Familial anetoderma is an extremely rare genetic skin disease characterized by loss of elastin tissue leading to localized areas of flaccid skin and a family history of the disorder.


Familial angiolipomatosis is a rare, genetic, subcutaneous tissue disorder characterized by the presence of benign, usually multiple, subcutaneous tumors composed of adipose tissue and blood vessels, typically manifesting as yellow, firm, circumscribed, 1-4 cm in diameter tumors located in the arms, legs and trunk, with deep extension of the lesions between muscles, tendons and joint capsules (without infiltration of these structures), in several members of a single family. Tumors may be tender or mildly painful when palpated and do not regress spontaneously.


Familial aortic dissection is the term used to describe rupture of the aortic wall at the level of the media, resulting in the formation of a false channel and deviation of part of the aortic flux. Familial predisposition to thoracic aortic aneurysms and type A dissections (concerning the ascending aorta and/or the aortic arch) has been demonstrated in around 19% of patients presenting with thoracic aortic dissections and several loci have been identified so far (16p12.2-p13.13, 3p24-25). This predisposition is transmitted in an autosomal dominant manner.


Familial articular hypermobility syndrome

A rare genetic disease characterized by generalized joint laxity leading to recurrent dislocation of major joints, such as the hip (often with congenital hip dislocation), shoulder, elbow, or patella. Patients often experience muscle and joint pain (sometimes with effusion) and may develop degenerative joint changes at a relatively early age. Skin abnormalities are absent.


Familial atrial fibrillation is a rare, genetically heterogenous cardiac disease characterized by erratic activation of the atria with an irregular ventricular response, in various members of a single family. It may be asymptomatic or associated with palpitations, dyspnea and light-headedness. Concomitant rhythm disorders and cardiomyopathies are frequently reported.


A rare, genetic cardiac tumor characterized by the presence of a primary, benign, gelatinous mass located in the atria and composed of primitive connective tissue cells and stroma (resembling mesenchyme) in several members of a family. Clinical presentation depends on the size, mobility and location of tumor, ranging from nonspecific and/or constitutional symptoms to sudden cardiac death, and includes dyspnea, hemoptisis, syncope, fatigue, fever, cutaneous rash, increases in venous pressure and/or peripheral edema.


Familial atrial tachyarrhythmia-infra-Hisian cardiac conduction disease

A rare genetic cardiac disease characterized by variably expressed atrial tachyarrhythmia (such as atrial flutter, paroxysmal or chronic atrial fibrillation, ectopic atrial tachycardia, or multifocal atrial tachycardia), infra-Hisian conduction system disease, and vulnerability to dilated cardiomyopathy. Age of onset ranges between childhood and adulthood.


Familial atypical multiple mole melanoma syndrome

Familial atypical multiple mole melanoma (FAMMM) syndrome is an inherited genodermatosis characterized by the presence of multiple melanocytic nevi (often >50) and a family history of melanoma as well as, in a subset of patients, an increased risk of developing pancreatic cancer (see this term) and other malignancies.

Summary:
Epidemiology
The prevalence is unknown. An accurate estimate of the prevalence of FAMMM syndrome is difficult to make given the highly variable phenotype displayed both between and within FAMMM syndrome kindreds and the limited data available.
Clinical description
The clinical phenotype of FAMMM syndrome shows wide heterogeneity in regards to the presence of nevi and familial predisposition to melanoma and pancreatic cancer (mainly adenocarcinoma). The disease most often presents in children and teenagers but can occur at any age. The presenting feature is usually a high total body nevi count (usually more than 50). The majority will be clinically typical but some may have an atypical appearance (asymmetrical, raised, and/or different shades of tan, brown, black, or red and often of different sizes) resembling early melanoma and most frequently occur on the back, chest, buttocks, breasts, and scalp. Melanomas can arise from atypical moles or de novo and have been reported in some FAMMM syndrome patients as early as the second to third decade of life. Those with CDNK2A mutations have a 90% risk of developing melanoma by the age of 80 and a 20% increased risk of developing pancreatic cancer by the age of 75. These mutations are also associated with a younger age of onset. Other cancers that can be rarely associated with FAMMM syndrome include breast cancer, esophageal cancer and sarcoma.
Etiology
FAMMM syndrome has been associated with mutations in the 16p locus of CDKN2A  (9p21), a tumor suppressor gene involved in cell cycle inhibition. However, approximately 60% of patients with FAMMM syndrome do not have a  CDKN2A  mutation.
Diagnostic methods
Diagnostic criteria for FAMMM syndrome are as follows: high total body nevi count (usually >50), nevi with certain histologies (i.e. lentiginous pattern, nuclear atypia) and melanomas in 1 or more first or second degree relatives. Nevi are evaluated for melanoma based on the ABCDE characteristics (asymmetry, border irregularity, color variation, diameter >6 mm, and evolution or elevation). Dermatoscopy is also a non-invasive method of identifying melanomas. Molecular genetic testing identifying a CDKN2A mutation confirms diagnosis but the absence of a mutation in this gene does not exclude a diagnosis of FAMMM syndrome.
Differential diagnosis
Differential diagnoses include cutaneous neurofibromas and pancreatic ductal adenocarcinoma as well as Neurofibromatosis type 1 (see this term).
Genetic counseling
FAMMM syndrome is inherited in an autosomal dominant manner with incomplete penetrance. Genetic counseling should be offered to patients and their families.
Management and treatment
Screening for melanoma in FAMMM syndrome kindreds should begin at age 10 and include a total body skin examination with the use of dermoscopy. Follow-up clinical exams or self-exams should then be performed every 6 months to monitor any changes in nevi. In families with a history of pancreatic cancer or a CDKN2A mutation, screening by computed tomography, magnetic resonance imaging, or endoscopic ultrasound can be offered starting at age 40. Melanoma, pancreatic cancer and other cancers should follow standard treatment guidelines.
Prognosis
In those with pancreatic cancer, the prognosis is poor. Early diagnosis and treatment of melanoma tends to lead to a better prognosis.

                            Last update:
                            February 2015

                            - Expert reviewer(s):
                            Dr Henry LYNCH


Familial avascular necrosis of femoral head

Avascular necrosis of femoral head (ANFH) is a severely disabling disease characterised by progressive groin pain, a limping gait, leg length discrepancy, collapse of the subchondral bone, limitation of hip function and eventual degeneration of the hip joint requiring total hip arthroplasty.

Summary:
Epidemiology
The prevalence of ANFH is unknown but around 15,000 cases are reported in each year in the USA. Familial forms of ANFH appear to be very rare, with only three families identified so far.
Clinical description
Age of onset in these familial cases ranges from 15-48 years (as opposed to between 3rd to 5th decade of life for other forms of ANFH).
Etiology
Most cases are associated with mechanical disruption (hip trauma or surgery), hypofibrinolysis, steroid use, smoking, alcohol intake, haemoglobinopathies and hyperlipidaemia.Transmission in familial cases is autosomal dominant and mutations in the type II collagen gene (COL2A1) have been detected in affected family members.

                            Last update:
                            May 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Familial benign copper deficiency is a rare disorder of mineral absorption and transport characterized by hypocupremia that manifests as failure to thrive, mild anemia, repeated seizures, hypotonia, and seborrheic skin. Spurring of the femur and tibia are also noted on radiographic imaging. Symptoms are reversible or improve with supplements of oral copper. There have been no further descriptions in the literature since 1988.


Familial benign flecked retina is a rare retinal dystrophy characterized by diffuse bilateral white-yellow fleck-like lessions extending to the far periphery of the retina but sparing the foveal region, with asymptomatic clinical phenotype and absence of electrophysiologic deficits.


Familial bicuspid aortic valve is a rare, genetic, aortic malformation defined as a presence of abnormal two-leaflet aortic valve in at least 2 first-degree relatives. It is frequently asymptomatic or may be associated with progressive aortic valve disease (aortic regurgitation and/or aortic stenosis, typically due to valve calcification) and a concomitant aortopathy (i.e. aortic dilation, aortic aneurysm and/or dissection).


A rare inherited rheumatologic disease which causes calcification of articular fibrocartilage or hyaline cartilage, a process termed chondrocalcinosis (CC). It often associates with acute synovitis and osteoarthritis (OA).

Summary:
Epidemiology
Familial calcium pyrophosphate deposition (CPPD) prevalence is unknown. It is rare: about 100 affected families have been identified to date.
Clinical description
Familial CPPD manifests in early adulthood (20-40 years old) and has a variable clinical phenotype. Generally, it is associated with acute CPP crystal arthritis involving the knees, the wrists, the shoulders, and/or a severe chronic inflammatory arthropathy, mimicking osteoarthritis (OA). In acute CPP crystal arthritis cases, acute episodes of pain, stiffness, swelling and sometimes ankylosis, can be observed in any joint, the knees or the wrist being the most affected. The attacks can last from hours (6-24) to days and can induce a limited range of motion. Chronic inflammatory arthropathy usually affects the knee, wrist, elbow, shoulder and hip, and can induce a severe OA-like arthropathy. Very rarely, familial CPPD can be associated with non rheumatological features, such as recurrent infantile seizures as was the case in a British family with CPPD and polyarticular chondrocalcinosis but without structural arthropathy.
Etiology
Mutations in the ANKH gene (human homologue of progressive ankylosis; 5p15.2), encoding a protein involved in cellular inorganic pyrophosphate transport, were identified in some cases of familial CPPD. Other familial cases have been linked to mutation in the Tumor Necrosis Factor Receptor Super Family member 11B (TNFRSF11B) gene coding for osteoprotegerin (OPG) Other causative genes are yet to be determined. Mutations in the collagen α-1(II) chain gene (COL2A1; 12q12-13.2), that codes for the major structural protein of cartilage, have been found to cause a particular form of chondrocalcinosis characterized by severe early onset OA, spondylo-epiphysial dysplasia and secondary CPPD.
Diagnostic methods
Diagnosis of CPPD is based on the identification of CPP crystals in synovial fluid by compensated polarized light. X-rays show calcium deposits within cartilage and fibro cartilage, mainly in knees, wrists and shoulders. X-ray findings support the diagnosis of CPPD, but the absence of radiographic CC does not exclude it. Ultrasonography allows for the detection of CC in peripheral joints, which typically appears as thin hyperechoic bands within hyaline cartilage and hyperechoic sparkling spots in fibrocartilage. Calcium deposits can be seen as well with Computed Tomography and DECT.
Differential diagnosis
Differential diagnosis includes other genetic conditions causing secondary CC such as chronic hypomagnesaemia (particularly the Gitelman syndrome), hereditary hemochromatosis and hypophosphatasia. In the large majority of cases, CPPD occur sporadically but it is a separate, much more common entity, with aging being the most important risk factor.
Antenatal diagnosis
Antenatal diagnosis could be possible when ANKH mutations in the family have already been found.
Genetic counseling
Familial CPPD has an autosomal dominant mode of inheritance with variable penetrance.
Management and treatment
Management is mainly symptomatic. To date, there are no effective treatments capable of dissolving calcium deposits. Acute CPP arthritis should be treated by non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroid injections. For difficult to treat patients, IL-1 blockers could be used Preliminary reports suggested Tocilizumab to be effective. CPPD with OA should be managed as primary OA, by a combination of non-pharmacological and pharmacological treatments (analgesics, NSAIDs).
Prognosis
Some forms may be severe and result in considerable pain and disability.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Augustin LATOURTE  - Pr Pascal RICHETTE


