900000000000509007: United States of America English language reference set (foundation metadata concept)

SNOMED CT Concept\SNOMED CT Model Component\Foundation metadata concept (foundation metadata concept)\Reference set\Language type reference set (foundation metadata concept)\English [International Organization for Standardization 639-1 code en] language reference set (foundation metadata concept)\US English

Status: current, Not sufficiently defined by necessary conditions definition status (core metadata concept). Date: 31-Jan 2002. Module: SNOMED CT model component module (core metadata concept)

Descriptions:

Expanded Value Set

Outbound Relationships	Type	Target	Active	Characteristic	Refinability	Group	Values
US English	Is a	English [International Organization for Standardization 639-1 code en] language reference set (foundation metadata concept)	true	Inferred relationship	Some

Members	acceptabilityId
A rare form of diffuse large B-cell lymphoma occurring most commonly in patients over the age of 50 (usually between 70-75 years of age), without overt immunodeficiency, and presenting with nodal and extranodal involvement (in sites such as the stomach, lung, skin and pancreas) and B symptoms (fever, night sweats, weight loss). The tumor is characterized by an aggressive course and a short survival rate.	Preferred (foundation metadata concept)
A rare form of genetic lipodystrophy with loss of subcutaneous adipose tissue from the trunk, buttocks and limbs; fat accumulation in the neck, face, axillary and pelvic regions; muscular hypertrophy; and usually associated with metabolic complications such as insulin resistance. Inherited in an autosomal dominant manner.	Preferred (foundation metadata concept)
A rare form of hereditary optic atrophy seen in only 4 families to date. With onset in early childhood the disease has characteristics of progressive loss of visual acuity, significant optic nerve pallor and occasionally additional neurological manifestations, with females being unaffected.	Preferred (foundation metadata concept)
A rare form of hereditary spastic paraplegia with characteristics of childhood (exceptionally adolescent) onset of a complex phenotype presenting with lower limb (followed by upper limb) spasticity with hyperreflexia and extensor plantar responses, with additional manifestations including progressive dysarthria, dystonia, mild cognitive decline, extrapyramidal features, optic atrophy and seizures. White matter abnormalities and brain iron accumulation have also been observed on brain magnetic resonance imaging.	Preferred (foundation metadata concept)
A rare form of hereditary spastic paraplegia with characteristics of delayed walking, toe walking, unsteady and spastic gait, hyperreflexia of the lower limbs, and extensor plantar responses. Upper limbs spasticity and dystonia, subclinical axonal neuropathy, cognitive impairment and intellectual disability have also been associated. Caused by homozygous or compound heterozygous mutation in the CYP2U1 gene on chromosome 4q25.	Preferred (foundation metadata concept)
A rare form of idiopathic inflammatory myopathy with clinical manifestation of acute or subacute proximal muscle weakness and histopathological features of myocyte necrosis and regeneration without significant inflammation. The main presenting feature is subacute severe symmetrical proximal myopathy with a markedly elevated creatine kinase level. The course is often severe but may be self-limiting and recovery may occur within weeks to months of discontinuing the causative agent, if identified. The disease is thought to be related to an immune response possibly triggered by drug therapy, connective tissue diseases, or cancer. The exact mechanism underling the disorder is not known but some autoantibodies appear to be a likely cause. Malignancy may be involved.	Preferred (foundation metadata concept)
A rare form of localized hypertrichosis characterized by hair growth near the laryngeal prominence during childhood. This isolated anomaly has been described in around 20 individuals. Transmission may be autosomal recessive or dominant with variable penetrance.	Preferred (foundation metadata concept)
A rare form of localized lichen myxedematosus characterized by the development of skin-colored mucinous nodules on the limbs and trunk, with mild or absent papular eruption.	Preferred (foundation metadata concept)
