A rare, genetic congenital malformation syndrome characterized by microcephaly, short stature, digital anomalies (brachymesophalangy, fifth finger clinodactyly, syndactyly of toes and hypoplastic thumbs) and mild intellectual disabilities but that lacks the manifestations of gastrointestinal atresia.

Summary:
Epidemiology
Feingold syndrome type 2 (FS2) is extremely rare with less than 20 patients described in the literature to date.
Clinical description
FS2 patients present with microcephaly, brachydactyly, brachymesophalangy of the second and fifth fingers, hypoplastic thumbs and toe syndactyly as seen in FS1. Mild intellectual disability is also noted. Unlike FS1, patients with FS2 lack any form of gastrointestinal atresia and they do not display short palpebral fissures.
Etiology
FS2 is thought to be caused by a hemizygous deletion in the MIR17HG gene on chromosome 13q31.3. This is the first example of a syndromic development deficit in humans that is caused by a miRNA gene.
Diagnostic methods
Diagnosis is suspected on clinical presentation and can be confirmed by high-resolution CGH (comparative genomic hybridization) arrays.
Differential diagnosis
Differential diagnosis of FS2 includes FS type 1 (FS1), VACTERL association, CHARGE syndrome, brachydactyly type A4 and Fanconi anemia.
Antenatal diagnosis
Prenatal testing is possible in FS2 families with a known MIR17HG mutation or deletion.
Genetic counseling
FS2 is inherited in an autosomal dominant manner; however, most cases arise de novo. Genetic counseling is possible.
Management and treatment
Extensive medical examinations are needed to identify possible anomalies of the heart or kidneys. Management of FS2 typically centers for long-term medical sequelae. Occupational therapy / surgical intervention for finger/toe anomalies may be required. Renal and cardiac anomalies should receive the standard treatments and prophylactic antibiotics may be beneficial. Special education is recommended for children and adults with learning deficits. Hearing loss should equally be monitored by an audiologist. Cochlear implants are possible in certain cases.
Prognosis
Prognosis depends on congenital malformations (especially cardiac and renal anomalies) present. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Loïc DE PONTUAL | ITHACA*

                                * European Reference Network


A rare genetic, congenital malformation syndrome characterized by microcephaly, short stature and numerous digital anomalies (brachymesophanlangy, fifth finger clinodactyly, syndactyly of toes and hypoplastic thumbs), mild learning deficit and short palpebral fissures. The two subtypes are clinically distinguished by the presence (type 1) or absence (type 2) gastrointestinal atresia.


Felty syndrome (FS), also known as ''super rheumatoid'' disease, is a severe form of rheumatoid arthritis (RA), characterized by a triad of RA, splenomegaly and neutropenia, resulting in susceptibility to bacterial infections.

Summary:
Epidemiology
FS is estimated to occur in about 1- 3% of RA patients after an average of 10 to 15 years of arthritis. FS is uncommon in the African American population.
Clinical description
FS is about 3 times more common in females during the third through fifth decades of life (earlier in men). Clinically, the disorder is characterized by chronic arthritis with severe joint destruction contrasting with moderate or absent joint inflammation and severe extra-articular disease. The knee, wrist, ankle, metacarpophalangeal and proximal interphalangeal joints are most commonly involved. Involvement of axial joints is less common. Symmetrical joint involvement is the characteristic feature of the disease. Hepato-splenomegaly and lymphadenopathy are commonly seen. Other extra-articular manifestations of FS are episcleritis, vasculitis, pleuritis, pulmonary fibrosis, rheumatoid nodules, neuropathy, leg ulcers, skin hyperpigmentation (usually on extensor surface of the lower leg), anemia and weight loss. The most critical manifestation of FS is neutropenia, resulting in a higher incidence of bacterial infections (affecting most frequently skin, mouth, and upper and lower respiratory tract). Rarely, FS may be revealed by neutropenia in an RA patient. FS can be associated with other autoimmune diseases such as Sjögren syndrome, vasculitis and systemic lupus erythematosus (SLE).
Etiology
The pathophysiology of FS is still not well understood butit has been proposed that an autoimmune response against neutrophil antigens might be the underlying mechanism. An increased incidence of infections may stimulate a neutrophil response that includes histone deimination and the expulsion of chromatin from the cell. Neutrophil extracellular chromatin traps (NETs) containing deiminated histones, in complex with bacterial adjuvants, are the most likely antigenic trigger for the production of autoantibodies to deiminated histones. These autoantibodies or their immune complexes may further stimulate neutrophils, thus completing a self-sustaining cycle that drives the depletion of mature neutrophils. A higher incidence of anti-deiminated histone autoantibodies is found in FS patients. About 95% of FS patients have a MHC class II HLA-DR4 allele. African Americans have a low incidence of this antigen.
Diagnostic methods
Diagnosis of FS includes physical examination as well as complete blood count revealing leucopenia, neutropenia, and thrombocytopenia and high serum titers of rheumatoid factor antibodies, antinuclear antibodies, antihistone antibodies and HLA-DR4 positivity. Microscopic analysis of spleen biopsies reveals enlargement of the germinal center in follicles, and infiltration of neutrophils and macrophages. Severe joint destruction may be observed radiologically.
Differential diagnosis
FS differs from RA by more severe arthritis and extra-articular manifestations. Differential diagnosis of FS also includes large granular lymphocyte (LGL) leukemia (when associated with RA, called pseudo Felty), RA, systemic lupus erythematosus (SLE), Still's disease, articular brucellosis, and chronic bacterial endocarditis.
Management and treatment
FS is difficult to treat and the standard of care is directed against underlying RA with an additional goal of treating neutropenia and recurrent infections. This comprises several disease-modifying anti-rheumatic drugs (including sulfasalazine, hydroxychloroquine) and methotrexate. Recombinant granulopoietic growth factors (G-CSF) have also been used to improve neutrophil counts. For treatment-resistant cases with splenomegaly, a splenectomy can be considered. Rituximab (RTX) have been used as second-line therapy in patients with refractory FS.
Prognosis
FS has a poor prognosis and recurrent infections may lead to increased mortality.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Nishant DWIVEDI  - Dr Marko RADIC


Female infertility due to oocyte meiotic arrest

A rare genetic female infertility characterized by oocyte maturation arrest during any of the various stages of meiosis I or II. In some patients, first polar body oocytes may be retrieved, but these either show fertilization failure or early embryonic arrest. Affected women have regular menstrual cycles.


Female infertility due to zona pellucida defect is a rare, genetic, female infertility disorder characterized by the presence of abnormal oocytes that lack a zona pellucida. Affected individuals are unable to conceive despite having normal menstrual cycles and sex hormone levels, as well as no obstructions in the fallopian tubes or defects of the uterus or adnexa.


Female restricted epilepsy with intellectual disability is a rare X-linked epilepsy syndrome characterized by febrile or afebrile seizures (mainly tonic-clonic, but also absence, myoclonic, and atonic) starting in the first years of life and, in most cases, developmental delay and intellectual disability of variable severity. Behavioral disturbances (e.g. autistic features, hyperactivity, and aggressiveness) are also frequently associated. This disease affects exclusively females, with male carriers being unaffected, despite an X-linked inheritance.


Femoral-facial syndrome is characterized by predominant femoral hypoplasia (bilateral or unilateral) and unusual facies.

Summary:
Epidemiology
To date, 55 cases have been reported in the literature.
Clinical description
Facial features include upslanting palpebral fissures, short nose with broad tip, long philtrum, thin upper lip, micrognathia and cleft palate. The complete syndrome with cleft palate has been reported only in females. The following associated anomalies may be present: vertebral segmentation defects, preaxial polydactyly, ear defects, genitourinary tract abnormalities, lung hypoplasia, dysplastic kidneys, patent arterial duct (see this term). Intellectual development has been reported normal. In two patients, central nervous system anomalies (corticosubcortical atrophy, colpocephaly, partial agenesis of corpus callosum, hypoplasia of the falx cerebri and absent septum pellucidum) have been described. Many patients show asymmetrical changes.
Etiology
Maternal diabetes has been recognized as a causative factor in more than 20% of the reported cases.
Genetic counseling
Majority of cases are sporadic. Familial occurrence has been reported in three cases.

                            Last update:
                            July 2009

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


A rare congenital limb malformation syndrome characterized by a highly variable combination of congenital anomalies of the femur, fibula, and/or ulna, which can appear along with finger/toe anomalies at the ulnar/fibular side. Limb defects are asymmetrical, with upper limbs more often affected than lower limbs, and the right side of the body more often affected than the left. Abnormalities of the upper limb include amelia, hypoplasia of the humerus, humero-radial synostosis, and malformation of the ulna and ulnar rays. Abnormalities of the lower limb include absence of the proximal part of the femur and absence of the fibula. Axial skeleton, internal organs and intellectual function are usually normal.


Ferro-cerebro-cutaneous syndrome is a rare, genetic, metabolic liver disease characterized by progressive neurodegeneration, cutaneous abnormalities, including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations, including microdontia, widely spaced and pointed teeth with delayed eruption, and gingival overgrowth.


The fetal akinesia/hypokinesia sequence (or Pena-Shokeir syndrome type I) is characterized by multiple joint contractures, facial anomalies and pulmonary hypoplasia. Whatever the cause, the common feature of this sequence is decreased foetal activity.

