Follicular lymphoma is a form of non-Hodgkin lymphoma (see this term) characterized by a proliferation of B cells whose nodular structure of follicular architecture is preserved.

Summary:
Epidemiology
Prevalence of follicular lymphoma is estimated at about 1/3,000.
Clinical description
The median age at diagnosis is 60-65 years. The disease is extremely rare in children. Follicular lymphoma is located primarily in the lymph nodes, but can also involve the spleen, bone marrow, peripheral blood and Waldeyer's ring. The skin and central nervous system are affected in rare cases. Symptoms appear at an advanced stage of the disease and can include fever, night sweats and weight loss. At diagnosis, patients usually present with adenopathy and, in 50% of cases, splenomegaly.
Etiology
In 85% of cases, follicular lymphomas are associated with a translocation t(14;18) (q32;q21), which activates the BCL2 gene encoding the BCL2 protein that is essential for some apoptosis processes.
Diagnostic methods
Diagnosis is based on histological analysis of the adenopathy, a complete blood count, measurement of lactate dehydrogenase (LDH) and biopsy analysis of a lymph node. Examination using imagery (particularly a chest radiograph) is required. The observation of the translocation t(14;18) by polymerase chain reaction (PCR), in addition to suggested histological results, confirms the diagnosis.
Differential diagnosis
Differential diagnoses include chronic lymphocytic B cell leukemia, diffuse large B cell lymphoma, mantle cell lymphoma and MALT lymphoma (see these terms).
Management and treatment
If the lymphoma is localized it should be treated by radiotherapy. In the case of advanced stage lymphoma, chemotherapy with immuno-chemotherapy should be offered (rituximab combined with CHOP). In cases of chemosensitive relapse, treatment can be intensified.
Prognosis
The survival rate at five years is 80-90% and medial survival is approximately 10-12 years.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Vincent RIBRAG


A rare variant of mycosis fungoides (MF), a form of cutaneous T-cell lymphoma, characterized by the presence of folliculotropic infiltrates in patch-plaque lesions usually involving the head and neck area.

Summary:
Epidemiology
The annual incidence of MF and its variants is estimated at between 1/350,000 and 1/110,000, with folliculotropic MF accounting for about 5% of MF cases. Males are more frequently affected than females.
Clinical description
Folliculotropic MF predominantly affects adults. Skin lesions usually consist of grouped follicular papules, plaques or tumors, preferentially located in the head and neck area. Infiltrated plaques under the eyebrows and alopecia are common. Pruritus is often severe. Most cases present with mucinous degeneration of the hair follicles: these cases are referred to as MF-associated follicular mucinosis. Secondary bacterial infections are frequent. Progression of the disease and involvement of the lymph nodes and/or internal organs may occur as in the classical variant of the disease (see this term).
Etiology
The etiology remains unknown.
Diagnostic methods
The diagnosis is based on clinical presentation and should be confirmed by a skin biopsy. Histological findings reveal variable infiltration of the follicular epithelium by small, medium-sized, or sometimes large hyperchromatic cells with cerebriform nuclei and sparing of the epidermis. Most cases show mucinous degeneration of the follicular epithelium. In most cases, immunohistology reveals a memory T-helper phenotype (CD3+, CD4+ and CD8-).
Differential diagnosis
The main differential diagnoses include inflammatory dermatoses with prominent involvement of the hair follicle, such as lichen planopilaris (see this term). The relationship between "idiopathic" follicular mucinosis and MF remains unclear.
Management and treatment
Management is symptomatic and includes the use of PUVA (photochemotherapy) combined with interferon alpha-2a and retinoids, total body electron beam irradiation, and local radiotherapy in cases of persistent tumors.
Prognosis
The overall 5-year survival rate is 70-80%.

                            Last update:
                            June 2009

                            - Expert reviewer(s):
                            Pr Lorenzo CERRONI


Foodborne botulism is the most common form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis due to botulinum neurotoxins (BoNTs). It is caused by consumption of contaminated food containing BoNTs.

Summary:
Epidemiology
Prevalence is unknown. The annual incidence in Europe is 1/900,000 to 1/500,000. To date, about 40,000 cases have been reported worldwide.
Clinical description
Onset of symptoms occurs in adults generally within 12 to 36-48 hours (range: 6 hours-15 days) after ingestion of contaminated food. The disease is characterized by an acute or subacute afebrile symmetrical cranial nerve palsy, followed by symmetrical descending flaccid motor paralysis. Gastrointestinal symptoms of nausea, abdominal pain, vomiting and diarrhea may precede the neurological signs. In the severe forms, paralysis concerns the neck, shoulder, and proximal muscles, followed by involvement of the muscles of the upper distal extremities, the diaphragm and respiratory muscles, which may result in respiratory compromise or arrest. The sensory system and intellectual functions remain unaffected. The rapidity of onset and severity of the illness depend on the amount and type of BoNTs ingested.
Etiology
The disease is caused by consumption of home-preserved foods (homemade or traditional canned-foods, ham, pork products, vegetables, etc.) contaminated by BoNT-producing Clostridia. Contamination results from the growth and toxin production in foods presenting an anaerobic medium, a pH of ≥4.5, low salt and sugar content, and stored at ≥ 3°C. Of the seven types of BoNTs (A-G), types A, B, E and, more rarely F, are associated with foodborne botulism. Microorganisms involved are Clostridium botulinum or, very rarely neurotoxigenic strains of C. butyricum and C. baratii. Ingested and absorbed BoNTs diffuse via the blood and lymphatic system to reach the neuromuscular junctions.
Diagnostic methods
Diagnosis is essentially clinical in the first stage, based on clinical suspicion together with a 2-5 day food history obtained from the patient. Ingestion of a suspected food, absence of fever, and possible gastrointestinal symptoms are considered typical of foodborne botulism. Confirmation is based on BoNT detection in serum, stools, vomit, gastric aspirate, and suspected food samples. The detection of BoNT-producing Clostridia in stool cultures of a patient presenting typical symptomatology is generally satisfactory for laboratory diagnosis.
Differential diagnosis
Differential diagnosis of foodborne botulism includes myasthenia gravis, Guillain-Barré and Miller-Fisher syndromes, Lambert-Eaton syndrome and, in addition, intestinal and wound botulism (see these terms).
Management and treatment
Antitoxin therapy is effective when it is administrated at the onset of symptoms. The antitoxin therapy must be associated with supportive care in an intensive care unit (ICU). In Europe, the formulation currently available for adults is trivalent (anti A, B, E). A heptavalent (anti A to G) product is also available. In the USA, a bivalent (anti A, B) and a monovalent (anti E) antitoxin are available. Prevention is based on following good practice guidelines for the preparation and storage of foods with the aim of destroying spores, preventing spore germination and/or toxin production. Prompt notification to the public health authorities of suspected cases may prevent further consumption of a contaminated home-preserved or commercial food product.
Prognosis
Foodborne botulism carries an overall worldwide mortality rate of 5-10% (in the USA 3-5%). Prognosis varies according to the amount of ingested toxin and the rapidity of medical assistance. With early, appropriate treatment, the prognosis is generally good and no long-term complications are observed. Complications may occur during hospitalization, including nosocomial adverse events and respiratory failure.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Lucia FENICIA


A rare disorder of folate metabolism and transport characterized, biochemically, by elevated formiminoglutamate in urine and plasma due to glutamate formiminotransferase deficiency, associated with a highly variable clinical phenotype, ranging from developmental delay, intellectual disability and anemia to normal development without anemia. Increased hydantoin-5-propionic acid and/or folate in plasma may also be associated.


Fountain syndrome is an extremely rare multi-systemic genetic disorder characterized by intellectual disability, deafness, skeletal abnormalities and coarse facial features.

Summary:
Epidemiology
The syndrome is exceedingly rare and has been reported in only a few patients to date. Male and female patients have been described.
Clinical description
The main clinical features of Fountain syndrome include moderate to severe intellectual deficit, congenital sensorineural hearing impairment, and broad, stubby hands and feet. A coarse face with full lips and cheeks is also found. These signs are reported to become more prominent with age. Additional reported signs are early-onset, generalized seizures, short stature, large head circumference, and remarkable behavior (friendly demeanor).
Etiology
The etiology of Fountain syndrome has not been elucidated.
Genetic counseling
The pattern of inheritance appears to be autosomal recessive.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Griet VAN BUGGENHOUT


A rare otorhinolaryngeal malformation characterized by a soft, fluctuant mass, abscess or draining tract along the anterior border of the lower half of sternocleidomastoid muscle, occasionally leading to development of retropharyngeal absces, acute suppurative thyroiditis, stridor, respiratory distress, odynophagia, and dysphagia. Anomaly occurs as a tract from the piriform sinus to the thyroid gland. A fourth branchial cleft fistula passes deep to the superior laryngeal nerve but superficial to the recurrent laryngeal nerve, which is the main difference in comparison to the third branchial cleft fistula.


Foveal hypoplasia-optic nerve decussation defect-anterior segment dysgenesis syndrome

A rare, genetic, eye disease characterized by foveal hypoplasia, optic nerve misrouting with an increased number of axons decussating at the optic chiasm and innervating the contralateral cortex, and posterior embryotoxon or Axenfeld anomaly (indicating anterior segment dysgenesis), in the absence of albinism. Patients present congenital nystagmus, decreased visual acuity, refractive errors and, ocassionally, strabismus. Microphthalmia and retinochoroidal coloboma may also be associated.


Foveal hypoplasia-presenile cataract syndrome

A rare genetic ocular disease characterized by congenital nystagmus (horizontal, vertical and/or torsional), foveal hypoplasia, presenile cataracts (with typical onset in the second to third decade of life), and normal irides. Corneal pannus and/or optic nerve hypoplasia may also be present.


Fowler urethral sphincter dysfunction syndrome

A rare urogenital disease characterized by otherwise unexplained chronic urinary retention of more than 1 liter of sterile urine on catheterization, an asensitive bladder with loss of urge to void, and no help of straining. Poor tolerance of self-catheterization is typically reported. The condition occurs in women between menarche and menopause.