A rare, genetic, developmental defect during embryogenesis disorder characterized by varying degrees of caudal dysgenesis, ranging from a single umbilical artery or imperforate anus to full sirenomelia, in several members of the same family. Phenotype includes lumbosacral agenesis, anal atresia or ectopia, genitourinary abnormalities, components of VATER or VACTERL association, and facial dysmorphism (flat facies, abnormal ears, bilateral epicanthic folds, depressed nasal bridge, micrognathia). Additional features reported include cardiovascular (e.g. endocardial cushion defect, hypoplasia of pulmonary artery) and skeletal (kyphosis, hemipelvis) anomalies.


A rare genetic eye disease characterized by congenital profound excavation of the optic nerve head with diminished visual field, in the absence of elevated intraocular pressure. Many patients lack a well-formed retinal artery and have multiple radial cilioretinal arteries instead. The condition is mostly bilateral, may worsen progressively, and is often complicated by serous macular detachment with profound visual loss.


A rare, capillary-venous malformations characterized by closely clustered irregular dilated capillaries that can be asymptomatic or that can cause variable neurological manifestations such as seizures, non-specific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages.

Summary:
Epidemiology
The overall prevalence of all CCMs has been estimated at 1/200 to 1/1,000 individuals. Familial cerebral cavernous malformation (FCCM) represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 -1/10,000 and is therefore rare, contrarily to sporadic CCMs which are not. A strong founder effect has been found in Hispanic-American CCM families.
Clinical description
Close to 60% of FCCM patients are symptomatic. FCCM usually manifests between 20 to 30 years of age, but clinical manifestations can occur at any age. Symptoms include seizures (40-70%), non-specific headaches (10-30%), progressive or transient focal neurologic deficits (35-50%), and/or cerebral hemorrhages (41%). FCCM patients most often present with multiple lesions, ranging from a few millimeters to a few centimeters in size. FCCMs occur predominantly in the brain, but have also been reported in the spinal cord, retina (5% of FCCM patients) and skin.
Etiology
To date, mutations in three genes have been demonstrated to cause familial CCM; KRIT1,  CCM2 and PDCD10, located on chromosome 7q21.2, 7p13, and 3q26.1 respectively, which encode proteins that, among their various functions, modulate junction formation between vascular endothelial cells.
Diagnostic methods
Cerebral magnetic resonance imaging (MRI) revealing the CCM(s) is the gold standard investigation to diagnose CCM and should include a T2 gradient echo sequence which is highly sensitive for hemosiderin. MRI shows multiple lesions in most FCCM patients in contrast with sporadic cases who harbor only one lesion. The detection of multiple CCM lesions is therefore strongly suggestive of the genetic nature of the disease. Molecular screening of FCCM genes is sometimes useful to ascertain the diagnosis in patients showing atypical MRI lesions; however, in most cases, it is used for genetic counseling.
Differential diagnosis
In cases presenting with atypical hemorrhagic MRI lesions, the differential diagnosis of FCCM includes multiple hemorrhagic metastases or hereditary cerebral hemorrhage with amyloidosis.
Antenatal diagnosis
Prenatal diagnosis is possible. However, in practice, very few prenatal diagnoses are requested in this disease (mostly in families where several patients have been severely affected with CCMs in the basal ganglia or spinal cord or pons).
Genetic counseling
FCCM is transmitted as an autosomal dominant trait with incomplete penetrance. Genetic counseling should be offered to the affected families informing them of the 50% risk of inheriting the mutated gene. Other important considerations in evaluating the genetic predisposition of CCMs include the number of lesions on the MRI brain scan, family history of CCM clinical characteristics, and the age of onset.
Management and treatment
Regular check-ups, generally with an MRI once a year, are recommended after the discovery of a CCM, as additional asymptomatic lesions may appear with time. These MRI check-ups can be spaced to once every 5 years in the absence of intercurrent symptoms. Treatment of seizures and headaches is symptomatic. Lesions causing severe disabling seizures and/or focal neurologic deficits and/or cerebral hemorrhages call for surgical removal of lesions whenever possible. Acetylsalicylic acid, heparin and warfarin may increase the risk of hemorrhage.
Prognosis
FCCM is an evolving condition with a strong correlation between the patient's age and the number of CCM lesions. The hemorrhagic event rate is estimated at 2-5% per lesion per year. Functional outcome is mostly conditioned by the location of CCM lesions, with brainstem and basal ganglia lesions having a worse prognosis. Available data suggest that in most patients the long-term prognosis is quite favorable with a preserved autonomy in 80% of cases.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Elisabeth TOURNIER-LASSERVE


A rare genetic neurovascular malformation characterized by sac-like bulging of cerebral arteries due to weakening of the endothelial layer. Familial occurrence is suspected when two or more affected first- to third-degree relatives are present in a family. Aneurysms may remain asymptomatic throughout life, or rupture and thereby cause potentially life-threatening subarachnoid hemorrhage. Patients with familial cerebral saccular aneurysm are more likely to develop more than one brain aneurysm, are at greater risk of rupture, and tend to have poorer outcome after rupture than patients with sporadic cerebral aneurysms.


A rare genetic neurological disorder characterized by dissection of the cervical artery in various members of a single family, presenting with variable manifestations which range from asymptomatic to the triad of ipsilateral pain in the head, neck, and face, Horner syndrome, and cerebral or retinal ischemic symptoms. Headache and cerebral ischemic features are most frequently observed.


A rare monogenic form of cutaneous lupus erythematosus characterized by infantile or childhood onset of cold-induced erythematous papules or plaques predominantly on the fingers, toes, nose, cheeks, and ears. Recurrent ulceration of the lesions may lead to necrotic tissue destruction and mutilation. Patients may experience ischemia of the affected acral regions. Histological findings include cutaneous perivascular inflammatory infiltrates with deposits of immunoglobulins or complement.


A rare genetic hyperlipidemia characterized by excessive increase in plasma triglyceride levels due to the accumulation of chylomicrons, which manifests biochemically as severe hypertriglyceridemia. Clinical manifestations include recurrent episodes of acute pancreatitis, abdominal pain, nausea, fatigue, diarrhea, hepatosplenomegaly, eruptive xanthomas, lipemia retinalis and failure to thrive. Children may be asymptomatic with later onset of symptoms. The condition is not associated with severe atherosclerosis.

Summary:
Epidemiology
Familial chylomicronemia syndrome (FCS) has an estimated prevalence of 1/300,000 (ranging from 1/100,000 to 1/1,000,000 in Europe and North America). Founder effects are seen in Quebec and the Cayman Islands.
Clinical description
Presentation in infancy includes failure to thrive, abdominal pain, nausea and vomiting progressing to acute pancreatitis. Symptoms and signs include fatigue, irritability, lipemia retinalis, eruptive xanthomas on trunk, back and gluteal region, and hepatosplenomegaly. Lipemic plasma indicates severely elevated plasma triglyceride levels due to pathological presence of chylomicrons (>10 mmol/L or >875 mg/dL).
Etiology
Most FCS patients have bi-allelic loss-of-function variants in LPL encoding lipoprotein lipase. Other minor causal genes encoding factors that interact with LPL, including apolipoprotein (apo) A-V (APOA5), apo C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and lipase maturation factor 1 (LMF1).
Diagnostic methods
Definitive diagnosis is made by DNA sequencing. Biochemical methods are non-specific with technical performance challenges.
Differential diagnosis
In young adults, multifactorial (polygenic) chylomicronemia is 50 to 100 times as common as FCS and is associated with many secondary factors, hepatosteatosis, renal impairment or proteinuria. Patients with autoimmune diseases can develop antibodies against GPIHBP1 and develop chylomicronemia secondarily. Patients with undiagnosed partial lipodystrophy may present with chylomicronemia and pancreatitis.
Antenatal diagnosis
Antenatal diagnosis is not commonly offered, since FCS is manageable with dietary intervention.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (i.e. parents of a known FCS child or where both individuals are known carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
The mainstay of treatment is fat restriction, reducing total fat to <10% of calories or <20 grams per day, in combination with weight maintenance, exercise, and avoidance of processed foods, alcohol and smoking. Standard lipid-lowering medications and plasmapheresis are ineffective. Volanesorsen (apo C-III antisense oligonucleotide) is available in the EU but not North America; similar agents are in development.
Prognosis
Some patients have lived for six decades after the initial FCS diagnosis with minimal sequelae reportedly by adhering to a strict diet. Chylomicrons are not atherogenic, so atherosclerosis is uncommon in FCS patients, unlike other severe hypertriglyceridemia patients.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Dr Robert HEGELE


Familial clubfoot due to 17q23.1q23.2 microduplication

17q23.1-q23.2 microduplication is a newly described cause of familial isolated clubfoot.