Summary:
Epidemiology
The syndrome is rare: about 100 cases have been described in the literature. About 30% are stillborn, and the majority of those live-born die of the complications of pulmonary hypoplasia.
Clinical description
Failure of normal deglutition results in polyhydramnios, and a lack of movement of the diaphragm and intercostal muscles leads to pulmonary hypoplasia. The lack of normal fetal movement also results in a short umbilical cord and multiple joint contractures. Ulnar deviation of the hands, rocker-bottom feet, camptodactyly, sparse dermal ridges and absence of palmar flexion creases are the other components of the fetal akinesia sequence. The face is expressionless, with hypertelorism, telecanthus and poorly folded, small, and posteriorly angulated ears, and the mouth is small with micrognathia and high-arched palate. Cleft palate and cardiac defects may occur occasionally. Many of these babies are born prematurely, and even when born at term their growth is delayed, they have a short neck and cryptorchidism. If they survive, they are likely to develop short-gut syndrome with malabsorption.
Etiology
The Pena-Shokeir syndrome is not a unitary entity but is etiologically heterogeneous. Maternal myasthenia gravis has been diagnosed in some cases, and experiments in animal models show that curarization of the mother induces fetal akinesia. All plausible causes of fetal immobility should be searched for (myogenic, neurogenic, ischemic/anoxic), with biopsies when possible.
Differential diagnosis
There are similarities between Pena-Shokeir syndrome type I and the trisomy 18 syndrome: both may include multiple ankyloses, camptodactyly, and rocker-bottom feet. Karyotyping permits differential diagnosis.
Antenatal diagnosis
Prenatal diagnosis after the birth of an index case relies on ultrasound, which may reveal polyhydramnios, ankyloses, scalp oedema, and decreased chest movements in a fetus with pulmonary hypoplasia.
Genetic counseling
Autosomal recessive inheritance (with parental consanguinity and/or recurrence in sibs) has been implied in about 50% of the published cases. The heterogeneity makes accurate recurrence risk counselling difficult. A 0.01 to 25% risk for recurrence seems most appropriate in apparently sporadic cases.

                            Last update:
                            July 2005


Fetal akinesia-cerebral and retinal hemorrhage syndrome is a rare, lethal, congenital myopathy syndrome characterized by decreased fetal movements and polyhydraminos in utero and the presence of akinesia, severe hypotonia with respiratory insufficiency, absent reflexes, joint contractures, skeletal abnormalities with thin ribs and bones, intracranial and retinal hemorrhages and decreased birth weight in the neonate.


Fetal alcohol syndrome (FAS) is a rare malformation syndrome caused by excessive maternal consumption of alcohol during pregnancy. It is characterized by prenatal and/or postnatal growth deficiency (weight and/or height <10th percentile), a unique cluster of minor facial anomalies (short palpebral fissures, flat and smooth philtrum, and thin upper lip) and severe central nervous system (CNS) abnormalities including microcephaly, and cognitive and behavioral impairment (intellectual disability, deficit in general cognition, learning and language, executive function, visual-spatial processing, memory, and attention).


Fetal and neonatal alloimmune thrombocytopenia

A rare hematological disease characterized by maternal alloimmunisation against fetal platelet antigens that are inherited from the father and different from those present in the mother, and usually presents as a severe isolated thrombocytopenia in otherwise healthy newborns.

Summary:
Epidemiology
The incidence of fetal/neonatal alloimmune thrombocytopaenia (FNAIT) has been estimated between 1/800 to 1/2 000 live births.
Clinical description
FNAIT has been considered to be the platelet counterpart of Rh Hemolytic Disease of the Newborn (RHD). Unlike RHD, FNAIT can occur during a first pregnancy. The spectrum of the disease may range from sub-clinical moderate thrombocytopenia to life-threatening bleeding in the neonatal period. Mildly affected infants may be asymptomatic. In those with severe thrombocytopenia, the most common presentations are petechiae, purpura or cephalohematoma at birth, associated with a major risk of intracranial hemorrhage (up to 20% of reported cases), which leads to death or neurological sequelae.
Etiology
FNAIT results from the transplacental passage of maternal alloantibodies (which are IgG) against fetal platelet antigens which are inherited from the father. In Caucasians, the most frequent platelet antigen (HPA) involved in FNAIT is HPA-1a (anti-HPA-1a alloantibodies), which is located on glycoprotein IIIa (GPIIIa), accounting for 75-80% of cases. The other main antigens involved are HPA-2, HPA-3, HPA-5, and HPA-15. The mechanisms of maternal immunization are only partly understood. Fetal syncytiotrophoblasts express GPIIIa on their cell surface and the spread of their extracellular vesicles in the maternal circulating blood system may possibly be at the origin of immunization, beginning with the first pregnancy.
Diagnostic methods
Alloimmune thrombocytopenia is more often unexpected and is usually diagnosed after birth. Once suspected, the diagnosis is confirmed by demonstration of maternal antiplatelet alloantibodies directed against a paternal antigen inherited by the fetus/neonate.
Differential diagnosis
Differential diagnosis includes sepsis/ infection, perinatal hypoxia, intrauterine growth restriction, prematurity, necrotizing enterocolitis, disseminated intravascular coagulation (DIC), other congenital conditions associated with thrombocytopenia, fetal intracranial hemorrhage without abnormal platelet count.
Antenatal diagnosis
To enable appropriate counseling for subsequent pregnancies, the father's HPA genotype should be determined wherever possible. If he is homozygous and particularly if the mother still has the relevant antiplatelet antibodies, the subsequent fetus is at risk. In the case of paternal heterozygosity for the offending antigen, or when paternity is uncertain, fetal HPA genotyping can be done on chorionic villi or amniotic cells. A noninvasive procedure of HPA genotyping from maternal serum is now available for some HPA.
Genetic counseling
Inheritance of the paternal HPA is autosomal dominant; genetic counselling should be offered to allo-immunized women, informing them that there is a 50% risk of having an HPA-incompatible fetus when the father is heterozygous for the offending antigen. All fetuses are HPA-incompatible if the father is homozygous for the offending antigen.
Management and treatment
Post-natal management involves transfusion of platelets devoid of this antigen, and should not be delayed by biological confirmation of the diagnosis (once the diagnosis is suspected), especially in case of severe thrombocytopenia. Prompt diagnosis and treatment are essential to reduce the chances of death and disability due to hemorrhage. Due to the high rate of recurrence and increased severity of the fetal thrombocytopenia in successive pregnancies, antenatal therapy should be offered. Fetal blood sampling by cordocentesis remains possible in situations of intermediate risk if there is a question about the indication of medical treatment and where vaginal delivery is requested.
Prognosis
The most feared complication of FNAIT is the occurrence of intracranial hemorrhage, leading to death or neurological sequelae. In addition, miscarriage has also been observed.

                            Last update:
                            March 2022

                            - Expert reviewer(s):
                            Dr Gérald BERTRAND  - Pr Norbert WINER


Fetal carbamazepine syndrome is a drug-related embryofetopathy that can occur when an embryo/fetus is exposed to carbamazepine and that is characterized by facial dysmorphism, with some similarities to that seen in fetal valproate syndrome (see this term), such as epicanthal folds, upward slanting palpebral fissures, short nose, micrognathia and malar hypoplasia, as well as nail dysplasia and major anomalies including cleft lip/palate, neural tube defects and cardiac anomalies. In utero exposure to carbamazepine, in combination with valproate, has been associated with significant developmental delay (particularly affecting verbal intelligence) and a high rate of congenital anomalies.


A fetopathy that is likely to occur when a cytomegalovirus (CMV) infected pregnant woman transmits the virus in utero. Children born with congenital CMV infection may present with hepatomegaly, splenomegaly, jaundice, pneumonitis, fetal growth retardation, petechiae, purpura, and thrombocytopenia. Congenital CMV infection can equally result in major neurological sequelae, including microcephaly, intracranial calcifications, sensorineural hearing loss, chorioretinitis, intellectual and motor disabilities, and seizure disorders. CMV disease sequelae caused by a primary infection are usually more severe than those caused by the reactivation of a latent infection.


Fetal encasement syndrome is a rare, lethal developmental defect during embryogenesis characterized by severe fetal malformations, including craniofacial dysmorphism (abnormal cyst in the cranial region, hypoplastic eyeballs, two orifices in the nasal region separated by a nasal septum, abnormal orifice replacing the mouth), omphalocele and immotile, hypoplastic limbs encased under an abnormal, transparent, membrane-like skin. Additional features include absence of adnexal structures of the skin on the outer aspect of the limbs, as well as underdeveloped skeletal muscles and bones. Association with tetralogy of Fallot, horse-shoe kidneys and diaphragm and lung lobulation defects is reported.


Fetal Gaucher disease is the perinatal lethal form of Gaucher disease (GD; see this term).

Summary:
Epidemiology
It is very rare with an incidence of less than 5% of GD cases.
Clinical description
This form is particularly severe. The disease manifests in the fetus with a decrease or absence of fetal movements, fetal and placental anasarca, hepatosplenomegaly, ichthyosis, arthrogryposis, facial dysmorphism and fetal thrombocytopenia. Death usually occurs in utero or shortly after birth (<3 months).
Etiology
Fetal Gaucher disease is a lysosomal storage disease caused by a mutation in the GBA gene (1q21) that encodes for the lysosomal enzyme, glucocerebrosidase. The enzyme deficiency resulting from the mutation leads to accumulation of glucosylceramide (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, spleen and bone marrow (Gaucher cells).
Diagnostic methods
Diagnosis is made by demonstrating a deficiency in the enzymatic activity of glucocerebrosidase.
Antenatal diagnosis
Biochemical prenatal diagnosis is recommended for couples who have already had a child diagnosed with Fetal Gaucher disease or GD type 2. It can be carried out by measuring the enzyme activity in chorionic villus samples at 10-12 weeks of pregnancy or in amniocytes in culture towards 16 weeks of pregnancy.
Genetic counseling
The transmission is autosomal recessive.
Management and treatment
There is no treatment for this severe form of the disease.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Nadia BELMATOUG  - Dr Jérôme STIRNEMANN


A drug-related embryofetopathy that can occur when an embryo/fetus is exposed to the anticonvulsant drug phenytoin, characterized by distinct craniofacial anomalies (hypertelorism and epicanthal folds, short nose and deep nasal bridge, malformed and low set ears, short neck) as well as hypoplastic distal phalanges and underdevelopment of nails of fingers and toes, prenatal and postnatal growth retardation, and neurological impairment (at a 2-3 times higher risk than that of the general population) including cognitive deficits and motor developmental delay. Less commonly, microcephaly, ocular defects, oral clefts, umbilical and inguinal hernias, hypospadias and cardiac anomalies have also been reported.