A rare, genetic neurological disorder characterized by hydranencephaly, distinctive glomeruloid vasculopathy in the central nervous system and retina, polyhydramnios and fetal akinesia with arthrogryposis. The disorder is usually prenatally lethal. In rare reported cases that survived beyond infancy, severe intellectual and neurologic disability with seizures, microcephaly and absence of functional movements were reported.


FOXG1 syndrome due to 14q12 microdeletion

14q12 microdeletion syndrome is a recently described syndrome characterized by severe intellectual deficit, with a normal neonatal period, followed by a phase of regression at the age of 3-6 months.

Summary:
Epidemiology
It has been clinically and molecularly characterized in 3 patients so far.
Clinical description
The neurological picture evokes the congenital variant of atypical Rett syndrome (see this term). The phenotype includes other features: postnatal growth retardation and microcephaly, hypotonia, epilepsy, stereotypic movements and feeding problems. Dysmorphic features associate prominent metopic suture, bilateral epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears.
Etiology
This syndrome is caused by an interstitial deletion encompassing 14q12. These de novo deletions were characterized by comparative genomic hybridization (CGH) microarray and fluorescence in situ hybridization (FISH). They have a variable size and include FOXG1 as the gene responsible for the intellectual deficit and severe microcephaly.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


A rare genetic neurological disorder characterized by early onset of microcephaly, severe global developmental delay and cognitive impairment, dyskinesia and hyperkinetic movements, visual impairment, autistic behavior, stereotypies, sleep disturbance, epilepsy, and cerebral malformations (such as corpus callosum hypogenesis, forebrain anomaly, and delayed myelination). Speech is minimal or absent, and ambulation is not attained. Patients with a larger 14q12 microdeletion show a more severe phenotype than those with intragenic alterations, with the addition of facial dysmorphism and agenesis of the corpus callosum.


A rare, genetic, syndromic intellectual disability disorder, with highly variable phenotype, typically characterized by mild to severe global development delay, severe speech and language impairment, mild to severe intellectual disability, dysphagia, hypotonia, relative to true macrocephaly, and behavioral problems that may include autistic features, hyperactivity, and mood lability. Facial gestalt typically features a broad, prominent forehead, hypertelorism, downslanting palpebral fissures, ptosis, a short bulbous nose with broad tip, thick vermilion border, wide, and open mouth with downturned corners. Brain, cardiac, urogenital and ocular malformations may be associated.


A rare genetic disease associated with mild to severe intellectual deficit that may be associated with behavioral disorders and characteristic physical features including a high forehead, prominent and large ears, hyperextensible finger joints, flat feet with pronation and, in adolescent and adult males, macroorchidism.

Summary:
Epidemiology
Prevalence is estimated at approximately 1/2400-1/6000 although the prevalence may vary, depending on where the screening is carried out in the world.
Clinical description
Fragile X syndrome (FXS) presents with a variable clinical phenotype. In males, the disease presents during childhood with delayed developmental milestones. Intellectual deficit can be of variable severity and may include problems with working and short-term memory, executive function, language, mathematics and visuospatial abilities. Behavioral anomalies can be mild (e.g. anxiety, mood instability) to severe (e.g. aggressive behavior, autism). Autistic-like behavior can include hand flapping, poor eye contact, hand biting, gaze avoidance, social phobia, social and communication deficits and tactile defensiveness. In females, intellectual and behavioral disorders are typically mild and usually consist of shyness, social anxiety, and mild learning problems with a normal IQ, although 25% of girls have an IQ less than 70. Attention deficit hyperactivity disorder (ADHD) is present in over 89% of males and 30% of females and behavioral disinhibition is very common. Recurrent otitis (60%) and seizures (16 to 20%) can also be observed.
Etiology
FXS is caused by the transcriptional silencing of the FMR1 gene (Xq27.3) due to the progressive expansion and subsequent methylation of (CGG)n trinuleotide repeats in the 5'-untranslated region of the gene. These full mutations originate from unstable alleles called premutations (55-200 CGG repeats). In some rare cases, FXS was shown to result from intragenic FMR1 point mutations or deletions. FMR1 codes for the FMRP, an RNA-binding protein that regulates protein synthesis and other signaling pathways in neuronal dendrites. FMR1 silencing is thought to reduce synaptic plasticity and modulation throughout the brain including the hippocampus.
Diagnostic methods
Diagnosis cannot be based on the clinical picture as physical features may be mild or absent and is therefore based on FMR1 DNA testing, that should be performed for all patients with an intellectual deficiency or autism.
Differential diagnosis
The differential diagnosis includes other X-linked intellectual deficiencies, Sotos syndrome, microdeletion syndromes (e.g. 22q11.2 deletion syndrome), fetal alcohol syndrome or idiopathic autism.
Antenatal diagnosis
Prenatal diagnosis is based on Southern blot hybridization and PCR on samples of chorionic villi or amniotic fluid.
Genetic counseling
FXS is an X-linked dominant disorder with reduced penetrance in females. Genetic counseling should be offered to families of an affected individual or carriers of the premutation.
Management and treatment
Management is symptom-based and requires a multidisciplinary approach. Speech, physical and sensory integration therapy as well as individualized educational plans and behavioral interventions may be combined with medication, such as stimulants for attention deficit-hyperactivity disorder; selective serotonin reuptake inhibitors (SSRIs) for anxiety, depression, obsessive-compulsive disorder; and atypical antipsychotic agents for self-injury and aggressive behaviors. New targeted treatments for FXS are being studied.
Prognosis
Life expectancy is assumed to be normal. The general outlook is variable and depends on the severity of the symptoms; independent living with limited support is possible although severely affected individuals will need more significant, life-long care due to intellectual disabilities and behavioral difficulties.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Randi HAGERMAN


Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder characterized by adult-onset progressive intention tremor and gait ataxia.

Summary:
Epidemiology
Prevalence and incidence are unknown. The disease primarily affects males and there is a lifetime cumulated risk for men in the general population of about 1/8,000.
Clinical description
The age of onset of tremor and/or ataxia in males is about 60 years. The clinical presentation is heterogeneous with variable dominant manifestations including: intention tremor, progressive cerebellar gait ataxia, frontal executive dysfunction, cognitive decline, peripheral neuropathy, and dysautonomia. Other signs include mild parkinsonism and psychiatric manifestations (depression, anxiety, agitation) with possible progression to dementia. Carrier females generally have less severe manifestations than males but also have an increased risk of primary ovarian insufficiency, chronic muscle pain, and hypothyroidism.
Etiology
FXTAS is caused by a CGG trinucleotide repeat expansion (55-200 repeats) in the permutation range of the FMR1 gene (Xq27.3). Approximately 1/260 females and 1/800 males in the general population are permutation carriers and penetrance is age dependent. The disease affects more than 33% of male and 10% of female carriers of the expansion. The severity of the clinical and neuropathological manifestations is correlated with the extent of the CGG expansion
Diagnostic methods
Diagnosis may be difficult because of the combination of signs that are common in elderly patients. Magnetic resonance imaging (MRI) shows global loss of brain volume, in particular cerebellar and cortical atrophy and hyperintensity white matter lesions around the periventricular area and in the middle cerebellar peduncles. Molecular genetic testing is needed to confirm diagnosis.
Differential diagnosis
Differential diagnoses include dementia, rare parkinsonian disorders and spinocerebellar ataxias (see these terms).
Antenatal diagnosis
As this is an adult-onset disorder, no antenatal diagnosis is possible.
Genetic counseling
Transmission follows an X-linked dominant pattern with variable penetrance. Genetic counseling should be provided to patients and their families.
Management and treatment
There is no specific treatment for FXTAS that targets the underlying pathological mechanism. Symptomatic treatment for the psychiatric and neurological manifestations should therefore be provided, along with specific monitoring for progression and degeneration.
Prognosis
The prognosis depends on the speed of progression of the disease, which is highly variable.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Ginevra ZANNI


A rare primary bone dysplasia characterized by megalocornea, multiple skeletal anomalies, characteristic facial dysmorphism (wide fontanels, prominent forehead, hypertelorism, prominent eyes, full cheeks and micrognathia) and developmental delay.


A rare congenital malformation mainly characterized by unilateral or bilateral cryptophthalmos, syndactyly and urogenital anomalies.

Summary:
Epidemiology
The estimated prevalence of Fraser syndrome (FS) in Europe is 1/500,000 births. The disorder affects both sexes equally.
Clinical description
FS is usually characterized by eye (unilateral or bilateral cryptophthalmos, microphthalmos/anophthalmos), urinary tract (renal agenesis, bladder atresia/hypoplasia) and genital anomalies (ambiguous genitalia, cryptorchidism, underdevelopment of male genitalia). Cutaneous syndactyly occurs in both hands and feet. Patients may also present craniofacial (dysplastic ears, bifid nose, cleft lip/palate, microglossia), respiratory (laryngeal stenosis/hypoplasia), cardiac (atrial and ventricular septal defect), digestive tract (anal agenesis/imperforation, diaphragmatic hernia, large bowel obstruction) and skeletal anomalies (skull/spine malformations, clubfoot). In case of severe manifestations, the disease may be fatal for the fetus and the major causes of early death after birth include laryngeal and/or kidney anomalies.
Etiology
FS is a genetically heterogeneous disorder, caused by mutations in FRAS1 (4q21.21), FREM2 (13q13.3) and GRIP1 (12q14.3) genes, coding for extracellular matrix proteins essential for the adhesion between basement membrane of epidermis and connective tissues of dermic layer during embryological development. Mutations in these genes are suggested to be responsible for a failure in apoptosis.
Diagnostic methods
The diagnosis of FS is based on clinical findings, imaging and genetic tests for causative mutations. Karyotype, and imaging of urogenital tract may be required in case of ambiguous genitalia. The diagnostic criteria for FS are divided into six major criteria (syndactyly, cryptophthalmos spectrum, urinary tract abnormalities, ambiguous genitalia, laryngeal and tracheal anomalies and a positive family history) and five minor criteria (anorectal defects, dysplastic ears, skull ossification defects, umbilical abnormalities, nasal anomalies). Diagnosis is confirmed in presence of either three major, or two major and two minor, or one major and three minor diagnostic criteria.
Differential diagnosis
The differential diagnoses include ablepharon-macrostomia, fronto-facio-nasal dysplasia, Fraser-like syndrome, Meckel syndrome, and syndromic microphthalmia caused by heterozygous mutations of SOX2 gene. Isolated cryptophthalmos, frontonasal dysplasia should also be considered.
Antenatal diagnosis
Pre-implantation or prenatal genetic diagnosis is possible if pathogenic mutations responsible for the disease have been identified in the family. Polyhydramnios or oligohydramnios, cryptophthalmos, echogenic lungs, renal abnormalities or agenesis may be detected by antenatal ultrasound.
Genetic counseling
FS is an autosomal recessive disease. Genetic counseling should be proposed to at risk families (both parents are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
The treatment of FS is symptomatic and requires a multidisciplinary team (including surgeon, ear nose throat (ENT) specialist, nephrologist, ophthalmologist and other specialists). Emergency surgery is required in case of respiratory distress. Patients may also need corrective oculoplastic/corneal, ear, digital or genital surgery. In case of feeding difficulties, a nasogastric tube or gastrostomy may be used, along with physiotherapy to get rid of nasal and oral secretions. Symptomatic treatment of chronic kidney disease may be required. Other treatments may include visual/hearing aids, physiotherapy and psychomotor/occupational/speech therapy. Psychological support should be proposed to the patients and their family.
Prognosis
FS survival depends on the severity of associated anomalies, with laryngeal and/or kidney malformations as the major causes of fatality. The disease can be suspected during the prenatal period by ultrasound detection of related malformations; affected fetuses with severe anomalies are delivered stillborn (about 25%). Nevertheless, in less severe case anomalies, extended or normal life expectancy has been reported.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Maria Francesca BEDESCHI | ITHACA* - Dr A.M. [Albertien] VAN EERDE | ERKNet*