Summary:
Epidemiology
It has been described in three families.
Clinical description
All cases with clubfoot were male and clubfoot was bilateral in all except one case. Clinically, the feet were short, with broad and overlapping toes. Mild nail hypoplasia was present in two affected individuals and mild short stature was common.
Genetic counseling
The microduplication segregated with autosomal-dominant clubfoot in all three families but with incomplete penetrance. This microduplication was identified by array CGH (comparative genomic hybridization).

                            Last update:
                            October 2010

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


Familial clubfoot with or without associated lower limb anomalies is a rare congenital limb malformation syndrome characterized by malalignment of the bones and joints of the foot and ankle, with presence of forefoot and midfoot adductus, hindfoot varus, and ankle equinus, presenting as rigid inward turning of the foot towards the midline, in various members of a single family. Hypoplasia of lower leg muscles is a frequently associated finding. Patients may present with other low-limb malformations, such as patellar hypoplasia, oblique talus, tibial hemimelia, and polydactyly.


Familial cold urticaria (FCAS) is the mildest form of cryopyrin-associated periodic syndrome (CAPS; see this term) and is characterized by recurrent episodes of urticaria-like skin rash triggered by exposure to cold associated with low-grade fever, general malaise, eye redness and arthralgia/myalgia.

Summary:
Epidemiology
The exact prevalence of FCAS is unknown. Most cases have been published in the USA, and this CAPS phenotype could be less frequent in Europe in comparison with MWS and CINCA.
Clinical description
FCAS generally starts in childhood (<10 years, often at birth), but may occasionally start later, and is characterized by recurrent episodes of non-pruritic urticaria-like rash triggered by exposure to cold (5 minutes to 3 hours and not necessarily by touch). Lesions last about 12 hours (range 30 minutes to 72 hours) and are typically associated with a burning sensation. Low-grade, daylong episodes of fever, malaise, conjunctivitis, and abdominal discomfort are also observed. Polyarthralgias involving hands, knees, and ankles are very common and incapacitating. Other joints involved are feet, wrists, and elbows. Profuse sweating, drowsiness, headache, extreme thirst, and nausea are also noticed after cold exposure. Amyloidosis, arthritis are uncommon while deafness, lymphadenopathy, and serositis are absent
Etiology
FCAS is caused by gain-of-function point mutations in the NLRP3 gene (1q44), which encodes cryopyrin. Mutations in NLRP3 gene ultimately lead to the increased secretion of the proinflammatory cytokine interleukin (IL)-1 beta and dysregulated inflammation. Mutations in this gene may also cause two additional forms of CAPS which are Muckle-Wells syndrome (MWS) and CINCA syndrome (see these terms), demonstrating that all three disorders are allelic. Some patients with a classical phenotype of FCAS, MWS or CINCA syndrome may not have mutations in NLRP3, suggesting involvement of additional genes. In addition, somatic NLRP3 mosaicism could explain 30-60% of patients with negative conventional genetic testing. Patients carrying identical amino acid substitution may present with distinctly different clinical subtypes, suggesting that additional genetic and/or environmental modifying factors are required to define the clinical phenotype.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling may be proposed and the recurrence risk is 50%.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Isabelle KONE-PAUT


A rare inherited cancer-predisposing syndrome characterized by the fulfilment of the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC) but without alterations, either somatic or germline, in the DNA mismatch repair (MMR) genes.

Summary:
Epidemiology
Cummulative evidence suggests that 40% of families with hereditary non-polyposis colorectal cancer (meeting Amsterdam criteria) do not show defects in the MMR machinery. A US population-based study finds that 2.6% of all colorectal cancer patients diagnosed meet the Amsterdam criteria for HNPCC, placing the estimated incidence of Familial Colorectal Cancer Type X (FCCTX) at approximately 1% of all CRC cases. There is no male or female predominance.
Clinical description
FCCTX includes a heterogeneous group of patients with familial aggregation of colorectal cancer (CRC), without gastrointestinal polyposis, and without evidence or molecular suspicion of Lynch syndrome. FCCTX is characterized by a strong aggregation of CRC cases in the family (fulfilment of Amsterdam criteria for hereditary nonpolyposis CRC) and absence of MMR deficiency, either germline or somatic. FCCTX tumors have normal expression of MMR proteins and no microsatellite instability, and no germline pathogenic variants in MMR genes are identified. FCCTX tumors are heterogeneous, likely due to their different etiologies. Compared to Lynch syndrome, FCCTX is not associated with extracolonic cancers, has a later mean age at CRC diagnosis (50-60 years vs 40 years), is more likely left-sided, and less likely associated with synchronous or metachronous cancers. FCCTX tumors have a more heterogeneous architecture, a predominant tubular growth pattern, less frequent mucinous histology, and less frequent peritumoral or tumor-infiltrating lymphocytes.
Etiology
The search for FCCTX causal genes has been large unsuccessful. Despite the identification of multiple candidate genes, only RSP20 has been unequivocally linked to the disease, explaining approximatively 0.07% of MMR-proficient familial/early-onset CRC cases.
Diagnostic methods
By definition, the diagnosis of FCCTX is based on the fulfilment of the clinical Amsterdam criteria for hereditary non-polyposis CRC and absence of an MMR defect. Amsterdam criteria include: having at least three relatives affected with histologically confirmed CRC or another HNPCC-associated cancer (endometrial, small bowel, ureter, renal pelvis), with at least one patient being a first-degree relative of the other two; at least two successive generations affected; at least one cancer diagnosed before age 50 (adenomatous polyposis excluded). MMR proficiency is evaluated under these criteria: Absence of microsatellite instability (MSI) in the tumors; normal expression of MLH1, MSH2, MSH6 and PMS2 proteins in the tumors; no germline pathogenic variants in the MMR genes. Multigene panel testing must be considered for CRC patients and/or families suspected of having a hereditary colorectal cancer syndrome and may reveal, although unfrequently, an RPS20 mutation in the case of FCCTX.
Differential diagnosis
Differential diagnosis includes Lynch syndrome and other forms of MMR-deficient hereditary nonpolyposis colon cancer. In rare cases, nonpolyposis CRC can occur in some forms of intestinal polyposis syndromes, caused by germline pathogenic variants in polyposis genes with a particularly broad polyposis expressivity—e.g. BMPR1A, MUTYH (biallelic), POLE, POLD1, or NTHL1. Other hereditary cancer syndromes may predispose to MMR-proficient CRC (and may be caused by mutations in BRCA1, BRCA2, ATM, CHEK2, or TP53).
Genetic counseling
A germline pathogenic variant in a hereditary cancer gene is hardly ever identified in FCCTX cases. Due to the increased risk of CRC, genetic counseling should be offered to family members based on the family history of cancer and ages at diagnosis following country-specific guidelines. RPS20-associated hereditary nonpolyposis CRC is an autosomal dominant disease. There is a 50% risk of transmitting the pathogenic allele at each pregnancy. The scarce data available suggests that this form of CRC occurs in the adulthood and that its penetrance is likely high.
Management and treatment
In the absence of a pathogenic variant in a cancer predisposition gene, cancer surveillance and clinical management of FCCTX families should be based on the personal and family history of cancer and the ages at cancer onset, as recommended by country-specific guidelines for colorectal cancer.
Prognosis
FCCTX cases show an excess of cancer-related mortality compared to Lynch syndrome, and an overall worse prognosis, both in terms of disease-free and overall survival.

                            Last update:
                            December 2022

                            - Expert reviewer(s):
                            Pr Stefan ARETZ | ERN GENTURIS* - Dr Marta PINEDA RÍU | ERN GENTURIS* - Dr Laura VALLE | ERN GENTURIS*

                                * European Reference Network


A rare, genetic, movement disorder characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side of the body, which are present in various first-degree members of a family, persist beyond the first decade of life, and have no associated comorbidities.


Familial congenital nasolacrimal duct obstruction

A rare, genetic, otorhinolaryngological malformation characterized by congenital impatency of the nasolacrimal draingage system in various members of a family. Presentation is not specific and may include a uni- or bilateral medial canthal mass, dacryocystitis, nasal obstruction, periorbital cellulitis, and epiphora. Dacryocystocele and lacrimal puncta agenesis may be associated.


Familial congenital palsy of trochlear nerve

A rare, genetic, neuro-ophthalmological disease characterized by congenital fourth cranial nerve palsy, manifesting with hypertropia in side gaze, unexplained head tilt, acquired vertical diplopia, and progressive increase in vertical fusional vergence amplitudes with prolonged occlusion. Facial asymmetry (i.e. hemifacial retrusion, upward slanting of mouth on the side of the head tilt, mild enophthalmos of paretic eye) and superior oblique tendon abnormalities (such as absence, redundance, misdirection) are frequently associated. Some asymptomatic cases have been reported.


Familial cortical myoclonus is a rare, genetic movement disorder characterized by autosomal dominant, adult-onset, slowly progressive, multifocal, cortical myoclonus. Patients present somatosensory-evoked, brief, jerky, involuntary movements in the face, arms and legs, associated in most cases with sustained, multiple, sudden falls without loss of consciousness. Seizures or other neurological deficits, aside from mild cerebellar ataxia late in the course of the illness, are absent.


Familial cutaneous collagenoma is a connective tissue nevus characterized by multiple, flesh-colored asymptomatic nodules distributed symmetrically on the trunk and upper arms (mainly on the upper two-thirds of the back), manifesting around adolescence. The skin biopsy reveals an accumulation of collagen fibers with reduction in the number of elastic fibers. Cardiac anomalies may be observed. Familial cutaneous collagenoma follows an autosomal dominant mode of transmission.


Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome

A rare, inherited cancer-predisposing syndrome characterized by an early development of cutaneous telangiectasia, mild dental and nail anomalies, patchy alopecia over the affected skin areas and increased lifetime risk for oropharyngeal cancer. Other types of cancer have also been reported.


Familial developmental dysphasia is a severe form of developmental verbal apraxia characterized by a deficit in spontaneous speech, writing, grammatical judgment and repetition, defective articulation, moderate to severe degree of dyspraxia, a reduced use of consonant clusters, and comprehension delay. Hearing and intelligence are normal.