Fetal iodine syndrome refers to symptoms and signs that may be observed in a fetus or newborn when the mother was exposed during pregnancy to inappropriate (insufficient or excessive) amounts of iodine. Iodine deficiency is associated with goiter and hypothyroidism. When severe iodine deficiency occurs during pregnancy, it is associated with congenital hypothyroidism that is manifested by increased neonatal morbi-mortality and severe mental dysfunction, hyperactivity, attention disorders and a substantial decrease of IQ of an irreversible nature. Excessive iodine ingestion during the third trimester of pregnancy can result in hypothyroidism and fetal goiter due to a prolonged inhibition of thyroid hormone synthesis, an increase in thyrotropin (TSH).


A toxic embryofetopathy characterized by a group of symptoms with unspecific neurologic involvement that may be observed in a foetus or newborn when the mother was exposed during pregnancy to excessive amounts of methylmercury.

Summary:
Epidemiology
Severe methylmercury poisoning cases were reported in the context of two large epidemics: in the Minamata area, in Japan, and in Iraq, both affecting hundreds of people. The Japanese cases resulted from local seafood consumption and sea mercury pollution by a local industrial installation. Iraqi cases resulted from contaminated flour consumption. Large cohort studies in New-Zealand, the Faroe Islands and the Seychelles have documented a risk of less severe prenatal (and/or postnatal) methylmercury poisoning associated with frequent fish consumption (more than 2 or 3 times a week) in thousands of individuals.
Clinical description
In severe cases, the clinical picture of prenatal methylmercury poisoning is one of unspecific infantile cerebral palsy, with ataxic motor disturbances, psychomotor retardation and seizures. In populations with high fish consumption, the only manifestations of methylmercury encephalopathy are impaired psychomotor and cognitive performances. They are associated with increased risks of preterm delivery, lower birth weight, and impaired postnatal growth.
Etiology
Methylmercury is absorbed from the intestinal tract, through the skin and by inhalation. Most of the human exposure is through food ingestion. In blood, methylmercury being lipophilic is mostly in red cells. It is transported through the placenta to the fetus and accumulated in fetal brain. In cells, methylmercury is partly demethylated into inorganic mercury which is mostly distributed in the liver and kidneys. Elimination is mainly through the fecal route; about 10 % of the amount excreted is in the urine, in the form of inorganic mercury. Methylmercury is also excreted in milk (where its concentration is about 5 % of the concentration in the maternal blood).
Diagnostic methods
The best biomarkers of methylmercury exposure and internal dose are mercury concentrations in hair and whole-blood. In most individuals from the general population, they are under 2 µg/g and 8 µg/L, respectively.
Differential diagnosis
The clinical picture in prenatal or postnatal severe methylmercury poisoning is one of unspecific encephalopathy. The responsibility of methylmercury should be considered when a high fish consumption is characterized.
Management and treatment
Since exposure to methylmercury is primarily through fish consumption, it is recommended to consume not more than 2 portions of fish per week, especially for children and women of childbearing age. Fish consumption should be reduced in individuals with hair or whole-blood mercury levels of more than 2.5 µg/g or 10 µg/L, and without delay, when these levels exceed 10 µg/g or 40 µg/L, respectively. Biomonitoring and search for neurodevelopmental disorders are recommended for children with hair or whole-blood mercury levels above 10 µg/g or 40 µg/L, respectively or born from mothers who exceeded these levels during pregnancy. Mercury chelation should be considered only in those cases where severe neurological complications are possible.
Prognosis
Methylmercury-induced cognitive and psychomotor impairments are not always completely corrected by the decrease of internal methylmercury dose. However, a correct diet, a careful surveillance of neurodevelopment with attentive learning stimulations, can counterbalance the effects of this neurotoxic substance.

                            Last update:
                            April 2023

                            - Expert reviewer(s):
                            Dr Robert GARNIER  - Dr Magali LABADIE  - Dr Christine TOURNOUD


Fetal minoxidil syndrome is characterized by a group of symptoms that may be observed in a fetus or newborn when the mother has taken minoxidil during pregnancy. Minoxidil is used in the treatment of malignant renal hypertension and as a topical solution to induce scalp hair growth. Hypertrichosis that gradually diminishes during the first six postnatal months has been reported. Additional reported features include cardiac (congenital great vessel transposition and pulmonary valve stenosis), neurodevelopmental (caudal regression sequence) (see these terms), gastrointestinal, renal, and limb malformations. Conclusive studies are however not available.


Foetal parvovirus syndrome is a foetopathy likely to occur when a pregnant woman is infected by parvovirus B19. In adults, the virus causes a butterfly erythema infectiosum (also called Fifth Disease; 'slapped cheek disease') and flu-like symptoms with symmetric polyarthralgias, which usually do not warrant prenatal diagnosis.

Summary:
Etiology
The pathogenesis of foetal parvovirus infections lies in the virus affinity for progenitor erythroid cells, with infection resulting in aplastic crisis. Anaemia induces a risk of hydrops and foetal death by cardiac failure in 10 to 20% of cases.
Diagnostic methods
Diagnosis is established by evidence of either a severe aregenerative anaemia and virus cells (by electronic microscopy) in foetal blood, or viral DNA in amniotic fluid by PCR analysis.
Antenatal diagnosis
In most cases, prenatal diagnosis of parvovirus infection is performed on the basis of a foetal hydrops.
Management and treatment
Management of aplastic crisis using foetal transfusions is debated, but experience has prompted the use of intrauterine transfusion for severely affected foetuses at less than 32 weeks of gestation.
Prognosis
No significant sequelae were found in the long-term outcomes of one third of children exposed in utero to maternal parvovirus B19 infection.

                            Last update:
                            February 2006

                            - Expert reviewer(s):
                            Dr Elisabeth ROBERT-GNANSIA


A drug-related embryofetopathy that can occur when an embryo/fetus is exposed to trimethadione and that is characterized by pre- and post-natal growth retardation, intellectual deficit, developmental and speech delay, craniofacial anomalies (with some similarities to those seen in fetal valproate syndrome), and less commonly, cleft palate, malformations of the heart, urogenital system and limbs. Trimethadione is an antiepileptic drug that has been removed from the market in Europe and is no longer used much in other countries due to teratogenicity and potential side effects.


A rare teratogenic disease due to embryo/fetal exposure to valproic acid (VPA) and subsequently characterized by a distinct facial dysmorphism, congenital anomalies and developmental delay (especially in language and communication).

Summary:
Epidemiology
Prevalence of fetal valproate syndrome (FVS) is unknown. An incidence of neural tube defects (NTDs) of 1-2% has been associated with the use of VPA during the first trimester of pregnancy (10-20 times the rate seen in the general population) while the incidence of congenital heart disease, neurodevelopmental delay and autism spectrum disorder (ASD) are estimated to be around 4 to 5 times higher than in the general population.
Clinical description
The majority of infants exposed to VPA in utero are born healthy. Intrauterine growth retardation is present in 10% of cases but postnatal growth is usually normal and general health is good. Characteristic facial features of FVS are many of the following: high/broad forehead with bifrontal narrowing, metopic craniosynostosis, epicanthal folds, medial deficiency of eyebrows, infraorbital groove, small/broad upturned nose, long and shallow philtrum, long upper lip with thin vermillion borders, thick lower lip and downturned angles of mouth. Congenital anomalies associated with FVS include neural tube defects (e.g. spina bifida aperta), congenital heart defects (e.g. ventricular septal defect), oral clefts, genital abnormalities (e.g. hypospadias with undescended testicles) and limb defects, and less commonly, inguinal and umbilical hernia, tracheomalacia, supernumerary nipples, bifid ribs and pre-axial defects of the feet. Children exposed to VPA have a higher risk of developmental problems such a decreased cognitive function (especially in verbal intelligence), attention deficit disorder, learning difficulties and often the communication problems of ASD.
Etiology
FVS is caused by the exposure during pregnancy to VPA (valproate), a mood stabilizer and broad-spectrum antiepileptic drug (AED. Primarily metabolized in the liver, VPA readily crosses the placenta, where concentrations are higher than in the mother. Embryos and fetuses exposed to VPA during the 1st trimester (especially to doses exceeding 600 mg/day but lower doses may also be teratogenic) have a higher risk of developing FVS, as this is the principal period of structural development.
Diagnostic methods
Diagnosis is based on the presence of the well-recognized cluster of clinical findings in infants born to mothers who took VPA during pregnancy.
Differential diagnosis
Differential diagnoses include other types of AED-related embryofetopathies (e.g. fetal hydantoin syndrome) and possibly fetal alcohol spectrum disorder.
Antenatal diagnosis
Prenatal diagnosis is possible by the detection of anomalies such as NTDs, cardiac and other organ anomalies by ultrasonographic examination and estimation of maternal serum alpha-fetoprotein (with a history of antenatal valproate intake).
Management and treatment
VPA should be avoided (if possible) during pregnancy and high dose folic acid (4-5 mg/day) should be started 6 weeks before conception and continued through the first trimester. In pregnant women with no effective alternative, VPA should be administered in slow release form at the lowest possible divided dosage and preferably as a monotherapy along with high dose folic acid. Surveillance of the newborn should include searching for dysmorphic facial features, congenital malformations and withdrawal symptoms at birth. Long-term follow-up of the child should include early diagnosis and management of any potential behavioral or neurodevelopmental effect and educational and psychosocial support, whenever needed. Management of congenital anomalies should follow standard treatment protocols. Children with ASD should receive the regular treatment offered to children with communication disorders.
Prognosis
The prognosis of newborns is highly variable and depends on the clinical and behavioral symptoms, timing of exposure and the dosage of VPA taken by the mother. Life expectancy may be decreased in those with multiple congenital anomalies (in particular of the cardiovascular system and NTD) or with significant intellectual disability.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Koren GIDEON  - Pr Asher ORNOY


Fever-associated acute infantile liver failure syndrome

A rare genetic parenchymatous liver disease characterized by infantile or early childhood onset of recurrent episodes of acute liver failure precipitated by a febrile illness. During the life-threatening episodes, patients present with vomiting, lethargy, jaundice, as well as elevated levels of liver enzymes and coagulopathy. There is usually complete recovery between the episodes with conservative treatment.


