TaoMedAI/RareMedData huggingface dataset:
Familial hyperaldosteronism type II (ORPHA:404)
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.
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
Familial hyperaldosteronism type III (ORPHA:251274)
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.
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 (ORPHA:235936)
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 (ORPHA:238475)
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 (ORPHA:306661)
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 (ORPHA:397685)
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 (ORPHA:424)
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.
Familial hypoaldosteronism (ORPHA:427)
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 hypofibrinogenemia (ORPHA:101041)
Familial hypofibrinogenemia is a coagulation disorder characterized by mild bleeding symptoms following trauma or surgery due to a reduced plasma fibrinogen concentration.
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 (ORPHA:1677)
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 (ORPHA:225154)
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.
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
Familial infantile myoclonic epilepsy (ORPHA:352582)
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.
Familial intestinal malrotation (ORPHA:508410)
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.
Familial isolated café-au-lait macules (ORPHA:2678)
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.
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 (ORPHA:295014)
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 (ORPHA:101351)
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.
Familial isolated hyperparathyroidism (ORPHA:99879)
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 (ORPHA:2239)
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 (ORPHA:189466)
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.
Familial isolated hypoparathyroidism (ORPHA:2238)
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.
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
Familial isolated retinal arteriolar tortuosity (ORPHA:75326)
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 (ORPHA:411788)
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 (ORPHA:180176)
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.
Familial keratoacanthoma (ORPHA:493)
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.
Familial median cleft of the upper and lower lips (ORPHA:401942)
A rare developmental defect during embryogenesis characterized by incomplete median clefts of both the lower lip (limited to the vermilion, with no muscle involvement) and upper lip (with muscle involvement), double labial frenulum and fusion of the upper gingival and upper labial mucosa (resulting in a shallow upper vestibular fold), in addition to poor dental alignment, and increased interdental distance between the lower and upper median incisors.
Familial medullary thyroid carcinoma (ORPHA:99361)
A rare thyroid tumor characterized by a malignant neoplasm derived from the calcitonin-secreting parafollicular C-cells of the thyroid and occurring familially, but not as a component of multiple endocrine neoplasia syndromes. The commonly multifocal, bilateral nodules are typically located at the junction of the upper and middle thirds of the thyroid lobes. Clinically, patients may present with diarrhea, flushing, or weight loss caused by excessive secretion of calcitonin by the tumor. In rare cases, the tumor can also cause Cushing syndrome due to ectopic corticotropin production.
Familial mesial temporal lobe epilepsy with febrile seizures (ORPHA:165805)
A rare, genetic, familial partial epilepsy disease characterized by simple partial seizures, complex partial seizures and/or secondarily generalized seizures, originating from the inner aspect of the temporal lobe, associated with an antecedant history of febrile seizures, ocurring in various members of a family. Hippocampal abnormalities (e.g. hippocampal sclerosis) may also be associated.
Familial mitral valve prolapse (ORPHA:741)
A rare familial congenital mitral malformation characterized by systolic displacement of one or both mitral leaflets >2 mm beyond the annular plane into the left atrium. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Patients may remain asymptomatic or develop complications such as severe mitral regurgitation, endocarditis, and heart failure.
Familial monosomy 7 syndrome (ORPHA:495930)
A rare neoplastic disease characterized by infantile to childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome or acute myeloid leukemia. Most patients present with petechiae, easy bruising, or anemia. Rapid progression is common, and prognosis is generally poor.