                                * European Reference Network


A rare genetic, syndromic glomerular disorder characterized by the association of progressive glomerular nephropathy and 46,XY complete gonadal dysgenesis with a high risk of developing gonadoblastoma.

Summary:
Epidemiology
To date, less than 150 cases have been described.
Clinical description
Nephropathy is the hallmark of the disease. It develops during childhood presenting as persistent proteinuria and subsequently steroid-resistant nephrotic syndrome (SRNS) and progresses to end-stage renal disease (ESRD) in the second or third decade of life. On renal biopsy, focal segmental glomeruloscrelosis (FSGS) is the most common histopathological finding. Individuals have a 46, XY karyotype and present with female external genitalia, complete gonadal dysgenesis and have a higher risk of gonadoblastoma. These individuals are later evaluated for delayed puberty or primary amenorrhea. Since (modest) breast development occurs also without estrogen stimulus, failure to recognize a delayed puberty is not rare. In addition, the clinical picture may be confused by attributing pubertal delay to previous immunosuppressive therapy, renal insufficiency itself or renal transplantation. Complete gonadal dysgenesis results in infertility, female external genitalia and presence of Mullerian structures. Wilms tumor is not common in individuals with Frasier syndrome.
Etiology
Frasier syndrome has been associated to specific pathogenic variants affecting nucleotides 4-5 of the intron 9 (previously referred to as IVS9+4; IVS9+5) in the WT1 gene (11p13). WT1 encodes for a protein that serves as regulatory transcription factor important both for renal and gonadal development.
Diagnostic methods
The diagnosis is suspected on childhood onset of progressive glomerulopathy with findings of FSGS on histological analysis. Phenotypic females with delayed puberty or primary amenorrhea, should be carefully evaluated for signs of nephropathy. When the clinical findings suggest the diagnosis of WT1 associated disorders, single gene testing of the hotspot 8-9 exons with adjacent introns can be performed. Karyotype testing is recommended for all individuals with WT1 intron 9 pathogenic variants.
Differential diagnosis
The main differential diagnosis is idiopathic steroid-resistant nephrotic syndrome, and other WT1 associated diseases including Denys-Drash syndrome, genetic steroid resistant nephrotic syndrome and disorders of testicular development.
Genetic counseling
Most affected individuals have a de novo pathogenic variant and hence negative family history; however, autosomal dominant inheritance has been reported. Where karyotyping is indicated, pre-testing genetic counselling on the possibility of detecting sex reversal should be offered.
Management and treatment
Management is multidisciplinary and should involve a nephrologist for management of chronic renal failure (initially with nephroprotective medical therapy and afterwards with renal replacement therapies or transplantation when ESRD occurs), an endocrinologists for treatment of associated disorder of testicular development, and oncologists and surgeons to evaluate the need for an early gonadectomy in order to prevent tumorigenesis. Preemptive bilateral gonadectomy at the time of renal transplant or placement of a peritoneal dialysis catheter might be an option.
Prognosis
There is limited information on life expectancy. After kidney transplantation, nephrotic syndrome does not recur. 46,XY individuals with complete gonadal dysgenesis are infertile.

                            Last update:
                            December 2019

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

                                * European Reference Network


A rare X-linked syndromic intellectual disability characterized by a variable clinical picture including developmental delay, mild to moderate intellectual disability, learning difficulties, communication deficits, and behavioral problems (such as aggression, attention deficit, hyperactivity, and autistic features). Personality disorder and psychotic behavior have also been reported.


FRAXF syndrome was originally identified in a family with developmental delay and an expanded CCG repeat at the folate-sensitive FRAXF fragile site. Since this initial description, FRAXF has been associated with a range of manifestations but no clear phenotype has been established.

Summary:
Epidemiology
Prevalence is unknown.
Etiology
The FRAXF fragile site is located at Xq28 within the 5'UTR of the TMEM185A gene.

                            Last update:
                            August 2008


A rare lysosomal storage disease characterized by a spectrum of clinical manifestations including neurological and developmental disorders with a severity ranging from the milder form, also called Salla disease (SD), to the most severe phenotype, also called infantile free sialic acid storage disease (ISSD).

Summary:
Epidemiology
The worldwide prevalence is approximately 1/1,000,000. In the Salla region of Finland, where the carrier frequency of the p.Arg39Cys variant of SLC17A5 is 1/100, the prevalence is estimated to be around 1-9/1,000,000. There have been ~250 patients with bi-allelic mutations in SLC17A5 reported in the literature, reflective of the suspected underdiagnosis of free sialic acid storage disorder (FSASD).
Clinical description
Patients with FSASD suffer from progressive neurologic deterioration with psychomotor delay and childhood onset of hypotonia, spasticity and ataxia. Other clinical signs include coarse facial features, organomegaly, bones anomalies, failure to thrive, short stature, neonatal ascites, microcephaly, seizures and cardiac anomalies. Patients with the intermediate form have earlier onset and more severe symptoms. Patients with the infantile form present with very severe symptoms and suffer from early death prenatally or in infancy.
Etiology
The disease is caused by biallelic mutations to the SLC17A5 gene which encodes the sialin protein responsible for the efflux of free sialic acid from lysosomes and the transport of certain neurotransmitters into synaptic vesicles. Loss of function of this transporter causes the symptoms associated with FSASD. There have been approximatey 50 mutations reported to be linked to this disease to date.
Diagnostic methods
Diagnosis is established by measurement of free (unbound) sialic acid accumulation in fibroblast lysosomes, urine or cerebrospinal fluid, and confirmed by genetic testing confirming bi-allelic mutations in the SLC17A5 gene. Quantification of free sialic acid in fibroblasts lysosomes and cytoplasm provides discrimination between sialuria and FSASD. Predominant lysosomal sialic acid overload is suggestive of FSASD, whereas increased concentrations of this metabolite in the cytoplasm are suggestive of sialuria. Normal concentrations of sialic acid in the urine may correlate with milder forms of FSASD. FSASD patients often experience diagnostic delays due to the rarity of the disorder, non-specific clinical symptoms, and absence of routine urine sialic acid testing.
Differential diagnosis
Differential diagnosis includes sialuria (urinary and cellular free sialic acid elevation) and galactosialidosis (sialic acid bound to glycoproteins or glycolipids). FSASD is in the differential diagnosis for severe hypomyelinating leukodystrophies.
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of free sialic acid concentration in chorionic villi or amniotic fluid cells and by genetic analysis of the SLC17A5 gene. Fetal ultrasound may reveal ascites, hydrops fetalis (NIHF), organomegaly, dysostosis, facial dysmorphia and in utero growth delay which can be indicative of lysosome overload.
Genetic counseling
Transmission of FSASD is autosomal recessive. Genetic counselling should be offered to at-risk couples (both individuals carry a mutation) informing them there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is no approved therapy for FSASD. Management is symptomatic and supportive and includes the provision of adequate nutrition, supplementation of calcium and vitamin D, the use of anticonvulsants (for seizures), physical therapy, speech therapy and adapted education.
Prognosis
Life expectancy fluctuates according to the severity of the disease, from 1 day for patients presenting symptoms before birth, to over 70 years for the least severe forms. Free sialic acid concentration correlates with the severity of the disease.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Dr David ADAMS  - Dr Marjan HUIZING  - Dr Melissa WASSERSTEIN


A rare congenital, distal arthogryposis syndrome characterized by microstomia, whistling-face appearance, Chin with V- or H- shaped creased, and prominent nasolabial folds; most patients present club foot and congenital joint contractures of the hands and feet. It is the most severe form of distal arthrogryposis.