A rare X-linked syndromic intellectual disability characterized by developmental delay and intellectual disability, early hypotonia, constipation, feeding problems, imperforate anus, characteristic behavior (affable, eager to please), and dysmorphic craniofacial features (such as relative macrocephaly, prominent forehead with frontal hair upsweep, hypertelorism, downslanting palpebral fissures, and open mouth). Additional manifestations are partial agenesis of the corpus callosum, sensorineural hearing loss, joint laxity, cardiac anomalies, and abnormalities of the fingers and toes, among others.


FGFR2-related bent bone dysplasia is a rare, genetic, lethal, primary bone dysplasia characterized by dysmorphic craniofacial features (low-set, posteriorly rotated ears, hypertelorism, megalophtalmos, flattened and hypoplastic midface, micrognathia), hypomineralization of the calvarium, craniosynostosis, hypoplastic clavicles and pubis, and bent long bones (particularly involving the femora), caused by germline mutations in the FGFR2 gene. Prematurely erupted fetal teeth, osteopenia, hirsutism, clitoromegaly, gingival hyperplasia, and hepatosplenomegaly with extramedullary hematopoiesis may also be associated.


A rare rheumatologic disease characterized by sudden onset of symmetric inflammatory distal polyarthritis and multiple firm cutaneous nodules with predilection for the upper and lower extremities. Patients often develop sclerodactyly and joint contractures. Skin biopsy shows fibroblastic proliferation in a matrix of thickened collagen fibers, with loss of elastic fibers and no mucin deposition.


Fibrochondrogenesis is a rare, neonatally lethal, rhizomelic chondrodysplasia. Eleven cases have been reported. The face is distinctive and characterized by protuberant eyes, flat midface, flat small nose with anteverted nares and a small mouth with long upper lip. Cleft palate, micrognathia and bifid tongue can occur. The limbs show marked shortness of all segments with relatively normal hands and feet. No internal anomalies other than omphalocele have been reported. Transmission is probably autosomal recessive. Recurrence in a consanguineous family (affecting both sexes) and concordance of affected male twins have been reported.


Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites.

Summary:
Epidemiology
The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP.
Clinical description
Children who have FOP appear normal at birth except for congenital malformations of the great toes (hallux valgus, malformed first metatarsal, and/or monophalangism). During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. If diagnosis of FOP is suspected, any invasive intervention (such as biopsy), which may lead to flare-ups, is contraindicated. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features (e.g. intercurrent aplastic anemia, craniopharyngioma, childhood glaucoma or growth retardation) (FOP plus), or present major variations in one or both of the two classic defining features of FOP (e.g., normal great toes or severe reduction deficits of digits) (FOP variants).
Etiology
Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1 (ALK2) encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids.
Diagnostic methods
The diagnosis of FOP is made by clinical evaluation. Plain radiographs can substantiate more subtle great toe abnormalities and the presence of heterotopic ossification. Confirmatory genetic testing is available.
Differential diagnosis
Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors (see these terms), aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification.
Antenatal diagnosis
Prenatal testing is not yet routinely available.
Genetic counseling
Although most cases of FOP are sporadic (non-inherited mutations), a small number of inherited FOP cases show germline transmission with an autosomal dominant pattern.
Management and treatment
At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls (e.g. improvement in household safety, use of protective headgear), respiratory decline (e.g., incentive spirometry), and viral infections.
Prognosis
The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Kaplan FREDERICK  - Dr Robert PIGNOLO  - Dr Eileen SHORE


Fibrohistiocytic inflammatory pseudotumor of the liver

A subtype of inflammatory pseudotumor of the liver characterized by a benign, well-circumscribed tumor with fibrohistiocytic infiltration (including xanthogranulomatous inflammation, multinucleated giant cells, and neutrophilic infiltration), typically localized in the peripheral hepatic parenchyma. Presentation may be of non-specific symptoms (fever, malaise, and abdominal pain) or as an incidental finding.


A rare variant of hepatocellular carcinoma (HCC) presenting in adolescents or young adults with no underlying liver disease. Clinical presentation is non specific, with abdominal mass, abdominal discomfort or pain, fatigue and weight loss. Patients can also be asymptomatic. HCC markers (alpha fetoprotein) are normal. Fibrolamellar HCC presents as a unique, well-delimited mass at imagery and a biopsy confirms the diagnosis, showing well-differentiated tumor cells surrounded by thick collagen bands.


A primary glomerular disease characterized by proteinuria, type IV renal tubular acidosis, microscopic hematuria and hypertension that may lead to end-stage renal failure in the second to sixth decade of life.

Summary:
Epidemiology
Fibronectin glomerulopathy exact prevalence is unknown. Only 20 families and 25 sporadic cases have been described in the literature so far.
Clinical description
Fibronectin glomerulopathy may present at different ages, although mostly in adolescence or early adulthood, with typical features of a nephrotic syndrome including hypertension, which can be severe, and edema, which initially develops around the eyes and legs but with time may become generalized. Patients may also present with varying degrees of renal failure that progressively worsen over several years, reaching end stage renal disease in the second to sixth decade of life.
Etiology
Clustering of the disease within families indicates a genetic origin. In 40% of families, the disease is caused by heterozygous mutations in the FN1 gene (2q34) encoding fibronectin. Whole-genome linkage analysis in a large pedigree showed another disease locus on 1q32, however no specific candidate genes has been identified so far.
Diagnostic methods
Diagnosis rests on renal biopsy. Typical findings at light microscopy are enlarged glomeruli with deposits in the mesangium and subendothelial space, usually with scant immunoreactivity for immunoglobulins or complement factors. Electron microscopy reveals deposits mainly located in the subendothelial space but also in the subepithelial and intramembranous spaces. Homogeneous granular deposits dominate in most cases; in some an admixture of fibrils is observed. The most striking finding is the immunoreactivity of the glomerular deposits to fibronectin. Family history is supportive of the diagnosis.
Differential diagnosis
Differential diagnosis includes other chronic non-amyloid glomerulopathies with organized deposits including mixed cryoglobulinemia, fibrillary glomerulonephritis, immunotactoid glomerulopathy, collagen type III glomerulopathy, systemic lupus erythematosus, diabetes glomerulopathy and other non-specific collagen deposition diseases. It is difficult to discriminate fibronectin glomerulopathy from membranoproliferative glomerulonephritis at light microscopy examination.
Genetic counseling
Segregation with disease appearance in successive generations is consistent with an autosomal dominant pattern of inheritance with age-related penetrance. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no specific treatment for fibronectin glomerulopathy. Treatment of symptoms can include corticosteroids, diuretics and treatment for hypertension. Antiproteinuric and renoprotective treatment with ACE inhibitors or anti-AT1R antagonists could be of help to slow renal disease progression. More advanced cases of renal failure require renal dialysis or transplantation.
Prognosis
Prognosis is uncertain, in some cases the disease follows an indolent course and in others it leads to end stage renal disease and chronic renal failure in the second to sixth decade of life.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Dr Marina NORIS | ERKNet*

                                * European Reference Network


A rare, benign, primary bone dysplasia characterized by progressive replacement of normal bone and marrow with fibrous connective tissue in either one (monostotic) or multiple (polyostotic) bones. Clinical manifestations depend on the anatomic location of the replacement and may include bone pain, deformities, pathological fractures, and cranial nerve deficits.

Summary:
Epidemiology
The prevalence is unknown and is difficult to estimate due to the frequent asymptomatic lesions.
Clinical description
FD can involve the craniofacial, axial, and/or appendicular skeleton separately or simultaneously, and ranges from isolated asymptomatic monostotic lesions to severely incapacitating polyostotic lesions leading to pain, fracture, deformity or loss of vision and hearing. The monostotic form represents approximately 70% of cases, may present with pain or a pathologic fracture, and is usually diagnosed between 10 to 30 years of age. The polyostotic form represents 20-30% of cases with the majority of patients becoming symptomatic before 10 years of age. The most common sites of involvement include the femur, tibia, skull and facial bones, pelvis, rib, humerus, radius and ulna, lumbar spine, clavicle, and cervical spine. Lesions may be unilateral or, less commonly, bilateral. Initial symptoms are usually pain in the involved limb(s), associated with a limp if the lower extremity is involved, and spontaneous fracture. Weakened structural integrity frequently leads to significant bowing and leg-length discrepancies in patients with limb involvement. Sphenoidal bone involvement is variably associated with cranial nerve deficits, essentially loss of vison (affecting less than 10% of individuals with optic nerve compression). Many patients with polyostotic forms also present with renal phosphate wasting, which accounts for an increased risk of fracture. At the extreme end of the spectrum, a small proportion of patients also have endocrine manifestations, the most common being a peripheral precocious puberty. Hyperthyroidism and growth hormone hypersecretion are also quite frequently observed, while Cushing syndrome is exceptional. These patients also have café-au-lait cutaneous spots. These endocrine or cutaneous features represent the McCune-Albright syndrome. Pancreatic intraductal papillary mucinous neoplasms have been described in patients with extended forms.
Etiology
Activating somatic mutations in the GNAS gene (20q13.32), which encodes the alpha-subunit of the Gs protein receptor (Gs alpha) in target cells, is responsible for bone cell alterations as well as for the involvement of other cells/tissues bearing the same molecular defect (melanocytes, endocrine cells).
Diagnostic methods
Imaging and, when necessary, histology are the cornerstones of diagnosis. The pathognomonic radiological picture includes radiolucency and a ''ground glass'' appearance (with no visible trabecular pattern in affected areas), variable presence of endosteal scalloping of the inner cortex (but with a smooth nonreactive periosteal surface), curvature of the femoral neck and proximal shaft (often causing a coxa vara deformity of the knee), and shepherd's crook deformity.
Differential diagnosis
Differential diagnoses includes osteofibrous dysplasia, osteochondroma, exostosis, osteosarcoma, chondrosarcoma, osteofibroma, skull meningioma, osteoma
Genetic counseling
Mutations affect only somatic cells and are therefore not hereditary, thus genetic counseling may provide reassurance but is not strictly necessary.
Management and treatment
The conventional therapeutic approach is essentially symptomatic (analgesics) and orthopedic (prevention and treatment of bone complications). Treatment is typically with intravenous pamidronate, which rapidly relieves bone pain in most patients, and progressively increases bone mineralization in osteolytic areas in about half of patients. In contrast, placebo controlled randomized trials have shown that oral bisphosphonates are no more efficacious than placebo to reduce bone pain. Tubular phosphate wasting is common and should be treated with phosphate supplementation and calcitriol.
Prognosis
Prognosis is generally good in patients with the monostotic form. Polyostotic patients need to be monitored more closely, but as disease has a tendency to stabilize after adolescence, outcomes are often good in adults.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Roland CHAPURLAT


Fibular aplasia-complex brachydactyly syndrome

A rare syndrome characterised by severe reduction or absence of the fibula and complex brachydactyly. Less than 30 cases have been described in the literature so far. The syndrome is inherited in an autosomal recessive manner and is caused by mutations in the cartilage-derived morphogenetic protein-1 gene (GDF5).