A rare form of myofibrillar myopathy characterized by predominantly proximal muscle weakness (that could be either non or slowly progressive), associated with spheroid body inclusions (composed of myofilament material within individual muscle fibers) in skeletal muscle biopsy. Presentation is varied and may range from asymptomatic to severe muscle weakness that manifests with absent Achilles reflexes, gait abnormality and/or other motor incapacitations.	Preferred (foundation metadata concept)
A rare form of neurodegeneration with brain iron accumulation (NBIA) with characteristics of early-onset developmental delay and further neurological deterioration in early adulthood. Caused by de novo heterozygous or hemizygous mutation in the WDR45 gene on chromosome Xp11.	Preferred (foundation metadata concept)
A rare form of patterned dystrophy of the retinal pigment epithelium characterized by a granular appearance in the macula, with coarse and punctiform mottling of the retinal pigment epithelium within the macular region. Association with choroidal neovascularization has been reported.	Preferred (foundation metadata concept)
A rare form of pontocerebellar hypoplasia with characteristics at birth of hypotonia, clonus, epilepsy, impaired swallowing and from infancy progressive microcephaly, spasticity and lactic acidosis. Reported in less than 10 cases to date. Caused by missense and splice site mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene located to 6q16.1. Prognosis is poor, exact life expectancy is unknown but in most cases does not exceed infancy.	Preferred (foundation metadata concept)
A rare form of porokeratosis occurring mainly in adolescence and characterized by small pruritic or painful keratotic papules that first appear on the palms and soles, and may gradually become generalized. The prevalence is unknown but it is one of the rarest forms of porokeratosis. The disease is more frequently seen in males. The exact etiology is unknown. A possible locus for PPPD has been found on chromosome 12q24.1-24.2. Usually follows a dominant (autosomal or X-linked) pattern of inheritance.	Preferred (foundation metadata concept)
A rare form of primary cutaneous T-cell lymphoma characterized by rapidly progressing localized or disseminated nodules, tumors or eczematous skin lesions. It has a particularly aggressive clinical course with a high tendency to spread, in advanced stages, to extracutaneous locations (central nervous system, lung, testes). Lymph nodes are often spared.	Preferred (foundation metadata concept)
A rare form of pseudohyperaldosteronism with characteristics of very early-onset and severe hypertension associated with low renin levels and hypoaldosteronism. Caused by homozygous or compound heterozygous loss-of-function mutations or deletions in the HSD11B2 gene (16q22). In all cases, these mutations lead to abolition or a marked decrease in the activity of 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2), an enzyme involved in the conversion of cortisol to cortisone. Transmission is autosomal recessive.	Preferred (foundation metadata concept)
A rare form of spinal muscular atrophy with characteristics of the neonatal onset of severe hypotonia, areflexia, profound weakness, multiple congenital contractures, facial dysmorphic features (myopathic face with open, tent-shaped mouth), cryptorchidism, and mild skeletal abnormalities (kyphosis, scoliosis), that is often preceded by polyhydramnios and reduced fetal movements in utero and followed by bone fractures shortly after birth. Patients have a limited life span, often succumbing to the disease within 2 years, as muscle weakness is progressive and chest muscle involvement eventually leads to ventilatory insufficiency and respiratory failure.	Preferred (foundation metadata concept)
A rare form of superficial corneal dystrophy with recurrent episodes of epithelial erosions from childhood in the absence of associated diseases. The erosions begin spontaneously or are precipitated by minor trauma, dust or smoke. The condition may become apparent by 6 months of age, but as a rule it only starts at 4 to 6 years of age. Most patients have attacks of redness, photophobia, epiphora, and ocular pain. Some experience a burning sensation and report sensitive eyes for years. Vision is sometimes impaired. Autosomal dominant pattern of inheritance.	Preferred (foundation metadata concept)
