-onset forms of leprechaunism, and moderate and late-onset forms of type A insulin resistance syndrome.
Genetic counseling
The condition is transmitted as an autosomal recessive trait and mainly affects children of consanguineous parents.
Management and treatment
Treatment is problematic and consists of high doses of insulin and/or recombinant insulin-like growth factor 1 (IGF1), sometimes associated with IGFBP3 (IGF binding protein).
Prognosis
Life expectancy may reach a few years.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Corinne VIGOUROUX


Radial deficiency-tibial hypoplasia syndrome is a rare, genetic dysostosis syndrome with combined reduction defects of upper and lower limbs characterized by bilateral radial aplasia, absent thumbs and bilateral tibial hypo/aplasia. Additional bone anomalies (including partial toe hypo/aplasia, short fibula and clubhand) may be associated. There have been no further descriptions in the literature since 1996.


Radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome is characterised by symmetric, nonopposable triphalangeal thumbs and radial hypoplasia. It has been described in eight patients (five females and three males) spanning generations of a family. The affected males also presented with hypospadias. The syndrome is inherited as an autosomal dominant trait.


Radial ray hypoplasia-choanal atresia syndrome

An extremely rare syndrome characterized by radial ray hypoplasia, choanal atresia and convergent strabismus.

Summary:
Epidemiology
It has been reported in a father and his two daughters.
Clinical description
The radial ray involvement varies from absent radius, first metacarpal and thumb to hypoplastic thumb or triphalangeal thumb.
Genetic counseling
The condition is most probably hereditary, transmitted as an autosomal dominant trait.

                            Last update:
                            January 2011


Radiation myelitis is a rare neurological disease characterized by the development of paresthesias, as well as, in severe cases, progressive paresis and paralysis following irradiation of tumors in which the spinal cord is included within the radiation field. Symptoms may develop months or years after radiation therapy was administered.


Radiation proctitis is a rare rectal disease directly induced by pelvic radiotherapy and characterized by rectal bleeding, change in bowel habits, tenesmus and sepsis.


A rare radiation-induced disorder characterized by impairment of the peripheral nervous system at the level of the brachial or lumbosacral plexus following radiation therapy. Onset of symptoms can occur between several months up to decades after the last dose of radiation. Patients with radiation-induced brachial plexopathy typically present with mostly unilateral progressive paresthesia, followed by weakness, atrophy, and pain. Symptoms in radiation-induced lumbosacral plexopathy include more variable combinations of numbness, paresthesia, pain, and weakness, and are more often bilateral.


Radio-renal syndrome is a rare developmental defect during embryogenesis characterized by variable upper limb reduction defects and renal anomalies. Patients typically present absence/hypoplasia of digits, radii and/or ulnae, short stature and mild external ear malformation, as well as kidney agenesis or ectopia. There have been no further descriptions in the literature since 1983.


Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome is characterised by the association of proximal fusion of the radius and ulna with congenital amegakaryocytic thrombocytopaenia. Less than 10 cases have been reported in the literature so far. The syndrome is transmitted as an autosomal dominant trait and is caused by mutations in the HOXA11 gene (7p15).


Radioulnar synostosis-developmental delay-hypotonia syndrome, also known as Der Kaloustian-McIntosh-Silver syndrome, is an extremely rare syndrome with synostosis described in about 4 patients to date with clinical manifestations including congenital unilateral radioulnar synostosis, generalized hypotonia, developmental delay, and dysmorphic facial features (long face, prominent nose and ears).


Radioulnar synostosis-microcephaly-scoliosis syndrome, also known as Guiffré-Tsukahara syndrome, is an extremely rare syndrome characterized by the association of radioulnar synostosis with microcephaly, scoliosis, short stature and intellectual deficit.


A rare, genetic, primary bone dysplasia syndrome characterized by bilateral, painless swelling of the face extending from the mandible to the inferior orbital margins (cherubism), epilepsy, gingival fibromatosis (possibly obscuring teeth), and intellectual disability. Other associated variable features include hypertrichosis, stunted growth, juvenile rheumatoid arthritis, and development of ocular abnormalities (e.g. pigmentary retinopathy, optic disc pallor, Axenfeld anomaly). Radiological images typically show bilateral multifocal radiolucency involving the body, angle and ramus of the mandible and coronoid process.


Ramos-Arroyo syndrome (RAS) is a very rare genetic disorder characterized by corneal anesthesia, retinal abnormalities, bilateral hearing loss, distinct facies, patent ductus arteriosus, Hirschsprung disease (see these terms), short stature, and intellectual disability.

Summary:
Epidemiology
Prevalence and incidence are not known. RAS is extremely rare with only six cases reported to date.
Clinical description
The phenotype in RAS is variable. Some affected individuals have only mild disease manifestations. Characteristic features include corneal anesthesia, nasolacrimal duct obstruction, absent peripapillary choriocapillaris and retinal pigment epithelium, poor visual acuity, and moderate to severe sensorineural deafness. Developmental delay and intellectual disability are common. Patent ductus arteriosus, Hirschsprung disease, and short stature have also been observed. Affected individuals have a distinct facial appearance with a broad face, prominent forehead, hypertelorism, upslanting palpebral fissures, concave nasal ridge, and underdeveloped midface. Feeding problems and failure to thrive are common in infancy. Challenging behavior has been reported in two cases. Overlap with the group of diseases known as hereditary sensory and autonomic neuropathy (HSAN, see this term) has been suggested.
Etiology
The etiology of this syndrome is not yet known. Mutations in an as of yet unidentified gene, involved in autonomic nervous system function, are suspected.
Genetic counseling
RAS follows an autosomal dominant pattern of inheritance, probably with variable expressivity.