A rare, genetic, congenital dysostosis disorder characterized by fibular aplasia (or hypoplasia) associated with ectrodactyly and/or brachydactyly or syndactyly. Additonal variable features include shortening of the femur, as well as tibial, hip, knee, and/or ankle defects.


A very rare, genetic, congenital limb malformation syndrome characterized by duplication of the fibula associated with pre-axial mirror polydactyly of the foot, that may occur as an isolated malformation or be assoicated with other anomalies, including ulnar dimelia, facial abnormalities and sacrococcygeal teratoma.


Fibulo-ulnar hypoplasia-renal anomalies syndrome is characterized by fibuloulnar dysostosis with renal anomalies. It has been described in two sibs born to nonconsanguinous parents. The syndrome is lethal at birth (respiratory failure). Clinical manifestations include ear and facial anomalies (including micrognathia), symmetrical shortness of long bones, fibular agenesis and hypoplastic ulna, oligosyndactyly, congenital heart defects, and cystic or hypoplastic kidney. It is transmitted as an autosomal recessive trait.


A parasitic disease caused by tissue-invasive, vector-borne nematodes which can be found anywhere in the human body and that are transmitted to humans through the bite of an infected mosquito or fly or by consumption of unsafe drinking water and which, depending on the subtype can manifest with lymphedema, dermatitis, subcutaneous edema and eye involvement. The disorder is a major public health problem in many tropical and subtropical countries. Six subtypes have been described in the literature: lymphatic filariasis, onchocerciasis, loiasis, mansonelliasis, dirofilariasis and dracunculiasis caused by Wuchereria bancrofti and filarioidea of the genus Brugia; Onchocerca volvulus; Loa loa; Mansonella; Dirofilaria; and Dracunculus medinensis, respectively. Tropical eosinophilia is considered a frequent manifestation.


Filippi syndrome is characterised by microcephaly, cutaneous syndactyly of the fingers and toes, intellectual deficit, growth retardation and a characteristic facies (high and broad nasal bridge, thin alae nasi, micrognathia and a high frontal hairline). So far, less than 25 cases have been reported. Cryptorchidism, polydactyly, and teeth and hair anomalies may also be present. Transmission is autosomal recessive.


Finger hyperphalangy-toe anomalies-severe pectus excavatum syndrome

A rare, genetic, congenital limb malformation syndrome characterized by bilateral short broad thumbs, short deviated index fingers, clinodactyly of the fifth fingers, broad, valgus-deviated halluces and laterally-deviated, overlapping second toe, associated with severe pectus excavatum and craniofacial dysmorphism (including brachycephaly, low anterior hairline, flat supraorbital ridges, telecanthus, upslanting palpebral fissures, maxillary hypoplasia, posteriorly rotated ears, microsomia and micrognathia). Radiological findings include thumb, index, and middle finger hyperphalangy, with severe delta phalanxes in affected fingers and halluces.


Fingerprint body myopathy is a congenital benign muscle disorder characterised by congenital hypotonia and weakness and by the presence of numerous fingerprint bodies located at the periphery of the muscle fibers. Prevalence is unknown. Less than 20 patients have been described. Few sporadic cases have been observed, as well as cases of recessive transmission.


Finnish upper limb-onset distal myopathy is a rare, genetic distal myopathy characterized by slowly progressive distal to proximal limb muscle weakness and atrophy, with characteristic early involvement of thenar and hypothenar muscles. Patients present with clumsiness of the hands and stumbling in the fourth to fifth decade of life, and later develop steppage gait and contractures of the hands. Progressive fatty degeneration affects intrinsic muscles of the hands, gluteus medium and both anterior and posterior compartment muscles of the distal lower extremities, with later involvement of forearm muscles, triceps, infraspinatus and the proximal lower limb muscles. Asymmetry of muscle involvement is common.


A rare otorhinolaryngological malformation characterized by recurrent infections, swelling, pain, discharge and abscess formation in the defect area. The anomaly results from incomplete fusion of the ventral part of the first and second branchial arch, presenting as either a fistula, sinus or cyst occurring anywhere between the external auditory canal and the mandibular angle, including parotid gland.


Fish eye disease (FED) is a form of genetic LCAT (lecithin-cholesterol acyltransferase) deficiency (see this term) characterized clinically by corneal opacifications, and biochemically by significantly reduced HDL cholesterol and partial LCAT enzyme deficiency.

Summary:
Epidemiology
Fish eye disease is very rare; about 30 cases have been reported to date. Fish eye disease seems to be less common than familial LCAT deficiency (see this term).
Clinical description
Corneal opacities are progressive and are observed from an early age (adolescence or young adulthood) and sometimes result in visual impairment. These lesions are generally more severe than in complete LCAT deficiency (familial LCAT deficiency, see this term) and form a mosaic pattern of small dot-like grey-white opacities. Signs of atherosclerosis have only been reported in rare cases although patients have low HDL cholesterol levels. Hepatomegaly, splenomegaly and lymphadenopathy are generally not present.
Etiology
18 different mutations in the LCAT gene (16q22.1), encoding the LCAT enzyme which catalyzes the formation of cholesterol esters in lipoproteins, have been identified in FED cases. In patients with this disorder, alpha-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within HDL) is abolished, but beta-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within other lipoproteins) is preserved. Impaired enzyme function is thought to result in deposition of lipids in the cornea.
Diagnostic methods
Initial diagnosis is suspected on the basis of corneal clouding. Definitive diagnosis requires molecular genetic testing of the LCAT gene and functional analysis of the gene product.
Differential diagnosis
Differential diagnosis includes Schnyder corneal dystrophy as well as familial LCAT deficiency and Tangier disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible.
Genetic counseling
FED follows an autosomal recessive pattern of inheritance. Genetic counseling should be offered to affected families.
Management and treatment
Treatment is symptomatic. Severe visual impairment may require corneal transplantation.
Prognosis
Morbidity is related to progressive corneal opacification, which may lead to visual impairment.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Pr Laura CALABRESI  - Pr Guido FRANCESCHINI


A rare hypersensitivity reaction characterized by the appearance of erythematous or violaceous, round, sometimes painful, plaques that may or may not result in long-lasting pigmentation and which recur (usually at the same site) upon re-exposure to the causative medication. The severe form of the disease, generalized bullous fixed drug eruption, occurs typically in the elderly and may be life-threatening. Onset usually occurs 30 minutes to several hours after administration of the causal medication. Many medications, including paracetamol, have been implicated. The disease may rarely be induced by food. Histology is characterized by interface dermatitis or epidermal necrolysis in bullous forms.


Fixed subaortic stenosis (FSS) is a rare heart malformation characterized by the obstruction by membranous or fibromuscular tissue of the left ventricular outflow tract (LVOT) below the aortic valve, that occurs as an isolated lesion or in association with additional cardiac malformations (e.g. ventricular septal defect, patent ductus arteriosus, coarctation of the aorta), that presents in childhood with signs of LVOT obstruction (e.g. dyspnea, chest pain, syncope, palpitations) and that can potentially lead to life-threatening complications (e.g. aortic regurgitation, infective endocarditis). It comprises three anatomical subforms: discrete fixed membranous subaortic stenosis (membranous tissue encircling the LVOT), discrete fibromuscular subaortic stenosis (fibromuscular tissue encircling the LVOT) and tunnel subaortic stenosis (fibromuscular diffuse tunnel-like narrowing of the LVOT), the two latter forms being generally more severe than the membranous form.


A form of autosomal recessive limb-girdle muscular dystrophy that presents a highly variable age of onset and phenotypic spectrum typically characterized by slowly progressive proximal weakness of the pelvic and shoulder girdle musculature (predominantly affecting the lower limbs), frequently associated with waddling gait, scapular winging, calf and tongue hypertrophy, exercise-induced myalgia, abdominal muscle weakness, cardiomyopathy, respiratory muscle involvement, and myoglobinuria and/or elevated creatine kinase serum levels.