A rare frontonasal dysplasia malformation syndrome with characteristics of an oxycephalic skull with craniosynostosis, wide nose with anteverted nostrils, hirsutism at base of nose, agenesis of the nasolacrimal ducts and bilateral symmetrical nasolabial cysts on upper lip. Additional features may include hypertelorism. There have been no further descriptions in the literature since 1991.	Preferred (foundation metadata concept)
A rare frontonasal dysplasia with characteristics of a craniofacial phenotype comprising frontal bossing with high anterior hairline, ptosis, hypertelorism, epicanthus inversus, flat nasal bridge and broad nasal tip. Large anterior fontanel, sagittal synostosis, and cranial base anomalies have also been described.	Preferred (foundation metadata concept)
A rare functional disorder with recurrent episodes of torticollis posturing of the head (inclination or tilting of the head to one side) in healthy children. The prevalence is unknown and the benign nature of the disorder probably means that it is under reported. Onset occurs within the first year of life with episodes occurring between every few weeks and every few months. The duration of the torticollis varies between patients, but usually lasts from a few hours to a few days. The frequency and duration of the torticollis episodes decrease as the patient gets older and episodes usually stop completely by 5 years of age. The disorder usually occurs sporadically, but familial occurrence has been reported.	Preferred (foundation metadata concept)
A rare functional neutrophil defect characterized by increased susceptibility to aggressive periodontitis in otherwise young, healthy individuals, due to impaired polymorphonuclear leukocyte chemotaxis toward bacterial formyl peptides. The periodontitis is rapidly progressive with progredient destruction of periodontal tissue and attachment loss.	Preferred (foundation metadata concept)
A rare functioning neuroendocrine tumor of pancreas characterized by a typically well-differentiated neoplasm composed of cells expressing serotonin. Patients may present with atypical carcinoid syndrome with abdominal pain, diarrhea, weight loss, and/or flushing. Carcinoid syndrome is usually present only when there are liver metastases. The tumors tend to be larger than non-functioning tumors and are associated with a poorer prognosis because they are almost always metastatic.	Preferred (foundation metadata concept)
A rare gastroenterologic disease characterized by the histopathological finding of a thickened gastric subepithelial collagen layer in association with an inflammatory infiltrate in the lamina propria. Patients typically present with upper abdominal pain and severe iron deficiency anemia. The condition is not commonly associated with autoimmune diseases, and involvement of the colon is less frequent than in the adult form. The disease takes a generally benign course with limited long-term morbidity and no increased mortality.	Preferred (foundation metadata concept)
A rare gastroenterologic disease characterized by typical clinical, endoscopic and histological features of eosinophilic esophagitis (symptomatic esophageal dysfunction associated with eosinophil-predominant mucose infiltrate), which completely remits upon proton pump inhibitor therapy.	Preferred (foundation metadata concept)
A rare gastroesophageal disease characterized by diffusely enlarged gastric folds, excessive mucus secretion, normal serum protein and gastric TGF-alpha levels. Patients typically present anemia, abdominal pain not related to eating or bowel habits and absence of peripheral edema.	Preferred (foundation metadata concept)
A rare generally benign lymphoproliferative hematological disease characterized by chronic, stable, persistent, polyclonal lymphocytosis of memory B-cell origin, the presence of binucleated lymphocytes in the peripheral blood, and a polyclonal increase in serum immunoglobulin M (IgM). Patients are most frequently asymptomatic or may present with mild splenomegaly.	Preferred (foundation metadata concept)
A rare genetic T cell negative B cell negative severe combined immunodeficiency disorder due to null mutations in recombination activating gene (RAG) 1 and/or RAG2 resulting in less than 1% of wild type V(D)J recombination activity. Patients present with neonatal onset of life threatening, severe, recurrent infections by opportunistic fungal, viral and bacterial microorganisms, as well as skin rashes, chronic diarrhea, failure to thrive and fever. Immunologic observations include profound T- and B-cell lymphopenia, normal NK counts and low or absent serum immunoglobulins, some patients may have eosinophilia.	Preferred (foundation metadata concept)