Familial digital arthropathy-brachydactyly is characterised by the association of arthropathy of interphalangeal, metacarpophalangeal and metatarsophalangeal joints with brachydactyly of the middle and distal phalanges. It has been described in numerous members from five generations of one large family. Inheritance is autosomal dominant.


Familial dilated cardiomyopathy with conduction defect due to LMNA mutation

A rare familial cardiomyopathy characterized by left ventricular enlargement and/or reduced systolic function preceded or accompanied by significant conduction system disease and/or arrhythmias including bradyarrhythmias, supraventricular or ventricular arrhythmias. Disease onset is usually in early to mid-adulthood. Sudden cardiac death may occur and may be the presenting symptom. In some cases, it is associated with skeletal myopathy.


A rare, genetic macular dystrophy disorder characterized by the presence of small yellow-white accumulations of extracellular material under the retinal pigment epithelium in the ocular posterior pole, and affecting multiple members of a family. The disease has a variable clinical presentation ranging from asymptomatic patients to progressive loss of vision and scotomas, possibly associated with subfoveal choroidal neovascularization, extensive pigmentary changes, geographic atrophy and/or subretinal hemorrhage.


A rare hereditary sensory and autonomic neuropathy characterized by decreased pain and temperature perception, absent deep tendon reflexes, proprioceptive ataxia, afferent baroreflex failure and progressive optic neuropathy.

Summary:
Epidemiology
The disease affects individuals of Ashkenazi Jewish ancestry. The prevalence at birth in the Ashkenazi Jewish population is estimated at 1/10,000 in North America and 1/3,700 in Israel.
Clinical description
The disease is present at birth and is progressive. Initial symptoms (from birth to 3 years) include swallowing problems, aspiration pneumonia, hypotonia, temperature and blood pressure instability, and delayed development. Lack of fungiform papilla on the tongue and absence of tears with emotional crying are classic features, but not easily recognized (the tongue appears inconspicuous and lack of overflow tears is normal until about seven months of age). No obvious dysmorphism is present at birth, but a characteristic facial expression develops over time. Pain and temperature perception are decreased, but not absent. Proprioception and vibration sense are markedly decreased. Deep tendon reflexes are absent. Feeding difficulties due to gastrointestinal dysmotility (oropharyngeal incoordination, abnormal esophageal peristalsis, erratic gastric emptying, gastroesophageal reflux) occur early and may persist throughout life. Episodes of protracted vomiting attacks and hypertension termed 'autonomic crises'' can be recurrent. Forty percent of the patients manifest a cyclical crisis pattern that can occur daily, weekly, or monthly with personality changes ranging from irritability and withdrawal to general excitation. Chronic lung disease (secondary to repeated aspirations), restrictive lung disease (imposed by scoliosis), and chemoreceptor dysfunction (resulting in blunted responses to hypoxemia) are frequent. Orthostatic hypotension without compensatory tachycardia is always present, as well as episodic hypertension in response to emotional stress or visceral pain. Chronic renal failure is common. Progressive optic neuropathy and neurotrophic keratopathy result in severe visual loss. There is ample phenotypic variation particularly in cognitive abilities. Severe kyphoscoliosis and short stature are common.
Etiology
The disease is due to a founder mutation in the ELP1 gene (9q31), encoding elongator-1 protein, resulting in a truncated unstable protein. ELP1 is implicated in the migration, survival, and myelination of neurons during development and, in humans, the mutation affects the development of primary sensory and autonomic neurons.
Diagnostic methods
Diagnosis is based upon clinical recognition of both sensory and autonomic dysfunction as well as alacrima, absent fungiform papillae, and abnormal histamine test with absent axon flare. Genetic testing provides a definitive diagnosis.
Differential diagnosis
Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN). Normal or increased sweating easily distinguishes familial dysautonomia (FD) from HSAN4, also hypertensive crises are unique to FD and not present in other HSANs. Deep tendon reflexes are absent in FD.
Antenatal diagnosis
Prenatal diagnosis is possible in families where the pathogenic variant has previously been identified.
Genetic counseling
The pattern of inheritance is autosomal recessive. Where both parents are unaffected carriers, the risk of disease transmission to offspring is 25%. Offspring of affected individuals are obligate carriers.
Management and treatment
Management should be tailored for each patient, as the clinical expression varies considerably. It is supportive and mainly directed towards protecting the cornea, and management of gastrointestinal dysfunction, respiratory dysfunction, and blood pressure lability.
Prognosis
Average age of death is in the third decade of life but patients may live into the seventh decade.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Horacio KAUFMANN  - Pr Jose-Alberto PALMA


Familial dysfibrinogenemia is a coagulation disorder characterized by a bleeding tendency due to a functional anomaly of circulating fibrinogen.

Summary:
Epidemiology
Prevalence is unknown but dysfibrinogenemia is more frequent than afibrinogenemia which has a prevalence of 1/1,000,000.
Clinical description
Most patients with dysfibrinogenemia are asymptomatic. The others may have mild bleeding symptoms or even thrombosis.
Etiology
The deficiency is due to various mutations in the FGA, FGB, or FGG genes.
Genetic counseling
Transmission is mainly autosomal dominant.

                            Last update:
                            October 2009


Familial dyskinesia and facial myokymia is a rare paroxysmal movement disorder, with childhood or adolescent onset, characterized by paroxysmal choreiform, dystonic, and myoclonic movements involving the limbs (mostly distal upper limbs), neck and/or face, which can progressively increase in both frequency and severity until they become nearly constant. Patients may also present with delayed motor milestones, perioral and periorbital dyskinesias, dysarthria, hypotonia, and weakness.


Familial encephalopathy with neuroserpin inclusion bodies

A rare serpinopathy characterized by progressive myoclonus epilepsy and/or pre-senile dementia with prominent frontal-lobe features and relative sparing of recall memory. In addition, other neurological manifestations like cerebellar symptoms and pyramidal signs may be present. Age of onset is variable, the disease having been reported in children as well as elderly patients. Neuropathological examination reveals the typical neuronal inclusions of mutated neuroserpin (Collins bodies).


Familial episodic pain syndrome with predominantly lower limb involvement

A subtype of familial episodic pain syndrome characterized by intense, episodic and/or cyclic pain mainly localized in the distal lower limbs (occasionally affecting upper limbs as well) which is triggered/exacerbated by fatigue, cold exposure and/or weather changes and alleviated with anti-inflammatory medication, that has a tendancy to diminish in frequency with age. Episodes usually occur late in the day, last 15-30 min and associate sweating and a cold sensation of affected area.


Familial episodic pain syndrome with predominantly upper body involvement

A subtype of familial episodic pain syndrome characterized by episodes of severe debilitating pain mainly affecting shoulders, thorax and arms (occasionally radiating to the abdomen and legs), triggered by fasting, fatigue, cold temperatures or physical exercise, which last for 60-90 min and respond poorly to conventional analgesia. Intense pain episodes are accompanied by dyspnea, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall and are followed by a period of exhaustion and somnolence.


A rare genetic peripheral neuropathy characterized by recurrent, stereotyped, episodic intense pain, ocurring predominantly in either the upper body or lower limbs in several members of a family, which is triggered or exacerbated by fatigue, cold exposure, fasting, weather changes and/or physical stress or exertion and may or may not diminish with age. Sweating and other manifestations, such as tachycardia, breathing difficulties and generalized pallor, may be associated.


A rare primary bone dysplasia characterized by abnormal bone metabolism with bone pain, deformity, pathological fractures, early conductive hearing loss, and dental abnormalities. Focal bone lesions are typically found in the appendicular skeleton and consist of progressively expanding lytic areas, while generalized disordered bone modeling and altered trabecular pattern are the result of the multifocal, progressive nature of the disease. Age of onset is variable, mode of inheritance is autosomal dominant.


Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinal disorder characterized by abnormal or incomplete vascularization of the peripheral retina leading to variable clinical manifestations ranging from no effects to minor anomalies, or even retinal detachment with blindness.

Summary:
Epidemiology
The prevalence of FEVR is unknown. It is usually inherited dominantly and many asymptomatic individuals may not come to medical attention as a result of non-penetrance. Males and females appear to be affected equally, except in the X-linked form which only affects males.
Clinical description
The clinical manifestations of FEVR are highly variable among patients in the same family and even between the two eyes. In many patients, retinal abnormalities do not affect vision. Most symptomatic individuals with FEVR present at an early age with peripheral vision disturbances, and flashes or floaters. Major objective signs are similar to retinopathy of prematurity (see this term) and include large angle kappa, retinal detachment, stretched posterior retinal vessels, dragged optic disc, and retinal folds. These ocular anomalies are followed by complications, such as retinal neovascularization and exudates, retinal and vitreous bleeding, vitreoretinal traction, ectopia of the macula, and cataracts. Strabismus and leukocoria are also reported. Patients with severe manifestations are often registered as blind in early infancy. Reduced bone mass with a predisposition to fractures has been reported in some patients (LRP5 mutations).
Etiology
Mutations in the FZD4 (11q14-q21) or LRP5 (11q13.4) genes have been associated with autosomal dominant FEVR as well as ZNF408 (11p11.2). LRP5 has also been associated with recessive cases. X-linked recessive FEVR is associated with mutations in the NDP gene (Xp11.4-p11.3). Some dominant or recessive cases have been reported to be associated with TSPAN12 (7q31.31). In about 50% of cases, the genetic mutations causing FEVR are unknown.
Diagnostic methods
Early diagnosis is very important in order to avoid serious complications that may develop within the first two decades of life. The diagnosis is based on ophthalmic and general history, including gestational age, birth weight and on ophthalmic examination for the presence of an avascular zone in the peripheral retina by slit lamp biomicroscopy and funduscopy of the peripheral retina in full mydriasis and, if possible, fluorescein angiography. A compatible inheritance pattern within the family may suggest the diagnosis, which can be confirmed by molecular genetic testing.
Differential diagnosis
Retinopathy of prematurity (see this term) is the main differential diagnosis and can generally be ruled out based on gestational age, if available. Other similar conditions include Norrie disease, Coats disease, and persistent hyperplastic primary vitreous (see these terms).
Antenatal diagnosis
FEVR is genetically and clinically heterogeneous, complicating prenatal diagnosis. Furthermore, requests for prenatal diagnosis of the disease are rare.
Genetic counseling
The disease most commonly shows autosomal dominant inheritance, and more rarely X-linked recessive or autosomal recessive patterns of inheritance. Significant non-penetrance has been reported. Corresponding genetic counseling should be provided to affected families.
Management and treatment
Presymptomatic testing can be offered to families in which the causative mutations have been identified. Standard surgical approaches are used to correct retinal detachment, but results are variable. Prophylactic cryotherapy or argon laser photocoagulation are recommended to reduce new vascularization caused by ischemia. Regular fundus examination is recommended to monitor symptomatic patients. Asymptomatic children and young adults showing avascularity should be monitored annually.
Prognosis
The clinical presentation of FEVR is highly variable. The usual course of the disease has not been well established making the prognosis difficult to ascertain. Progressive loss of vision is reported in severe cases.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Dr F.N. [Nienke] BOONSTRA  - Dr Rob COLLIN