                            Last update:
                            August 2014

                            - Expert reviewer(s):
                            Pr Daniela PILZ


A rare infectious disease characterized by herpes zoster oticus associated with peripheral facial nerve palsy, often also with other cranial nerve lesions. Patients present with a painful erythematous vesicular rash in and around one ear and facial paralysis on the same side. Other frequent manifestations include hearing loss, tinnitus, vertigo, nausea, vomiting, and nystagmus.


A rare syndrome for which the acronym indicates the principal signs: RA for radial ray defect, PA for both patellae hypoplasia or aplasia and cleft or highly arched palate, DI for diarrhea and dislocated joints, LI for little size and limb malformations, NO for long, slender nose and normal intelligence.

Summary:
Epidemiology
Prevalence is unknown, but the disease is rare. It was first described in families originating from different parts of Finland, but non-Finnish cases were later identified.
Clinical description
Growth delay is both pre- and postnatal. It is aggravated by feeding problems and diarrhea of no known cause.
Etiology
RAPADILINO syndrome is caused by mutations of the RECQL4 gene, a member of the family of RecQ-helicase genes which are at the origin of diseases predisposing to cancer.
Differential diagnosis
Differential diagnoses include Rothmund-Thomson syndrome (RTS) and Baller-Gerold syndrome (see these terms), which show considerable overlap with RAPADILINO syndrome. Mutations of the RECQL4 gene have also been described for these syndromes.The presence of poikiloderma, a major symptom of RTS, distinguishes this syndrome from RAPADILINO. Radial hypoplasia or aplasia, which is constant in RAPADILINO syndrome, is occasional in RTS. Equally, the presence of craniosynostosis in Baller-Gerold syndrome differentiates it from RAPADILINO syndrome. The three syndromes predispose the risk of developing malign pathologies, although this is significantly greater for RTS (mainly osteosarcoma and cutaneous cancers). The clinical differences can be explained by phenotype-genotype correlation, in particular by preservation of helicases in RAPADLINO syndrome.
Genetic counseling
RAPADILINO syndrome is transmitted in an autosomal recessive manner.
Management and treatment
Orthopedic and nutritional management is recommended when needed and appropriate investigation is recommended in the event of signs suggestive of osteosarcoma.

                            Last update:
                            April 2009

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


Rapid-onset childhood obesity-hypothalamic dysfunction-hypoventilation-autonomic dysregulation syndrome

A rare syndromic endocrine disease characterized by childhood-onset hyperphagia and obesity, alveolar hypoventilation, dysautonomia, hypothalamic dysfunction and neurobehavioral disorders. Central hypothyroidism, endocrine anomalies, electrolyte imbalances and respiratory failure may also be associated.

Summary:
Epidemiology
Fewer than 100 cases have been reported in the medical literature to date.
Clinical description
Disease onset is between 1.5 to 7 years of age with dramatic weight gain (approximately 9-13 kg over a 3-12 month period) associated with alveolar hypoventilation in a previously healthy child. This rapid-onset obesity is considered as the first sign of hypothalamic dysfunction. Other symptoms of hypothalamic dysfunction may include hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorders. Autonomic dysfunction is principally characterized by an alveolar hypoventilation but may also manifest later with thermal dysregulation, excessive sweating, cardiovascular manifestations (arrhythmias or blood pressure dysregulation), strabismus, abnormal pupillary reaction to light, gastrointestinal or sensory disturbances. Some behavioral (such as aggressiveness) or mood disorders may also be present and seem to be linked with a suboptimal ventilation management. The risk of neuroendocrine tumors in patients is estimated at 50%. These tumors typically include ganglioneuromas and ganglioneuroblastoma and are essentially intra-abdominally located. Patients associating neuroendocrine tumors are described as ROHHADNET.
Etiology
Etiology is currently unknown. Genetic studies have investigated numerous genes involved in neuronal development as well as candidate genes of hypothalamic and autonomic dysfunction without identifying any specific mutation. Apart from genetic etiologies, other hypotheses include an epigenetic, autoimmune or even paraneoplastic process.
Diagnostic methods
Diagnosis is based on the clinical criteria of dramatic weight gain in a previously healthy child in association with alveolar hypoventilation and at least one other sign of hypothalamic dysfunction (e.g. hyperprolactinemia, central hypothyroidism, water balance disorder, abnormal growth hormone response, adrenocortical insufficiency or puberty disorder). Mutation in the PHOX2B gene must be excluded.
Differential diagnosis
The primary differential diagnosis is Ondine syndrome, which is defined by a congenital absence of central respiratory control, diffuse involvement of the autonomic nervous system and, in 90% of cases, presence of a PHOX2B mutation. Other diagnoses to be considered include Genetic non-syndromic obesity, Cushing syndrome, a hypothalamic tumor or other conditions with hypothalamic dysfunction, such as Narcolepsy type 1.
Management and treatment
Specific pediatric multidisciplinary approach is required, with regular follow-up by a cardiologist, pulmonologist, endocrinologist, surgeon, psychiatrist, neurologist and sleep medicine physician. Early recognition of the symptoms is essential as management is based on the rapid instauration of the appropriate therapeutic for each symptom. Hypoventilation, the most life-threatening feature, requires either ventilator support during sleep or 24 hour/day support with BPAP (bilevel positive airway pressure) ventilation through a facial mask or a tracheostomy. Cardiac pacemaker is required in cases of severe bradycardia. Specific hormonal therapies are established based on the endocrine disturbances. Oncologic and surgical management is required in cases of neuroendocrine tumors.
Prognosis
The long-term outlook is variable. Children who are diagnosed early and appropriately managed can have a relatively good quality of life. On the contrary, if the diagnosis is delayed or the symptoms are not anticipated, children present an increased risk for sudden death (typically due to respiratory failure or cardiorespiratory arrest) with demise occurring on average around 10 years of age.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Julie HARVENGT