Summary:
Epidemiology
Approximately 100 cases of Freeman-Sheldon syndrome (FSS) have been reported to date; no gender predominance is reported and the distribution is worldwide.
Clinical description
Facial features include prominent forehead and eyebrow ridges, hypertelorism, epicanthus, telecanthus, down-slanting palpebral fissures, deep-set eyes, full cheeks, low-set ears, midface hypoplasia, a short nose and long philtrum, deep nasolabial folds, high-arched palate, and chin with a V- or H-shaped crease. The hallmark feature is small mouth with a whistling appearance. Dental crowding and difficulty in maintaining oral hygiene are reported, as well as hearing loss. Multiple contractures in the hands and feet are found at birth and are non-progressive; they cause camptodactyly, ulnar deviation of wrist and fingers, clubfoot, and overlapping fingers. Kyphoscoliosis is a frequent feature; congenital dislocation of the hip is rare. Ocular features include hypertelorism, strabismus, ptosis and blepharophimosis. Delayed growth is almost universal, but cognitive performances are generally normal. Infancy may be characterized by failure-to-thrive, due to microstomia, micrognathia and high palate. Other problems occurring with higher frequency in FSS are sleep apnea, dysglycemia, hyperhidrosis, diarrhea, constipation and gastro-esophageal reflux disease. An increased risk of adverse event during anesthesia is reported, mainly due to difficult intubation (because of orofacial contractures and structural anomalies, limited neck mobility, spinal deformities), difficult vascular access, and susceptibility to malignant hyperthermia.
Etiology
FSS is caused by homozygous mutations in MYH3, encoding for embryonic myosin heavy chain 3, a primary component of fetal myotubules; this protein has a central role during fetal muscular development, while postnatally it is progressively replaced by other isoforms. The switch in myosin expression pattern could explain why contractures are congenital and non-progressive. Mutations in NALCN have been identified in a few cases.
Diagnostic methods
Diagnosis is based on both physical findings and genetic testing on MYH3. Diagnostic criteria have been proposed and include two or more of the following signs: distal arthrogryposis, microstomia, whistling-face, nasolabial creases, and H-shaped chin dimple. In some cases of clinically diagnosed FSS, mutations in NALCN have been detected. Of note, at least 7% of clinical FSS cases are not explained by known pathological allelic variations.
Differential diagnosis
Differential diagnosis mainly includes other distal arthrogryposis such as digitotalar dymorphism (which lacks craniofacial features), Sheldon-Hall syndrome (clinically less severe), Gordon syndrome, trismus-pseudocamptodactyly syndrome, and autosomal dominant multiple pterygium syndrome. Schwartz-Jampel syndrome and CLIFAHDD (congenital contractures of the limbs and face, hypotonia, and developmental delay) are also to be considered.
Antenatal diagnosis
Pre-conception and pre-natal tests are possible, when a relative carries a known pathogenic variant. Prenatal ultrasound can also be useful.
Genetic counseling
Most cases are sporadic (de novo) autosomal dominant mutations; an autosomal recessive inheritance pattern has also been described and seems to be associated with a more severe clinical presentation. Genetic counselling may be offered for patients who have a child with FSS.
Management and treatment
No specific pharmacological therapy is available. Patients should have craniofacial and orthopedic consultation as early in life as possible, in order to undertake proper operative measures (e.g. oral commissuroplasties, dental treatment, blepharoplasty, myringotomies). Operative correction of lower deformities often results in poor outcome. Bracing and physiotherapy (including the Ponseti method) are the cornerstones of non-operative therapy.
Prognosis
Aspiration and respiratory complications may lead to early mortality. Surviving infants usually have normal life expectancy. Quality of life is generally impaired by the multiple malformations and functional repercussions.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Valeria CAPRA | ITHACA* - Dr Gianluca PICCOLO  - Dr Marcello SCALA

                                * European Reference Network


Fried syndrome is a rare X-linked mental retardation (XLMR) syndrome characterized by psychomotor delay, intellectual deficit, hydrocephalus, and mild facial anomalies.

Summary:
Epidemiology
Prevalence is unknown, but the syndrome was originally described in a large Scottish family.
Etiology
Mutations in the AP1S2 gene (Xp22), coding for a subunit of the clathrin-associated adaptor protein complex involved in intracellular protein trafficking and synaptic vesicle recycling, have been identified in seven families.
Diagnostic methods
The presence of basal ganglia calcifications, detectable by CT scan, and elevated CSF protein levels are characteristic features of Fried syndrome and should prompt genetic analysis when found in individuals with XLMR.
Management and treatment
Beyond the management of hydrocephalus and follow-up of psychomotor development, no specific treatment is available.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Ginevra ZANNI


A rare, ectodermal dysplasia syndrome characterized by hypodontia of primary or permanent dentition, and nail dysplasia manifesting as dystrophic fingernails and toenails, and thin, flat nail plates. Additional signs and symptoms may include sparse, slow-growing and fine scalp hair, thin scanty eyebrows, poor jaw development, everted lower lip, dry skin, and sweat gland involvement.


Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder classically characterized by progressive gait and limb ataxia, dysarthria, dysphagia, oculomotor dysfunction, loss of deep tendon reflexes, pyramidal tract signs, scoliosis, and in some, cardiomyopathy, diabetes mellitus, visual loss and defective hearing.

Summary:
Epidemiology
The prevalence of FRDA in Caucasians is estimated at 1/20,000 to 1/50,000.
Clinical description
The classical presentation of FRDA begins in childhood or adolescence. General clumsiness and gait ataxia are usually the first signs to appear, often followed by pyramidal signs, upper-limb ataxia and dysarthria. Oculomotor manifestations present early and include fixation instability (square wave jerks) and nystagmus. Visual loss may occur later. Auditory neuropathy (8-39% of cases), leads to hearing difficulties. Intelligence seems unaffected. Areflexia and distal sensory loss is present in most cases. Dysphagia is mild at first but in advanced disease can lead to choking on foods and liquids. Scoliosis and foot deformities (pes cavus and talipesequinovarus) can be mild or debilitating. Spasticity, seen later in the disease course, can lead to discomfort, pain, positioning problems and contractures in some. Cardiac involvement (typically hypertrophic cardiomyopathy) usually develops later in the disease course, but may rarely precede neurological manifestations. Diabetes mellitus, seen in up to 30% of cases, often presents later. Bladder hyperactivity has been reported in some. The average time from symptom onset to wheelchair dependence is 15.5 years (range 3 to 44). Several atypical phenotypes have been described but overlap is significant.
Etiology
FRDA is caused by an unstable GAA expansion situated in intron 1 of the FXN gene (9q21.11) encoding frataxin. The function of this protein is currently unknown, but the most accepted theory is that it has a role in the biogenesis of iron-sulfur clusters. A deficiency in this protein leads to the progressive central and peripheral nervous system damage seen in FRDA. The length of the shorter allele is inversely correlated to both age of onset and time between onset and wheelchair confinement, and positively with the prevalence of cardiomyopathy.
Diagnostic methods
Motor nerve conduction studies reveal a velocity of greater than 40m/s with absent or reduced sensory nerve action potential. ECG reveals inferolateral or widespread T-wave inversion. MRI may show spinal and cerebellar atrophy. Molecular genetic testing identifies mutations in the FXN gene, confirming diagnosis.
Differential diagnosis
Differential diagnoses include Charcot-Marie-Tooth type 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia type 1 and 2 and other early-onset ataxias.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known mutation.
Genetic counseling
FRDA is inherited autosomal recessively. Genetic counseling is possible.
Management and treatment
There is no cure for FRDA and management is multidisciplinary. Physical therapy and the use of walking aids, prostheses and wheelchairs help maintain an active lifestyle. A speech therapist may be necessary. Stretching programs and the use of frame splints and pharmacologic agents (baclofen and botulinum toxin) help with spasticity. Treatment of cardiac disease includes anti-coagulants, anti-arrhythmic agents and pacemakers. Patients with diabetes mellitus usually require insulin. In later stages, a percutaneous endoscopic gastrostomy tube may be needed. Psychological counseling can be offered. Annual follow-up should include ECG, echocardiography and testing of blood glucose and glycated hemoglobin (HbA1c).
Prognosis
Prognosis has improved but quality of life is still significantly affected. Mean life expectancy is about 40 years, depending on age of onset and presence of diabetes and cardiomyopathy. Death is mainly due to heart disease (cardiac failure or arrhythmia) and bronchopneumonia.

                            Last update:
                            March 2014


Frontal fibrosing alopecia (FFA) is a rare variant of lichen planopilaris (see this term) characterized by symmetrical, progressive, band-like anterior hair loss of the scalp.

Summary:
Epidemiology
Prevalence is unknown. It most commonly affects postmenopausal women, although it has also been reported in men and premenopausal women.
Clinical description
Progressive recession of the frontal and temporal hairline is observed. Approximately half of all cases of FFA also have eyebrow loss; less often there is hair loss in other parts of the body. It is only very rarely associated with classic lichen planus lesions elsewhere. Histopathologically, perifollicular lymphocytic infiltrate and follicular hyperkeratosis are observed at the edge of the affected area, while the rest of the lesion appears pale with loss of the follicular ostia. It is histologically indistinguishable from other forms of lichen planopilaris.
Etiology
It was suggested that the disease could have a hormonal origin, but to date the precise etiology remains unknown.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Stephanie ARNOLD  - Dr Susan COOPER


A rare genetic disease characterized by variable multiple congenital craniofacial anomalies, including brachycephaly, cranium bifidum occultum, hypertelorism, midface hypoplasia, nasal hypoplasia, or cleft lip/palate, among others, as well as abnormalities of the eyes and eyelids. Encephalocele and spina bifida have also been reported in association.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by anomalous ossification and skeletal patterning of the axial and appendicular skeleton, facial dysmorphism and conductive and sensorineural hearing loss.

Summary:
Epidemiology
To date, over 100 cases have been described in the literature.
Clinical description
Frontometaphyseal dysplasia (FMD) is a congenital disorder and the cardinal manifestations in males are skeletal dysplasia (skull base sclerosis; distal phalangeal hypoplasia; progressive contractures of the hand over the first two decades resulting in marked limitation of movement at the interphalangeal, metacarpophalangeal joints, wrists, elbows, knees, and ankles); mild but progressive scoliosis; limb bowing; campomelia), facial dysmorphism (supraorbital hyperostosis, downslanting palpebral fissures, ocular hypertelorism, broad nasal bridge and nasal tip, hypodontia, oligodontia and occasionally craniosynostosis) and conductive and sensorineural hearing loss. Extraskeletal manifestations include congenital heart malformation (interauricular communication, ventricular septal defect, congenital pulmonary valve stenosis, aortic dilatation), congenital subglottic stenosis, an asthenic build, and underdevelopment of the musculature, most notably around the shoulder girdle and in the intrinsic muscles of the hands (common). Males with FMD can present with ureteric and/or urethral obstruction most frequently at the vesicoureteric junction (leading to hydronephrosis). Intelligence is normal. Females are less severely affected and present the characteristic craniofacial features, scoliosis but absent or attenuated digital, cardiorespiratory, and urologic anomalies.
Etiology
The exact pathogenesis of FMD is still unknown, however around half of cases of FMD are caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. There is evidence for a second autosomal locus for FMD that to date remains uncharacterized. FMD is allelic with 4 other skeletal dysplasias (otopalatodigital syndrome type 1 and 2 (OPD1 and OPD2, respectively), terminal osseous dysplasia - pigmentary defects (TOD) and Melnick-Needles syndrome (MNS)).
Genetic counseling
Many pedigrees are consistent with X-linked dominant inheritance. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.

