Familial LCAT (lecithin-cholesterol acyltransferase) deficiency (FLD) is a form of lecithin-cholesterol acyltransferase deficiency (LCAT; see this term) characterized clinically by corneal opacities, hemolytic anemia, and renal failure, and biochemically by severely decreased HDL cholesterol and complete deficiency of the LCAT enzyme.

Summary:
Epidemiology
Prevalence and incidence of FLD are unknown. The disease is very rare: about 70 cases have been reported to date.
Clinical description
Age of onset and severity of clinical manifestations are variable. Corneal opacities usually develop in early childhood and are characterized by grayish dots throughout the corneal stroma. Over time, corneal opacities may lead to severe visual impairment requiring corneal transplantation. The degree of hemolytic anemia is variable. Renal insufficiency is often observed from the second or third decade of life and may present with proteinuria. Renal disease may progress to end-stage renal failure requiring hemodialysis and/or kidney transplantation. Signs of atherosclerosis, hepatomegaly, splenomegaly, and lymphadenopathy have been reported in rare cases.
Etiology
FLD is caused by mutations in the LCAT gene (16q22.1) encoding the LCAT enzyme which catalyzes the formation of cholesterol esters in lipoproteins, leading to progressive lipid deposition in body tissues. More than 70 different mutations have been identified and appear to result in absence of LCAT production or synthesis of an enzyme with no alpha- or beta-LCAT activity (i.e., the activity of LCAT in esterifying cholesterol within HDL or other lipoproteins, respectively). There is no clear genotype-phenotype correlation since family members with the same mutation have been found to have different clinical and biochemical pictures. Environmental factors or other minor genes may therefore also be involved in the disorder.
Diagnostic methods
Family history of characteristic disease features may be useful in diagnosis of the disorder. Diagnostic suspicion is also based on clinical signs and on laboratory tests showing a severe reduction of plasma HDL cholesterol. Kidney biopsy showing distinctive lipid deposits in the glomeruli on histology may also assist in diagnosis. Definitive diagnosis requires molecular genetic testing of the LCAT gene and functional analysis of the gene product.
Differential diagnosis
Differential diagnosis includes fish eye disease (FED) and Tangier Disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible.
Genetic counseling
FLD follows an autosomal recessive pattern of inheritance. Genetic counseling is recommended in affected families.
Management and treatment
Kidney function and visual acuity should be monitored in affected patients. Treatment for anemia and renal insufficiency is symptomatic. Hemodialysis or even kidney transplantation may be needed. Severe visual impairment may require corneal transplantation.
Prognosis
Prognosis is variable. End-stage renal disease is the most serious outcome.

                            Last update:
                            March 2012

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


A rare group of genetic, cardiac rhythm diseases characterized by a prolongation of the QT interval at basal electrocardiography (ECG) and by a high risk of life-threatening arrhythmias.

Summary:
Epidemiology
The most prevalent form, Romano-Ward syndrome (RWS), has a prevalence close to 1/2,500 live births. The other forms of familial LQTS are extremely rare.
Clinical description
The two cardinal manifestations of LQTS are syncopal episodes, which may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities: prolongation of the QT interval and T wave abnormalities. Where there are no extracardiac features, the disease is referred to as RWS. RWS related to SCN5A is sometimes associated with 2:1 atrioventricular block and very early occurrence of cardiac arrhythmias, especially in de novo cases. The Jervell and Lange-Nielsen syndrome also has congenital deafness. Timothy syndrome can be associated with syndactyly, facial dysmorphism and neurodevelopmental features. The Andersen-Tawil syndrome is no longer considered part of LQTS.
Etiology
All the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in the genes that encode the cardiac potassium and sodium channels (KCNQ1, 11p15.5-p15.4 ; KCNH2, 7q36.1 ; SCN5A, 3p22.2) mainly cause the disease by prolonging the duration of repolarization and, thus, of the action potential. KCNQ1 is the most common LQTS variant.
Diagnostic methods
Given the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in the specific diagnostic criteria (the Schwartz score). The molecular screening is now part of the diagnostic process.
Differential diagnosis
Differential diagnosis must be made with epilepsy, catecholaminergic polymorphic ventricular tachycardia (CPVT), and drug-induced LQTS.
Antenatal diagnosis
Prenatal diagnosis should be considered when one of the parents has LQTS.
Genetic counseling
Inheritance may be autosomal dominant or autosomal recessive and depends on the genes involved and the form of familial LQTS. Genetic counseling should be offered to affected families.
Management and treatment
Treatment should always begin with beta-blockers, unless there are valid contraindications. If the patient has a further syncopal episode despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation. Implantable cardioverter-defibrillator (ICD) therapy should be considered when the degree of protection afforded by beta-blockers and LCSD does not appear sufficient, with the final decision being based on individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, and the presence of ECG signs from 24-hour Holter recordings, indicating high electrical instability).
Prognosis
The prognosis is usually good in patients that are correctly diagnosed and treated. The exceptions are patients with Timothy syndrome, Jervell and Lange-Nielsen syndrome patients carrying KCNQ1 mutations and patients with LQTS related to either Calmodulin, TRDN or SCN5A variants.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr Peter SCHWARTZ


Familial median cleft of the upper and lower lips

A rare developmental defect during embryogenesis characterized by incomplete median clefts of both the lower lip (limited to the vermilion, with no muscle involvement) and upper lip (with muscle involvement), double labial frenulum and fusion of the upper gingival and upper labial mucosa (resulting in a shallow upper vestibular fold), in addition to poor dental alignment, and increased interdental distance between the lower and upper median incisors.


Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent short episodes of fever and serositis resulting in pain in the abdomen, chest, joints and muscles.

Summary:
Epidemiology
FMF is primarily found in the south-eastern Mediterranean area. Populations having a high prevalence (1/200-1/1000) of the disease are non-Ashkenazi Jews, Turks, Armenians and Arabs. It is not considered rare in Italy, Greece or Spain.
Clinical description
Disease onset usually occurs before the age of 30 with an earlier onset corresponding to a more severe phenotype. FMF can be divided into 2 types: FMF type 1 and 2. Type 1 is characterized by attacks (as often as once a week or every few years) of fever and serositis lasting 1-4 days and resolving spontaneously. Stress, exposure to cold, fat-rich meals, infections, certain drugs and menstrual cycles are possible attack triggers. Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours. Attacks manifest as fever (38°C-40°C lasting 12-72 hours and not responding to antibiotics), diffuse or localized abdominal pain (often mimicking acute abdomen), constipation (diarrhea in children), arthralgias (in large joints), arthritis (in upper/lower limb/knee joints) and chest pain caused by pleuritis and/or pericarditis (see this term). In 7-40% of patients cutaneous involvement is also present. Amyloidosis type AA (see this term) can be a serious long term complication. FMF type 2 describes a phenotype where amyloidosis occurs as the first and only manifestation of the disease.
Etiology
To date, 218 mutations in the MEFV gene on chromosome 16 encoding the pyrin/marenostrin protein are responsible for the phenotypic variance (M694V homozygous mutations are associated with increased severity) seen in the disease. As not all patients have a mutation in the MEFV gene, other factors may be involved.
Diagnostic methods
The Tel-Hashomer criteria states that 2 major criteria (fever and serositis, amyloidosis AA, effectiveness of colchicine) or 1 major and 2 minor criteria (recurrent attacks of fever, erysipela-like erythema, relatives affected by FMF) must be present for diagnosis. Genetic testing only has a 70-80 % positive predictive value.
Differential diagnosis
Differential diagnoses include hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), TNF receptor-associated periodic syndrome and periodic fever (TRAPS), Marshall's syndrome with periodic fever, transthyretin-related amyloidosis and Behçet's disease (see these terms).
Antenatal diagnosis
Antenatal testing is possible, but not advised.
Genetic counseling
FMF follows an autosomal recessive pattern of inheritance. Genetic counseling for parents with an MEFV mutation can inform them of their risk of passing it on to their children.
Management and treatment
Colchicine (oral or by I.V.) is the drug used to treat FMF. It reduces or eliminates FMF attacks and prevents the occurrence of amyloidosis type AA (see this term). Dosage ranges up to 0.03mg/kg/body weight/daily, or to a maximum of 3mg/daily, and must be taken regularly on a life-long basis. During an attack a nonsteroidal anti-inflammatory drug can be administered.Patients intolerant to colchicine have no alternative of matching efficacy, but Anakinra, interferon-alpha and selective serotonin reuptake inhibitors (SSRIs) have shown encouraging results in some patients. Annual physical examinations along with regulary monitoring of serum amyloid A protein (SAA) is recommended to prevent amyloidosis; colchicine can enhance B12 malabsorption and in rare cases can causes alopecia (see this term) and bone marrow suppression. Macrolides, diltiazem, grapefruit and cyclosporine should not be taken with colchicine as fatal toxicity can occur. Dialysis and organ transplantation might be necessary for those with renal amyloidosis.
Prognosis
Although there is no cure for FMF, colchicine treatment improves patient quality of life. Untreated FMF patients and those with renal amyloidosis have a less favorable prognosis.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Pr Raffaele MANNA


A rare thyroid tumor characterized by a malignant neoplasm derived from the calcitonin-secreting parafollicular C-cells of the thyroid and occurring familially, but not as a component of multiple endocrine neoplasia syndromes. The commonly multifocal, bilateral nodules are typically located at the junction of the upper and middle thirds of the thyroid lobes. Clinically, patients may present with diarrhea, flushing, or weight loss caused by excessive secretion of calcitonin by the tumor. In rare cases, the tumor can also cause Cushing syndrome due to ectopic corticotropin production.


Familial melanoma (FM) is a rare inherited form of melanoma characterized by development of histologically confirmed melanoma in two first degrees relatives or more relatives in an affected family.