Rapid-onset dystonia-parkinsonism (RDP) is a very rare movement disorder, characterized by the abrupt onset of parkinsonism and dystonia, often triggered by physical or psychological stress.

Summary:
Epidemiology
The prevalence is unknown. Fewer than 100 patients have been described worldwide to date.
Clinical description
RDP typically presents in childhood or early adulthood (but age of onset can range from 4-55 years) with the abrupt onset of dystonia along with parkinsonism (bradykinesia and postural instability) with a rostrocaudal gradient and prominent bulbar symptoms (dysarthria and dysphagia) that do not respond to dopaminergic medication. Symptoms may develop over several minutes to 30 days, after which time they stabilize. Often onset is triggered by physical exertion, fever, extreme heat, childbirth, excessive alcohol consumption or emotional stress. Some patients experience mild upper limb dystonia (mainly in the hands) and cramping before disease onset occurs. In most cases the disease stabilizes, but a few cases have been reported where a second episode of worsening of symptoms occurred 1-9 years after initial onset. In rare cases seizures, anxiety and depression have been reported. Recently, a variant phenotype in infants (<4 years of age) has been reported with initially episodic hypotonia, gait ataxia, motor delay, and speech and swallowing difficulties.
Etiology
RDP is caused by several missense mutations in the ATP1A3 gene (19q13.2) encoding the sodium/potassium-transporting ATPase subunit alpha-3 protein, which is important for maintaining the electrochemical gradients of potassium and sodium across the plasma membrane. These mutations are thought to lead to neuronal dysfunction. Other genes, which have not yet been identified, may also be involved.
Diagnostic methods
Diagnosis is based on the sudden onset of clinical manifestations (parkinsonism and dystonia), the finding of low homovanillic acid concentrations in cerebrospinal fluid (CSF), normal brain imaging studies and the lack of response to levodopa (L-dopa) therapy. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies show normal dopamine reuptake in dopamine transporters. A mutation in the ATP1A3 gene may confirm diagnosis.
Differential diagnosis
Differential diagnosis includes other forms of dystonia-parkinsonism, such as young adult-onset parkinsonism, dopa-responive dystonia (DRD), dystonia 16 (DYT16) and X-linked dystonia parkinsonism (DYT3). Unlike DYT3 and other forms of young-onset parkinsonism, RDP is not a neurodegenerative disorder.
Antenatal diagnosis
Prenatal diagnosis is possible in families where a disease causing mutation is known.
Genetic counseling
RDP is inherited in an autosomal dominant manner with reduced penetrance, and genetic counseling is possible and recommended. De novo mutations are also observed.
Management and treatment
There is no effective treatment for RDP at present. L-dopa is ineffective. Pallidal deep brain stimulation (DBS) has shown limited or no therapeutic effects. If present, seizures, anxiety and depression can be treated with standard therapy. High-dose benzodiazepines and possibly other muscle relaxants may offer some symptomatic relief. All known triggers of RDP should be avoided. Physical therapy is recommended.
Prognosis
There is no effect on life expectancy, but quality of life is severely affected.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Rapidly involuting congenital hemangiomas (RICH) are a distinctive type of congenital hemangioma that are fully formed in utero and differ from non-involuting congenital haemangiomas (NICH; see this term) mainly because they undergo rapid postnatal involution.