A rare genetic X-linked syndromic intellectual disability disorder characterized by mild to severe intellectual disability, infancy-onset seizures, post-natal microcephaly, cerebral cortical malformations, dysmorphic facial features (including long, narrow face, almond-shaped palpebral fissures, epicanthic folds, high nasal bridge, malar flattening, posteriorly rotated ears, high arched palate, crowded teeth, micrognathia) and thin body habitus. Long and slim fingers/toes, strabismus, hypotonia, spasticity, optic disc atrophy, and behavioral problems (aggression, attention deficit hyperactivity disorder and irritability) are additional features. Caused by hemizygous mutation in the NSDHL gene on chromosome Xq28.	Preferred (foundation metadata concept)
A rare genetic X-linked syndromic intellectual disability disorder with characteristics of moderate to severe intellectual disability associated with epilepsy, short stature, autistic features and behavioral problems, such as self- injury and aggressive outbursts. Observed facial dysmorphism includes brachycephaly, prominent supraorbital ridges, and deep-set eyes. Additional variable manifestations include malposition of feet, asthenic habitus, hyporeflexia, bowel occlusions, hydronephrosis, horseshoe kidney, delayed motor development and disturbed sleep-wake cycle. Caused by mutation in the GRIA3 gene.	Preferred (foundation metadata concept)
A rare genetic adrenal disease with characteristics of diminished corticosteroid-binding capacity associated with normal or low plasma corticosteroid-binding globulin concentration and reduced total plasma cortisol levels. Patients typically present chronic pain, fatigue and hypo/hypertension. Can be caused by heterozygous or homozygous mutation in the SERPINA6 gene on chromosome 14q32.	Preferred (foundation metadata concept)
A rare genetic adrenal disorder with characteristics of congenital bronzed hyperpigmentation, cutis laxa of the hands and feet, body disproportion (comprising large hands, feet, nose and ears), hirsutism and severe intellectual disability. Patients additionally present hyperadrenocorticism, cushingoid features, premature adrenarche and diabetes mellitus, as well as skeletal deformities (not present at birth and which progress with age). There have been no further descriptions in the literature since 1981.	Preferred (foundation metadata concept)
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 (such as aortic dilation, aortic aneurysm and/or dissection).	Preferred (foundation metadata concept)
A rare genetic autoinflammatory syndrome with immune deficiency disease characterized by recurrent and severe flares of generalized pustular psoriasis associated with high fever, asthenia and systemic inflammation due to IL36R antagonist deficiency. Psoriatic nail changes (for example pitting and onychomadesis) and ichthyosis may occasionally be associated.	Preferred (foundation metadata concept)
A rare genetic autosomal dominant hereditary axonal motor and sensory neuropathy disorder with characteristics of childhood-onset palmoplantar keratoderma associated with motor and sensory polyneuropathy manifesting with late-onset, predominantly distal, lower limb muscle weakness and atrophy (later associating mild proximal weakness and upper limb involvement), moderate sensory impairment and normal or near normal nerve conduction velocities. Additional variable manifestations include impaired vibratory sensation, reduced tendon reflexes, pain, talipes equinovarus, pes cavus and nail dystrophy.	Preferred (foundation metadata concept)
A rare genetic autosomal dominant spastic ataxia disorder with characteristics of lower-limb spasticity and ataxia in the form of head jerks, ocular movement abnormalities, dysarthria, dysphagia and gait disturbances. Caused by heterozygous mutation in the VAMP1 gene on chromosome 12p13.	Preferred (foundation metadata concept)
A rare genetic autosomal recessive axonal hereditary motor and sensory neuropathy disease with characteristics of prenatal onset of a severe sensorimotor axonal polyneuropathy reflected by reduced fetal movement and polyhydramnios. The disease manifests at birth with respiratory failure requiring mechanical ventilation, profound muscular hypotonia, rapidly progressing distal muscle weakness and absent deep tendon reflexes in the absence of contractures leading to death before 8 months of age. Neuropathological findings show severe loss of large and medium sized myelinated fibers without signs of demyelination.	Preferred (foundation metadata concept)