Summary:
Epidemiology
FM is thought to account for about 10% of all cases of cutaneous melanoma. Melanoma primarily affects populations of European origin. Incidence is higher in geographical regions with greater sun exposure (southern USA, Australia, New Zealand). Incidence was estimated at 1/90,000 in Europe in 2012.
Clinical description
Familial melanoma tends to occur earlier than non-familial melanoma. The average age of onset is often between 30 and 40 years, while non-familial melanoma typically occurs in the general population between 50 and 60. Earlier and later onset is nonetheless reported in some families. A higher frequency of multiple primary melanomas is also found. Melanoma generally presents as a pigmented lesion on the skin. It is often asymmetrical with irregular borders and color variegation. The diameter is often greater than 6 mm. The most common sites are the trunk, lower legs and back. All four main clinicopathologic subtypes of primary cutaneous melanoma described (spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma) are observed. A variety of growth patterns are found with progression to a potential for metastasis to other organs. Atypical moles are often found in families with FM.
Etiology
The risk of familial melanoma is closely related to a wide range of genetic alterations in susceptibility genes but also appears to be influenced by phenotypic risk factors, such as pigmentation, freckling and nevi and sun reactions but also exposure to UV radiation. Complex interactions between genetic and environmental factors are therefore thought to underlie FM. The most common high-penetrance susceptibility gene implicated in FM is CDKN2A, accounting for predisposition in approximately 20% of FM. CDK4, another high risk gene, is rarely involved. Mutations of BAP1,POT1, TERF2IP, ACD,and TERT have recently been reported and penetrance remains to be determined. Medium penetrance genes include MITFandMC1R.Some twenty common genetic variants modulate risk for melanoma in low clustering families.
Diagnostic methods
FM is suspected in individuals when two or more close relatives have developed melanoma. A new or changing skin mole should be assessed to identify melanoma. Changes include color, border, size, and symmetry.
Differential diagnosis
The main differential diagnoses are seborrheic keratosis, atypical mole, familial atypical multiple mole melanoma and skin carcinoma.
Genetic counseling
In some affected families, susceptibility is consistent with autosomal dominant inheritance but in most cases, a polygenic mode of inheritance appears likely. Patients should be informed that a family history of melanoma in one close relative is associated with an average 2-fold increased risk. History in more than one relative and relevant personal phenotypic characteristics such as multiple pigmented atypical melanocytic lesions result in a significantly higher risk.
Management and treatment
Long-term screening of individuals at high risk and monitoring in FM families is recommended. This involves a total-body skin examination by a qualified dermatologist every six months. Self-examination of skin should be encouraged. Treatment is similar to sporadic melanoma and is largely based on surgery at initial stages.
Prognosis
Prognosis is variable and depends on time of diagnosis, thickness, presence of ulceration, mitotic index, and possible lymph node involvement, and distant metastatic disease. Early diagnosis (with thin Breslow thickness) is associated with a high percentage of cure. Monitoring of melanoma families aims to detect melanoma offering skin surveillance resulting in a favorable prognosis.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Pr Marie-Françoise AVRIL  - Pr Eve MAUBEC


Familial mesial temporal lobe epilepsy with febrile seizures

A rare, genetic, familial partial epilepsy disease characterized by simple partial seizures, complex partial seizures and/or secondarily generalized seizures, originating from the inner aspect of the temporal lobe, associated with an antecedant history of febrile seizures, ocurring in various members of a family. Hippocampal abnormalities (e.g. hippocampal sclerosis) may also be associated.


A rare familial congenital mitral malformation characterized by systolic displacement of one or both mitral leaflets >2 mm beyond the annular plane into the left atrium. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Patients may remain asymptomatic or develop complications such as severe mitral regurgitation, endocarditis, and heart failure.


A rare neoplastic disease characterized by infantile to childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome or acute myeloid leukemia. Most patients present with petechiae, easy bruising, or anemia. Rapid progression is common, and prognosis is generally poor.


A rare thyroid disease characterized by familial occurrence of thyroid enlargement due to the development of multiple hyperplastic nodules with onset in childhood or adolescence. The condition is commonly associated with the development of other benign or malignant tumors.


A rare, genetic, skin tumor disorder characterized by childhood-onset of multiple, benign, asymptomatic, white to flesh-colored papules predominently located on the face, ears, neck and trunk, not associated with systemic organ involvement, malignancies or FLCN gene locus mutation.


Familial multiple lipomatosis is a rare, benign, genetic skin disease characterized by numerous, painless, encapsulated lipomas located in the subcutaneous adipose tissue of the trunk and extremities, with relative sparing of the neck and shoulders. Association with gastroduodenal lipomatosis, brain anomalies or lipomatosis, and refractory epilepsy has been reported.


Familial multiple meningioma is a rare, benign neoplasm of the central nervous system characterized by the development of multiple or, rarely, solitary meningiomas in two or more blood relatives, without other apparent syndromic manifestations. Depending on the localization, growth rate and size of the tumors, patients can present with subtle, gradually worsening or abrupt and severe neurological compromise or can be completely asymptomatic.


Familial multiple nevi flammei is a rare, genetic capillary malformation disorder characterized by dark red to purple birthmarks which manifest as flat, sharply circumscribed cutaneous lesions, typically situated in the head and neck region, in various members of a single family. The lesions grow proportionally with the individual, change in color and often thicken with age.


Familial nasal acilia is a rare genetic otorhinolaryngologic disease characterized by respiratory morbidity due to lack of cilia on the respiratory tract epithelial cells. The disease manifests from birth with respiratory distress, neonatal pneumonia, dyspnea, lobar atelectasis and bronchiectasis. Recurrent infections of the upper and lower respiratory tract, chronic humid coughing, and chronic sinusitis, otitis and rhinitis are typical lifelong presenting conditions.


A rare non-syndromic form of thyroid cancer characterized by occurrence of thyroid carcinoma (TC) as the primary feature in a familial setting.


Familial omphalocele syndrome with facial dysmorphism is a rare genetic developmental defect during embryogenesis characterized by omphalocele associated with facial dysmorphism including flat face, short, upturned nose, long and wide philtrum and flattened maxillary arch and abnormalities of hands.


Familial or sporadic hemiplegic migraine

A rare variety of migraine with aura characterized by the presence of a motor weakness during the aura. There are two main forms depending on the familial history: patients with at least one first- or second-degree relative who has aura including motor weakness have familial hemiplegic migraine (FHM); patients without such familial history have sporadic hemiplegic migraine (SHM).

Summary:
Epidemiology
The prevalence of hemiplegic migraine (HM) is one in 10,000, with FHM and SHM being equally frequent.
Clinical description
Typical HM attacks are characterised by motor weakness that is always associated with other aura symptoms, the most frequent being sensory, visual and speech disorders. In addition, basilar-type symptoms occur in up to 70% of patients. Severe attacks may occur in both FHM and SHM with prolonged hemiplegia, confusion, coma, fever and seizures. The clinical spectrum also includes permanent cerebellar signs (nystagmus, ataxia, dysarthria) and less frequently various types of seizures and intellectual deficit.
Etiology
The three causative genes identified so far encode ion-transporters (CACNA1A, ATP1A2 and SCNA1). Molecular diagnosis is now possible through screening of these three genes.
Genetic counseling
FHM is transmitted in an autosomal dominant manner.
Management and treatment
Treatment involves the same approaches used for other varieties of migraine with aura, with the exception that triptans are contraindicated in FHM/SHM. Based on new pathophysiological insights, preventive treatments using various antiepileptic agents seem promising.
Prognosis
Prognosis is usually good.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Dr Anne DUCROS


A rare genetic bone disease characterized by multifocal, painless, benign fibrocemento-osseous lesions of the jaws which expand progressively and can cause severe facial deformity. It usually manifests at an early age and is often associated with abnormalities of the long bones and pathologic fractures. Radiologically, the lesions are of mixed radiopaque/radiolucent appearance. Incomplete surgical removal may lead to more rapid growth of the residual lesion.


Familial osteochondritis dissecans is a rare genetic skeletal disorder characterized clinically by abnormal chondro-skeletal development, disproportionate short stature and skeletal deformation mainly affecting the knees, hips, ankles and elbows with onset generally in late childhood or adolescence.


Familial osteodysplasia, Anderson type is a rare, genetic dysostosis disorder characterized by craniofacial bone abnormalities (i.e. midface hypoplasia, broad, flat nasal bridge, narrow, thin prognathic mandible with pointed chin, malocclusion, partial dental agenesis) associated with additional osseous anomalies, including scoliosis, calvarial thinning, pointed spinous processes, clinodactyly and abnormal phalanges. Elevated erythrocyte sedimentation rate, hyperuricemia and hypertension have also been reported. There have been no further descriptions in the literature since 1982.


Familial pancreatic carcinoma is defined by the presence of pancreatic cancer (PC) in two or more first-degree relatives.

Summary:
Epidemiology
The annual incidence has been estimated at approximately 1-10/1,000,000, representing 5-10% of all PC cases.
Clinical description
In familial cases, disease onset occurs before 50 years of age, earlier than for the other forms of PC. A high incidence of familial PC has been observed within hereditary syndromes (Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, hereditary breast and ovarian cancer syndrome, and hereditary nonpolyposis colorectal cancer; see these terms). Smoking represents a significant risk factor associated with familial PC. PC can arise from the exocrine (95%) or endocrine portions of the pancreas. In 60% of cases it occurs within the head of the pancreas. The main symptoms are non-specific and include pain in the upper abdomen that typically radiates to the back, loss of appetite, significant weight loss and painless jaundice due to bile duct obstruction. As the clinical course is silent, PC often goes undetected until the advanced stages of the disease. In more than 80% of cases, the cancer is either locally advanced or disseminated at the time of diagnosis. A rapid growth pattern, early vascular dissemination, spread to regional lymph nodes, and metastases to distant organs (liver, peritoneum, lungs) are characteristic. PC can also invade the surrounding visceral organs.
Etiology
Mutations in the KRAS,  CDKN2A, TP53, and SMAD4 genes have been shown to play a role in the etiology of PC. However, they are still not clinically useful for screening or for diagnosing the disease.
Diagnostic methods
Diagnostic methods include ultrasound, contrast-enhanced multidetector computed tomography (MDCT); magnetic resonance (MR) imaging, and integrated positron emission tomography (PET)/computed tomography (CT). Invasive diagnostic techniques are endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound. CA 19-9 is a sensitive tumor serum marker but is not specific.
Differential diagnosis
Differential diagnoses include a wide variety of diseases such as acute and chronic pancreatitis, cholangitis, cholecystitis, cholelithiasis, bile duct tumors and strictures, and gastric cancer and ulcers.
Management and treatment
Surgical resection is the only potentially curative treatment. However, most patients (80%) present with advanced non-resectable tumors. In these cases, chemotherapy (gemcitabine) or radiotherapy, alone or in combination, are alternative treatments, although rather ineffective.
Prognosis
Prognosis is poor (with an overall 5-year survival rate of 5%). Even after complete resection of the tumor, recurrence rates remain high. Patients with a family history of PC should be strongly advised to avoid or cease smoking.