Summary:
Epidemiology
Prevalence is unknown but the lesions appear to be rare.
Clinical description
RICH have long been confused with infantile immature hemangiomas but are now clearly distinguished on the basis of their distinctive clinical, histological and immunephenotypic features. RICH are round or oval-shaped, solitary and raised or infiltrating vascular tumors that are most commonly located close to a joint on the limbs, or on the scalp, forehead or around the ear. They develop in utero but there is no postnatal growth and involution is achieved in about 1 year. RICH located on the scalp seem to originate from the subperiosteal region and may permeate the vault bone during fetal life, a defect that heals after birth as the tumor regresses. The surface of RICH may be mildly or massively telangiectatic, with telangiectasia radiating from the centre in some cases, resulting in varying hues from pink to purple. A ring of pallor of variable size encircles the tumor. A central linear scar, depressed area or necrotic wound may be observed. In a few cases, the overlying skin appears almost normal. After regression, two types of sequelae can occur: lipoatrophy with a white-bluish skin hue, or a telangiectatic plaque. The term hepatic RICH has been applied to a solitary, involuting vascular liver tumor in newborns that, in resected cases, shows similar pathological features to those of external RICH.
Etiology
The etiology of RICH is unknown.
Diagnostic methods
Imaging studies are useful for diagnosis and should include color Doppler ultrasound (revealing a high-flow vascular tumor), and postnatal, and often antenatal MRI (showing a heterogeneous tumor with cystic aspects and calcifications). When clinical and radiological data are ambiguous, a biopsy is indicated in the newborn. Pathologic studies of RICH reveal large and densely cellular lobules, areas of fibrosis, and other lobules with larger vessels of irregular shape. GLUT1, the phenotypic marker for infantile hemangioma, is negative in RICH.
Differential diagnosis
RICH must be differentiated from other congenital vascular tumors, tufted angiomas and kaposiform hemangioendotheliomas, as well as from other congenital possibly benign (infantile myofibromatosis) or malignant tumors (rhabdomyosarcoma or fibrosarcoma; see these terms). In rare cases, moderate transient thrombocytopenia occurs in the first week of life: this should not be misdiagnosed as Kasabach-Merritt syndrome (see this term).
Antenatal diagnosis
Antenatal diagnosis of RICH during prenatal ultrasound follow-up is feasible in the 3rd trimester, and sometimes as early as the 20th week of pregnancy. Elevated rates of arterial supply and venous drainage are associated with these large tumors. They are best imaged with MRI in the 3rd trimester, not only for diagnostic purposes but also to enable decisions to be made concerning a vaginal or caesarean delivery.
Genetic counseling
Genetic counseling should not be recommended as the lesion is sporadic.
Management and treatment
Management is often limited to observation until the end of spontaneous involution. In case of residual lesions, surgical lipofilling can be considered for a bluish atrophoderma, and surgical resection for a reddish-pink plaque. Early resection in the neonatal period is only performed for lesions in selected locations, when there is a risk of hemorrhage (ulceration and fast-flow vessels located underneath the RICH). Occasionally, corticosteroid treatment may be beneficial for very large lesions.
Prognosis
The prognosis is good; however, a few exceptional cases of fatal hemorrhage have been reported.

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Dr Odile ENJOLRAS  - Pr Marie-Paule VAZQUEZ


A rare malignant breast tumor disease encompassing special rare types of adenocarcinoma of the breast, i.e. tubular adenocarcinoma, mucinous carcinoma, medullary carcinoma NOS, papillary adenocarcinoma NOS, cribriform carcinoma, apocrine adenocarcinoma, secretory carcinoma, glycogen-rich clear cell carcinoma, lipid-rich carcinoma, and oncocytic carcinoma.


Rare cutaneous lupus erythematosus (CLE) is an autoimmune disease that denotes a heterogeneous spectrum of clinical manifestations affecting the skin and can be divided into 4 categories: acute CLE (ACLE); subacute CLE (SCLE); chronic CLE (CCLE; the most diverse form); and intermittent CLE (ICLE). CLE can either occur alone or associated with systemic lupus erythematosus (SLE).

Summary:
Epidemiology
Incidence is estimated to be 1/25,000 in USA, and it affects predominantly women. CLE occurs more in patients with a family history of lupus or other autoimmune diseases.
Clinical description
CLE usually appears between 20-70 years but it has also been described in children (0-18 years). There are 4 main types of CLE: ACLE which presents as prominent non scarring-rash on cheeks and nose (''butterfly rash'', localized form) or more rarely, by a widespread eruption of red, symmetric, maculopapular lesions with accentuation of the UV-exposed areas (''maculopapular lupus rash'', generalized form); SCLE which presents with red, raised, scaly rash on sun-exposed areas of the body (annular/polycyclic form or papulosquamous form); CCLE which presents either as red to purple, well demarcated, scaly rash on the scalp, face, ears, and other sun-exposed areas (discoid LE; DLE), as frostbites (Chilblain LE; ChLE), or as painful subcutaneous nodules (LE profundus; LEP); and ICLE or LE tumidus (LET) presenting as red, swollen, urticaria-like plaques. Cutaneous manifestations appear in 72-85% of SLE patients.
Etiology
Etiology is still elusive but it is thought to be multifactorial, involving a genetic predisposition. The disease is then triggered by UV radiation, infections (cytomegalovirus, hepatitis C, Epstein-Barr virus), hormones (estrogens, prolactin), and exposure to drugs and chemicals, which initiate an inflammatory process. Cytokines and chemokines are involved in propagating inflammatory responses, suppressing tolerogenic components of the immune system. Autoreactive B cells are intrinsic to lupus pathogenesis.
Diagnostic methods
Diagnosis is based on family history, clinical and laboratory findings (detection of antibodies anti-nuclear antigens (ANA)), histological examinations of skin biopsy which show superficial and deep perivascular and periadnexal lymphocytic infiltrate, interface-dermatitis and thickening of the basement membrane as a late consequence. The epidermis is atrophic with necrotic keratinocytes. Diagnosis is confirmed by direct immunofluorescence (detects deposits of immunoglobulins and complement component C3 and IgG at the dermo epidermal junction) and photoprovocation.
Differential diagnosis
Differential diagnosis depends on subtypes and includes: ACLE: dermatomyositis, erythema multiforme, drug-induced photosensitivity, dermatitis (atopic, contact), exanthema (viral, drug-induced), rosacea, seborrheic dermatitis. SCLE: classic mycosis fungoides, pityriasis rubra pilaris, vitiligo, tinea corporis, erythema anulare centrifugum, granuloma annulare, erythema gyratum repens, psoriasis. DLE: sarcoidosis, tuberculosis, leprosy, classic mycosis fungoides, cutaneous pseudolymphoma, granuloma faciale, nummular eczema, psoriasis, squamous and basal cell carcinoma, rosacea, lichen planus. ChLE: frostbites. LEP: subcutaneous panniculitis-like T-cell lymphoma, erythema nodosum. LET: Jessner lymphocytic infiltration of the skin, polymorphous light eruption, reticular erythematosus mucinosis.
Management and treatment
Treatment goals are to improve skin appearance, limit scarring, and prevent new skin lesions. This includes use of UV light protection; topical therapy (corticosteroids and/or calcineurin inhibitors); and antimalarial therapy that may improve CLE and delay progression to SLE. For patients refractory to antimalarials, immunosupressive and immunomodulatory therapy (systemic corticosteroids, methotrexate, oral retinoids) may be proposed.
Prognosis
CLE is a chronic skin disease, with significant impact on the patients' quotidian. Risk of SCLE and CCLE patients developing SLE is <10%. ACLE is associated with SLE.