                            Last update:
                            May 2015

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON


Frontonasal arteriovenous malformation is a rare vascular anomaly characterized by abnormal communication between arteries and veins, bypassing the capillary bed, located in the frontonasal area. It may present with intermittent nasal bleeding, blurred vision, pustule formation and/or disfigurement. Overlying skin may be of normal appearance or may manifest a red, pulsatile mass with local rise of temperature. Other features may include pain, ulceration, excessive growth and/or congestive heart failure.


Frontonasal dysplasia-alopecia-genital anomalies syndrome

A rare, genetic, frontonasal dysplasia characterized by coronal craniosynostosis, large skull defect with aplasia of ethmoid and nasal bones, hypertelorism, severely depressed nasal bridge and bifid nasal tip in association with total alopecia and hypogonadism. Intellectual disability is mild to moderate.


Frontonasal dysplasia-bifid nose-upper limb anomalies syndrome

A rare syndromic frontonasal dysplasia characterized by distinctive facial dysmorphic features including hypertelorism, almond-shaped palpebral fissures, nasal deformity with creased ridge, depressed or absent tip, and asymmetry and partial absence of nasal bones, and downturned corners of the mouth. Additional reported manifestations are limb anomalies (e. g. Poland anomaly, transverse limb agenesis, and anomalies of the hands and feet, such as camptodactyly, oligodactyly, clinodactyly, and syndactyly), frontonasal encephalocele, choanal atresia, congenital renal/cardiac malformations, and corpus callosum agenesis.


Frontonasal dysplasia-severe microphthalmia-severe facial clefting syndrome is a rare, genetic, orofacial clefting malformation syndrome characterized by severe frontonasal dysplasia with complete cleft palate, facial cleft, extreme microphtalmia and hypertelorism, frequently associated with eyelid colobomata, sparse or absent eyelashes/eyebrows, wide nasal bridge with hypoplastic alae nasi, low-set, posteriorly rotated ears and caudal appendage in the sacral region.


A group of rare bone development disorders characterized by an array of abnormalities affecting the eyes, forehead, and nose, and linked to midfacial dysraphia. The clinical picture is highly variable, but the major findings include hypertelorism, a broad nasal root, a large and bifid nasal tip, and widow's peak. Occasionally, abnormalities can include accessory nasal tags, cleft lip, ocular abnormalities (coloboma, cataract, microphthalmia), conductive hearing loss, basal encephalocele and/or agenesis of the corpus callosum. Intellectual deficit is rare and more likely to occur in cases where hypertelorism is severe or where there is extra-cranial involvement.


A rare frontonasal dysplasia characterized by hypertelorism, wide nasal bridge, broad columella, widened philtrum, widely separated narrow nares, poor development of nasal tip, midline notch of the upper alveolus, columella base swellings and a low hairline. Additional features reported in some include upper eyelid ptosis and midline dermoid cysts of craniofacial structures and philtral pits or rugose folding behind the ears.


Frontotemporal dementia with motor neuron disease (FTD-MND) is a type of frontotemporal lobar degeneration characterized by the insidious onset (between the ages of 38-78 years) of dementia-associated psychiatric symptoms (e.g. personality changes, uninhibited behavior, irritability, aggressiveness), memory difficulties, global intellectual impairment, emotional disorders and transcortical motor aphasia that eventually leads to mutism, in addition to the manifestations of motor neuron disease such as neurogenic muscular wasting (similar to what is seen in amyotrophic lateral sclerosis; see this term). The disease is progressive, with death occurring 2-5 years after onset.


Frontotemporal dementia (FTD) comprises a group of neurodegenerative disorders, characterized by progressive changes in behavior, executive dysfunction and language impairment, as a result of degeneration of the medial prefrontal and frontoinsular cortices. Four clinical subtypes have been identified: semantic dementia, progressive non-fluent aphasia, behavioral variant FTD and right temporal lobar atrophy (see these terms).


Fructose-1,6-biphosphatase (FBP) deficiency is a disorder of fructose metabolism (see this term) characterized by recurrent episodes of fasting hypoglycemia with lactic acidosis, that may be life-threatening in neonates and infants.

Summary:
Epidemiology
FBP deficiency birth prevalence has been estimated at 1/147,575 in Italy. This disorder has been reported in Japanese, Asian, European, North American, Arab and Moroccan patients.
Clinical description
FBP deficiency may occur neonatally with hepatomegaly, but it usually presents in infants of 3-4 months of age or early childhood, with manifestations including fast-induced hypoglycemia and metabolic acidosis, episodes of tachypnea/apnea, hypoglycemia, ketosis and lactic acidosis. Episodes are often triggered by catabolic conditions such as prolonged fasting (more than 8 to 10 hours), fructose, sorbitol or glycerol ingestion, vomiting, diarrhea or febrile infectious diseases. Patients are asymptomatic between episodes.
Etiology
FBP deficiency is due to homozygous or compound heterozygous mutations in the FBP1(9q22) gene encoding fructose-1,6-bisphosphatase1, resulting in impaired gluconeogenesis. To date, 11deleterious mutations have been reported.
Diagnostic methods
FBP deficiency diagnosis is based on clinical presentation, along with glycemia and lactacidemia levels. Enzyme activity may be measured in leukocytes, and genetic testing of the FBP1 gene confirms diagnosis.
Differential diagnosis
Differential diagnosis includes glycogen storage disease due to glucose-6-phosphatase deficiency (see this term).
Antenatal diagnosis
Prenatal diagnosis is feasible through molecular analysis of amniocytes or chorionic villous cells.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
FBP deficiency management aims at avoiding hypoglycemia and lactic acidosis through frequent feeding, enriched with glucose or maltodextrin, especially in illness associated with fever. Prevention and treatment of metabolic decompensation (with glucose orally or intravenously) is essential. Fasting periods longer than 8 hours should be avoided and infectious episodes should be carefully monitored. Fructose or sucrose should be avoided during acute episodes.
Prognosis
With timely adapted management and proper treatment, FPB deficiency prognosis is excellent, even if this condition may be potentially fatal in the newborn period and early infancy.

                            Last update:
                            September 2015

                            - Expert reviewer(s):
                            Pr Philippe LABRUNE


A rare multiple congenital anomaly syndrome characterized by congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia, distal limb hypoplasia and facial anomalies in addition to variable expression of additional birth defects.

Summary:
Epidemiology
The birth prevalence of Fryns syndrome (FS) has been estimated at 1/14,000 births. FS has been estimated to be present in 4-10% of patients with CDH.
Clinical description
Polyhydramnios is often noted during pregnancy and neonates present with a spectrum of anomalies at birth. The classical features of FS include CDH (unilateral in 75% of cases) together with the associated complications such as lung hypoplasia and left heart hypoplasia. Craniofacial anomalies include a 'coarse' facial appearance, widely spaced eyes, microphthalmia, low-set and anomalous ears, a wide and flat nasal bridge, thick nasal tip with anteverted nares, long philtrum, tented vermilion of the upper lip, wide mouth and small jaw. Distal limb hypoplasia is characteristic and includes short and broad hands, short digits and short terminal phalanges, small or absent nails, and clinodactyly. The thorax can be small with widely spaced nipples. Brain anomalies (ventricular dilation, hydrocephalus, Dandy-Walker malformation) and cardiac malformations (atrial and ventricular septal defects, aortic abnormalities) are reported frequently in affected individuals. Additional anomalies include orofacial clefting, malrotation of the gastrointestinal tract, anal atresia, omphalocele, uro-genital anomalies (renal cysts, ureteral dilation and cryptorchidism), talipes and broad clavicles. In those that survive the neonatal period, severe developmental delay and intellectual disability have been reported.
Etiology
The etiology in many cases is not clear. Several recurrent chromosome aberrations, including microdeletions involving chromosome bands 15q26.2 and 8p23.1, have been reported in probands with clinical presentations similar to FS, but the causal genes in these intervals are yet to be identified. More recently, bi-alleic variants in PIGN have been associated with a FS phenotype. Variants in other genes involved in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway (PIGV and PIGA) have also been identified in several patients with a phenotype overlapping FS.
Diagnostic methods
Diagnosis is primarily based on clinical findings and six clinical criteria have been suggested, comprising CDH, pulmonary hypoplasia, characteristic facial anomalies, distal limb hypoplasia, at least one other characteristic additional anomaly and a family history consistent with autosomal recessive inheritance. FS is classically associated with a normal karyotype; thus array comparative genomic hybridization and copy number variation analysis can be useful in differentiating FS from other chromosomal conditions. Exome sequencing (particularly for PIGN variants or genes of the GPI-anchor biosynthesis pathway), skin biopsy and karyotyping can also be performed to rule out overlapping conditions.
Differential diagnosis
Differential diagnosis includes Donnai-Barrow syndrome, Matthew-Wood syndrome, Simpson-Golabi-Behmel syndrome, craniofrontonasal syndrome, Cornelia de Lange syndrome, tetrasomy 12p, distal monosomy 15q and other chromosome aberrations. Bi-allelic variants in PIGN can also cause multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1) that is not typically associated with CDH.
Antenatal diagnosis
CDH and the other anomalies associated with FS can be diagnosed by ultrasound scanning during a pregnancy.
Genetic counseling
Classically, FS has been inherited as an autosomal recessive (AR) condition. If no cytogenetic or molecular defect is identified, ultrasound scanning can be recommended in future pregnancies of at-risk couples.
Management and treatment
Management is multidisciplinary and may necessitate pediatric specialists in neurology, cardiology, gastroenterology, and nephrology as well as clinical geneticists, developmental pediatricians and regular follow-up in a specialized center. Supportive treatments are directed at the management of the CDH and include extra-corporeal membrane oxygenation (ECMO), nitric oxide and surfactant as therapies for persistent pulmonary hypertension. Other malformations are managed with standard treatment.
Prognosis
Prognosis depends on the severity of the anomalies present, although it is generally guarded with survival beyond the neonatal period being relatively rare. Patients without diaphragmatic defects have a better prognosis.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr Anne SLAVOTINEK


A rare, genetic, syndromic intellectual disability disorder characterized by severe psychomotor development delay (without development of primary motor abilities and speech) and severe intellectual disability, associated with marfanoid habitus, joint laxity, bilateral hip luxation, hypotonia, scoliosis, and characteristic facial dysmorphism (i.e. high nasal bridge, sharp nose, short philtrum, large mouth, full lips and maxillary hypoplasia). There have been no further description in the literature since 1994.