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Pr Dominique VALLA


Familial papillary or follicular thyroid carcinoma is a rare, hereditary nonmedullary thyroid carcinoma characterized by the presence of differentiated thyroid cancer of follicular cell origin in two or more first-degree relatives, in the absence of other familial tumor syndromes or radiation exposure. Frequent capsular invasion is observed. Biopsy reveals multicentric tumors with multiple adenomatous nodules with or without oxyphilia and follicular or papillary carcinoma histology.


Familial papillary thyroid carcinoma with renal papillary neoplasia

An extremely rare inherited tumor syndrome within the familial nonmedullary thyroid cancer group.


A form of hereditary episodic ataxia (EA) characterized by paroxysmal episodes of ataxia lasting hours, with interictal nystagmus and mildly progressive ataxia.


A rare, genetic lipodystrophy characterized by a loss of subcutaneous adipose tissue from the trunk, buttocks and limbs; fat accumulation in the neck, face, axillary and pelvic regions; muscular hypertrophy; and usually associated with metabolic complications such as insulin resistance, diabetes mellitus, dyslipidemia and liver steatosis.

Summary:
Epidemiology
Familial partial lipodystrophy, Dunnigan type (FPLD2) is the most frequent form of familial partial lipodystrophy (FPLD) for which the prevalence is estimated at less than 1/100,000 in Europe; although, this is likely an underestimate.
Clinical description
Onset of lipodystrophy usually occurs at or around puberty, with regional loss of subcutaneous adipose tissue from the limbs, buttocks and trunk, followed by a progressive fat accumulation on the face, neck and axillary regions giving patients a cushingoid appearance. Females often have a more severe phenotype than males. An increased skeletal muscle volume and mass is also noted. Prominent veins (due to lipoatrophy) are noted in the limbs. Metabolic complications appear progressively in adolescence or in adulthood and include insulin resistance, diabetes, hepatic steatosis, acanthosis nigricans, high blood pressure, and premature atherosclerosis with an increased risk of coronary heart disease. Some patients may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. All patients are typically predisposed to early cardiovascular diseases. Other manifestations may include complications of diabetes, recurrent acute pancreatitis and liver steatohepatitis or cirrhosis.
Etiology
FPLD2 is caused by mutations in the LMNA gene (1q22) encoding the nuclear intermediate filaments A-type lamins. Typical forms of FPLD2 are mainly due to heterozygous substitutions at the 482nd codon of the gene (p.R482W/Q or L mutation). Other monoallelic or biallelic LMNA pathogenic variants are rarely found, and are more frequently associated with atypical forms of lipodystrophies, associated or not with other laminopathic phenotypes (muscular and/or cardiac dystrophies, accelerated aging).
Diagnostic methods
Diagnosis is made by clinical examination, analysis of fat distribution by imaging (MRI, CT-scan and whole-body dual-energy X-ray absorptiometry) and evaluation of metabolic status (hypertriglyceridemia, low levels of high density lipoprotein (HDL)-cholesterol in the blood, hyperinsulinemia, altered glucose tolerance, low circulating levels of leptin and adiponectin). Body mass index is usually normal. Liver enzyme levels should be measured and ultrasonography of liver should be performed, and with transient elastography if a fatty liver disease is suspected. Cardiovascular investigations are needed to search for rhythm and conduction disturbances, and early atherosclerosis. Molecular genetic testing confirms diagnosis.
Differential diagnosis
Differential diagnoses include other forms of FPLD as well as Cushing syndrome, type 2 diabetes, metabolic syndrome and acquired lipodystrophy.
Antenatal diagnosis
Prenatal diagnosis could be discussed in families with a known disease causing mutation.
Genetic counseling
FPLD2 is inherited in an autosomal dominant manner; where there is an affected parent, the risk of disease transmission is 50%.
Management and treatment
Treatment consists of correcting metabolic abnormalities and managing complications. Monitoring diet (reduced intake of dietary fats and carbohydrates) and maintaining daily physical activity can improve the metabolic complications of lipodystrophy. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) can also be helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized under exceptional circumstances in Europe for the treatment of metabolic complications of partial forms of lipodystrophies, in adults and children above the age of 12 years, where standard treatments have failed. Further studies are required to investigate the benefits and risks of treatment. Regular cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with FPLD2. Plastic surgery can help some patients.
Prognosis
Prognosis is linked to the severity of associated comorbidities (diabetes, pancreatitis, cardiovascular diseases).

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Corinne VIGOUROUX


Familial partial lipodystrophy, Köbberling type, is a very rare form of familial partial lipodystrophy (FPLD; see this term) of unknown etiology characterized by lipoatrophy that is confined to the limbs and a normal or increased fat distribution of the face, neck, and trunk. Arterial hypertension and diabetes have also been associated. Inheritance is thought to be autosomal dominant.


A group of rare genetic lipodystrophies characterized, in most cases, by fat loss from the limbs and buttocks, from childhood or early adulthood, and often associated with acanthosis nigricans, insulin resistance, diabetes, hypertriglyceridemia and liver steatosis.

Summary:
Epidemiology
The prevalence of familial partial lipodystrophy (FPLD) is estimated at less than 1/100,000 in Europe; however, this is likely an underestimate.
Clinical description
Whilst FPLD is clinically and genetically heterogeneous, each form of FPLD shows a varying degree of lipoatrophy of trunk and/or extremities with sparing subcutaneous fat or even fat accumulation in the cervico-facial and/or truncal region. Patients appear normal at birth and throughout childhood regarding fat distribution but develop clinically apparent changes near puberty. Metabolic complications appear progressively in adolescence or in adulthood and include insulin resistance, diabetes, hepatic steatosis, acanthosis nigricans, high blood pressure, and premature atherosclerosis with an increased risk of coronary heart disease. Some females may display the features of polycystic ovary syndrome such as hirsutism, oligomenorrhea, polycystic ovaries and infertility. Patients are typically predisposed to early cardiovascular diseases. Other manifestations may include complications of diabetes, recurrent acute pancreatitis and liver steatohepatitis or cirrhosis. FPLD3 is frequently associated with severe hypertension.
Etiology
FPLD2, the most common form of FPLD, is caused by a mutation in the LMNA gene (1q22) encoding the nuclear intermediate filaments A-type lamins. Other mutations in this gene can lead to atypical lipodystrophies, more frequently associated with other laminopathic phenotypes (muscular and/or cardiac dystrophies, accelerated aging) such as autosomal codominant severe lipodystrophic laminopathy. Other genes associated with rarer genetic variants of FPLD include PPARG (3p25; FPLD3), AKT2 (19q13.1-q13.2), PLIN1 (15q26; FPLD4), CIDEC (3p25; FPLD5) and LIPE (19q13.1-q13.2; FPLD6). FPLD1 is probably of oligogenic or polygenic origin including different etiological subtypes . Many patients with a FPLD phenotype do not display any pathogenic variants in these genes and thus other disease-causing genes are yet to be discovered.
Diagnostic methods
Diagnosis is made by clinical examination, analysis of fat distribution by imaging (MRI, CT-scan and whole-body dual-energy X-ray absorptiometry) and evaluation of metabolic status (hypertriglyceridemia, low levels of high density lipoprotein (HDL)-cholesterol in the blood, hyperinsulinemia, altered glucose tolerance, low circulating levels of leptin and adiponectin). Body mass index is usually normal. Liver enzyme levels should be measured and ultrasonography of liver should be performed, and with transient elastography if a fatty liver disease is suspected. Cardiovascular investigations are needed to search for rhythm and conduction disturbances, and early atherosclerosis. Molecular genetic testing confirms diagnosis.
Differential diagnosis
Differential diagnoses include other forms of FPLD as well as Cushing syndrome, type 2 diabetes, metabolic syndrome and acquired lipodystrophy.
Antenatal diagnosis
Prenatal diagnosis could be discussed in families with a known disease causing mutation.
Genetic counseling
Depending on the causal mutation involved, FPLD can be inherited in an autosomal dominant or recessive manner. Genetic counseling is possible in families with a known disease-causing mutation.
Management and treatment
Treatment consists of correcting metabolic abnormalities and managing complications. Monitoring diet (reduced intake of dietary fats and carbohydrates) and maintaining daily physical activity can improve the metabolic complications of lipodystrophy. Insulin sensitizers (mainly metformin) and lipid-lowering drugs (statins, or fibrates in case of major hypertriglyceridemia) can also be helpful. Diabetes may require other non-specific treatments, along with insulin. The orphan drug metreleptin is authorized under exceptional circumstances in Europe for the treatment of metabolic complications of partial forms of lipodystrophies, in adults and children above the age of 12 years, where standard treatments have failed. Further studies are required to investigate the benefits and risks of treatment. Regular cardiac monitoring is recommended. Ethinylestradiol should be avoided in women with FPLD and hypertriglyceridemia. Plastic surgery can help some patients.
Prognosis
Prognosis is linked to the severity of associated comorbidities (diabetes, pancreatitis, cardiovascular diseases).