A rare genetic autosomal recessive cerebellar ataxia disease with characteristics of adulthood-onset of slowly progressive spinocerebellar ataxia, manifesting with gait and appendicular ataxia, dysarthria, ocular movement anomalies (for example horizontal, vertical, and/or downbeat nystagmus, hypermetric saccades), increased deep tendon reflexes and progressive cognitive decline. Additional variable features may include proximal leg muscle wasting and fasciculations, pes cavus, inspiratory stridor, epilepsy, retinal degeneration and cataracts. Brain imaging reveals marked cerebellar atrophy and electromyography shows evidence of lower motor neuron involvement. Caused by homozygous or compound heterozygous mutation in the ANO10 gene on chromosome 3p22.	Preferred (foundation metadata concept)
A rare genetic autosomal recessive cerebellar ataxia disease with characteristics of nonprogressive cerebellar ataxia, with onset in infancy, manifesting with delayed motor and speech development, gait ataxia, dysmetria, hypotonia, increased deep tendon reflexes and dysarthria. Additional variable manifestations include moderate nystagmus on lateral gaze, mild spasticity, intention tremor, short stature and pes planus. Brain imaging reveals cerebellar vermis atrophy.	Preferred (foundation metadata concept)
A rare genetic autosomal recessive cerebellar ataxia disease with characteristics of slowly progressive spinocerebellar ataxia developing during childhood, manifesting with gait and limb ataxia, postural tremor, dysarthria, sensory alterations (for example decreased vibration sense), eye movement anomalies (such as nystagmus, saccadic pursuit, oculomotor apraxia), upper and lower limb fasciculations and hyperreflexia with Babinski signs. Brain imaging reveals cerebellar, pontine, vermian and medullar atrophy. There is evidence the disease is caused by compound heterozygous mutation in the TPP1 gene on chromosome 11p15.	Preferred (foundation metadata concept)
A rare genetic autosomal recessive spastic ataxia disease with characteristics of cerebellar ataxia, spasticity, cerebellar (and in some cases cerebral) atrophy, dystonia and leukoencephalopathy. Caused by homozygous or compound heterozygous complex genomic rearrangements involving the MARS2 gene on chromosome 2q33.	Preferred (foundation metadata concept)
A rare genetic autosomal recessive spastic ataxia disease with characteristics of the onset in early childhood of spastic paraparesis, cerebellar ataxia, dysarthria and optic atrophy. Caused by homozygous mutation in the MTPAP gene on chromosome 10p11.	Preferred (foundation metadata concept)
A rare genetic axonal hereditary motor and sensory neuropathy disorder with characteristics of adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes. Gait anomalies and variable autonomic disturbances, such as erectile dysfunction and urinary urgency, may be associated. The disease can be caused by homozygous or heterozygous mutation in the LRSAM1 gene on chromosome 9q33.	Preferred (foundation metadata concept)
A rare genetic axonal peripheral sensorimotor neuropathy with an X-linked recessive inheritance pattern and the neonatal to early childhood-onset of severe, slowly progressive, distal muscle weakness and atrophy (in particular of the peroneal group) as well as sensory impairment (with the lower extremities being more affected than the upper extremities), pes cavus, areflexia and hammertoes. Sensorineural hearing loss and cognitive impairment may also be associated. Females are asymptomatic and do not display the phenotype. The disease is caused by mutation in the AIFM1 gene on chromosome Xq26.	Preferred (foundation metadata concept)
A rare genetic biliary tract disease with characteristics of severe neonatal-onset cholangiopathy with patent bile ducts and absence of ichthyosiform skin lesions. Patients present with jaundice, acholic stools, hepatosplenomegaly and high serum gamma-glutamyltransferase activity. Liver histology shows portal fibrosis, ductular proliferation, hepatocellular metallothionein deposits and intralobular bile-pigment accumulations. Some patients may also have renal disease.	Preferred (foundation metadata concept)