                            Last update:
                            June 2015

                            - Expert reviewer(s):
                            Pr Marzia CAPRONI  - Dr Carla CARDINALI  - Pr Paolo FABBRI  - Dr Barbara GIOMI


Rare disorder potentially indicated for transplant

A group of rare disorders with irreversible organ and/or system dysfunction(s), or the effects of dysfunction after alternative medical and surgical treatments have been utilized, for which the benefits of transplantation outweigh the risk of continuing alternative modalities.


Rare form of salmonellosis is a group of rare invasive salmonellosis that includes infection with Salmonella enterica typhoidal species (S. typhi and S. paratyphi) that results in enteric fever, and infection by invasive non-typhoidal species (typically strains of S. typhimurium and S. enteritidis) which have a high burden amongst immunocompromised or malnourished individuals, and results in bacteriemia, systemic febrile disease, and variable manifestations including lower respiratory tract infection and splenomegaly.


Rare isolated myopia is a rare, genetic, refraction anomaly disorder characterized by non-syndromic severe myopia, which may be associated with cataract and vitreoretinal degeneration (retinal detachment) that may lead to blindness.


Lichen planus (LP) is a common inflammatory dermatosis characterized by the development of pruritic violaceous papules or plaques on mucocutaneous surfaces. Eruptions can involve the face, neck, limbs, back, genitalia, tongue, buccal mucosa, nails, and scalp. LP comprises rare variants affecting the skin and the mucosa. Rare cutaneous LP includes linear LP (referring to blaschkoid and zosteriform distributions of lichenoid lesions), actinic LP, annular LP, atrophic LP, annular atrophic LP, lichen planopilaris (comprising Graham Little-Piccardi-Lassueur syndrome and frontal fibrosing alopecia), lichen planus pigmentosus, and lichen planus pemphigoides (see these terms). Rare mucosal LP includes vulvovaginal gingival syndrome and LP sialadenitis (see these terms).


Rare non-syndromic intellectual disability is a rare, hereditary, neurologic disease characterized by early-onset cognitive impairment as a sole disability. The disease may be associated with autism, epilepsy and neuromuscular deficits.


Rare surgically correctable form of primary aldosteronism

A rare primary hyperaldosteronism characterized by unilateral aldosterone hypersecretion and renin suppression, associated with varying degrees of hypertension and hypokalemia.

Summary:
Epidemiology
The prevalence of primary aldosteronism in the general population is not known. Its prevalence in referred hypertensive populations is estimated to be between 6 and 13%, of which 1.5 to 5% have an aldosterone-producing adenoma or primary unilateral adrenal hyperplasia. Taking into account referral biases, the prevalence of surgically correctable primary aldosteronism is probably less than 1.5% in the hypertensive population and less than 0.3% in the general adult population.
Etiology
nilateral aldosterone hypersecretion is caused by an aldosterone-producing adenoma (also known as Conn's adenoma and aldosteronoma), primary unilateral adrenal hyperplasia and rare cases of aldosterone-producing adrenocortical carcinoma (see these terms). In these forms, unilateral adrenalectomy can cure aldosterone excess and hypokalemia, but not necessarily hypertension.
Diagnostic methods
Surgically correctable primary aldosteronism is sought in patients with hypokalemic, severe or resistant forms of hypertension. Recent recommendations suggest screening for primary aldosteronism using the aldosterone to renin ratio. Patients with a raised ratio then undergo confirmatory suppression tests. Once the diagnosis is confirmed, adrenal computed tomography is performed for all patients.
Differential diagnosis
The differential diagnosis of hypokalemic hypertension with low renin includes mineralocorticoid excess, with the mineralocorticoid being cortisol or 11-deoxycorticosterone, exposure to glycyrrhizic acid and apparent mineralocorticoid excess caused by mutations in the HSD11B2 gene and pseudo-hypermineralocorticoidism in Liddle syndrome (see these terms).
Management and treatment
If surgery is considered, taking into consideration the clinical context and the desire of the patient, adrenal vein sampling is performed to detect whether or not aldosterone hypersecretion is unilateral.
Prognosis
Laparoscopic surgery for unilateral aldosterone hypersecretion is associated with a morbidity of about 8%, with most complications being minor. It generally results in the normalization of aldosterone secretion and kalemia, and in a large decrease in blood pressure, but normotension without treatment is only achieved in half of all cases. Normotension following adrenalectomy is more frequent in young patients with recent hypertension than in patients with long-standing hypertension or a family history of hypertension.