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Corinne VIGOUROUX


Familial patent arterial duct is a rare, genetic, non-syndromic, congenital anomaly of the great arteries characterized by the presence of an isolated patent arterial duct (PDA) (i.e. failure of closure of ductus arteriosis after birth) in several members of the same family. Clinical presentation is similar to the sporadic form and may range from neonatal-onset tachypnea, diaphoresis and failure to thrive to adult-onset atrial arrhythmia, signs and symptoms of heart failure and cyanosis limited to the lower extremities.


Familial peripheral male-limited precocious puberty

Familial male limited precocious puberty (FMPP) is a gonadotropin-independent familial form of male-limited precocious puberty, generally presenting between 2-5 years of age as accelerated growth, early development of secondary sexual characteristics and reduced adult height.

Summary:
Epidemiology
FMPP is a very rare condition; prevalence is less than 1/1,000,000.
Clinical description
FMPP presents in boys from 2-5 years of age with precocious signs of puberty including growth acceleration, penile enlargement, acne, pubic hair and facial hair. Spontaneous erection and masturbatory behavior are commonly observed. Testicular volume is moderately increased, in contrast to central precocious puberty (see this term) where testicular volume is markedly enlarged, similar to normal puberty. Presentation is variable, even between siblings, but most untreated patients have been reported to have premature epiphyseal fusion resulting in a compromised adult height. Aggressive behavior and social exclusion may occur. Mild oligospermia has been reported in some adults, but most individuals retain fertility. An increased risk of attention-deficit hyperactivity disorder (ADHD) has been observed.
Etiology
FMPP is caused by an activating mutation of the Lutropin-Choriogonadotropic Hormone Receptor gene (LHCGR, 2p21) which leads to increased levels of sex steroids in the context of low luteinizing hormone. This receptor's chronic activation leads to precocious testosterone production by Leydig cells. No effect is observed in female carriers due to the dual luteinizing hormone (LH)/ follicle stimulating hormone (FSH) signal necessary to promote ovarian stimulation.
Diagnostic methods
Patients display increased serum testosterone levels (typically 3- 20 nmol/l) and decreased secretion of gonadotropins, even after stimulation with luteinizing hormone-releasing hormone (LHRH). Radiological examination reveals skeletal maturation. Diagnosis is confirmed by genetic testing identifying activating mutations in the LHCGR gene.
Differential diagnosis
Differential diagnoses include other causes of precocious puberty associated with low levels of gonadotropins such as adrenal tumors, testicular Leydig cell tumors (ruled out by testicular ultrasound since they can be of small size), human chorionic gonadotropin (HCG)-secreting tumors, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CAH due to 11-beta-hydroxylase deficiency, central precocious puberty (with detectable LH levels that can be stimulated by gonadotropin-releasing hormone (GnRH) or GnRH agonists) (see these terms), and occult exposure to androgens.
Antenatal diagnosis
Prenatal genetic screening is feasible when a proband has been identified.
Genetic counseling
Transmission is autosomal dominant. Mothers may act as silent carriers, with each son having a 50% risk of displaying FMPP.
Management and treatment
Treatment consists in reducing hyperandrogenism in children (sexual maturation, stature). Two options have been proposed. The first one consists of administrating the androgen antagonist bicalutamide (12.5-100 mg/d) together with aromatase inhibitors such as anastrozole (1 mg/d) or letrozole (2.5 mg/d) to normalize the growth rates until adult height has been reached. The second option consists of administrating androgen biosynthesis inhibitors such as ketoconazole (15 mg/kg/d) that result in a decrease in testosterone levels. In both cases, the treatments may be supplemented by GnRH therapy if central (gonadotropin-dependent) precocious puberty develops. Psychological counseling is needed to help the patient and family adjust to the stimulative effects of high androgen levels.
Prognosis
Prognosis is good; with treatment most patients reach an appropriate adult height. The disease does not seem to have any consequence during adulthood but this is based on limited clinical reports.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Pr Jean-Claude CAREL


Familial platelet disorder with associated myeloid malignancy

A rare, genetic, constitutional thrombocytopenia disease characterized by mild to moderate thrombocytopenia, abnormal platelet function and a propensity to develop hematological malignancies, mainly of myeloid origin.

Summary:
Epidemiology
The estimated prevalence at birth is less than 1/ 1 000 000. There are no available data on the incidence of the disease.
Clinical description
Patients present mild to moderate thrombocytopenia (with normal platelet size) and/or abnormalities of platelet function, in particular defective release of delta granules and/or aggregation defects. However, a clear bleeding history (i.e., severe epistaxis, easy bruising, petechial or prolonged bleeding) is absent in many affected individuals. In the event of severe thrombocytopenia or profound platelet dysfunction, thrombocytopenia is usually recognized during the perinatal or infancy period.
Etiology
Heterozygous germline nonsense or missense variants as well as deletions in or of RUNX1 gene (21q22.12) have been identified as the causative alteration of the disease.
Diagnostic methods
Diagnosis is suspected in patients who present with mild to moderate thrombocytopenia, thrombocyte aggregation defect and/or a hematological malignancy (mainly MDS/AML, but also T-ALL) and may have a history of the same in various other family members. Genetic testing including sequencing and copy number analyses that identifies a pathogenic variant in RUNX1 confirms diagnosis.
Differential diagnosis
Differential diagnoses for familial platelet disorder with associated myeloid malignancy include several inherited disorders such as congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR), and Wiskott-Aldrich syndrome (WAS).
Antenatal diagnosis
Prenatal diagnosis is possible in families in which a causative gene mutation has been previously identified in an affected family member.
Genetic counseling
The disease is inherited as an autosomal dominant trait exhibiting incomplete penetrance and variable expressivity. Genetic counseling informing patients with a causative mutation of the 50% risk of transmission to future offspring and their risk to leukemia should be offered in expert centers.
Management and treatment
Currently, hematopoietic stem cell transplantation (HSCT) in preleukaemic patients with the disease remains debatable due to transplantation-associated risks and incomplete penetrance of the disease. In patients with a hematologic malignancy, HSCT may be indicated. However, HSCT using cells of HLA-matched relatives carrying the familial gene variant have to be avoided.
Prognosis
Prognosis depends on the development of a hematological malignancy and its disease course.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Tim RIPPERGER


Familial primary localized cutaneous amyloidosis

A rare primary cutaneous amyloidosis characterized by familial occurrence of lichen and/or macular amyloidosis due to fibrillary degeneration and apoptosis of basal keratinocytes, followed by conversion of filamentous masses into amyloid material in the papillary dermis. Patients typically present with a pruritic eruption of grouped hyperkeratotic papules, which may coalesce to form hyperkeratotic plaques, with a predilection for the lower limbs (lichen amyloidosis), or with hyperpigmented macules, sometimes with a reticulate pattern, most commonly arising on the back, chest or interscapular areas (macular amyloidosis).


A genetic cardiac rhythm disease that may progress to complete atrioventricular (AV) block. The disease is either asymptomatic or manifests as dyspnea, dizziness, syncope, abdominal pain, heart failure or sudden death.

Summary:
Epidemiology
To date more than 50 Familial progressive cardiac conduction defect (PCCD) cases have been described in the literature.
Clinical description
The age of disease onset is variable. Familial PCCD is either asymptomatic or manifests as dyspnea, dizziness, syncopal episodes, abdominal pain, heart failure or sudden death when complete heart block develops. Syncope during exertion has been reported and the disease can progress from a normal electrocardiography (ECG) to right or left bundle branch block and from the latter to complete heart block.
Etiology
Familial PCCD is a degenerative process affecting the His-Purkinje pathway. Mutations in three genes have been identified as disease-causing: SCN5A, SCN1B and TRPM4. Mutations in the genes NKX2-5, TBX5, PRKAG2 and LMNA have been identified when familial PCCD is accompanied by congenital heart disease. Isolated PCCD has also been described in families with carriers of a mutation in one of these genes. A candidate gene, GJA5, has been associated with severe, early onset PCCD and has been described in 2 blood relatives.
Diagnostic methods
Diagnosis of familial PCCD relies on family history of syncope, pacemaker implantation, and sudden death as well as on echocardiogram (ECG) findings showing a major conduction defect (complete right bundle branch block, complete left bundle branch block, left anterior fascicular block / hemiblock or left posterior hemiblock, prolonged PR interval or complete AV block with broad QRS complexes). In most cases, normal cardiac structure and contractile function are observed, but in some, complete AV block can lead to dilation of the left ventricle and heart failure. Ventricular tachycardia and torsade de pointes may be recorded during the recovery phase of an exercise stress test or during complete AV block. Potential congenital heart disease or cardiomyopathy is investigated by ECG or cardiac MRI. Screening of the genes involved in familial PCCD should be achieved even in cases of isolated PCCD at a young age.
Differential diagnosis
The differential diagnosis includes Brugada syndrome, idiopathic ventricular fibrillation, long QT syndrome, lupus neonatal, progressive familial heart block type II, and sudden infant death syndrome.
Genetic counseling
Transmission is autosomal dominant with incomplete penetrance and variable expressivity. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% of passing the mutation to offspring. Recessive or sporadic forms are rare.
Management and treatment
Treatment of PCCD includes the timely implantation of a permanent pacemaker. Follow-up at 6-month intervals is recommended in patients with any degree of heart block and at least a yearly examination is recommended in members of the affected families with a normal ECG. Medications with conduction-slowing properties should be restricted, and fever, an aggravating trigger in individuals with SCN5A mutations, should be preemptively treated. When a clinical diagnosis of PCCD potentially from genetic origin is established in an index case (i.e; PCCD at early age, several cases of PCCD within the family) clinical investigation of first-degree family members is necessary.
Prognosis
There is no genotype-based risk stratification for patients with PCCD. A high incidence of sudden death is observed in patients with either first-degree AV block in association with bifascicular block or in those with symptomatic advanced AV block. In patients who receive pacemaker implantation, the prognosis is excellent and is very close to that of the general population, except in those with LMNA mutations that can lead to ventricular tachycardia and sudden cardiac death. In this population, ICD implantation is recommended in case of severe cardiac conduction defect. For this reason, rapid genetic evaluation to screen LMNA gene is advise in case of PCCD in patient with clinical evaluation in favor of LMNA mutation (presence of ventricular tachycardia, LGE in the septum on the MRI).