A rare genetic bone development disorder characterized by involvement of the clavicles and symmetrical generalized metaphyseal enchondromas particularly in the distal femur, proximal humerus, and bones of the wrists, hands, and feet. Lesions regress later in life with growth cartilage obliteration. Clinical examination is normal and the course of the disease is benign.	Preferred (foundation metadata concept)
A rare genetic bone development disorder characterized by normal clavicles and symmetrical generalized metaphyseal enchondromas particularly in the distal femur, proximal humerus, and bones of the wrists, hands, and feet. Lesions regress later in life with growth cartilage obliteration. Clinical examination is normal and the course of the disease is benign.	Preferred (foundation metadata concept)
A rare genetic bone development disorder characterized by occipital and parietal bone hypoplasia leading to occipital encephalocele, calvarial mineralization defects, craniosynostosis, radiohumeral fusions, oligodactyly and other skeletal anomalies (arachnodactyly, terminal phalangeal aplasia of the thumbs, bilateral absence of the great toes, pronounced bilateral angulation of femora, shortened limbs, advanced osseous maturation). Fetal death in utero is associated. There is evidence the disease can be caused by homozygous mutation in the CYP26B1 gene on chromosome 2p13.	Preferred (foundation metadata concept)
A rare genetic bone development disorder with characteristics of hand camptodactyly associated with facial dysmorphism (flat face, hypertelorism, telecanthus, symblepharon, simplified ears, retrognathia) and neck anomalies (short neck with pterygia, muscle sclerosis). Additional features include spinal defects (e.g. cervical and dorso-lumbar spina bifida occulta), congenital shortness of the sternocleidomastoid muscle, flexed wrists and thin hands and feet. Brain structural anomalies, multiple nevi, micropenis and mild intellectual disability are also observed. Imaging reveals widened femoral necks, cortical thickening of long bones and delayed bone age.	Preferred (foundation metadata concept)
A rare genetic bone development disorder with characteristics of multiple congenital fractures, slender ribs and long bones, deficient ossification of the skull and dysmorphic facial features reminiscent of Hallermann-Streiff syndrome (such as high forehead and triangular face with small jaw, deep-set eyes, beaked, narrow nose, downturned mouth and posteriorly angulated ears). Bilateral microphthalmia, cataracts and pulmonary hypoplasia have also been reported. The disease is fatal in the neonatal period.	Preferred (foundation metadata concept)
A rare genetic bone development disorder with characteristics of parietal foramina in association with hypoplasia of the clavicles (short abnormal clavicles with tapering lateral ends, with or without loss of the acromion). Additional features may include mild craniofacial dysmorphism (macrocephaly, broad forehead and frontal bossing). No dental abnormalities were reported. There is evidence the disease is caused by heterozygous mutation in the MSX2 gene on chromosome 5q35.	Preferred (foundation metadata concept)
A rare genetic bone development disorder with characteristics of proportionate short stature, nail dysplasia (enlarged, convex, hypertrophic nails), hypodontia and night blindness. Osteopenia, a tendency to present fractures, talipes varus with abnormal gait, ear infections, and watering eyes due to narrow tear ducts are frequently associated. Radiologically presents with delayed bone age on wrist X-rays, platyspondyly, and broad metaphyses of humeri with dense and thickened growth plates.	Preferred (foundation metadata concept)
A rare genetic bone developmental disorder characterized by generalized vertebral segmentation and fusion defects, disproportionate short stature (with predominant truncal shortness) and thoracolumbar scoliosis, associated with mild intellectual disability, hypospadias, partial cutaneous finger syndactyly and mild swan neck-like deformities of the fingers.	Preferred (foundation metadata concept)
A rare genetic bone developmental disorder with characteristics of short stature, orbital region and ocular abnormalities (e.g. asymmetric orbits, anophthalmia, down-slanted and S-shaped palpebral fissures, sparse eyebrows/eyelashes, abnormal eyelids, ectropion, symblepharon, corneal leukoma), abnormal nose (e.g. broad nasal root, bridge and tip, lateral deviation), malar hypoplasia, cleft lip/palate, and oblique facial clefts. Intellectual disability, microcephaly, micrognathia and limb anomalies (e.g. hemimelia, abnormal scapular girdle, brachydactyly, syndactyly, broad halluces) have also been reported.	Preferred (foundation metadata concept)