                            Last update:
                            September 2010

                            - Expert reviewer(s):
                            Pr Laurence AMAR  - Pr Pierre-François PLOUIN  - Dr Olivier STEICHEN


RARS-related autosomal recessive hypomyelinating leukodystrophy

A rare, genetic leukodystrophy characterized by developmental delay, increased muscle tone leading later to spasticity, mild ataxia, nystagmus, dysarthria, intentional tremor, and mild intellectual disability. Brain imaging reveals supratentorial and infratentorial hypomyelination.


RAS-associated autoimmune leukoproliferative disease (RALD) is a rare genetic disorder characterized by monocytosis, autoimmune cytopenias, lymphoproliferation, hepatosplenomegaly, and hypergammaglobulinemia.

Summary:
Epidemiology
Prevalence of this disorder is not known. It is extremely rare with fewer than 20 patients reported to date.
Clinical description
Age of onset of the clinical signs is invariably in infancy or early childhood. Most patients have atypical features such as elevated counts for cells of myeloid origin (monocytosis and granulocytosis) making their clinical presentation indistinguishable from juvenile myelomonocytic leukemia (JMML; see this term). Many patients undergo repeated bone marrow assessments showing normal cytogenetics despite dysplastic marrow morphology. Lymphoma in adulthood in one patient and only one case of unexplained sudden death in adolescence have been reported. Hypergammaglobulinemia, autoantibodies and expansion of B lymphocytes in peripheral blood have also been noted.
Etiology
RALD is caused by somatic mutations in the NRAS (1p13.2) and KRAS (12p12.1) genes encoding RAS proteins involved in regulating cell proliferation causing impairment of the intrinsic apoptosis pathway.
Diagnostic methods
Double-negative T-cells (DNTs) may be mildly elevated in patients with RALD but are usually normal. Apoptosis assay can identify these patients due to their distinct cellular phenotype showing impaired cell death following serum or IL2 withdrawal.
Genetic counseling
The pattern of inheritance for RALD is not known. RAS mutations are considered somatic and limited to the circulating peripheral blood mononuclear cells.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Koneti RAO


A rare inflammatory and autoimmune disease with epilepsy characterized by unilateral hemispheric atrophy, associated with drug-resistant focal epilepsy, progressive hemiplegia, and cognitive decline. The disease mainly affects children and begins with a prodromal period with mild hemiparesis or infrequent seizures lasting up to several years. The acute stage is marked by frequent seizures arising from one cerebral hemisphere, followed by a residual stage with persistent severe neurological deficits and relapsing epilepsy.


Rat-bite fever (RBF) is a systemic bacterial zoonosis occurring in individuals that have been bitten or scratched by Streptobacillus moniliformis or Spirillum minus-infected rats and characterized by high fever, a rash on the extremities, and arthralgia.

Summary:
Epidemiology
The exact incidence is unknown.
Clinical description
The clinical manifestations include high fever followed by headaches, chills, vomiting, a rash generally developing on the palms and soles, and symmetric polyarthritis of the joints that generally restricts movement.
Etiology
Most reported cases of rat-bite fever in the USA are caused by S. moniliformis (streptobacillary rat-bite fever), whereas in Asia the disease is mainly due to Spirillum minus (spirillary rat-bite fever; see these terms). Rat-bite fever is also contracted through contact with secretions of infected rats and less often through contact with other S. moniliformis and S. minus hosts, such as gerbils, mice and squirrels. In rare cases, the disease is transmitted through animal hosts such as dogs, cats and ferrets.
Diagnostic methods
Diagnosis is mainly based on the clinical symptoms, reported occurrence of a rat bite, clinical course and characteristic growth of the infectious agents in cultures from blood, synovial fluid or wound tissue.
Differential diagnosis
The differential diagnosis includes Haverhill fever (caused by S. moniliformis but transmitted via the consumption of water, milk or food contaminated by rat excrement; see this term) and several bacterial and viral infections (Lyme disease, leptospirosis, brucellosis, Rocky Mountain spotted fever (see these terms), S. pyogenes and S. pyogenes-associated diseases, S. aureus infection, disseminated gonorrhea, meningococcemia, viral exanthemas, and secondary syphilis).
Management and treatment
Management requires a prophylactic (avoiding direct or indirect contact with host animals) and therapeutic approach (local treatment and antimicrobial therapy). The most effective antibiotic treatment is penicillin G administration in non-allergic patients, and tetracycline and streptomycin in penicillin-allergic patients.
Prognosis
Prognosis is excellent if the disease is treated. If left untreated, RBF presents a mortality rate of approximately 10% due to complications.