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Vincent PROBST


Familial progressive hyper- and hypopigmentation is a rare, genetic, skin pigmentation anomaly disorder characterized by progressive, diffuse, partly blotchy, hyperpigmented lesions that are intermixed with multiple café-au-lait spots, hypopigmented maculae and lentigines and are located on the face, neck, trunk and limbs, as well as, frequently, the palms, soles and oral mucosa. Dispigmentation pattern can range from well isolated café-au-lait/hypopigmented patches on a background of normal-appearing skin to confetti-like or mottled appearance.


Familial progressive hyperpigmentation is a rare, genetic, skin pigmentation anomaly disorder characterized by irregular patches of hyperpigmented skin which present at birth or in early infancy and increase in size, number and confluence with age. Affected areas of the body include the face, neck, trunk and limbs, as well as the palms, soles, oral mucosa and conjuctiva. No hypogmentation macules are observed and no systemic diseases are associated.


Familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome

A rare, genetic retinal disorder characterized by bilateral iris coloboma, progressive retinal dystrophy and marked loss of vision, with or without congenital cataracts. Iridolenticular adhesions, scattered retinal pigmented epithelia mottling, and mild hypermetropic astigmatism may be associated.


Familial prostate cancer (FPC) is a malignant tumor of the prostate with an early onset. FPC is either asymptomatic or causes mictionary symptoms, erectile dysfunction, bone pain, venous compression and infectious or inflammatory syndrome (for the metastatic forms). It is also characterized by familial antecedents.


Familial pseudohyperkalemia (FP) is an inherited, mild, non-hemolytic subtype of hereditary stomatocytosis that is associated with a temperature-dependent anomaly in red cell membrane permeability to potassium that leads to high in vitro potassium levels in samples stored below 37°C. FP is not associated with additional hematological abnormalities, although affected individuals may show some mild abnormalities like macrocytosis.

Summary:
Epidemiology
The prevalence is unknown. Less than 15 kindreds have been reported in the literature so far (the majority being from the United Kingdom). The Arg723Gln substitution in ABCB6 leading to FP-Cardiff (a temperature-dependent pattern of cation leak previously recognized in a UK family) may affect 1/500 Europeans.
Clinical description
FP is an asymptomatic condition that presents through blood tests as unexpectedly high plasma potassium levels, after storage at or below room temperature.
Etiology
All families identified so far have mutations in the ABCB6 gene (2q36), leading to an inherited abnormality in the movement of ions across the red cell membrane, such that when the red cells are cooled they lose potassium into the plasma. Mutations in the PIEZO1 gene have been found in a kindred diagnosed as having FP but actually having dehydrated hereditary stomatocytosis (DHS; see this term), a condition that can have a similar presentation as FP due to the low number of stomatocytes.
Diagnostic methods
Diagnosis of FP may be suspected in patients with apparent hyperkalemia, but otherwise normal clinical and hematological findings, in whom pseudohyperkalemia due to other causes (cell lysis, extreme leukocytosis or thrombocythemia, or use of EDTA anticoagulant) has been excluded. The presence of red-cell based pseudohyperkalemia can be tested by taking heparinized blood, aliquoting, and storing aliquots at 37, 20 and 0°C over 24 hours. At time points, aliquots are taken and spun and the plasma potassium measured in the sample. In the 'pseudohyperkalemic' sample the plasma potassium will typically be normal at time zero, then rise with time in the samples which are stored at 20 and 0°C. In normal samples there is very little change at any temperature. The affected individuals may show mild abnormalities in the red cells (e.g. macrocytosis).
Differential diagnosis
FP needs to be differentiated from true hyperkalemia associated with reduced renal function, acidosis, the use of certain medications and rare diseases such as Addison's disease and pseudohypoaldosteronism type 2 (see these terms). Pseudohyperkalemia can also be caused by leukemic and thrombocythemic conditions, lysis during venipuncture and by the use of EDTA anticoagulant.
Genetic counseling
FP is inherited as an autosomal dominant trait. Genetic counseling may be provided to patients and their families to explain the autosomal dominant and fully penetrant nature of the disorder.
Management and treatment
No treatment is required. However, correct diagnosis is important so that needless urgent calls to hospital, and occasionally misplaced insulin/glucose and/or fludrocortisone treatment (for supposed true hyperkalemia) can be avoided. Because some FP variants show quite large abnormalities at refrigerator temperatures, affected individuals should not donate blood for transfusion.
Prognosis
The prognosis for patients is excellent. Most patients remain asymptomatic.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Lesley BRUCE  - Pr Gordon STEWART


Familial reactive perforating collagenosis is a very rare genetic skin disease characterized by transepidermal elimination of collagen fibers presenting as recurrent spontaneously involuting keratotic papules or nodules.


Familial recurrent peripheral facial palsy

A rare peripheral neuropathy characterized by an acute onset of unilateral facial muscle weakness with Bell's phenomenon. It is non-progressive, resolves spontaneously, and it might be recurrent with no obvious precipitating factors.


A rare, genetic, glucose transport disorder characterized by the presence of persistent isolated glucosuria in the absence of both proximal tubular dysfunction and hyperglycemia. The disorder is benign in the majority of cases although it may occasionally manifest with polyuria, enuresis, a mild growth and pubertal maturation delay, hypercalciuria, aminoaciduria and, in severe cases, increased incidence of urinary infections and episodic dehydration and ketosis during pregnancy and starvation.


A rare, genetic cardiac disease characterized by an early onset of retinal artery macroaneurysms formation and concomitant supravalvular pulmonic stenosis, often requiring surgical correction.


Familial scaphocephaly syndrome, McGillivray type is a rare newly described craniosynostosis (see this term) syndrome characterized by scaphocephaly, macrocephaly, severe maxillary retrusion, and mild intellectual disability.

Summary:
Epidemiology
It has been reported in 11 patients from a three-generation family.
Clinical description
The patients had variable dysmorphic features including high forehead, marked midface hypoplasia with severe maxillary retrusion, relative or absolute prognathism, and malocclusion. More severely affected patients were male and had intellectual disability.
Etiology
Molecular analysis revealed a K526E mutation of the fibroblast growth factor receptor 2 gene, FGFR2.
Genetic counseling
In this family, findings are consistent with autosomal dominant inheritance.

                            Last update:
                            November 2010


A rare, genetic cardiac rhythm disease characterized by a short QTc interval on the surface electrocardiogram (ECG) with a high risk of syncope or sudden death due to malignant ventricular arrhythmia.

Summary:
Epidemiology
This extremely rare syndrome affects mainly young adults or infants and has been reported in nearly 80 families. The disease has been predominantly reported in males.
Clinical description
Whilst the disease may remain asymptomatic, the most common clinical presentation is a cardiac arrest (CA), with approximately 40% of patients suffering an episode of CA between birth and 40 years of age. Other symptoms include syncope and arrhythmias including atrial fibrillation, ventricular fibrillation (VF), supraventricular tachycardia (SVT), and polymorphic ventricular tachycardia. There is a high risk of recurrent arrhythmic events in symptomatic patients. The risk of sudden cardiac death (SDC) is highest in the first year of life and between 20 to 40 years.
Etiology
Mutations in the genes KCNQ1 (11p15.5), KCNH2 (7q36.1), and KCNJ2 (17q24.3), encoding cardiac ionic potassium channels, and the gene encoding the calcium channel, CACNA2D1 (7q21.11), have been identified in affected patients. 40% of patients do not have a genetic cause identified.
Diagnostic methods
According to the European Society of Cardiology Guidelines, SQTS is diagnosed by the presence of a corrected QT (QTc) interval less than or equal to 340 ms on resting 12-lead ECG or should be considered in the presence of a QTc less than or equal 360 ms and one or more of the following: a confirmed pathogenic mutation, a family history of SQTS, a family history of sudden death at young age (less than 40 years of age), or history of ventricular tachyarrhythmia/ventricular fibrillation (VT/VF) in the absence of heart disease. When a patient is diagnosed, clinical assessment is recommended in all family members, including an ECG in newborns.
Differential diagnosis
Differential diagnosis includes other repolarizing disorders such as Brugada syndrome and early repolarization syndrome. Of note, a few rare patients with Brugada syndrome have been reported to have a short QTc.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to affected families. First-degree relatives of an affected individual have a 50% risk of being affected. Sporadic cases have also been reported.
Management and treatment
Currently, an automatic implantable cardioverter-defibrillator (ICD) is recommended for patients who have experienced a sustained VT/VF episode or have survived an aborted cardiac arrest. However, ICD is complicated by a high probability of inappropriate ICD shocks, particularly in pediatric patients, and requires appropriate programming to prevent T-wave oversensing. Quinidine prophylaxis may be considered in patients where ICD is contraindicated/refused or in asymptomatic SQTS patients with a family history of SDC. Patients on quinidine should be carefully monitored for QT prolongation and possible pro-arrhythmic events.
Prognosis
The risk of sudden cardiac death is high, and a history of survived cardiac arrest at the initial presentation is a strong predictor of recurrent ventricular arrhythmias over the course of time.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Isabelle DENJOY


A rare cardiac rhythm disease, usually of the elderly, characterized by electrocardiographic findings of sinus bradycardia, atrial fibrillation, atrial tachycardia sinus arrest, or sino-atrial block, and that manifest with symptoms like syncope, dizziness, palpitations, fatigue, or even heart failure. It results from malfunction of the cardiac conduction system, probably secondary to degenerative fibrosis of nodal tissue in the elderly or secondary to cardiac disorders in younger patients.