A rare disorder of iron metabolism and transport characterized by elevated serum ferritin levels, increased serum iron, increased transferrin saturation, and heavy iron deposition in hepatocytes. Iron deposition has also been indicated in heart and bone marrow, while hematological examination of peripheral blood shows no abnormalities.


A disorder that is the most frequent form of posterior corneal dystrophy and is characterized by excrescences on a thickened Descemet membrane (corneal guttae), generalized corneal edema, with gradually decreased visual acuity.

Summary:
Epidemiology
The exact prevalence is not known but extreme geographical variability has been reported. FECD is the most prevalent corneal dystrophy in the USA but has been found to be uncommon in Saudi Arabia and in Singaporean Chinese, and very rare in Japan.
Clinical description
The condition is more common and more severe in women (sex ratio 3-4:1). Patients with FECD are initially asymptomatic. Clinical onset is generally in the 5th or 6th decade of life. Discomfort and painful episodes of recurrent corneal erosions occur, along with gradually developing opacification leading to hazy vision. Over time, discomfort may diminish but severe impairment of visual acuity, and even blindness in elderly patients, may be observed. The clinical course often spans 10 to 20 years. The condition is often associated with cataracts. Microbial keratitis and corneal neovascularization are extremely rare complications. Stromal edema produces a blue-gray haze anterior to Descemet membrane followed by eventual thickening of the entire corneal stroma and development of a ground-glass corneal appearance.
Etiology
The etiology of FECD is unknown, but it seems to be a heterogenous complex inherited disorder caused by the interaction of genetic and environmental factors. Mutations in certain genes have been reported in some cases of FECD. Rare cases of early onset have been related to mutations in the COL8A2 gene (1p34.2-p32.3). Heterozygous mutation in the SLC4A11 gene (20p12) has been reported in some late-onset cases of FECD. Other cases have been mapped to chromosomes 13 (13pter-3q12.13) and 18 (18q21.2- q21.32)(TCF4) and to ZEB1 (10p11.22).
Genetic counseling
Although most patients with FECD lack a positive family history, blood relatives sometimes manifest corneal guttae. FECD may also affect siblings and two or more successive generations, apparently as an autosomal dominant disorder having incomplete penetrance, but a simple autosomal dominant pattern is unlikely.
Management and treatment
Most patients with FECD ultimately require a penetrating keratoplasty or a procedure for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK). Visual acuity is markedly improved after a penetrating keratoplasty, DSEK or DSAEK.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Fuchs heterochromic iridocyclitis (FHI) is an ocular disease of unknown etiology occurring in a very small percentage (0.5-6.2%) of uvietis cases, characterized by diffuse iris heterochromia or atrophy, keratic precipitates in the absence of synechiae, and in some cases evolving to glaucoma and vitreous opacities.


A rare lysosomal storage disease characterized by widespread tissue buildup of glycolipids and oligosaccharides rich in fucose. Patients present with broad clinical characteristics such as intellectual disability, developmental delay associated with psychomotor regression and bone abnormalities, visceromegaly, hyperhidrosis, and dermatological abnormalities.

Summary:
Epidemiology
To date, less than 200 cases have been reported in the literature. The estimated incidence is less than 1/200,000 births, but is higher in some regions of Southern Italy, Cuba, Tunisia, and some populations in the USA.
Clinical description
The disease manifests in a spectrum ranging from a rapidly progressing severe form which starts approximately at 6 months of age (type I) to a moderate form with slower evolution (type II). Clinical symptoms and signs primarily include neurological damage leading to intellectual deficiency, psychomotor regression, speech difficulties, posture and walking difficulties, seizures and spasticity. They are often accompanied by coarse facial features, small stature, and dermatological abnormalities such as angiokeratomas. Other symptoms include cardiomyopathy, hepatosplenomegaly, dysostosis multiplex, joint contractures, recurrent lung infections and eye problems.
Etiology
The disease results from mutations in the FUCA1 gene (1p36-p34) which encodes the lysosomal α-L-fucosidase enzyme that catalyzes the hydrolysis of α-L-fucose residues in glycoproteins and oligosaccharides. Loss of function mutations in FUCA1 lead to a defect in synthesis or to the production of a non-functional enzyme and results in intralysosomal accumulation of fucosylated oligosaccharides and glycoproteins. To date, 60 pathogenic and likely pathogenic variants have been reported in the literature or genetic databases.
Diagnostic methods
Diagnosis is based primarily on clinical symptoms and signs as well as biochemical tests measuring fucosylated oligosaccharides and glycoprotein overload. An increase in fucosylated oligosaccharides in urine, accompanied by a reduction of α-L-fucosidase protein activity in the blood, is a strong indication of fucosidosis. The diagnosis may be further confirmed by genetic testing.
Differential diagnosis
Lysosomal storage diseases of the mucopolysaccharidosis type (MPS type 1 to 7), sphingolipidoses (Gaucher's and Fabry's disease), oligosaccharidoses (mannosidosis and Shindler's disease), and juvenile idiopathic arthritis all share some clinical features with fucosidosis. Careful clinical examination, biochemical analysis, and molecular genetic testing allow the exclusion of these diseases.
Antenatal diagnosis
Antenatal screening may be performed by amniocentesis or chorionic villus sampling for families with a pathogenic variant.
Genetic counseling
Inheritance is autosomal recessive. Genetic counseling is recommended to at-risk couples to inform them that there is a 25% chance of having an affected child at each pregnancy.
Management and treatment
Early diagnosis with a multi-systemic supportive care approach, and a multidisciplinary follow-up, can improve the quality of life and the longevity of these patients. Treatment consists of symptom-specific supportive care, such as antibiotic therapy for chronic respiratory infections, and fluid replacement for hyperhidrosis. Hematopoietic stem cell transplantation from bone marrow performed before the onset of severe symptoms may be effective but long-term results have yet to be determined.
Prognosis
In fucosidosis type I, severe neurologic deterioration happens rapidly and death from cachexia usually occurs between 5 and 10 years of age. In fucosidosis type II, neurological deterioration has a slower progression and most patients reach adulthood. There is no known correlation between location of the pathogenic variant in the FUCA1 gene and severity of clinical symptoms.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Elzbieta CIARA  - Pr Aleksandra JEZELA-STANEK  - Dr Karolina STEPIEN


Fuhrmann syndrome is mainly characterized by bowing of the femora, aplasia or hypoplasia of the fibulae and poly-, oligo-, and syndactyly.

Summary:
Epidemiology
It has been reported in 11 patients.
Clinical description
Most of the patients also had a hypoplastic pelvis and hypoplasia of the fingers and fingernails. Some had congenital dislocation of the hip, absence or fusion of tarsal bones, absence of various metatarsals, and hypoplasia and aplasia of the toes. Autosomal recessive inheritance is presumed.
Etiology
The syndrome is caused by a partial loss of WNT7A function (gene mapped to 3p25).
Differential diagnosis
The syndrome is allelic to Schinzel phocomelia (or Al-Awadi-Raas-Rothschild syndrome), which results from null mutations in the same gene.

                            Last update:
                            September 2006


Fukutin-related limb-girdle muscular dystrophy R13

A form of limb-girdle muscular dystrophy characterized by an infantile onset of hypotonia, axial and proximal lower limb weakness (with severe weakness noted after febrile illnesses), cardiomyopathy and normal or reduced intelligence. Hypertrophy of calves, thighs, and triceps have also been reported in some cases.


Neurofibromatosis type 2 (NF2) is a tumor-prone disorder characterized by the development of multiple schwannomas and meningiomas.

Summary:
Epidemiology
Prevalence (initially estimated at 1: 200,000) is around 1 in 60,000.
Clinical description
Affected individuals inevitably develop schwannomas, typically affecting both vestibular nerves and leading to hearing loss and deafness. The majority of patients present with hearing loss, which is usually unilateral at onset and may be accompanied or preceded by tinnitus. Vestibular schwannomas may also cause dizziness or imbalance as a first symptom. Nausea, vomiting or true vertigo are rare symptoms, except in late-stage disease. The other main tumors are schwannomas of the other cranial, spinal and peripheral nerves; meningiomas both intracranial (including optic nerve meningiomas) and intraspinal, and some low-grade central nervous system malignancies (ependymomas). Ophthalmic features are also prominent and include reduced visual acuity and cataract. About 70% of NF2 patients have skin tumors (intracutaneous plaque-like lesions or more deep-seated subcutaneous nodular tumors).
Etiology
NF2 is caused by mutations in the NF2 gene on chromosome 22. More than 50% of patients represent new mutations and as many as one-third are mosaic for the underlying disease-causing mutation. Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common. A strategy for detection of the latter is vital for a sensitive analysis.
Diagnostic methods
Diagnosis is based on clinical and neuroimaging studies. Presymptomatic genetic testing is an integral part of the management of NF2 families.
Differential diagnosis
The main differential diagnosis of NF2 is schwannomatosis.
Antenatal diagnosis
Prenatal diagnosis and pre-implantation genetic diagnosis is possible.
Genetic counseling
NF2 is a dominantly inherited tumor predisposition syndrome.
Management and treatment
NF2 represents a difficult management problem with most patients facing substantial morbidity and reducedlife expectancy. Surgery remains the focus of current management although watchful waiting with careful surveillance and occasionally radiation treatment have a role.
Prognosis
Prognosis is adversely affected by early age at onset, a higher number of meningiomas and having a truncating mutation.