Summary:
Epidemiology
Due to a founder mutation in Scandinavia (excluding Finland) the prevalence figures for FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) is much higher than the rest of the world (about 1/50,000). In countries with Scandinavian immigration (Northern Europe and northern states of America) the prevalence is also relatively high.
Clinical description
The age of onset is correlated to the genotype and residual expression of fukutin-related protein. Thus, patients homozygous for the common, mild mutation (c.826C>A) usually have an onset in the third decade, while patients compound heterozygous for this mutation have onset before age 10, and loose ambulation around age 20 and need assisted ventilation 5-10 years after that. The manifesting symptoms start in the lower extremities with difficulties raising from a chair, climbing stairs and running. Later proximal weakness starts in the arms with visible scapular winging. Of note, a third of patients may present with myoglobinuria on physical exertion, before weakness is noticed. Patients may develop a cardiomyopathy that requires medical treatment. In rare cases, a cardiac transplant is required. Left ventricular ejection fraction drops on average 0.4% per year. Patients homozygous for the c.826C>A mutation in FKRP loose ambulation around age 60 and may need assisted ventilation at night, but the timing of these losses is highly variable.
Etiology
The loss of glycosylation of alpha-dystroglycan due to pathogenic variants in FKRP (19q13.32) leads to poor linkage of the myocyte to the extracellular matrix, which produces muscle damage.
Diagnostic methods
The diagnosis is directed towards a limb girdle muscular dystrophy based on clinical presentation with proximal wasting and weakness, most pronounced in legs. The primary diagnosis is based on finding of two pathogenic variants in FKRP. Creatine kinase is usually elevated above 1,000 and can reach undetectable levels after strenuous exercise that can also result in myoglobinuria. A muscle biopsy shows dystrophic changes, and staining for glycosylation of alpha-dystroglycan with VIA4 and IIH6 antibodies shows loss of glycosylation.
Differential diagnosis
The list of other muscle disease which present with proximal weakness is long. First and foremost, the other, numerous, limb girdle dystrophies should be considered. Other differential diagnoses include Becker muscular dystrophy, Bethlem myopathy, mitochondrial myopathy, poly-/dermatomyositis, and muscle glycogenosis (especially Pompe disease and debrancher deficiency). Spinal muscular dystrophy in mild forms and congenital myasthenia patients are also valid differential diagnoses.
Genetic counseling
For parents of an affected child, the risk of having another affected child is 25% at each pregnancy. As this is a recessive rare disease, genetic counselling for affected individuals is rarely needed due to the low carrier frequency in the background population. However, carrier testing of an unaffected spouse is relevant in Scandinavia (excluding Finland) as the carrier frequency is 1/150-200 people.
Management and treatment
Currently, there are no approved specific drugs for the disease. Supportive therapies with assisted ventilation, medical treatment for heart failure, early retirement if weakness becomes too severe, and assisted devices for ambulation and general mobility (e.g. handles in the toilet) are recommended. Different gene therapies and substrate (ribitol) therapies are being researched and clinical trials are imminent.
Prognosis
Quality of life is highly influenced by the loss of motor function and respiratory limitations. Life expectancy is unknown, but usually normal in patients homozygous for the c.826C>A mutation. Patients compound heterozygous for the mutation likely have reduced life expectancy because of invasive ventilation from early age and the subsequent complications.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr John VISSING


Flat face-microstomia-ear anomaly syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by dysmorphic facial features, including high forehead, elongated and flattened midface, arched and sparse eyebrows, short palpebral fissures, telecanthus, long nose with hypoplastic nostrils, long philtrum, high and narrow palate and microstomia with downturned corners. Ears are characteristically malformed, large, low-set and posteriorly rotated and nasal speech is associated. There have been no further descriptions in the literature since 1994.


Fleck corneal dystrophy (FCD) is a rare generally asymptomatic form of stromal corneal dystrophy (see this term) characterized by multiple asymptomatic, non-progressive opacities disseminated throughout the corneal stroma with no effect on visual acuity.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known. FCD affects males and females equally.
Clinical description
The condition may occur throughout life and has been reported in children as young as 2 years of age. Corneal sensation is usually normal. Vision is not affected but mild photophobia may occur.
Etiology
Fleck corneal dystrophy is caused by a mutation in the  PIKFYVE gene (2q34).
Diagnostic methods
Lesions are mostly minute and symmetrical. Opacities are sometimes small, oval, round, or semi-circular with distinct borders resembling flecks in the central and peripheral cornea. Opacities may also resemble snowflakes or clouds and consist of small grayish aggregations with ill-defined margins, occurring particularly in the central third of the cornea.
Genetic counseling
An autosomal dominant pattern of inheritance has been reported.
Management and treatment
Fleck dystrophy does not require specific treatment.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


FLNA-related X-linked myxomatous valvular dysplasia

A rare genetic cardiac malformation characterized by progressive myxomatous degeneration predominantly of the mitral valve (but not uncommonly with multivalvular involvement), presenting as valve thickening and dysfunction with variable stenosis, prolapse, and/or regurgitation, and potentially resulting in lethal heart failure. Hyperextensible skin and joint hypermobility have been reported in some patients. Hemizygous males display a more severe phenotype than heterozygous females.


A multiple congenital anomalies/dysmorphic syndrome-intellectual disability that is characterized by facial dysmorphism, short stature with delayed bone age, and expressive language delay.

Summary:
Epidemiology
Floating-Harbor syndrome prevalence and incidence are unknown. Around 100 cases have been reported in the literature to date.
Clinical description
Facial features include a triangular-shaped face, a prominent bulbous nose with a broad nasal bridge, a wide columella, deep-set eyes with long eyelashes, a wide mouth with a thin upper lip, low-set ears and sometimes broad thumbs and big toes. The speech defect is marked by impairment of expressive language and is often associated with a peculiar hypernasal voice. Stature is usually reported to be below the third percentile and between 2 and 4 SD below the mean. Bone age is always delayed. Other variable manifestations include celiac disease, pseudoarthrosis of the clavicle, intellectual disability, dental anomalies (malocclusion, microdontia, supernumerary upper teeth), a short neck, brachydactyly, and clinodactyly of the 5th finger. Associated genitourinary and cardiac anomalies have been reported in a few cases.
Etiology
The syndrome is associated with heterozygous mutations in exon 33 or mostly in exon 34 of the SRCAP gene (16p11.2), with two recurrent mutations (Arg2444* and Arg2435*). SRCAP encodes an ATPase which is involved in chromatin remodeling and is the cofactor of CREBBP, the gene responsible for Rubinstein-Taybi syndrome.
Diagnostic methods
Diagnosis is based on clinical examination and can be confirmed by genetic testing.
Differential diagnosis
The differential diagnosis should include other dysmorphic syndromes, in particular Rubinstein-Taybi syndrome.
Antenatal diagnosis
Prenatal diagnosis can be considered for families in which the disease-causing mutation has been identified.
Genetic counseling
The majority of reported cases are sporadic, but a few familial cases with autosomal dominant inheritance have been reported.
Management and treatment
Management is only symptomatic. Patients may benefit from developmental and educational programs and should receive regular orthodontic care. Growth hormone therapy may be of benefit in some patients.
Prognosis
Despite the presence of short stature and learning difficulties, in general patients appear to remain in good health and have a good quality of life.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


Florid cemento-osseous dysplasia (FCOD) is a rare fibro-osseous lesion in the jaw that predominantly affects middle-aged women of African descent. It is generally asymptomatic or may manifest with pain and gingival swelling. Radiologically, it is characterized by multiple dense lobulated bone lesions, often symmetrically located in various regions of the jaw.


FLOTCH syndrome is a rare, genetic, cutaneous disorder characterized by leuchonychia and multiple, recurrent pilar cysts, associated or not with ciliar dystrophy and/or koilonychia. Renal calculi have also been reported.


A rare genetic disease characterized by childhood onset of bilateral progressive sensorineural hearing loss, ocular anomalies (myopia, cataract, retinitis pigmentosa), central and peripheral nervous system features (dementia, epilepsy, ataxia, peripheral neuropathy), ectodermal features (skin atrophy, alopecia, dental caries), and skeletal anomalies (bone cysts, joint stiffness, scoliosis, kyphosis). Laboratory examination may reveal elevated cerebrospinal fluid protein.


A rare epidermal disease characterized by multiple, usually asymptomatic, yellowish to flesh colored hyperkeratotic papules and plaques on the palms and soles, with a preference for the palmar and plantar margins. Histological examination shows pronounced orthohyperkeratosis overlying a crateriform depression in the epidermis, with hypergranulosis and mild acanthosis, while elastorrhexis is absent. The lesions appear in the second or third decade of life and gradually increase in number over several years. The condition may be sporadic or familial.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by abnormalities in ectodermal- and mesodermal-derived tissues, classically manifesting with skin abnormalities, limb defects, ocular malformations, and mild facial dysmorphism.

Summary:
Epidemiology
The exact prevalence of focal dermal hypoplasia (FDH) is unknown. To date, around 300 cases have been reported in the literature. Female to male ratio is 9:1, with no racial or ethnic predilection.
Clinical description
FDH usually manifests in the neonatal period and characteristic skin findings include congenital patchy skin hypoplasia, nodular, subcutaneous fat herniation, hyper/hypo-pigmentation in Blaschko linear distribution, telangiectasia and ridged, dysplastic or hypoplastic nails. Sparse hair/alopecia and later-onset, verrucoid, periorificial, skin and mucous membrane papillomas are also frequently associated. Characteristic limb malformations include ectrodactyly, syndactyly, oligodactyly and marked long bone reduction, as well as occasionally observed costovertebral abnormalities (e.g. fused or bifid ribs, hemi- or butterfly vertebrae), which may lead to kyphosis/kyphoscoliosis. Typical ocular abnormalities include congenital microphtalmia (occasionally anophtalmia), cataracts and iris and chorioretinal colobomas. Dental abnormalities are also frequently observed and include enamel defects, as well as abnormal number and form of the primary and secondary dentition. Craniofacial dysmorphism, including facial asymmetry, notched nasal alae, small, underfolded pinnae and a pointed chin, may be associated. Other system abnormalities, such as genital labial hypoplasia, abdominal wall defects, and, occasionally, malrotation of the gut may be additional features.
Etiology
FDH is caused by mutations in the PORCN gene (Xp11.23), which encodes the porcupine O-acyltransferase, involved in the secretion and signaling of WNT proteins, important for embryonic tissue development. Different types of PORCN mutations, including nonsense, missense, and frameshift mutations, as well as partial- or whole-gene deletions, have been described. In familial cases, affected parents usually display a milder form of FDH.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical findings and is confirmed or established, in cases of inconclusive clinical presentation, by molecular genetic testing which reveals a pathogenic variant in the PORCN gene.
Differential diagnosis
Differential diagnoses should include microphtalmia with linear skin defects (MLS) and incontinentia pigmenti (IP), as well as oculocerebrocutaneous syndrome and Rothmund-Thompson syndrome.
Antenatal diagnosis
Prenatal testing for at-risk pregnancies is possible when a mutation has been previously identified in the family.
Genetic counseling
FDH follows an X-linked dominant pattern of inheritance and is usually lethal in utero in hemizygous, non-mosaic male fetuses. Approximately 95% of females with FDH have a de novo PORCN pathogenic variant and only 5% inherit it from a parent. Live-born affected males are rare (about 10% of FDH cases) and are nearly always mosaic for a de novo postzygotic mutation. Genetic counseling should be offered to affected females informing them of the 33% risk of giving birth to an affected daughter, an unaffected son, or and unaffected daughter.
Management and treatment
Treatment is symptomatic and involves dermatological, orthopedic, ophthalmologic and dental care. Verrucous papillomas may require surgical intervention.
Prognosis
Prognosis is variable depending on severity on manifestations. Individuals with severe forms of the syndrome usually die during infancy, however, a normal life expectancy may be reached in patients with less severe findings.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Maria Paola LOMBARDI


Focal epilepsy-intellectual disability-cerebro-cerebellar malformation is a rare, genetic neurological disorder characterized by early infantile-onset of seizures, borderline to moderate intellectual disability, cerebellar features including dysarthria and ataxia and cerebellar atrophy and cortical thickening observed on MRI imaging. Seizures are typically focal (with prominent eye blinking, facial and limb jerking), precipitated by fever and often commence with an oral sensory aura (anesthetized tongue sensation). When not properly controlled by anti-epileptic medication, weekly frequency and persistance into adult life is observed.