Familial spontaneous pneumothorax is a rare, genetic pulmonary disease characterized by the uni- or bilateral accumulation of air in the pleural cavity in persons with a positive family history and no underlying lung disease or previous chest trauma. Patients typically present dyspnea associated with acute onset of sharp and steady pleutiric chest pain of variable severity (which resolves within 24h even though pneumothorax is still present). Reflex tachycardia and/or respiratory or circulatory compromise may be observed. Other syndromes (e.g. Birt-Hogg-Dube, Marfan or Ehlers-Danlos syndromes) may be associated.


Familial steroid-resistant nephrotic syndrome with adrenal insufficiency

A rare disorder with multisystemic involvement and glomerulopathy characterized by progressive steroid-resistant nephrotic syndrome typically associated with focal segmental glomerulosclerosis, as well as primary adrenal insufficiency with adrenal calcifications. Age of onset and disease course are variable, with some cases presenting as severe fetal hydrops, while most patients present in infancy or early childhood and progress to end-stage renal disease within a few years. Additional features include ichthyosis, primary hypothyroidism, hypogonadism, immunodeficiency, and neurological manifestations (such as cognitive impairment, ataxia, sensorineural hearing loss, or seizures).


Familial steroid-resistant nephrotic syndrome with sensorineural deafness

A rare, genetic coenzyme Q10 deficiency characterized by sensorineural deafness and severe, progressive nephrotic syndrome not responding to steroid treatment. Clinical manifestations include early onset proteinuria, hypoalbuminemia and edema, leading to end-stage renal disease. The renal biopsy reveals focal segmental glomerulosclerosis and diffuse mesangial sclerosis. Rarely, seizures, ataxia and dysmorphic features have been described.


Familial supernumerary nipples is a rare breast malformation characterized by the presence, in various members of a single family, of one or more nipple(s) and/or their related tissue, in addition to the normal bilateral chest nipples. The anomaly is usually situated along the embryonic milk line, from axillae to inguinal regions, but other locations are also possible. Association with dental abnormalities, Becker nevus, renal or underlying breast tissue malignancy and genitourinary malformations has been reported.


A rare, genetic epilepsy characterized by mostly benign simple or complex partial seizures with autonomic or psychic auras. Seizures occur infrequently, are of short duration and are usually well controlled with medication. Development and cognition are normal.


Familial thoracic aortic aneurysm and aortic dissection is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch or descending aorta) in the absence of any other associated disease. Depending on the size, location and progression rate of dilatation/dissection, patients may be asymptomatic or may present dyspnea, cough, jaw, neck, chest or back pain, head, neck or upper limb edema, difficulty swallowing, voice hoarseness, pale skin, faint pulse and/or numbness/tingling in limbs. Patients have increased risk of presenting life threatening aortic rupture.


Familial thrombocytosis is a type of thrombocytosis, a sustained elevation of platelet numbers, which affects the platelet/megakaryocyte lineage and may create a tendency for thrombosis and hemorrhage but does not cause myeloproliferation.

Summary:
Epidemiology
The prevalence of familial thrombocytosis is not known.
Clinical description
The disease usually presents at birth but can be discovered at any time during life and thus can affect all ages. Patients present with thrombocytosis which is often discovered on a routine blood test. The clinical presentation is similar to sporadic essential thrombocythemia (ET; see this term) and may include impaired microcirculation resulting in brief episodes of fainting and dizziness, an increased risk of thrombotic events, hemorrhage, and mild splenomegaly. Patients with mutations in the MPL gene also experience frequent development of bone marrow fibrosis and seem to be free of hemorrhagic complications. The course of the disease is milder than sporadic ET and is devoid of the risk of leukemic transformation or progression toward myelofibrosis with myeloid metaplasia.
Etiology
Familial thrombocytosis is caused by germline mutations in the THPO gene (3q26.3-q27) or in the MPL (MPL S505N) gene (1p34)
Diagnostic methods
Diagnosis is based on the observation of elevated levels of platelets (over 450 x 109/L) and the elimination of secondary causes of thrombocythemia. Genetic testing is required to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include causes of thrombocytosis with myeloproliferative neoplasm including chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, sporadic or familial ET and myelodysplasic disorders with thrombocytosis including sideroblastic anemia or 5q- syndrome (see these terms), although these can be excluded by the presence of myeloproliferation. Differential diagnoses also include causes of secondary thrombocytosis including iron deficiency, malignancy, chronic inflammatory disease, splenectomy or aspleny and protracted marrow regeneration.
Genetic counseling
Transmission is autosomal dominant with high penetrance.
Management and treatment
Treatment is based on low dose aspirin at diagnosis. There is no consensus for using platelet lowering therapy despite an increased risk of thrombosis. Patients may have an increased risk of thrombotic events and hemorrhage.
Prognosis
The predominant clinical feature is impaired microcirculation resulting in brief episodes of fainting and dizziness responding well to aspirin when the THPO gene is mutated and an increased risk of thrombosis and a frequent development of marrow fibrosis when MPL gene is mutated. All these may affect life expectancy.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Pr Jean BRIERE


A rare, life-threatening, genetic coagulation disorder characterized by an increased risk of blood clot formation in several members of a family due to a thrombomodulin gene mutation. Patients may manifest with venous thromboembolic disease, premature myocardial infarction and/or arterial thrombosis.


A very rare inherited form of TDC characterized by a mass measuring 3 cm in diameter or less in the midline area of the neck.


Familial thyroid dyshormonogenesis is a type of primary congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth, which results from inborn errors of thyroid hormone synthesis.

Summary:
Epidemiology
Thyroid dyshormonogenesis accounts for 10-15% of permanent congenital hypothyroidism (see this term).
Clinical description
Clinical manifestations are those of other forms of congenital hypothyroidism (see this term). In addition to features of hypothyroidism, patients with dyshormonogenesis can present with goiter.
Etiology
Dyshormonogenesis is caused by hereditary defects in the steps of thyroid hormone synthesis and secretion, the majority of which are transmitted in an autosomal recessive manner but at least one condition has autosomal dominant inheritance. The most common defect is that of thyroid peroxidase activity, which leads to total iodide organification defects (TIOD) and can be caused by autosomal dominant mutations in the DUOX2 and DUOX2A genes (15q15.3, 15q15). Less severe defects cause partial iodide organification defects (PIOD) and can include defects in sodium/iodide transport, defective thyroglobulin action or a defect in the enzyme iodotyrosine deiodinase.
Diagnostic methods
In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up thyroid-stimulating hormone (TSH) or primary TSH test), infants with congenital hypothyroidism are diagnosed after detection by screening tests. However, goiter is rarely seen in babies detected by newborn screening. Diagnosis should be confirmed by elevated serum TSH level and low T4 or free T4 level. TIOD diagnosis is based on high radioactive iodine (RAI) uptake of the thyroid gland followed by more than 90% release after sodium perchlorate administration. Genetic testing can also be used. PIOD is diagnosed with 50-90% release after perchlorate administration (and can be confirmed by genetic testing).
Differential diagnosis
Differential diagnoses include other forms of congenital hypothyroidism (see this term).
Antenatal diagnosis
Genetic counseling and antenatal diagnosis can be offered in families where a genetic defect has been identified.
Management and treatment
Levothyroxine is the treatment of choice (starting dose 10-15mcg/kg/day), with the immediate goal to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.
Prognosis
The prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started at a later age (>30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.

                            Last update:
                            August 2010

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


A phosphocalcic metabolism anomaly, occuring particularly among younger age groups, characterized by the presence of calcified masses in the juxta-articular regions (hip, elbow, ankle and scapula) without joint involvement. Histologically, lesions display collagen necrobiosis, followed by cyst formation and a foreign-body response with calcification. Two forms have been described: normocalcemic tumoral calcinosis and familial tumoral calcinosis.


Familial vesicoureteral reflux is a rare, non-syndromic urogenital tract malformation characterized by the familial occurrence of retrograde flow of urine from the bladder into the ureter and sometimes the kidneys. Patients may be asymptomatic or may present with recurrent, sometimes febrile, urinary tract infections that, in case of acute pyelonephritis, may lead to serious complications (renal scarring, hypertension, renal failure). Spontaneous resolution of the disorder is possible.


Familial visceral myopathy is a rare hereditary myopathic degeneration of both gastrointestinal and urinary tracts that causes chronic intestinal pseudo-obstruction. It usually presents after the first decade of life with megaduodenum, megacystis and symptoms such as abdominal distension and/or pain, vomiting, constipation, diarrhea, dysphagia, and/or urinary tract infections.n.


A rare genetic multisystem disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors.