                            Last update:
                            June 2009

                            - Expert reviewer(s):
                            Pr Gareth EVANS  - Pr D GARETH


A rare form of neurofibromatosis characterized by the development of multiple schwannomas (nerve sheath tumors), without involvement of the vestibular nerves, and often associated with chronic pain. Dysesthesia and paresthesia may also be present. Common localizations include the spine, peripheral nerves, and the cranium.


Fulminant viral hepatitis is a rapid and severe impairment of liver functions (acute liver failure) with hepatic encephalopathy developing less than 8 weeks after the onset of jaundice, secondary to viral hepatitis mainly due to HBV, but also to HAV.


Fumaric aciduria (FA), an autosomal recessive metabolic disorder, is most often characterized by early onset but non-specific clinical signs: hypotonia, severe psychomotor impairment, convulsions, respiratory distress, feeding difficulties and frequent cerebral malformations, along with a distinctive facies. Some patients present with only moderate intellectual impairment.

Summary:
Epidemiology
FA is very rare, fewer than 100 cases have been reported to date.
Clinical description
Newborns are frequently microcephalic and may present with facial dysmorphisms. Severe encephalopathy manifests with poor feeding, failure to thrive, hypotonia, lethargy and epileptic seizures. In the most severe cases APGAR scores are low immediately following birth, and bradycardia and respiratory failure may follow. Most children do not achieve visual fixation and are unable to speak or walk. Less severely affected individuals survive beyond childhood, most nonetheless displaying moderate cognitive impairment. Some patients have been reported to present with only moderate cognitive deficits. An increased risk of certain tumors has also been reported, in particular familial leiomyomatosis (see this term).
Etiology
FA is caused by mutations in the FH gene (1q42.1) encoding fumarate hydratase, an enzyme that catalyzes the transformation of fumarate into malate in the Krebs cycle. Complete deletions of FH have been reported to be fatal, whereas more mildly affected individuals retain some residual enzymatic activity.
Diagnostic methods
Chromatography of organic acids provides evidence of excreted fumaric acid, often associated with succinic acid and alphacetoglutaric acid. Hyperlactacidemia and moderate hyperammonemia are other common findings. Diagnosis can be confirmed by measuring fumarate hydratase activity in leukocytes or cultured fibroblasts. Brain MRI reveals a variety of anomalies including cerebral atrophy, enlarged ventricles and enlarged extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum and an abnormally small brain stem. Developmental malformations including bilateral polymicrogyria and absence of the corpus callosum may also be observed.
Differential diagnosis
An elevated level of fumaric acid in urine may be caused by metabolic stress; therefore testing for fumaric aciduria must be repeated after the patient has been stabilized. Differential diagnoses include polymicrogyria and Leigh syndrome (see these terms).
Antenatal diagnosis
Polyhydramnios, intrauterine growth delay and premature birth occur in over one third of cases. Fetal ultrasound reveals enlarged cerebral ventricles and other brain abnormalities.
Genetic counseling
FA is transmitted as an autosomal recessive trait.
Management and treatment
Only symptomatic treatment is available to FA patients. Gastrostomy may be necessary to facilitate feeding in newborns. Therapies to control seizures should not include a ketogenic diet, which is contraindicated for this family of enzymatic defects. Physical therapy to reduce scoliosis and improve mobility may be helpful in some cases. Special education and occupational therapy are required to attempt to improve motor skills and language development in less severely affected cases. For patients that survive long-term, regular tumor testing is required.
Prognosis
Prognosis is poor, except for those patients with only moderate cognitive impairment. Complete losses of enzymatic activity are fatal during childhood with severe psychomotor handicap: verbal communication and independent mobility remain limited. Some milder cases have been reported to survive longer, a diagnosis that is most likely underestimated.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY  - Dr Chris OTTOLENGHI


Functioning gonadotropic adenoma is a very rare pituitary tumor, macroscopically characterized by a soft, well vascularized, variable sized adenoma, with occasional areas of hemorrage or necrosis, that secretes biologically active gonadotropins. In addition to common neurological signs due to mass effect (headache and/or visual field deterioration), additional clinical manifestations include menstrual irregularities (secondary amenorrhea, oligomenorhea or severe menorrhagia), galactorrhea, infertility or ovarian hyperstimulation syndrome (in premenopausal women), testicular enlargement and, occasionally, hypogonadism (in men) and isosexual precocious puberty (in children).


Fundus albipunctatus is a rare, genetic retinal dystrophy disorder characterized by the presence of numerous small, round, yellowish-white retinal lesions that are distributed throughout the retina but spare the fovea. Patients present in childhood with non-progressive night blindness with prolonged cone and rod adaptation times. The macula may or may not be involved, which may result in a decrease of central visual acuity with age.


Fundus pulverulentus is a rare form of patterned dystrophy of the retinal pigment epithelium characterized by a granular appearance in the macula, with coarse and punctiform mottling of the retinal pigment epithelium within the macular region. Association with choroidal neovascularization has been reported.


A rare disorder of the anterior segment of the eye characterized by ocular infection by human-pathogenic fungi, most commonly Aspergillus, Candida, or Fusarium species, which gain access into the corneal stroma through a defect in the corneal epithelium. Risk factors include trauma, ocular surface disease, contact lenses, or immunocompromised state. Patients present with pain, foreign body sensation, redness, photophobia, tearing, secretion, or blurred vision. The condition may be complicated by corneal destruction and perforation, endophthalmitis, scleritis, and panophthalmitis.


A rare acquired skeletal muscle disease characterized by inflammation of a muscle due to infection with a fungus, usually occurring in an immunocompromised host. General symptoms are pain, tenderness, swelling, and/or weakness in the affected muscle. Most common causative agent are Candida species, with myositis developing in the setting of systemic candidiasis, typically as diffuse, multiple microabscesses. Other fungal pathogens potentially causing myositis are Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides species, or Aspergillus species, among others.


A parasitic disease characterized by infestation of the skin with larvae of a variety of fly species. Furuncular myiasis specifically involves flies whose eggs are able to breach healthy skin, which concerns three species: Cordylobia anthropophaga (also called the African tumbu fly or Cayor worm for the larvae) and Cordylobia rodhaini (the Lund's fly), and Dermatobia hominis (the human botfly).

Summary:
Epidemiology
There is no solid data for the incidence of this tropical disease but the cases reported in Europe occur following visits to affected regions (Latin America, Sub-Saharan Africa) or in association with animal importation. The disease is probably underdiagnosed and its incidence underestimated.
Clinical description
Furuncular myiasis only occur on healthy skin. The lesion looks like a bacterial furuncle. However, the head of the larva can be spotted through the central cavity. The patient often reports an intense pain and a feeling of creeping in his skin. The lesion occurs on uncovered areas (lower and upper limbs, head and neck mostly), usually during the rainy season. Infection becomes obvious within 10 to 15 days with the formation of a pseudo-furuncle or emergence of a maggot.
Etiology
Furuncular myiasis can be observed in most countries of Africa and South America, and is not uncommon among international travelers. In the case of Cordylobia anthropophaga and Cordylobia rodhaini, the females lay their eggs on damp fabric or on the ground. The larvae penetrate the skin following contact with the ground or with non-ironed contaminated fabric. Dermatobia hominis is found in Latin America. The egg is laid by the fly under the abdomen of a mosquito, through a phoresis process. The egg is then inoculated to a human during a mosquito bite. Poverty, lack of hygiene and proximity with animals are risk factors. Though primarily affecting low-resources populations in hot humid areas, the disease can also happen in wealthy individuals during outdoor activities in endemic countries.
Diagnostic methods
The diagnosis relies on clinical examination. Ultrasound is rarely performed but can be useful in referral centers.
Differential diagnosis
Differential diagnosis includes furunculosis, abscess, insect bite, prurigo, cutaneous cyst and tungiasis.
Management and treatment
The treatment relies on manual extraction of the larva. It can be achieved by pressing around the lesions with two or four fingers. A punch biopsy can be used if the manual extraction is impossible. When available, intravenous ivermectin can be injected in the lesion cavity to kill the larva and make the extraction easier. Oral ivermectin is not useful. The larva should be extracted as a whole in order to leave no foreign body in the skin. Antibiotics should be used only in case of clinical secondary infection. Tetanus immunization status should be checked.
Prognosis
The condition is not life-threatening and easily treated.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Dr Romain BLAIZOT


Fusariosis describes a superficial, locally invasive, disseminated infection with the pathogenic fungus species, Fusarium, often found in soil and water, which is mainly transmitted to humans through traumatic inoculation and that manifests with keratitis, onychomycosis and less frequently peritonitis and cellulitis. In the immunocompromised, disseminated fusariosis is more common and it manifests with refractory fever, skin lesions (ecthyma-like, target, and multiple subcutaneous nodules), severe myalgias and sino-pulmonary infections.


Fused manidbular incisors is an extremely rare dental anomaly that is characterized by the union of two, normally separated, incisor tooth germs of the primary dentition. It is frequently associated with hypodontia (see this term) and an increased risk of pulp exposure.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable developmental delay and intellectual disability, movement disorder or gait abnormalities, and dysmorphic craniofacial features (such as facial asymmetry, broad forehead, posteriorly rotated ears, thick lower lip, micrognathia, or cleft palate). A variety of congenital malformations have been reported in addition, including ocular, renal, cardiac, and joint anomalies, among others. Some patients show behavioral alterations (autism, hyperactivity, or anxiety).


Gaisbock syndrome is characterised by secondary polycythemia.

Summary:
Epidemiology
It occurs mainly in male sedentary individuals, on a high-calorie diet. Prevalence is unknown.
Clinical description
The clinical picture includes mild obesity, hypertension and decrease in plasma volume with relative increase in hematocrit, blood viscosity, serum cholesterol, triglycerides and uric acid. The reduction in plasma volume seems related to the elevation of the diastolic blood pressure.
Prognosis
Prognosis is impaired by the development of cardiovascular complications.

                            Last update:
                            December 2007


A rare mild form of galactosemia characterized by early onset of cataract and an absence of the usual signs of classic galactosemia, i.e. feeding difficulties, poor weight gain and growth, lethargy, and jaundice.