Familial focal epilepsy with variable foci is a rare genetic epilepsy disorder characterized by autosomal dominant lesional and nonlesional focal epilepsy with variable penetrance. Focal seizures emanate from different cortical locations (temporal, frontal, centroparietal, parietal, parietaloccipital, occipital) in different family members, but for each individual a single focus remains constant throughout lifetime. Seizure type (tonic, tonic-clonic or hyperkinetic) and severity varies among family members and tends to decrease (but do not disappear) during adulthood. Many patients have an aura and show automatisms during diurnal seizures whereas others have nocturnal seizures. Most individuals are of normal intelligence but patients with intellectual disability, autistic spectrum disorder and obsessive-compulsive disorder have been described.


Familial gastric type 1 neuroendocrine tumor

A rare neoplastic disease characterized by occurrence of atypical and aggressive gastric type 1 neuroendocrine tumors (NET) in early adulthood. The tumors often show nodal infiltration requiring total gastrectomy. Synchronous gastric adenocarcinoma has also been reported. Patients present high serum gastrin concentrations and iron-deficiency anemia (rather than megaloblastic anemia, which is a typical feature in patients with sporadic gastric type 1 NET, where the tumor usually arises on the background of autoimmune atrophic gastritis).


Familial generalized lentiginosis is a rare, inherited, skin hyperpigmentation disorder characterized by widespread lentigines without associated noncutaneous abnormalities. Patients present multiple brown to dark brown, non-elevated macula of 0.2 to 1 cm in diameter, spread over the entire body, sometimes including palms or soles, but never oral mucosa.


A rare genetic hyperthyroidism characterized by hyperemesis gravidarum associated with hyperthyroidism due to hypersensitivity of the thyrotropin receptor to chorionic gonadotropin, in the absence of abnormally high serum chorionic gonadotropin levels. Clinical manifestations include severe nausea, vomiting, weight loss, tachycardia, excessive sweating, and hand tremor, but no signs of ophthalmopathy.


Familial glucocorticoid deficiency (FGD) is a group of primary adrenal insufficiencies characterized clinically by neonatal hyperpigmentation, hypoglycemia, failure to thrive, and recurrent infections, and biochemically by glucocorticoid deficiency without mineralocorticoid deficiency.

Summary:
Epidemiology
The prevalence is unknown. In Ireland there is a prevalence of around 1/200,000, but this is likely to be skewed by a high prevalence in the Irish Traveler sub-population.
Clinical description
FGD usually presents in infancy or early childhood with hyperpigmentation of the skin and gums (present at birth or that develops over time), hypoglycemic seizures and failure to thrive. Recurrent infections are also a common finding (and may be the presenting sign in older children). Weakness, fatigue, weight loss, anorexia, vomiting, flank or abdominal pain, constipation and diarrhea are additional symptoms seen in some patients due to hypocortisolemia. Hypoglycemic crises resulting in convulsions can lead to coma or death if untreated and recurrent hypolglycemia may lead to neurological sequelae (i.e. learning disabilities, intellectual deficit, and sometimes severe, neuronal damage leading to major sensory and motor defects such as quadriplegia). Tall stature has been reported in some patients with FGD, typically those with MC2R gene defects. MRAP defects have been associated with a more severe disease and an earlier age of onset while a milder phenotype is seen in those with defects in the MCM4 gene (Irish Traveler FGD).
Etiology
FGD is due, in most cases, to defects in the adrenocorticotropin (ACTH) receptor, or its signaling pathway, resulting in a failure of the cells of zona fasciculata in the adrenal cortex to respond appropriately to adrenocorticotrophic hormone (ACTH), leading to a glucocorticoid deficiency. These defects are most commonly caused by mutations in MC2R (18p11.2), accounting for 25% of cases, and MRAP (21q22.1), accounting for 20% of cases. Other mutations reported in patients with FGD include MCM4 (8q12-q13), probably uniquely in the Irish Traveler population;  NNT (5p12), accounting for around 15% of cases; and TXNRD2 (22q11.21). Certain partially inactivating mutations of STAR (8p11.2) or CYP11A1 (15q23-q24) can cause a phenotype that masquerades as FGD.
Diagnostic methods
Diagnosis is based on clinical and laboratory findings. Patients have high plasma ACTH and low serum morning cortisol levels that do not respond to exogenous ACTH stimulation. Mineralocorticoid function is normal. Molecular genetic testing revealing a mutation in one of the disease causing genes confirms diagnosis of FGD.
Differential diagnosis
The main differential diagnosis of FGD is Addison's disease (usually of autoimmune origin), in which case a mineralocorticoid deficiency is present. Other differential diagnoses include triple A syndrome, congenital adrenal hyperplasia and other acquired causes of primary adrenal insufficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation but is rarely performed.
Genetic counseling
FDG is inherited in an autosomal recessive manner. Genetic counseling is possible.
Management and treatment
Treatment consists of a replacement therapy with oral hydrocortisone. A dosage of 10-12 mg/m2/day (usually divided into three doses) normalizes cortisol and reduces, but rarely normalizes, ACTH. Dose modification is necessary during stresses such as surgery or intercurrent illness, and patients should have injectable hydrocortisone available for emergencies and carry a medical alert type bracelet or card. Prompt and adequate treatment of a hypoglycemic crisis is essential. Treatment is life-long.
Prognosis
The prognosis is good for patients who are diagnosed and treated early. Only when left untreated is FGD a disease with high morbidity (neurological sequelae) and mortality.

                            Last update:
                            April 2015

                            - Expert reviewer(s):
                            Pr Adrian CLARK


Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare primary immunodeficiency characterized by a macrophage activation syndrome (see this term) with an onset usually occurring within a few months or less common several years after birth.


A rare heritable, glucocorticoid remediable form of primary aldosteronism (PA) characterized by early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol.

Summary:
Epidemiology
PA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of PA cases. Familial hyperaldosteronism type I (FH-I) is estimated at approximately 1% of all PA cases, but may reach 3% in the hypertensive pediatric population.
Clinical description
Hypertension of varying severity, even among members of the same family, manifests often before the age of 20. It can be accompanied with symptoms of severe hypertension such as headaches and nausea. Exogenous glucocorticoids are effective in reducing hyperaldosteronism and normalizing blood pressure. Cardiovascular complications due to aldosterone excess, such as fibrosis, left ventricular (LV) dysfunction, arrhythmias, and myocardial infarction, can be associated with the disease; abnormal cardiac function may manifest even in young normotensive patients. In adults, FH-I is associated with high risk of hemorrhagic stroke and ruptured intracranial aneurysms occurring at a young age.
Etiology
FH-I is due to an unequal crossing over on the long arm of chromosome 8 between the CYP11B2 gene (coding for cytochrome P450 11B2 or aldosterone synthase), normally expressed in the zona glomerulosa (ZG), and the CYP11B1 gene (coding for the cytochrome P450 11B1 or steroid 11-beta-hydroxylase), normally expressed in the zona fasciculata (ZF), resulting in a chimeric gene composed of the adrenocorticotropic hormone (ACTH)-sensitive promoter of the CYP11B1 gene and the coding region of the CYP11B2gene. This leads to an excessive aldosterone synthase production in the zona fasciculata of the adrenal cortex, regulated by ACTH rather than by the renin-angiotensin system. Excessive aldosterone synthesis leads to increased sodium reabsorption, loss of potassium and subsequent increased water reabsorption.
Diagnostic methods
The diagnosis is suggested by the clinical picture and a family history of early-onset hypertension and/or stroke. Blood and urinary tests show biological signs of primary aldosteronism, i.e. increased aldosterone levels and low plasma renin activity (tested after correction of potassium levels) with an abnormal aldosterone/renin ratio, associated or not with low serum potassium levels, and elevated urinary levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing providing evidence of the hybrid gene by Southern blot and/or long-range PCR. Many patients are diagnosed during familial genetic screening in case of family history.
Differential diagnosis
The clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-II, FH-III). Specific features of FH-I are the presence of hybrid steroids 18-hydroxycortisol and 18-oxocortisol in the urine and the suppression of aldosterone by dexamethasone.
Genetic counseling
Transmission is autosomal dominant and genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Once the diagnosis is ascertained, small doses of glucocorticoids (dexamethasone at 0.125-0.250 mg/day or prednisone at 2.5 -5 mg/day) are sufficient to correct hypertension and reduce the production of aldosterone. Small doses are essential in order to avoid side effects of glucocorticoid treatment; complete suppression of ACTH-regulated hybrid gene activity is not necessary for controlling hypertension. In severe cases, dexamethasone can be combined with a mineralocorticoid receptor antagonist and other non-specific antihypertensive drugs. Because of the side effects of glucocorticoids, in children eplerenone can be given instead.
Prognosis
With treatment, hypertension can be controlled for many years, and echocardiographic parameters maintained at normal values.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Maria-Christina ZENNARO


A heritable form of primary aldosteronism (PA) characterized by hypertension of varying severity, non-glucocorticoid remediable hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA) and increased aldosterone-to-renin ratio.