                            Last update:
                            August 2009

                            - Expert reviewer(s):
                            Dr François TREMOLIERES


Ravine syndrome is an extremely rare genetic neurological disorder, reported in a small number of patients in a specific community on Reunion Island (Ravine region), characterized by infantile anorexia with irrepressible and repeated vomiting, acute brainstem dysfunction, severe failure to thrive, and progressive encephalopathy with MRI showing vanishing of medulla oblongata and cerebellar white matter and severe atrophy of pons, along with supra-tentorial periventricular white-matter hyperintensities and basal ganglia anomalies.


A rare spondyloarthritis characterized by acute or chronic sterile synovitis with or without extra-articular manifestations, becoming manifest after an infection.

Summary:
Epidemiology
Annual incidence for acute reactive arthritis is conservatively estimated between 1/11,000-166,000, although this may be an underestimate. The prevalence of the chronic form is unknown. The disease most commonly affects young adults and is associated with HLA-B27 allele, especially in its chronic form.
Clinical description
Age of onset varies widely, with a peak at 15-35 years of age. The disease usually occurs within 1-3 weeks after a urogenital or gastrointestinal infection. Urinary symptoms are often the first manifestation. Prostatitis in men, and cervicitis, salpingitis and/or vulvovaginitis in women are frequent findings. Arthritis generally appears several weeks or months after the initial symptoms. It often affects one (knee) or a few major joints (knees, ankles or toes). The tendons and ligaments next to the joints may also be inflamed, particularly the Achilles tendon and the lower back joints. Extraarticular manifestations may involve the eye with conjunctivitis, iritis, or uveitis, as well as the skin with rashes on the hands or feet. Balanitis, nail changes, mucosal ulcers, fever, weight loss, and cardiac manifestations may also occur. In most patients, the symptoms last for 1-6 months, but the disease can also become chronic.
Etiology
Reactive arthritis is typically triggered by Gram-negative infections (commonly due to Chlamydia, Shigella, Salmonella, or Yersinia) in genetically predisposed individuals.
Diagnostic methods
The diagnosis relies on a compatible clinical scenario and history, the identification of a trigger infection and is supported by HLA-B27 positivity.
Differential diagnosis
Differential diagnosis includes other spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease-associated spondyloarthropathy, juvenile-onset spondyloarthropathy, and undifferentiated spondyloarthropathy). Septic arthritis, gonococcal infection, and viral arthritis should also be excluded.
Genetic counseling
Genetic testing for HLA-B27 is not recommended in the absence of a clinical suspicion.
Management and treatment
Management aims at eradication of the underlying infection (antibiotics) and reduction of joint pain and inflammation (analgesics, anti-inflammatory drugs, steroids and immunosuppressants), as well as rest and specific treatment of extraarticular manifestations.
Prognosis
Prognosis is variable. One-third of patients may develop chronic disease which requires prolonged or life-long treatment. However, the majority of patients have a normal life span and nearly normal lifestyle.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr Francesca MOTTA  - Pr Carlo SELMI


A rare reflex epilepsy characterized by reading-induced seizures which in most cases present with orofacial/jaw myoclonus possibly extending to the upper limbs but can also manifest as dyslexia or alexia and visual symptoms. In both variants secondary generalized tonic-clonic seizures may evolve if the stimulus is not interrupted. The disease typically begins in the second or third decade of life and may be inherited in an autosomal dominant pattern. It usually takes a benign course with little tendency to spontaneous seizures.


Recessive dystrophic epidermolysis bullosa inversa

A rare subtype of dystrophic epidermolysis bullosa (DEB) characterized by blisters and erosions which from adolescence or early adulthood are primarily confined to flexural skin sites.

Summary:
Epidemiology
Less than 100 cases of recessive dystrophic epidermolysis bullosa inversa (RDEB-I) have been reported to date; it is probably underreported.
Clinical description
The disease manifests at birth or shortly thereafter with generalized blistering and superficial erosions of intermediate severity that heal with atrophic scarring and milia formation. From adolescence to early adulthood, blistering tends to localize to folds, particularly axillae, groin, perianal area and natal cleft. Women may present with marked vulvovaginal and inframammary skin blistering. Other predilection sites include the base of the neck, the uppermost back, and the lumbosacral area. Nail dystrophy is typical but of variable severity. Mucosal lesions with blistering and scarring in the mouth are characteristic and can lead to microglossia (loss of lingual papillae and fusion of the tongue to the mouth floor) and ankyloglossia (obliteration of the oral vestibules and progressive restriction of oral aperture). Esophageal involvement is often severe and is associated with a risk of esophageal stricture that can impair intake of nutrients. Lesions of the lowermost portion of the genitourinary tract are also common and may lead to the development of vaginal strictures that may impair normal sexual function. Other less common extracutaneous features include external auditory canal stenosis or complete occlusion with varying degrees of hearing loss; corneal erosions, and anemia. Growth delay is rare. Patients may develop squamous cell carcinomas, with a cumulative risk reaching 23% by age 50 which is much lower than in either of the two generalized forms of RDEB (severe RDEB and intermediate RDEB).
Etiology
The disease is caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This impairs collagen VII assembly into anchoring fibrils which anchor the basement membrane to the underlying dermis. This in turn causes reduced skin resistance to minor trauma. Compound heterozygosity for a loss-of-function COL7A1 mutation in combination with a missense mutation is prototypic. Specific glycine and arginine substitutions are implicated to affect the thermostability of type VII and cause this phenotype.
Diagnostic methods
Diagnosis is suspected at clinical examination and is confirmed by immunofluorescence antigen mapping and/or transmission electron microscopy on skin samples showing a cleavage plane located below the lamina densa of the cutaneous basement membrane zone. Genetic testing confirms the diagnosis.
Differential diagnosis
The differential diagnosis includes other forms of epidermolysis bullosa. In the neonatal period also herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, and staphylococcal scalded skin syndrome may need to be considered.
Antenatal diagnosis
Genetic prenatal diagnosis may be considered where the mutations have previously been identified in and affected sibling.
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 of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is symptomatic and includes wound management, treatment of pain and pruritus, nutritional supply, and regular examinations of skin and visible mucous membranes to screen for skin cancer.
Prognosis
Prognosis is generally good.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Martin LAIMER | ERN-Skin*