Summary:
Epidemiology
The expected prevalence at birth is at least 1/160,000.
Clinical description
The first signs of Fanconi anemia (FA) are typically non-hematological features. Limb anomalies typically affect the extremities, are unilateral or (usually asymmetric) bilateral. Minor anomalies can also be present such as low birth length and weight, microcephaly and/or microphthalmia. Skin pigmentation abnormalities (café-au-lait spots) and hypoplastic thenar eminence are frequent. Almost 20% of patients have ear malformations with or without hearing loss. Congenital malformations may involve other organ systems and vary within families. Short stature is syndromic and/or associated to endocrinopathies. Fertility is frequently impaired in males, and is highly disturbed in half of females. When congenital malformations are not prominent, diagnosis may be delayed until the onset of hematological anomalies. Bone marrow failure (BMF) occurs at a median age of 7 years, developing in 90% of patients by 40 years of age. The first manifestations are macrocytosis (very early) and thrombocytopenia. In patients with somatic mosaïcism, blood counts may stay normal until occurrence of hematological malignancy. In general, patients are highly predisposed to solid tumors (most frequently head and neck or anogenital regions).
Etiology
FA is genetically heterogeneous and the implicated variants are involved in DNA repair and genomic stability. More than 90% of patients have mutations within FANCA, FANCC, FANCG or FANCD2 genes. Mutations in genes with an upstream role in the FA-core complex are associated with classic FA. Some of ''Downstream'' variants (e.g.BRCA2) are associated with a very high risk of solid tumors in infancy and early childhood.
Diagnostic methods
Diagnosis relies on the evaluation of chromosomal breakage induced by diepoxybutane (DEB) or mitomycin C (MMC). This test may be normal in patients with somatic mosaicism; in which case, tests should be performed on fibroblasts.
Differential diagnosis
FA clinical manifestations overlap with many malformation syndromes (Dubowitz, Seckel, Holt-Oram, Baller-Gerold, thrombocytopenia-absent radius, Nijmegen breakage syndromes, VACTERL association, dyskeratosis congenital, Blackfan-Diamond anemia) and diagnosis of FA is often delayed until a patient develops BMF or malignancies. FA should be considered in the differential diagnosis of all young patients with BMF of unknown etiology, and in other cancer predisposition syndromes (Bloom, Rothmund-Thomson or Werner syndromes) or syndromes with either constitutional or acquired BMF.
Antenatal diagnosis
Prenatal diagnosis is feasible with a chromosomal breakage assay on fetal blood or, when the mutation is known, by genetic testing.
Genetic counseling
The disorder is usually autosomal recessive. Very rarely, X-linked (FANCB, < 1%) or autosomal dominant (FANCR, <1%) transmission may occur. If the variant is known, medical assisted reproduction should be offered to parents.
Management and treatment
Supportive care includes transfusions of packed red blood cells (RBC) or leucodepleted platelets but if regular transfusion is required, hematopoietic stem cell transplantation (HSCT) should be considered. Currently, the only curative treatment for hematologic manifestations is HSCT. Symptomatic treatment includes oral androgen administration, which improves blood counts in most patients but is associated with severe liver toxicity and does not suppress the leukemic risk. Administration of G-CSF, best after bone marrow aspirate, should be considered in patients with acute severe infections. Regular screening for hematological malignancies is recommended during childhood in non-transplanted patients; with the exception of 1q anomalies, identification of a clonal event should lead to transplantation. Screening for solid tumors should start in adolescence, especially in the post-transplant setting; risk may be higher in patients with chronic GVHD. Any suspect lesion should be biopsied. When malignancies develop, treatment is complicated by the sensitivity to radiation and chemotherapy of FA patients.
Prognosis
HSCT efficiently treats BMF. Solid tumors prevention and treatment are the main challenge for transplanted patients.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Thierry LEBLANC | ITHACA*

                                * European Reference Network


A rare glycogen storage disease due to a deficiency in solute carrier family 2, facilitated glucose transporter member 2 and characterized by hepatorenal glycogen accumulation leading to severe renal tubular dysfunction and impaired glucose and galactose metabolism.

Summary:
Epidemiology
The prevalence is unknown but less than 200 cases have been described in the literature to date.
Clinical description
Onset occurs during the first few months of life with failure to thrive, polyuria, normo/hypokalemic metabolic acidosis, fasting hypoglycemia and post-feeding hyperglycemia. Metabolic acidosis, hypokalemia, hypophosphatemia and rickets are the consequence of severe proximal tubule dysfunction. Growth retardation and hepatosplenomegaly resulting in a protruding abdomen are evident by early childhood. Puberty can be delayed. Generalized osteoporosis can lead to fractures already during childhood. Some patients also display an abnormal fat distribution.
Etiology
The disease is due to homozygous or compound heterozygous mutations in the SLC2A2 gene (3q26.2-q27), encoding the protein, solute carrier family 2, facilitated glucose transporter member 2.
Diagnostic methods
Diagnosis may be suspected on the basis of the clinical manifestations, radiological findings revealing rickets, and from characteristic results from laboratory investigations showing proximal renal tubular dysfunction (massive glucosuria, proteinuria, phosphaturia, hypophosphatemia, aminoaciduria and hypouricemia). However, several cases have been detected through neonatal screening of galactose levels. Additional laboratory findings include fasting hypoglycemia, ketonuria and hypercholesterolemia. Elevated serum biotinidase activity is also found in patients and has recently been proposed as a diagnostic marker for this syndrome and other glycogen storage diseases. Analysis of biopsy samples reveals liver steatosis, and glycogen accumulation in the hepatocytes and proximal renal tubular cells. The diagnosis can be confirmed by identification of a mutation in the SLC2A2 gene.
Differential diagnosis
The principle differential diagnosis is type I glycogen storage disease, which is caused by glucose-6-phosphatase deficiency. The renal phenotype must be differentiated from other forms of genetically determined Fanconi Syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible for families in which the SLC2A2 mutation has already been identified.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling is recommended for affected families. The risk of offspring inheriting the disease is 25% where both parents are unaffected carriers.
Management and treatment
There is no causal treatment. Therapy consists of replacing water and electrolytes lost through urine excretion as a result of the proximal tubule dysfunction. In addition, Vitamin D replacement is also fundamental for preventing hypophosphatemic rickets. Patients should follow a galactose-restricted diabetic diet with fructose as the main source of carbohydrate. During infancy, night feeding can be necessary in order to avoid hypoglycemia.
Prognosis
The long-term prognosis is unknown. However, the description of the first identified patients reveals that renal function is preserved in adulthood despite renal tubular dysfunction and liver involvement also persisting.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Francesco TREPICCIONE | ERKNet*

                                * European Reference Network


A subcutaneous tissue disease characterized by a spectrum of clinical signs ranging from the classical triad of painful and progressively deformed joints, subcutaneous nodules, and progressive hoarseness (due to laryngeal involvement) that presents in infancy, to varying phenotypes with respiratory and neurologic involvement.

Summary:
Epidemiology
Approximately 200 cases of Farber disease have been reported worldwide in the literature to date.
Clinical description
A high clinical variability is seen between patients. The classic phenotype presents at around 3-6 months of age with painful, swollen and stiff joints of the hands and feet, prominent subcutaneous nodules over pressure points, and progressive hoarseness leading to aphonia due to vocal cord infiltration. Patients can also develop cardiac, pulmonary and neurological defects. Progressive neurological deterioration can be marked in some forms with seizures, paraparesis and developmental delay. The most severe neonatal form presents at birth with hydrops fetalis, lethargy, and failure to thrive, as well as hepatosplenomegaly, rapid neurological deterioration, and granulomatous infiltrations to various other organs (i.e. liver, spleen, lungs). Milder forms have also been described with no neurological defects and a longer life-expectancy. In some patients, the disease manifests in childhood as a spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME) in the absence of subcutaneous nodules.
Etiology
Farber disease is caused by mutations in the N-acylsphingosine amidohydrolase (ASAH1) gene (8p22) which encodes acid ceramidase, a lysosomal enzyme that hydrolyzes ceramide into sphingosine and free fatty acid. A deficient activity of this enzyme leads to an accumulation of ceramide in most tissues.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings by assaying the activity of acid ceramidase in peripheral blood leukocytes, cultured lymphoid cells or cultured skin fibroblasts. Alternatively, diagnosis can be performed by determining ceramide concentration in cultured cells or tissues or by studying lysosomal ceramide catabolism in cultured living cells. Identification of mutations in the ASAH1 gene by molecular genetic testing usually allows for diagnostic confirmation.
Differential diagnosis
Differential diagnoses include juvenile idiopathic arthritis, stiff skin syndrome and lethal restrictive dermopathy. Encephalopathy due to prosaposin deficiency should also be excluded.
Antenatal diagnosis
Prenatal diagnosis by DNA testing is possible in families with a known disease-causing mutation. Alternatively, prenatal diagnosis can be performed by measuring acid ceramidase activity in cultured amniotic fluid cells or chorionic villi.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be proposed to affected families informing them of a 25% risk of transmitting the disease where both parents are unaffected carriers.
Management and treatment
There is currently no effective specific therapy for Farber disease, and symptomatic treatment is based on analgesics, corticotherapy, and plastic surgery. However, allogeneic hematopoietic stem cell transplantation provides a promising approach for patients with limited neurological involvement.
Prognosis
The prognosis varies, with some patients dying within the first few days of life (severe neonatal form) and others living until adolescence or early adulthood (milder forms).

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Pr Thierry LEVADE


Farmer's lung disease is the main form of occupational hypersensitivity pneumonitis (see this term), caused by chronic inhalation of microorganisms, often thermophilic actinomycetes and less commonly saccharopolyspora rectivirgula, living in mouldy hay, straw, or grain. It is characterized by variable degrees of dyspnea, cough, tiredness, headaches and occasional fever/night sweats, with acute, sub-acute or chronic clinical course


FASTKD2-related infantile mitochondrial encephalomyopathy

A rare, genetic, mitochondrial oxidative phosphorylation disorder characterized by infantile-onset encephalomyopathy presenting with developmental delay, slowly progressive hemiplegia, intractable epileptic seizures and asymmetrical brain atrophy with dilatation of the ipsilateral ventricle system. Additional features include optic atrophy, mildly increased plasma and/or CSF lactate and decreased cytochrome c oxidase activity in skeletal muscle biopsy.


Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease

A rare glycogen storage disease characterized by fetal or neonatal onset of severe cardiomyopathy with non-lysosomal glycogen accumulation and fatal outcome in infancy. Patients present with massive cardiomegaly, severe cardiac and respiratory complications, and failure to thrive. Non-specific facial dysmorphism, bilateral cataracts, macroglossia, hydrocephalus, enlarged kidneys, and skeletal muscle involvement have been reported in some cases.


A rare inherited human prion disease characterized by adult onset of progressive disturbance and loss of circadian rhythms, dysautonomia with increased sympathetic activity, and cognitive impairment with fluctuating vigilance, impaired long-term memory, disorientation, and oneiric states. Motor disturbances include myoclonus, cerebellar ataxia, and pyramidal signs. The disease rapidly leads to a somnolent or comatose state and is typically fatal after 9 or 30 months on average (bimodal course). Neuropathologic examination shows marked neuronal loss and gliosis predominantly in thalamic nuclei and inferior olives, while deposition of abnormal prion protein may be relatively sparse.