Focal facial dermal dysplasia type I (FFDD1), also known as Brauer syndrome, is a focal facial dysplasia (FFDD; see this term) characterized by congenital bitemporal cutis aplasia.

Summary:
Epidemiology
FFDD1 has been reported in over 80 cases including three large multi-generational families (German, English, Australian) and several sporadic cases.
Clinical description
The bitemporal, rarely unilateral, hypoplastic scar-like lesions in FFDD, resembling forceps marks, are usually the only manifestations of FFDD1. Other very rarely described and usually mild facial dysmorphic features may comprise a low frontal hairline, sparse hair, sparse lateral eyebrows, distichiasis (upper lashes), flattened nasal tip, bulbous nasal tip, prominent upper lip, skin dimples lateral to lips, horizontal chin furrow, vertical chin cleft, and linear grooves on the forehead. Most patients usually have normal intelligence.
Etiology
Etiology is unknown.
Diagnostic methods
Clinical examination reveals bitemporal scars.
Differential diagnosis
Differential diagnosis includes focal facial dermal dysplasia type 2 and 3 (see these terms).
Antenatal diagnosis
Prenatal diagnosis is not available
Genetic counseling
FFDD1 is transmitted in an autosomal dominant manner with full penetrance.
Management and treatment
No specific treatment exists. There is limited experience with plastic surgery for the facial scar-like lesions.
Prognosis
Affected individuals have a normal intelligence and life span.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Robert DESNICK  - Dr Beomhee LEE


Focal facial dermal dysplasia type II (FFDD2) is a focal facial dermal dysplasia (FFDD; see this term), characterized by congenital bitemporal scar-like depressions and other facial and organ abnormalities.

Summary:
Epidemiology
To date, FFDD2 has been reported in over 20 cases from 8 families.
Clinical description
FFDD2 is characterized by congenital bitemporal hypoplastic scar-like lesions resembling forceps marks with additional facial dysmorphic features. These frequently include low frontal hairline, sparse hair, periorbital puffiness, sparse lateral and upward lifting eyebrows, distichiasis (upper lashes), lack of lower lashes, flattened and/or bulbous nasal tip, and a prominent upper lip (with an inverted ''V'' contour). Occasionally epicanthal folds , linear grooves on forehead, skin dimples lateral to lips and redundant skin are reported. Cardiac and genital or urinary abnormalities have been rarely noted. Developmental delay, severe intellectual disability, behavioral problems, and learning difficulties may be observed.
Etiology
The etiology of FFDD2 is unknown.
Diagnostic methods
FFDD2 is diagnosed in patients bearing autosomal dominant bitemporal scar-like lesions and multiple FFDD2 features.
Differential diagnosis
Differential diagnosis includes focal facial dermal dysplasia type I (FFDD1) and focal facial dermal dysplasia type III (FFDD3; see these terms).
Genetic counseling
FFDD2 is transmitted in an autosomal dominant manner with variable expressivity and incomplete penetrance.
Management and treatment
Management comprises opthalmologic evaluations periodically. There is limited experience with plastic surgery for the facial scar-like lesions.
Prognosis
Affected individuals have a normal life span, but involvement of other organ systems may alter the prognosis.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Robert DESNICK  - Dr Beomhee LEE


Focal facial dermal dysplasia type III (FFDD3) is a rare focal facial dermal dysplasia (FFDD; see this term), characterized primarily by congenital bitemporal scar-like depressions and a typical, but variable facial dysmorphism, which may include distichiasis (upper lids) or lacking eyelashes, slanted eyebrows and a flattened and/or bulbous nasal tip and other features such as a low frontal hairline, sparse hair, redundant skin, epicanthal folds, low-set dysplastic ears, blepharitis and conjunctivitis.

Summary:
Epidemiology
FFDD3 is reported in over 20 patients from more than 15 families, but only 4 consanguineous families have had TWIST2 mutations.
Clinical description
FFDD3 is characterized by congenital bitemporal hypoplastic scar-like lesions resembling forceps marks with typical facial dysmorphic features. In addition, they may have periorbital puffiness (leonine facies), sparse lateral and upward lifting eyebrows, distichiasis (upper lashes), a lack of lower lashes and a prominent upper lip (with an inverted ''V'' contour). Nose abnormalities are very frequent and comprise a flattened and/or bulbous nasal tip with septum extended below the alae nasi. Additional frequent features describe a low frontal hairline, sparse hair, epicanthal folds, blepharitis, conjunctivitis, low-set dysplastic ears, and redundant skin. Other eye abnormalities less often reported include short and/or slanting palpebral fissures, as well as impaired vision, nystagmus, exotropia, hypertelorism and absent meibomian glands. Skin dimples lateral to lips, vertical chin clefts, horizontal chin furrows and linear grooves on forehead occur occasionally. Other features such as a pectum deformities and cardiac and genitorurinary abnormalities are rare. Patients generally have normal growth and development. Heterozygous family members may present with minor manifestations, such as partial absence of lower eyelashes and distichiasis of upper lashes. Developmental delay, severe intellectual disability, behavioral problems, and learning difficulties may be observed.
Etiology
FFDD3 is caused by homozygous mutations in the TWIST2 gene, which encodes a bHLH transcription factor involved in dermal facial development in mammals. To date two nonsense mutations, c.324C>T (p. Q65X) and c.486C>T (p.Q119X), and two small deletions that caused frameshift mutations, c.168delC (p.S57AfsX45) and c.91delC (p.R31GfsX71), have been reported. However, the majority of unrelated FFDD3 patients evaluated have had normal TWIST2 sequences, indicating the molecular genetic heterogeneity of the disorder. Studies are under way to interrogate whole exome or genome sequencing in these patients and their parents to determine the causative defects.
Diagnostic methods
FFDD3 is diagnosed in patients bearing autosomal recessive bitemporal scar-like lesions and typical FFDD3 facial features, and is confirmed by genetic testing of TWIST2. However, many patients with typical FFDD3 features have normal TWIST2 sequences (~80%). Thus, diagnosis is clinically based for most patients on the characteristic bitemporal lesions and facial dysmorphism regardless of inheritance. Also, the facial phenotype may be milder in patients without TWIST2 mutations.
Differential diagnosis
Differential diagnosis includes FFDD1 and FFDD2 (see these terms).
Genetic counseling
Many cases are sporadic. Inheritance is autosomal recessive for patients with TWIST2 mutations. Heterozygous parents will have a 1 in 4 risk of an affected child with each pregnancy. For other patients, the inheritance is unclear.
Management and treatment
Pursed lips and eye abnormalities may be surgically corrected, but there is limited experience with plastic surgery.
Prognosis
In patients with normal intelligence, normal life span is expected. Patients with developmental delay may have other organ system involvement which may affect health and longevity.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Robert DESNICK  - Dr Beomhee LEE


Focal facial dermal dysplasia type IV (FFDD4) is a rare focal facial dysplasia (FFDD; see this term), characterized by congenital isolated preauricular and/or cheek blister scar-like lesions.

Summary:
Epidemiology
To date, FFDD4 is reported in over 20 patients.
Clinical description
FFDD4 is characterized by isolated congenital bilateral hypoplastic atrophic skin lesions distributed in a distinctive, curvilinear manner between the maxillary and manibular prominences in the preauricular region and/or cheek. Affected FFDD4 patients typically do not present with extra-cutaneous manifestations, although in a small number of cases, a hair collar sign (circumscription of the cutaneous lesion with terminal hairs), polyps on the buccal mucosa with a similar distribution pattern, and developmental delay have been reported.
Etiology
FFDD4 is caused in a subset of affected cases (four out of five unrelated families) by a 7 base pair duplication, c.844_851dupCCATGCA (p. p.Glu284fsX128) or a missense mutation, c.1433G>A (p.Arg478His) in the CYP26C1 gene, which is involved in retinoic acid metabolism and important in the formation of the mandibular and maxillary prominences. The short duplication occurs in 0.3% of the healthy control population, suggesting that heterozygosity for the alteration does not result in phenotypic manifestations.
Diagnostic methods
FFDD4 is diagnosed in patients with isolated preauricular scar-like lesions, typically in the absence of other manifestations. These patients were homozygous for the seven base pair duplication or were heteroallelic for the seven base pair duplication and the missense mutation in the CYP26C1 gene. Histologic findings include epidermal atrophy with the presence of loose connective tissue replacing the dermis, diminished fragmented elastic tissue, and a lack of subcutaneous tissues and adnexal structures.
Differential diagnosis
Differential diagnosis may include membranous aplasia cutis congenita (see this term), but in FFDD4 cutaneous lesions are isolated and do not occur in combination with other extra-cutaneous manifestations.
Genetic counseling
Appropriate counseling should be provided for this autosomal recessive trait. The fact that not all the patients with FFDD4 had CYP26C1 mutations indicates the occurrence of genetic heterogeneity for this developmental disorder.
Management and treatment
There is limited experience with plastic surgery for the facial scar-like lesions
Prognosis
Affected individuals have normal life span.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Robert DESNICK  - Dr Beomhee LEE


Focal facial dermal dysplasias (FFDD) are rare ectodermal dysplasias, characterized by congenital bitemporal (resembling forceps marks) or preauricular scar-like lesions associated with additional facial and or systematic manifestations. 4 types of FFDD are described (FFDD I to IV; see these terms). FFDD types II and III present with a variable facial dysmorphism including distichiasis (upper lashes) or lacking eyelashes, and upward slanting and thinned lateral eyebrows with a flattened nasal bridge and full upper lip. FFDD types I and IV are infrequently associated with extra-cutaneous anomalies.