                                * European Reference Network


Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome is a rare, genetic, syndromic intellectual disabilty disorder characterized by severe intellectual disability, progressive, postnatal, multiple joint contractures and severe motor dysfunction. Patients present arrest and regression of motor function and speech acquisition, as well as contractures which begin in lower limbs and slowly progress in an ascending manner to include spine and neck, resulting in individuals presenting a specific fixed position.


A rare, mitochondrial DNA maintenance syndrome characterized by early-onset cerebellar ataxia, and variable combination of epilepsy, headache, dysarthria, ophthalmoplegia, peripheral neuropathy, intellectual disability, psychiatric symptoms and movement disorders.


A rare genetic skin disease belonging to the Mendelian Disorders of Cornification (MeDOC) and characterized by generalized hyperkeratosis and scaling of the skin. The condition is rather mild.

Summary:
Epidemiology
RXLI affects almost exclusively males. It is the second most common type of ichthyosis with an estimated prevalence of 1/2,000 to 1/6,000 males.
Clinical description
Onset may occur within the first days of life with the development of generalized non-erythematous, polygonal, loosely adherent scales. These scales later evolve into grayish or blackish adherent scales that are pronounced on the trunk, the extensor and flexor sites of the extremities, and the neck (giving the ''dirty-neck'' appearance). Skin's folds, palms and soles, are normally spared. Scaling improves with age and during summer. Delayed birth (insufficient cervical dilatation) may be observed. Extracutaneous manifestations like testicular maldescent, attention deficit and hyperactivity disorder (ADHD) and/or corneal opacities are possible. Large deletions involving adjacent genes may result in more complex phenotypes (contiguous gene deletion syndromes like Kallman´s syndrome, the recessive form of X-linked chondrodysplasia punctata, short stature, intellectual disability, or central nervous systems anomalies).
Etiology
X-linked ichthyosis is an epidermal lipid metabolism anomaly due to inactivating mutations or deletions in the steroid sulfatase STS gene (Xp22.3). STS codes for a lipid hydrolase of the stratum corneum that participates in the regulation of permeability, barrier homeostasis and desquamation by catalyzing the hydrolysis of steroid sulfates (e.g. cholesterol sulfate CSO4, sulfated steroid hormones). STS deficiency leads to increased amounts of CSO4 that inhibit epidermal serine proteases, which in turn results in decreased desquamation of corneocytes with retention hyperkeratosis. There are some much rarer syndromic RXLI cases that are due to contiguous gene deletion affecting neighboring genes of the STS gene.
Diagnostic methods
Diagnosis is based on clinical findings and family history (scaling in male relatives, history of delayed birth). It is confirmed by biochemical (serum protein electrophoresis, STS activity test of fibroblasts or leukocytes) and molecular/cytogenetic analyses (polymerase chain reaction (PCR), multiple ligation-dependent probe amplification (MLPA), comparative genomic hybridization/comparative microarray analysis (CMA), fluorescent in situ hybridization (FISH)). Histology or ultrastructure of the skin is helpful for the differentiation of ichthyosis vulgaris.
Differential diagnosis
Differential diagnosis includes ichthyosis vulgaris, autosomal recessive congenital ichthyosis (ARCI), namely lamellar ichthyosis, syndromic RLXI, or multiple sulfatase deficiency.
Antenatal diagnosis
Maternal urine and serum steroid measurements may show decreased estrogen levels. Therefore, RXLI may be detected in utero, when maternal estriol levels are measured for prenatal screening for Down syndrome and other disorders.
Genetic counseling
XLRI is transmitted as an X-linked recessive trait: it affects males and is inherited through female carriers. Female patients have rarely been reported.
Management and treatment
Treatment consists in hydrating and softening the skin with the use of lubricating bath oils and emollients containing humectants and keratolytics (e. g. urea, lactic acid, and glycolic acid). For adult patients, systemic retinoids are an option, e. g. during winter, when the ichthyosis is often more severe.
Prognosis
RXLI represents a benign form of ichthyosis. The ichthyosis is life-long but hyperkeratosis and scaling may improve with age. Life expectancy is normal.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Dr Ángela HERNÁNDEZ MARTÍN