Summary:
Epidemiology
PA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of adult PA cases. Familial hyperaldosteronism type II (FH-II) is considered the most common form of familial hyperaldosteronism and it is estimated at around 6% of all PA cases.
Clinical description
The clinical and biochemical presentation of FH-II is indistinguishable from sporadic PA, although early onset PA may be observed. Hypertension of varying severity, even within members of the same family, is noted in most patients and occurs at different ages. Fatigue, and muscle weakness are reported. Complications due to hypertension and aldosterone excess (including sodium retention and hypokalemia) may occur. Patients with PA are at increased risk of cardiovascular events, such as coronary artery disease, stroke, non-fatal myocardial infarction, atrial fibrillation and heart failure.
Etiology
FH-II is due to heterozygous gain-of-function mutations in the CLCN2 gene (3q27.1) coding for the CLC-2 chloride channel. Mutations are located in different domains of the ClC-2 channel and affect channel function to different degrees, explaining phenotypic heterogeneity. The mutations result in constitutive channel activation, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-gated calcium channels, and activation of the calcium signaling pathway that triggers aldosterone biosynthesis.
Diagnostic methods
FH-II is diagnosed when PA is confirmed in two or more family members and other familial forms are excluded. Patients show a non-specific variable aldosterone response to upright posture or AngII infusion. Early onset PA may be observed associated with specific CLCN2 mutations.
Differential diagnosis
FH-II is clinically and biochemically indistinguishable from sporadic PA, although in some cases, CLCN2 mutations are associated with early onset PA. Differential diagnosis also includes the other forms of FH (FH-I, FH-III and FH-IV).
Genetic counseling
FH-II is transmitted in an autosomal dominant mode with variable penetrance. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of transmitting the pathogenic variant at each pregnancy.
Management and treatment
FH-II does not respond to glucocorticoid treatment and no specific treatment has been identified for carriers of CLCN2 mutations. Treatment consists of medical therapy with mineralocorticoid receptor antagonists, associated to additional antihypertensive medication if required.
Prognosis
With treatment prognosis is good.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Maria-Christina ZENNARO


A rare heritable form of primary aldosteronism (PA) that is characterized by early-onset severe hypertension, non- glucocorticoid-remediable hyperaldosteronism, overproduction of 18-oxocortisol and 18-hydroxycortisol, and profound hypokalemia.

Summary:
Epidemiology
PA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of adult PA cases. The frequency of familial hyperaldosteronism type III (FH-III) is unknown.
Clinical description
Severe hypertension associated with profound hypokalemia generally manifests during early childhood. It can be accompanied with polydipsia, polyuria, and headaches. Marked bilateral adrenal hyperplasia has been described. In some cases, a mild form of FH-III with normal appearing adrenals and treatable with medical therapy, resembling family hyperaldosteronism type II (FH-II) or type IV (FH-IV), has been reported.
Etiology
FH-III is due to heterozygous missense mutations of the KCNJ5 gene (11q24), encoding the G-protein-activated inward rectifier potassium channel GIRK-4. These mutations result in loss of channel selectivity, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-activated calcium channels, and activation of the calcium signaling pathway that triggers aldosterone biosynthesis. There is a genotype-phenotype correlation, with the mild phenotype observed in patients with the p.G151E and p.Y152C mutations.
Diagnostic methods
Blood and urinary tests show profound hypokalemia, increased aldosterone levels not suppressible by dexamethasone, suppressed plasma renin activity, with an abnormal aldosterone/renin ratio and elevated levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing.
Differential diagnosis
The severe form of FH-III presents with severe and treatment resistant hypertension and profound hypokalemia. In mild forms, the clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-II, FH-IV).
Genetic counseling
Transmission is autosomal dominant. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of transmitting the pathogenic variant at each pregnancy.
Management and treatment
FH-III does not respond to glucocorticoid treatment. Severe cases require bilateral adrenalectomy to normalize blood pressure and hypokalemia, whereas mild cases are treated with medical therapy with mineralocorticoid receptor antagonists and/or other antihypertensive drugs if required.
Prognosis
In severe cases treated with bilateral adrenalectomy, life-long glucocorticoid and mineralocorticoid replacement therapy is required. In mild cases, prognosis is good with medical treatment.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Maria-Christina ZENNARO


Familial hyperaldosteronism (FH) is the heritable form of primary aldosteronism (PA) which comprises three identified subtypes to date: FH type I (FH-I; see this term) characterized by early-onset hypertension, glucocorticoid remediable adrenocorticotropic hormone (ACTH)-dependent hyperaldosteronism, variable hypokalemia, and overproduction of 18-oxocortisol and 18-hydroxycortisol; FH type II (FH-II; see this term) characterized by hypertension of varying severity and hyperaldosteronism not suppressible by dexamethasone; and FH type III (FH-III; see this term) characterized by profound hypokalemia, early-onset severe hypertension, non glucocorticoid-remediable hyperaldosteronism, and overproduction of 18-oxocortisol and 18-hydroxycortisol.


Familial hypercholanemia is a very rare genetic disorder characterized clinically by elevated serum bile acid concentrations, itching, and fat malabsorption reported in patients of Old Order Amish descent.


Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome

A rare autosomal recessive disorder characterized by the occurrence of cutaneous and subcutaneous calcified masses, usually adjacent to large joints, such as hips, shoulders and elbows. It can occur in the setting of hyperphosphatemia or normophosphatemia, depending on the type of gene mutation involved.


Familial hyperprolactinemia is a rare, genetic endocrine disorder characterized by persistently high prolactin serum levels (not associated with gestation, puerperium, drug intake or pituitary tumor) in multiple members of a family. Clinically it manifests with signs usually observed in hyperprolactinemia, which are: secondary medroxyprogesterone acetate (MPA)-negative amenorrhea and galactorrhea in female patients, and hypogonadism and decreased testosterone level-driven sexual dysfunction in male patients. Oligomenorrhea and primary infertility have also been reported in some female patients.


Familial hyperthyroidism due to mutations in TSH receptor

A rare hyperthyroidism characterized by mild to severe hyperthyroidism, presence of goiter, absence of features of autoimmunity, frequent relapses while on treatment and a positive family history.


A rare genetic hypoaldosteronism that typically presents in infancy (earl-onset familial hypoaldosternism) as a life-threatening electrolyte imbalance (failure to thrive, recurrent vomiting, and severe dehydration). A history of fever, diarrhoea, lethargy, poor weight gain, poor feeding since birth may also be present. Older subjects (late-onset familial hypoaldosteronism) are less severely affected or asymptomatic.


Familial hypocalciuric hypercalcemia (FHH) is a generally asymptomatic genetic disorder of phosphocalcic metabolism characterized by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma parathyroid hormone (PTH) concentration.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
FHH is biologically characterized by moderate but significant hypercalcemia associated with levels of PTH and urinary calcium excretion that appear inappropriate in the presence of the hypercalcemia: serum levels of PTH are, in general, normal or slightly increased and calciuria is low. FHH is usually asymptomatic but rarely symptoms of fatigue, weakness, excessive thirst and concentration problems are experienced. Some adults suffer from relapsing pancreatitis, chondrocalcinosis and premature vascular calcification.
Etiology
There are 3 genetic types of FHH based on chromosome location. FHH type 1 accounts for 65% of cases and is due to inactivating mutations in the CASR gene, localized to 3q21.1. This gene encodes the calcium-sensing receptor (CaSR). Loss of CaSR function results in a reduction in the sensitivity of parathyroid and renal cells to calcium levels so hypercalcemia is perceived as normal. The other 35% have either a mutation GNA11 (19p13.3) seen in FHH type 2 or AP2S1 (19q13.2-q13.3) seen in FHH type 3 (see these terms) or in genes not yet discovered. FHH is rarely caused by auto-antibodies against CaSR in those without a mutation.
Diagnostic methods
FHH is suspected when mild hypercalcemia is seen along with normal or slightly elevated PTH, relative hypocalciuria, and normal phosphate levels. FHH must be suspected in the presence of persistent hypercalcemia despite surgical removal of a parathyroid adenoma. Family members are screened for serum calcium concentrations and CASR mutation analysis is performed in order to confirm a diagnosis. As de novo mutations are frequently described, the CASR gene must also be sequenced in the presence of typical biological features even in the absence of familial history of hypercalcemia. In FHH type 2, marked hypocalciuria is noted. FHH type 3 exhibits mild hypophosphatemia and elevated plasma PTH concentrations.
Differential diagnosis
Primary hyperparathyroidism is clinically similar to FHH, apart from the presence of hypercalcemia. Other differential diagnoses include humoral malignant hypercalcemia and sarcoidosis (see this term).
Antenatal diagnosis
As FHH is benign, prenatal testing is not recommended. It can be considered if both parents have FHH type 1, as their offspring have a higher risk of developing neonatal severe primary hyperparathyroidism (NSHPT; see this term), a particular clinical identity which can be life-threatening.
Genetic counseling
FHH is inherited as a dominant trait. Genetic counseling can be offered to family members of affected individuals and genetic screening for the CASR familial mutation.
Management and treatment
As FHH is usually asymptomatic, treatment is not necessary. The hypercalcemia seen in FHH does not respond to diuretics or bisphosphonates. For those with constantly elevated serum calcium concentrations >14mg/dL or in those with NSHPT or relapsing pancreatitis, a total parathyroidectomy can be beneficial. Pregnant women with FHH must be identified, as in the developing fetus a context of marked hypercalcemia leads to the inhibition of endogenous secretion of PTH and a high risk of developing severe hypocalcemia during the first days of life. In newborns of two FHH parents, calcium levels should be monitored for the first days of life as NSHPT can develop.
Prognosis
FHH does not lower life expectancy and has a benign, stable course.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Pr Anne LIENHARDT-ROUSSIE


Familial hypofibrinogenemia is a coagulation disorder characterized by mild bleeding symptoms following trauma or surgery due to a reduced plasma fibrinogen concentration.