Fatal infantile cytochrome C oxidase deficiency is a very rare mitochondrial disease characterized clinically by cardioencephalomyopathy resulting in death in infancy.


Fatal infantile hypertonic myofibrillar myopathy is a rare, genetic skeletal muscle disease characterized by muscle stiffness and rigidity, hypertonia, weakness, respiratory distress and normal cognition. Patients have persistently elevated creatine kinase and histopathology is typical of myofibrillar myopathy. The manifestation onset follows the short period of normal infantile development and leads to progressive respiratory insufficiency and early death.


Fatal infantile lactic acidosis with methylmalonic aciduria is a rare neurometabolic disease characterized by infantile onset of severe encephalomyopathy, lactic acidosis and elevated methylmalonic acid urinary excretion. Clinically it manifests with severe psychomotor delay, hypotonia, failure to thrive, feeding difficulties and dystonia. Epilepsy and multiple congenital anomalies may be associated.


Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.


Fatal post-viral neurodegenerative disorder

A rare neuroinflammatory disease characterized by the onset of ataxia, dysarthia and cerebral white matter changes which are triggered by viral infection. Episodic progressive neurodegeneration (manifesting with loss of motor and verbal skills, muscle weakness, further cerebral white matter degeneration and, eventually, death) is observed in the absence of hematopathology, cytokine overproduction, fever, hypertrigliceridemia, hypofibrinogenemia and hyperferritinemia.


A rare, genetic, congenital limb malformation syndrome characterized by unilateral or bilateral fibular aplasia/hypoplasia, tibial campomelia, and lower limb oligosyndactyly involving the lateral rays. Upper limb oligosyndactyly and cleft lip/palate may also be associated.


Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a very rare, autosomal recessive form of neurodegeneration with brain iron accumulation (NBIA) characterized by childhood-onset focal dystonia, progressive spastic paraplegia that progresses to tetra paresis, ataxia, dysarthria, intellectual decline, and oculomotor disturbances (optic atrophy), accompanied by iron deposition in the globus pallidus.


A rare disorder of plasmalogen biosynthesis characterized by syndromic severe intellectual disability with congenital cataracts, early-onset epilepsy, microcephaly, global developmental delay, growth retardation and short stature, and spastic quadriparesis. Dysmorphic facial features may be present, including high-arched eyebrows, flattened nasal root, hypertelorism, and long and smooth philtrum. Rhizomelia is not part of the syndrome. Cerebellar atrophy, white matter abnormalities, and Dandy-Walker malformation have been described on brain imaging.


FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by delayed motor development, intellectual disability, dysarthria, pseudobulbar signs, cryptorchidism, and syndactyly associated with a  FLBN1  gene point mutation. Macular degeneration and signs of brain atrophy and spinal cord compression have also been reported.


A rare, potentially fatal , epileptic encephalopathy characterized by explosive-onset of recurrent multifocal and bilateral tonic-clonic seizures following an unspecific febrile illness. The syndrome develops without a clear acute structural, toxic or metabolic cause, in a patient without previous epilepsy. FIRES is a subgroup of new-onset refractory status epilepticus (NORSE), and requires a preceding febrile infection as a mandatory feature.

Summary:
Epidemiology
Based on a small cohort study, in Germany the prevalence is estimated at 1/100,000 and annual incidence at 1/1,000,000 in children and adolescents. Global epidemiological date is lacking. In pediatric cases there is a male predominance, while females seem to be more frequently affected in adulthood. Familial cases have not been reported.
Clinical description
Febrile infection-related epilepsy syndrome (FIRES) is most common in school-age children. Typically, a previously healthy individual manifests with a sudden onset of recurrent multifocal and bilateral tonic-clonic seizures, following an unspecific febrile illness. Refractory, and usually superrefractory, status epilepticus develops. The acute phase can last for weeks or months. A chronic phase follows, without a latent period, characterized by refractory focal epilepsy along with, often severe, impairments in memory, cognition and behavior. Motor disability is less common.
Etiology
The etiology is not fully known. Most likely FIRES is an immune-inflammatory-mediated epileptic encephalopathy, with a vicious circle of inflammation and hyperexcitability. Findings in cerebrospinal fluid (CSF), and the poor response to immune therapies, point to the innate immune system and autoinflammatory rather than autoimmune mechanisms. Variants in known epilepsy genes do not seem to predispose to FIRES.
Diagnostic methods
An extensive work-up is needed to exclude treatable conditions. Initial magnetic resonance imaging is normal or shows temporal lobe signal abnormalities. Diffuse brain atrophy and mesial temporal lobe changes are common in the chronic phase. Analysis of CSF shows normal findings or mild pleocytosis but no presence of pathogens and usually no oligoclonal bands or neuronal antibodies. Metabolic investigations are negative. Genetic investigations to exclude genetic epilepsies such as those related to POLG. Continuous electroencephalogram (cEEG) is required to monitor seizures and depth of anesthesia. Beta-delta complexes resembling extreme delta brush is recorded in some patients in the early phase.
Differential diagnosis
Differential diagnoses include, but are not limited to, infectious or autoimmune encephalitis (e.g. anti-NMDAR encephalitis and other antineuronal antibody-related encephalitides, acute disseminated encephalomyelitis), primary angiitis of the central nervous system, acute necrotizing encephalopathy, other infection-induced encephalopathies, metabolic diseases (e.g. mitochondrial disorders, citrullinemia, thiamin metabolism disorders) and genetic epilepsies (e.g. Dravet syndrome, PCDH19 epilepsy).
Management and treatment
Monitoring in intensive care during the acute phase is mandatory. Anti-seizure medications are often ineffective. High-dose benzodiazepines can have a transient efficacy. Usually, general anesthesia with barbiturates (titrated to burst suppression) are needed to stop seizures, even if prolonged burst-suppression can be associated with a worse cognitive outcome. Recurrence is common on awakening, necessitating repeated anesthesia. Immune therapy is usually disappointing but anakinra or tocilizumab has been highly effective in a few cases. So far, the ketogenic diet has seemed most beneficial, especially if initiated early, but no controlled trials exist. Ketamine, inhalation anesthetics, cannabidiol, hypothermia and neurostimulation have shown transient efficacy in a few cases.
Prognosis
FIRES has a poor prognosis with a high risk of chronic drug-resistant epilepsy and significant cognitive impairment, but a few patients have fully recovered. The mortality rate is around 12% in children.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Pr Rima NABBOUT | EpiCARE* - Pr Nicola SPECCHIO | EpiCARE* - Pr Tommy STÖDBERG | EpiCARE*

                                * European Reference Network


A rare, genetic congenital malformation syndrome characterized by digital anomalies (shortening of the 2nd and 5th middle phalanx of the hand, clinodactyly of the 5th finger, syndactyly of toes 2-3 and/or 4-5, thumb hypoplasia), microcephaly, facial dysmorphism (short palpebral fissures and micrognathia), gastrointestinal atresia (primarily esophageal and/or duodenal), and mild-to-moderate learning disability.

Summary:
Epidemiology
The exact prevalence is unknown. Feingold syndrome type 1 (FS1) accounts for the vast majority of FS cases. An estimated 120 cases have been reported to date.
Clinical description
Characteristic clinical findings of FS1 are present at birth with digital anomalies being the most frequent and including: brachymesophalangy (most commonly affecting the 2nd and 5th fingers), thumb hypoplasia and toe syndactyly. Microcephaly and facial dysmorphism (short palpebral fissures, micrognathia) are also noted in most cases. The most serious manifestations that are noted in approximately half of cases are esophageal and duodenal (rarely jejunal or anal) atresia, with or without tracheo-esophageal fistula. The presence of a fistula can be indicated by signs such as coughing, gagging, vomiting, abdominal distension and, in some cases, respiratory distress. Gastrointestinal atresia must be treated immediately or it can be fatal. Mild learning deficits can become apparent in early childhood but severe intellectual disability is very rarely seen.
Etiology
FS1 is caused by a mutation or deletion in the proto-oncogene MYCN (2p24.3). It encodes a protein with a basic helix-loop-helix domain that is expressed at various stages of human embryonic development.
Diagnostic methods
Diagnosis is based on characteristic clinical features and imaging studies. Gastrointestinal atresia can be seen with pre-natal or post-natal ultrasound or by MRI. Molecular genetic testing can identify a MYCN mutation, confirming a diagnosis of FS1.
Differential diagnosis
Differential diagnosis of FS1 includes FS type 2 (FS2), VACTERL association, CHARGE syndrome, brachydactyly type A4 and Fanconi anemia.
Antenatal diagnosis
Prenatal testing is possible in FS1 families with a known MYCN mutation or deletion.
Genetic counseling
FS1 is inherited autosomal dominantly; however, most cases arise de novo. Genetic counseling is possible.
Management and treatment
Extensive medical examinations are needed to identify possible anomalies of the heart or kidneys. Management of FS1 (and FS2) typically centers on surgical correction of the specific congenital anomalies (certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae. Gastrointestinal atresia requires prompt treatment involving IV fluid administration and surgery. Optimal surgical treatment of infants with esophageal atresia and tracheoesophageal fistula remains controversial and gastroesophageal reflux (GER) is extremely frequent in patients treated for the two conditions. GER is refractory to medical treatment and often requires anti-reflux surgery. Renal and cardiac anomalies should receive the standard treatments and prophylactic antibiotics may be beneficial. Special education is recommended for children and adults with learning deficits. Hearing loss should equally be monitored by an audiologist. Cochlear implants are possible in certain cases.
Prognosis
Prognosis depends on congenital malformations (especially cardiac and renal anomalies) present. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life.

                            Last update:
                            August 2020

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

                                * European Reference Network