A rare idiopathic inflammatory myopathy characterized by a localized swelling of skeletal muscle that is usually located in the lower extremities.

Summary:
Epidemiology
Focal myositis prevalence is unknown. There have been approximately 200 cases described to date.
Clinical description
The disease can occur at any age. It presents as a mass (ranging in size from 1.0 to 20.0 cm) localized to a single skeletal muscle that may be painless or tender to the touch and that grows insidiously over several weeks to months. The mass is usually located in the lower extremities and the muscles most commonly affected include the adductor, vastus lateralis and gastrocnemius. It can rarely occur in muscles of the head and neck region. Additional rare systemic manifestations include fever, myalgia, generalized weakness and weight loss. It does not appear to invade the adjacent tendons, fascia or skin and usually regresses spontaneously with time. Recurrence is possible (seen in around 18% of cases) but uncommon. Rarely, classical inflammatory myopathies can present focally, thus mimicking focal myositis.
Etiology
The etiology is unknown. Possible causes include trauma (20%), genetic factors (that remain unknown), viral infections and autoimmune disease. Some regard focal myositis as a localized form of polymyositis. Chronic nerve irritation caused by compression of a nerve is another suspected cause of muscle fiber hypertrophy that consequently leads to focal myositis.
Diagnostic methods
Clinical and histological findings of an enlarged single muscle are indicative of focal myositis. Magnetic resonance imaging (MRI) is helpful to diagnose focal myositis as it reveals increased signal intensity and hypertrophy of the affected muscle. Electromyography shows spontaneous activity associated with a myopathic pattern. A minor elevation in the level of creatine kinase (CK) is sometimes seen.
Differential diagnosis
Clinically, focal myositis can be mistaken for many other conditions such as soft tissue sarcomas (rhabdomyosarcoma, liposarcoma, leiomyosarcoma), myositis ossificans progressiva, inflammatory myofibroblastic tumor, lymphoma, fibromatosis, rhabdomyoma, intramuscular lipoma, venous thrombosis and other conditions of inflammatory or vascular origin. Pathologically it can resemble an inflammatory myopathy and muscular dystrophy.
Management and treatment
Treatment is often not necessary as most cases resolve spontaneously. Anti-inflammatory drugs (steroid or nonsteroidal) such as oral prednisolone can be given to minimize any pain and inflammation. In cases complicated by limited joint motion, physical and/or surgical therapy may be necessary.
Prognosis
Prognosis is very good as most cases of focal myositis resolve spontaneously.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Dr Elisabeth RUSHING


Focal palmoplantar and gingival keratoderma is a very rare form of focal palmoplantar keratoderma characterized by painful circumscribed hyperkeratotic lesions on weight-bearing areas of soles, moderate focal hyperkeratosis of palmar pressure-related areas and an asymptomatic leukokeratosis confined to labial- and lingual- attached gingiva. Additional occasional features may include hyperhidrosis, follicular keratosis and extended oral mucosa involvement.


Focal palmoplantar keratoderma with joint keratoses

A rare, genetic, isolated palmoplantar keratoderma characterized by focal hyperkeratotic lesions affecting the pressure- and mechanical trauma-bearing areas of the palms and soles, as well as hyperkeratotic plaques involving joints, including knees, elbows, ankles and dorsa of interphalangeal joints.


A rare stiff person spectrum disorder characterized by painful episodic spasms (which are often precipitated by touch, pain, cold, movement, or negative emotions), increased stimulus sensitivity including hyperekplexia, as well as stiffness, in a lower or upper limb, typically with insidious onset and progression over months or years. The condition may eventually progress into classic stiff person syndrome. Fear of leaving the house and walking unaided is characteristic. Most patients have autoantibodies in serum and CSF, in particular anti-glutamic acid decarboxylase (GAD) antibodies. In rare cases, the syndrome is of paraneoplastic origin.


A rare neurologic movement disorder characterized by sustained muscle contractions of a single body region, usually producing twisting and repetitive movements or abnormal postures or positions.


Foix-Alajouanine syndrome, also called subacute ascending necrotising myelitis, results from chronic congestion of the extrinsic pial veins of the spinal cord and of the intrinsic subpial network. It is characterised by progressive ascending deficit over a period of several months or years.

Summary:
Epidemiology
The prevalence is unknown. The syndrome most commonly affects men over the age of 50.
Clinical description
The initial symptoms are variable and include dysesthesia of the inferior members (symmetrical in most cases) associated with progressive ascending motor deficit. The ascending paraplegia eventually leads to urinary incontinence. Unilateral or painful manifestations at presentation are rare but have been reported.
Etiology
The causative lesion is a dural arteriovenous shunt of the medullary emissary vein. The arteriovenous shunt is acquired. It is fed by branches of the spinal meninges. The shunt is associated with reflux into the venous drainage of the cord, leading to congestion and chronic medullary ischemia.
Diagnostic methods
Radiological investigations and magnetic resonance imaging (MRI) of the spinal cord reveal dilated perimedullary veins associated with a hypersignal from the interior of the cord and, in chronic forms, variable degrees of spinal cord atrophy. Medullary angiography may be used to identify the arteriovenous shunt zone.
Management and treatment
Endovascular treatment is possible in around two thirds of cases. In the remaining cases, surgical disconnection of the emissary vein from the shunt zone leads to resolution of the fistula. In 80% of cases, improvement is immediate and symptoms regress progressively in a manner that is chronologically inverse to that of their appearance. In more evolved cases, no improvement is obtained. In some rare forms, secondary thrombosis may occur, aggravating the preoperative clinical manifestations. Early diagnosis of the disease allows more effective treatment. The most severe forms are most often associated with delayed diagnosis.

                            Last update:
                            July 2006

                            - Expert reviewer(s):
                            Pr Pierre LASJAUNIAS


A rare cortico-subcortical suprabulbar or pseudobulbar palsy of the lower cranial nerves, characterized by severe dysarthria and dysphagia associated with bilateral central facio-pharyngo-glosso-masticatory paralysis, with prominent automatic-voluntary dissociation in which involuntary movements of the affected muscles are preserved.

Summary:
Epidemiology
Less than 150 cases have been described in the literature so far.
Clinical description
Foix-Chavany-Marie syndrome (FCMS) can occur at any age and patients present with acute-onset bilateral paresis of the facial, lingual, pharyngeal and masticatory muscles (innervated by the V, VII, IX, X and XII cranial nerves). However, the reflexive, emotional and automatic innervations of these muscles are preserved and smiling, crying or yawning under natural circumstances is possible. Facial appearance is atonic and the mouth is half open. Patients with FCMS have severe speech disturbances and most are mute. Chewing and swallowing are severely impaired. The oral stage of swallowing is severely disturbed in most patients, but the swallowing reflex can be adequate if the bolus is delivered into the pharynx. The tongue is almost immobile and does not show muscular atrophy and fibrillation. The jaw reflex is exaggerated (sometimes leading to trismus). In children, FCMS is usually associated with delayed psychomotor milestones and epilepsy.
Etiology
FCMS is caused by developmental or acquired bilateral lesions of the anterior opercula. In children, it presents congenitally (bilateral opercular polymicrogyria) or as an acquired disorder due to encephalitis, epilepsy and neurodegenerative disorders. The syndrome is generally sporadic but some familial cases have been described. In adults, FCMS is associated with vascular events (generally ischemic), infections of the central nervous system, neoplasms, trauma and epileptic disorders.
Diagnostic methods
Diagnosis is based on patient history, clinical examination and magnetic resonance imaging (showing bilateral opercular lesions).
Differential diagnosis
Differential diagnoses include syndromes that present with bulbar palsy (amyotrophic lateral sclerosis, myasthenia gravis and Brown-Vialetto-van Laere syndrome; see these terms). Clinical overlap of FCMS with congenital bilateral perisylvian polymicrogyria and Worster-Drought syndrome (see these terms) has been noted, suggesting a possible continuum of these conditions.
Management and treatment
Management depends on the degree of feeding difficulties and speech problems, and requires a multidisciplinary therapeutic approach. It aims at improving the patient's ability to return to oral feeding. Early percutaneous endoscopic gastrostomy and use of modified feeding techniques and postures may be of benefit.
Prognosis
The disease may have a persistent or intermittent course. Reversible forms have also been described. The prognosis for life expectancy is usually good, but usually patients do not recover voluntary swallowing and speech ability.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Jaime CAMPOS-CASTELLÓ


Folinic acid-responsive seizures is a very rare neonatal epileptic encephalopathy disorder characterized clinically by myoclonic and clonic, or clonic seizures associated with apnea occurring several hours to 5 days after birth and responding to folinic acid.


Follicular cholangitis and pancreatitis is a rare pancreatobiliary disease characterized by marked duct-centered lymphoid follicular inflammation that develops in both biliary and pancreatic ductal systems, mainly affecting the hilar bile ducts and the pancreatic head. Patients present with jaundice, abdominal pain, liver dysfunction, pruritus and/or weight loss. Histology shows lymphoplasmacytic infiltration with formation of numerous, large lymphpoid follicles around the affected bile and pancreatic ducts.


A rare dendritic cell neoplasm characterized by a proliferation of spindled to ovoid cells with morphological and immunophenotypic features of follicular dendritic cells. Conventional follicular dendritic cell sarcomas are negative for EBV. The tumor arises as a painless, slow-growing mass in lymph nodes (most often cervical), extranodal sites (such as tonsils, gastrointestinal tract, soft tissue, mediastinum, or lung, among others), or both. Paraneoplastic pemphigus may occur in rare cases. Predictive factors are tumor size, presence of coagulative necrosis, mitotic count, and presence of significant cytological atypia.