Summary:
Epidemiology
Prevalence is unknown but hypofibrinogenemia is more frequent than afibrinogenemia which has a prevalence of 1/1,000,000.
Etiology
The deficiency is due to various mutations in the FGA, FGB, or FGG genes.
Genetic counseling
Transmission is mainly autosomal dominant.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Jenny GOUDEMAND


Familial idiopathic dilatation of the right atrium

A rare congenital heart malformation of unknown etiology that is characterized by an extremely dilated right atrium, and that is usually asymptomatic and fortuitously discovered by echocardiography or chest radiography, and can be sometimes associated with other anomalies such as atrial arrhythmias (e.g. atrial flutter, atrial fibrillation, supraventricular tachycardia), severe tricuspid regurgitation, or atrial thrombus that could lead to potentially life-threatening thromboembolic complications.


Familial infantile bilateral striatal necrosis is the familial form of infantile bilateral striatal necrosis (IBSN; see this term), a syndrome of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis.

Summary:
Epidemiology
The prevalence of familial IBSN has been estimated at less than 1/1,000,000.
Clinical description
The age of onset varies between 7 months and 15 months. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus. The disease has an insidious onset and a slowly progressive downhill course.
Etiology
Autosomal recessive infantile striatonigral degeneration is caused by mutation in the NUP62 gene (19q13.33) and mitochondrial infantile striatonigral degeneration is caused by mutation in the ATP synthase-6 gene (MTATP6).
Diagnostic methods
Diagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images.
Differential diagnosis
Differential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma.
Genetic counseling
Antenatal diagnosis and genetic counseling is offered to families of affected patients.
Management and treatment
There is no standard therapy for familial IBSN. Treatment with oral biotin has been observed to slow disease progress initially.
Prognosis
Prognosis is usually poor with patients progressing to spastic quadriparesis followed by death, usually due to infection.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Rachel STRAUSSBERG


A rare, genetic, infantile epilepsy syndrome disease characterized by neonatal- to infancy-onset myoclonic focal seizures occurring in various members of a family, associated in some with mild dysarthria, ataxia and borderline-to-moderate intellectual disability.


A rare familial intestinal malformation characterized by failure of the rotation of the developing gastrointestinal tract around the superior mesenteric artery during embryonic development, resulting in a spectrum of abnormalities of intestinal position and fixation. Patients most typically present in the neonatal period with midgut volvulus, which can lead to short bowel syndrome or even death. Signs and symptoms include bilious vomiting, feeding intolerance, failure to thrive, constipation, bloody stools, or intermittent apnea. The condition may also manifest later in life with complications like kinking or hernias and a broad range of intestinal symptoms. It can be an isolated finding or occur in association with other anomalies.


Neurofibromatosis type 6 (NF6), also referred as café-au-lait spots syndrome, is a cutaneous disorder characterized by the presence of several café-au-lait (CAL) macules without any other manifestations of neurofibromatosis or any other systemic disorder.

Summary:
Epidemiology
Prevalence is unknown, but the disease appears to be extremely rare.
Clinical description
The macules may appear in infancy, but usually they are detected after 2 years of age. CAL lesions are hyperpigmented with smooth or irregular borders. Their size may vary from a few millimeters to more than 10 cm.
Etiology
The etiology of NF6 remains unknown. Close linkage to the NF1 gene (17q11.2) has been reported in some cases.
Diagnostic methods
The diagnosis is based on the presence of six or more CAL macules.
Differential diagnosis
Differential diagnoses include neurofibromatosis type 1, McCune-Albright syndrome, and tuberous sclerosis (see these terms).
Genetic counseling
Transmission is autosomal dominant.
Management and treatment
Isolated CAL lesions do not require medical care.
Prognosis
CAL spots are benign and may resolve with age.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Pr Pierre WOLKENSTEIN


Familial isolated clinodactyly of fingers is a rare, genetic, non-syndromic, congenital limb malformation disorder characterized by angulation of a digit in the radio-ulnar (coronal) plane, away from the axis of joint flexion-extension, in several members of a single family with no other associated manifestations. Deviation is usually bilateral and commonly involves the fifth finger. Affected digits present trapezoidal or delta-shaped phalanges on imaging.


Familial isolated congenital asplenia is a rare, non-syndromic, potentially life-threatening visceral malformation characterized by the absence of normal spleen function, resulting in a primary immunodeficiency. Typically, the condition manifests with severe, recurrent, overwhelming infections (especially pneumococcal sepsis) in otherwise apparently healthy infants. In adults with no history of severe sepsis in infancy, thrombocytosis may be the presenting sign. Howell-Jolly bodies on blood smears and an absent spleen on abdominal ultrasound examination are highly suggestive associated findings.


A rare familial cardiomyopathy characterized by the dilation of left ventricle and progressively impairing of systolic ventricular function, in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. The disease may cause heart failure or arrhythmia. The disease is isolated when no additional atypical cardiac or extracardiac manifestations are present.

Summary:
Epidemiology
The prevalence and incidence of Familial isolated dilated cardiomyopathy (FDC) is unknown; however, the incidence of dilated cardiomyopathy (DCM) is estimated between 1/12,000-28,000 worldwide; the prevalence of dilated cardiomyopathy is estimated at 1/2500; FDC is reported to make up about 20-30% of DCM case (range 2-65%).
Clinical description
The disease is defined by the presence of two major clinical criteria: left ventricular (LV) fractional shortening less than 25% and/or LV ejection fraction less than 45% with LV end diastolic diameter greater than 117% of the predicted value (corrected for age and body surface area based on Henry's formula), in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. The disease can develop at any age, in either sex. LV mass is often greatly increased in this disorder but LV wall thickness is normal. Symptoms of heart failure may be present as well as arrhythmias. Other presentations include the incidental detection of asymptomatic cardiomegaly and symptoms related to coexisting conduction disturbance or thromboembolic complications. Typically, there is a history of DCM in the family.
Etiology
Around 30-40% of FDC has an identified genetic origin attributed to over 50 genes, a number that is constantly increasing as new genes are discovered. Most mutations include titin (TTN; 15-27%), lamins A/C (LMNA; 6%), Beta-myosin heavy chain (MYH7; 4.20%), myopalladin (MYPN; 3.50%) and cardiac troponin T (TNNC1, TNNI3 and  TNNT2; 2.90%).
Diagnostic methods
Clinical screening of relatives, in particular first degree relatives, of primary DCM cases using electrocardiogram (ECG) and echocardiography allow the identification of familial FDC. Two or more affected relatives with dilated cardiomyopathy meet the above major criteria for the disease. Cardiac catheterization and CT or MRI scan are used also. Genetic screening of the family is also possible.
Differential diagnosis
Differential diagnosis include the various non-genetic causes of dilated cardiomayopathy, such as cardiac AL amyloidosis or senile amyloidosis, peripartum cardiomyopathy, sarcoidosis, myocarditis, autoimmune cardiomyopathy.
Antenatal diagnosis
Fetal echocardiography, B and M-mode, is the main diagnostic tool to determine the neonatal outcome. A hemodynamic evaluation can be performed by Doppler mode. Antenatal diagnosis is very rare due to the manifestation of the pathology later on during adult life. Fetal echocardiography is therefore not widely recommended unless there is a family history of neonatal case. Prenatal genetic testing may be considered on a case-by-case basis in the context of a pathogenic variant identified in the family.
Genetic counseling
Familial dilated cardiomyopathy is primarily an autosomal dominant disease, but autosomal recessive, X-linked and mitochondrial forms have also been described. Genetic counseling is therefore possible. The transmission outcome is 50% in an autosomal dominant case and 25% for a recessive transmission.
Management and treatment
The pathology is treated with a combination of medications, depending on the symptoms. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, diuretics, digoxin, blood-thinning medications are used. The management of alimentation is important in affected families, and exercise and healthy habits are essential.
Prognosis
The prognosis of dilated cardiomyopathy is very poor in the absence of therapeutic management but mortality is largely reduced by medical and non-medical treatments. The prognosis may be influenced by the associated mutations.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Philippe CHARRON


A rare, hereditary, familial primary hyperparathyroidism disease characterized by primary hyperparathyroidism due to single or multiple parathyroid tumors in at least two first-degree relatives in the absence of evidence of other endocrine disorders, tumors and/or systemic manifestations.


Familial isolated hypoparathyroidism due to agenesis of parathyroid gland

A rare genetic endocrine disease characterized by severe hypocalcemia, seizures, hyperphosphatemia, and impaired secretion of the parathyroid hormone (PTH) by the parathyroid glands (not affecting other endocrine glands). Complications include psychomotor and growth delay, delayed dentition, and cataracts.


Familial isolated hypoparathyroidism due to impaired PTH secretion

A rare genetic endocrine disease characterized by impaired secretion of the parathyroid hormone (PTH) by the parathyroid glands not causing other endocrine or developmental disturbances. Complications include impaired renal function, psychomotor and growth delay, delayed dentition, and cataracts.


A rare heterogeneous group of metabolic disorders characterized by abnormal calcium metabolism causing hypocalcemia due to insufficient serum levels of bioactive parathormone (PTH), without other endocrine disorders or developmental defects.