Summary:
Epidemiology
Prevalence of this form of galactosemia is not known but is estimated to be less than 1/ 100,000.
Clinical description
Patients with galactokinase deficiency generally have elevated plasma galactose and increased urinary excretion of galactitol. They develop cataracts during the first weeks or months of life as a result of accumulation of galactitol in the lens. Patients are otherwise healthy.
Etiology
Galactokinase deficiency is caused by mutations in the GALK1 gene (17q24) coding for the galactokinase enzyme.
Genetic counseling
The disorder is inherited in an autosomal recessive manner.
Prognosis
Development of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Pr M.E. [Estela] RUBIO-GOZALBO


A very rare, moderate to severe form of galactosemia characterized by moderate to severe signs of impaired galactose metabolism.

Summary:
Epidemiology
Overall prevalence is not known but the disorder is thought to be very rare. Annual incidence is not known.
Clinical description
The disorder represents a continuum from peripheral to generalized states with corresponding disease severity. When ingesting breast milk or lactose-containing formula, patients may develop hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, splenomegaly, liver disorders, aminoaciduria, impaired growth, cataracts and cognitive deficiency. In severe cases, the disease can be life-threatening.
Etiology
Galactose epimerase deficiency is caused by mutations in the GALE gene (1p36) encoding the UDP-galactose 4-epimerase enzyme.
Genetic counseling
Galactose epimerase deficiency is inherited in an autosomal recessive manner.
Prognosis
Occurrence of these symptoms can be resolved or prevented by implementing a galactose-restricted diet.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Pr M.E. [Estela] RUBIO-GOZALBO


A rare disorder of galactose metabolism characterized by persistent congenital galactosemia due to deficiency of the enzyme galactose mutarotase. Patients may present bilateral cataract, while gastrointestinal symptoms or severe liver dysfunction are absent. The natural history of the disease is unknown. Severe complications, such as neurological symptoms, have not been reported under early treatment with a galactose-restricted diet.


Galactosemia is a group of rare genetic metabolic disorders characterized by impaired galactose metabolism resulting in a range of variable manifestations encompassing a severe, life-threatening disease (classic galactosemia), a rare mild form (galactokinase deficiency) causing cataract, and a very rare form with variable severity (galactose epimerase deficiency) resembling classic galactosemia in the severe form (see these terms).

Summary:
Epidemiology
Overall prevalence is unknown. The annual incidence of classic galactosemia is estimated to be between 1/40,000 and 1/60,000 in Western countries. Incidence appears to be variable in other ethnic groups with a higher rate reported in the Irish Traveler population possibly due to consanguinity.
Clinical description
Infants usually develop feeding difficulties, poor weight gain and growth, lethargy, and jaundice in the common severe form of the disorder, i.e. classic galactosemia. The rare, less severe clinical subtype of galactosemia (galactokinase deficiency) causes primarily cataracts while other signs of galactosemia are absent. The very rare subtype (galactose epimerase deficiency) has a variable clinical picture including the usual signs of galactosemia (hypotonia, poor feeding, vomiting, weight loss, jaundice) and complications such as impaired growth, cognitive deficit and cataracts.
Etiology
The different galactosemia types are caused by mutations in the GALT, GALK1, and  GALE genes (9p13, 17q24, 1p36) coding for the three enzymes essential in galactose metabolism resulting in impairment of the Leloir galactose degradation metabolic pathway. All three diseases follow an autosomal recessive pattern of inheritance.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Pr M.E. [Estela] RUBIO-GOZALBO


Galactosialidosis is a lysosomal storage disease characterized by coarse facial features, macular ''cherry red spot'', and dysostosis multiplex. Clinical presentation can be heterogenous ranging from a severe, early-onset, rapidly progressive infantile form to late onset, slowly progressive juvenile/adult form.


A rare, very aggressive neuroendocrine neoplasm characterized by the presence of nodular mass(es) arising from the neck, fundus or body of the gallbladder or by diffuse thickening of the gallbladder wall. Patients may be asymptomatic (diagnosed incidentally after surgical resection of the gallbladder) or may present epigastric pain, abdominal mass and/or non-specific symptoms, such as nausea, jaundice, flushing, cough, wheezing, ascites, and anepithymia. Paraneoplastic syndromes, such as Cushing syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis and the Leser-Trélat sign, may be associated.


A rare, genetic multisystem disorder characterized by a neurodegenerative disorder associating global developmental delay, progressive microcephaly, and progressive cerebral and cerebellar atrophy with extrapyramidal involvement, progressive optic atrophy, and in many patients early-onset steroid-resistant nephrotic syndrome.

Summary:
Epidemiology
More than 100 cases have been reported to date. Males and females are equally affected.
Clinical description
Disease onset is typically within the first few months of life, but may be detected in childhood with later onset nephrotic syndrome (NS). Clinical manifestations, primarily involving the kidney and central nervous system, are heterogeneous. Renal manifestations range from isolated proteinuria to full blown early-onset nephrotic syndrome (NS), which is multidrug resistant and rapidly progresses to end-stage kidney disease (ESKD). Neurodegenerative manifestations include progressive microcephaly of prenatal or postnatal onset, global development delay and often severe intellectual disability (most patients never reach independent ambulation and are not verbal) and, more variably, epilepsy, hypotonia, ataxia, spasticity and extrapyramidal dystonia. Structural brain abnormalities are variable and include neural migration defects (lissencephaly-pachygyria spectrum), cerebellar and cortical atrophy, ventricular dilation, encephalomalacia, porencephaly, leukomalacia, generalized hypomyelination, and/or thin corpus callosum. Dysmorphic features include short stature, facial dysmorphism (including a high, narrow forehead, hypertelorism, almond-shape eyes, large and low set ears, and micrognathia) and more variably arachnodactyly, camptodactyly and clasp thumb. Additional frequent features include hiatus hernia and ocular abnormalities (progressive optic atrophy, nystagmus and strabismus).
Etiology
Galloway-Mowat is a genetically heterogeneous condition with causative mutations in at least seven genes, four of which code subunits of Kinase, Endopeptidase and Other Proteins of small Size (KEOPS) complex. The most common form is associated with variations in OSGEP (14q11), are associated with early onset NS (median age 3 months). Whereas, mutations in WDR73 (15q25.2), encoding WD repeat-containing protein 73, or NUP107 (12q15), encoding Nuclear pore complex protein Nup107, are typically associated with a later onset NS.
Diagnostic methods
The coexistence of albuminuria and CNS abnormalities, or of CNS anomalies and functional visual impairment in infants and children is suggestive of the diagnosis. Molecular analysis may confirm the diagnosis.
Differential diagnosis
The main differential diagnoses include Pierson syndrome, ARHGDIA mutations, coenzyme Q deficiency, other mitochondrial disorders, sialidosis and congenital disorders of glycosylation. In patients with no renal involvement at the time of assessment, differential diagnosis extend to syndromes with progressive microcephaly (including those of prenatal onset) and CNS malformations such as the complex cortical dysplasias with other brain malformations (which encompass among others several dominant syndromes causes by mutation in the tubulin genes).
Antenatal diagnosis
The occurrence of microcephaly and intra-uterine growth retardation with oligohydramnios in late second trimester suggests the diagnosis and fetal MRI is recommended as further investigation. In cases with an identified causative mutation, prenatal diagnosis can be offered to the family.
Genetic counseling
The pattern of inheritance is either X-linked (LAGE3) with a 50% risk of recurrence in male siblings of a carrier mother, or autosomal recessive with a 25% risk of recurrence in both male and female siblings.
Management and treatment
There is no specific treatment available. Epilepsy may be intractable. The nephrotic syndrome does not respond to either steroid or immunosuppressive therapy. Renal transplant may be considered for ESKD. Multidisciplinary approach is encouraged to offer a global symptomatic care.
Prognosis
The prognosis is poor; children with early-onset NS typically die during the first year of life due to ESKD. Longer survival is reported for children with later onset NS.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Dr Laurence HEIDET | ERKNet* - Pr Alain VERLOES | ITHACA*

                                * European Reference Network


Gamma-aminobutyric acid transaminase deficiency

A rare disorder of gamma-aminobutyric acid (GABA) metabolism characterized by a severe neonatal-infantile epileptic encephalopathy (manifesting with symptoms such as seizures, hypotonia, hyperreflexia and developmental delay) and growth acceleration.

Summary:
Epidemiology
Five patients from three affected families have been reported in the literature to date.
Clinical description
Onset occurs in the neonatal/infantile period. Manifestations reported include hypotonia, impaired psychomotor development, hyperreflexia, lethargy, seizures, high-pitched cry, accelerated linear growth and developmental delay. The phenotype of GABA-T deficiency is more severe than what is seen in succinic semialdehyde dehydrogenase (SSADH) deficiency (see this term), although some patients have survived infancy but with severe neurodevelopmental impairment including myoclonic seizures and choreoathetosis.
Etiology
GABA-T deficiency is caused by a mutation in the ABAT gene (16p13.2) encoding mitochondrial 4-aminobutyrate aminotransferase (GABA-T). GABA-T is responsible for catalyzing the conversion of gamma-aminobutyrate to succinate semialdehyde in the GABA metabolic pathway. A mutation in this gene leads to an increased accumulation of GABA in central nervous tissue, leading to encephalopathy.
Genetic counseling
GABA-T deficiency is inherited in an autosomal recessive manner.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Dr Mahsa PARVIZ  - Dr Phillip PEARL


A disorder that is characterized by increased glutathione concentration in the plasma and urine.

Summary:
Epidemiology
Gamma-glutamyl transpeptidase deficiency has been detected in seven patients in five families worldwide.
Clinical description
Five of the patients also had central nervous system involvement.
Etiology
Gamma-glutamyl transpeptidase catalyses the first step in the degradation of glutathione. No mutations have been identified in patients with gamma-glutamyl transpeptidase deficiency.
Diagnostic methods
The diagnosis is based on the finding of glutathionuria, elevated levels of glutathione in plasma and decreased activity of gamma-glutamyl transpeptidase in nucleated cells.
Genetic counseling
As the disease is transmitted as an autosomal recessive trait, patients should be offered genetic counseling.
Management and treatment
No specific treatment has been proposed or tested.
Prognosis
The prognosis of gamma-glutamyl transpeptidase deficiency is hard to predict as only seven patients have been described worldwide.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Agne LARSSON  - Dr Ellinor RISTOFF