Summary:
Epidemiology
Cases have been reported around the world, including in Denmark, the USA, and Korea. There is no apparent gender predominance.
Clinical description
Disease onset can occur at any age (from the neonatal period to adulthood) but symptoms generally start within the first decade of life. The clinical signs are mainly those of non-surgical hypoparathyroidism with hypocalcemia, causing myopathy, muscular weakness, cramps, tetany, lenticular cataracts, and teeth anomalies.
Etiology
Possible mechanisms causing FIH include: 1) an inappropriate low calcium set-point due to variants in the CASR gene, causing autosomal dominant hypocalcemia; 2) recessive loss of function or dominant negative variants in the GCM2 gene (6p24.22), which encodes a transcription factor of importance to development, proliferation and maintenance of the parathyroid cells; 3) dominant or recessive variants in the PTH gene (11p15.3) causing either impaired secretion of PTH, apoptosis of parathyroid cells, or secretion of bioinactive PTH, with either undetectable or elevated serum levels of immunoreactive PTH, 4) variants in the autoimmune regulator (AIRE) gene without signs of other diseases associated with loss of AIRE function.
Diagnostic methods
Diagnosis is based on biochemistry showing low serum calcium and PTH levels, and confirmed by genetic testing. If PTH levels are high, the bioactivity of the PTH molecule may have to be evaluated.
Differential diagnosis
The differential diagnosis includes other non-surgical hypoparathyroidism with hypocalcemia and low PTH levels such as autoimmune hypoparathyroidism, and autoimmune polyendocrinopathy type 1, or syndromes with hypoparathyroidism as a feature like 22q11.2 deletion syndrome. In patients presenting with hypocalcemia with high PTH levels, pseudohypoparathyroidism or secondary hyperparathyroidism should be considered.
Antenatal diagnosis
Antenatal diagnosis is possible if the genetic variant is known in the family.
Genetic counseling
Isolated hypoparathyroidism may be sporadic or familial, with autosomal dominant or recessive inheritance.
Management and treatment
Management consists of symptomatic treatment with supplementary calcium and active vitamin D.
Prognosis
If well treated, life expectancy is normal but quality of life may be negatively impacted.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Pr Lars REJNMARK | Endo-ERN*

                                * European Reference Network


A rare, hereditary endocrine tumor characterized by a benign pituitary adenoma that is either secreting (e.g. prolactin, growth hormone, thyroid stimulating hormone) or non-secreting. Symptoms may occur due to either the hormonal hypersecretion and/or the mass effect of the lesion on local structures in the brain.

Summary:
Epidemiology
Familial isolated pituitary adenoma (FIPA) prevalence is unknown. However, FIPA represents around 2-5% of pituitary adenoma cases. A female predominance is reported.
Clinical description
In FIPA, pituitary adenomas can be of any secretory type (e.g. prolactinoma, acromegaly, Cushing's disease, TSH-secreting) or can be non-secreting. FIPA kindreds usually have 2-4 members affected with pituitary adenomas, while larger numbers of affected patients per family can occur infrequently. In FIPA, pituitary adenomas generally begin at a younger age and are larger than corresponding sporadic non-FIPA cases. Pituitary adenomas in FIPA can cause symptoms due to hormonal hypersecretion and/or due to the mass effect of the pituitary adenoma on local structures in the brain (e.g. visual disturbance). In FIPA families with AIP mutations pituitary adenoma growth characteristics are often aggressive and hormonal hypersecretion may be marked.
Etiology
In up to 80% of FIPA families, the etiology of pituitary adenomas is unknown. However, mutations in the gene AIP (11q13.2 ) account for about 20% of FIPA kindreds. AIP is thought to act as a tumor suppressor gene. Pituitary adenomas due to germline AIP mutations are accompanied by a second hit of the other allele (e.g. deletion or mutation) and this is thought to favor or stimulate tumorigenesis.
Diagnostic methods
FIPA kindreds usually have 2-4 members affected with pituitary adenomas. Hormonal testing is used to identify abnormal hormonal secretion in FIPA. Magnetic resonance imaging (MRI) is used to confirm the presence and dimensions of a pituitary adenoma. AIP mutations can lead to pituitary apoplexy in FIPA kindreds, so MRI and hormonal signs of apoplexy may be present in affected family members.
Differential diagnosis
Differential diagnosis include multiple endocrine neoplasia type 1 and familial infantile gigantism, which may present as FIPA.
Genetic counseling
In children of FIPA cases with AIP mutations, the pattern of inheritance is autosomal dominant and, thus, there is a 50% risk of inheriting the mutation from an affected parent. For families with unidentified gene, an autosomal dominant inheritance pattern has been suggested. Large international studies have shown that only about 20% of AIP mutation carriers eventually develop a pituitary adenoma.
Management and treatment
Pituitary adenomas in the setting of FIPA are generally managed according to guideline recommendations for non-FIPA pituitary adenomas. However, in FIPA families with AIP mutations, pituitary adenomas (often growth hormone secreting) can be large and poorly responsive to treatment with surgery and medical therapy.
Prognosis
Formal outcome studies for patients with FIPA as compared with sporadic pituitary adenoma patients have not been performed. However, due to larger tumor size, younger age at onset and lower responses to medical therapies (particularly in FIPA families with AIP mutations), hormonal and tumoral effects may be more difficult to control and may require a larger burden of treatment.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Albert BECKERS  - Dr Adrian DALY


Familial isolated restrictive cardiomyopathy

A rare genetic cardiac disease characterized by restrictive ventricular filling due to high ventricular stiffness that results in severe diastolic dysfunction in the absence of dilated or hypertrophied ventricles.

Summary:
Epidemiology
The prevalence is unknown; however, from a European registry the familial form is reported to account for 30% of restrictive cardiomyopathy.
Clinical description
Clinical presentation of restrictive cardiomyopathy (RCM) is heterogeneous, with onset at any age. Dyspnea is the most common symptom, followed by edema, palpitation, fatigue, orthopnea and chest pain. The typical symptoms upon examination include jugular venous distension, elevated systemic and pulmonary venous pressures, systolic murmur, lower-extremity edema, atrial fibrillation, cardiomegaly, and less frequently atrioventricular block. In advance disease, symptoms include pulmonary congestion, hepatomegaly, ascites and edema. Diastolic volumes are normal or reduced, and whilst initial systolic function is normal or near-normal, it may deteriorate with diseases progression. The ejection fraction is typically above 50%. Mild-to-moderate tricuspid and mitral valve regurgitation is common. Bi-atrial dilatation due chronic elevation of atrial pressure usually develops which along with pulmonary venous congestion and pleural effusions can result in moderate to generalized cardiomegaly. Other changes in cardiac morphology, such as ventricular dilatation, septal and ventricular hypertrophy, typically do not occur in RCM. Myocardial biopsy typically demonstrates interstitial fibrosis, and mild to moderated myocyte hypertrophy, without evidence of amyloid deposition, eosinophil infiltration or other systemic infiltration. Death can occur suddenly or as a result of congestive heart failure, cardiac arrhythmias, or other associated complications.
Etiology
RCM is due to increased ventricle stiffness resulting in restricted ventricular filling either unilaterally or bilaterally. Most cases of RCM remain idiopathic; however, an increasing number of disease causing mutations have been identified and include the sarcomere subunits, such as troponin T (TNNT2, 1q32.1), troponin I (TNNI3, 19q13.42), alpha-actin (ACTC, 15q14), beta-myosin heavy chain (MYH7, 14q11.2), myopalladin (MYPN, 10q21.3), and filamin C (FLNC, 7q32.1) as well as kinesin-like protein KIF20A (KIF20A, 5q31.2).
Diagnostic methods
Diagnosis is made with cardiac echocardiography supported by electrocardiogram, cardiac catheterization, and endomyocardial biopsy. Typical findings on echography include enlargement of atria, normal or reduced left ventricular end diastolic dimension and/or volume, restrictive left ventricular filling pattern, normal or near normal systolic function, and normal ventricular wall thickness. Thorough hemodynamic evaluation with cardiac catheterization may be required to exclude the differential diagnosis.
Differential diagnosis
Differential diagnosis includes constrictive pericarditis and infiltrative myocardial disease such as cardiac amyloidosis, and other secondary causes of restrictive myopathy such as storage disease.
Genetic counseling
For patients with known mutation, the pattern of inheritance is autosomal dominant and, therefore, there is a 50% risk of disease transmission from an affected parent to offspring. Autosomal recessive inheritance has been observed in one family. Genetic counseling should be offered to affected families, with clinical screening of asymptomatic family members.
Management and treatment
Cardiac transplant is the sole effective procedure in treating the disease. Pediatric patients should obtain preference on the waiting list due to the high risk of sudden death and to prevent the need for heart-lung transplantation. No single drug improves prognosis of RCM. Whilst diuretics are commonly used to reduce preload, excessive reduction may decrease ventricular filling. Thus, diuretics should be limited to patients presenting with symptomatic pulmonary venous congestion and/or right heart failure. ACE (angiotensin-converting enzyme) inhibitors and vasodilators are considered detrimental for the treatment of RCM. Anti-dysrhythmic therapy or implantable cardioverter defibrillators (AICD) may be an option for patients presenting with atrial fibrillation or ischemia. Pacemaker is considered in the presence of high degree atrioventricular block. Anti-coagulants reduce the risk of thromboembolic events.
Prognosis
Prognosis is usually poor, especially in pediatric patients, with 50 percent of deaths occurring within 2 years of diagnosis. For patients 10 years of age and above, the 5-year survival rate is 64 percent.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Philippe CHARRON


Familial isolated retinal arteriolar tortuosity

A rare genetic cerebral small vessel disease characterized by isolated marked tortuosity of second-order and third-order retinal arteries with normal first-order arteries and venous system, typically located in the macular and peripapillary area and developing during childhood or early adulthood. The disease may be asymptomatic, although most patients present variable degrees of transient vision loss due to retinal hemorrhage following physical exertion or minor trauma.


Familial isolated trichomegaly is a rare genetic hair anomaly characterized by a prolonged anagen phase of the eyelash hairs, leading to extreme eyelash growth that may result in corneal irritation. Increased growth of hair on other parts of the face (eyebrows, cheeks, forehead) and/or the body (chest, arms, legs) may be associated.


Familial juvenile hypertrophy of the breast

A rare breast malformation disorder characterized by unilateral or bilateral, symmetrical or asymmetrical, uncontrolled, rapid and massive enlargement of the breast(s) in peripubertal females, occurring in various members of a family. Additional associated manifestations may include skin hyperemia, dilated subcutaneous veins, skin necrosis, kyphosis, lordosis and anonychia. Growth and development are otherwise normal.


A rare inherited skin cancer syndrome characterized by the coexistence of features typical of both multiple self-healing squamous epithelioma and generalized eruptive keratoacanthoma, such as multiple small miliary-type lesions, larger self-healing lesions, and nodulo-ulcerative lesions. Lesions do not have a predilection for the mucosal surfaces.