A rare genetic bone disease with characteristics of multifocal, painless, benign fibro-cemento-osseous lesions of the jaw which expand progressively and can cause severe facial deformity. It usually manifests at an early age and is often associated with abnormalities of the long bones and pathologic fractures. Radiologically, the lesions are of mixed radiopaque/radiolucent appearance. Incomplete surgical removal may lead to more rapid growth of the residual lesion.	Preferred (foundation metadata concept)
A rare genetic bone disease with characteristics of short stature, bilateral congenital hip dislocation, radial head dislocation, carpal coalition, scoliosis, pes cavus and atlantoaxial subluxation. Dysmorphic facial features include broad forehead, broad nasal bridge, hypertelorism and mild midface hypoplasia. Association with bilateral sensorineural hearing loss has also been described. Caused by homozygous or compound heterozygous mutation in the COL27A1 gene on chromosome 9q32.	Preferred (foundation metadata concept)
A rare genetic bone disorder with characteristics of chondrodysplasia, intrauterine growth retardation, hydrocephaly and facial dysmorphism in the affected males. The disease is severe and probably lethal in males, the clinical picture in females is less severe. The disease is due to a mutation in the histone deacetylase 6 HDAC6 gene (Xp11.3-q13.1) that causes a nucleotide substitution in the 3' untranslated region (UTR) of the HDAC6 transcript. This mutation lies in the seed sequence of microRNA-433 (hsa-miR-433) and abolishes the post-transcriptional regulation of HDAC6 expression by hsa-miR-433, resulting in the overexpression of the HDAC6 protein. Inheritance is X-linked dominant.	Preferred (foundation metadata concept)
A rare genetic bone disorder with the presence of two non-fused talar bone fragments, with the posterior fragment located at the level of the posterior talar process. Patients may present with foot and/or ankle pain (exercise-induced or not), repetitive ankle sprains, chronic ankle ligamentous laxity, restricted ankle motion (i.e. plantar flexion, eversion, and inversion), and mild swelling.	Preferred (foundation metadata concept)
A rare genetic brachydactyly syndrome with the association of brachydactyly type E and hypertension (due to vascular or neurovascular anomalies) as well as the additional features of short stature and low birth weight (compared to non-affected family members), stocky build and a round face. The onset of hypertension is often in childhood and if untreated, most patients will have had a stroke by the age of 50.	Preferred (foundation metadata concept)
A rare genetic capillary malformation characterized by dark red to purple birthmarks which manifest as flat, sharply circumscribed cutaneous lesions, typically situated in the head and neck region, in various members of a single family. The lesions grow proportionally with the individual, change in color and often thicken with age. There is evidence that congenital capillary malformations can be caused by somatic mosaic mutation in the GNAQ gene on chromosome 9q21.	Preferred (foundation metadata concept)
A rare genetic cardiac disease with characteristics of 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. The age of onset ranges between childhood and adulthood.	Preferred (foundation metadata concept)
A rare genetic cardiac malformation with characteristics of progressive myxomatous degeneration predominantly of the mitral valve (but not uncommonly with multivalvular involvement), presenting as valve thickening and dysfunction with variable stenosis, prolapse, and/or regurgitation and potentially resulting in lethal heart failure. Hyperextensible skin and joint hypermobility have been reported in some patients. Hemizygous males display a more severe phenotype than heterozygous females.	Preferred (foundation metadata concept)
A rare genetic central nervous system malformation characterized by dysplasia of the superior cerebellum (especially the vermis), brainstem asymmetry, dysplasia of the basal ganglia and cortical irregularities with asymmetric abnormalities in gyral size and orientation, as well as varying sulcal depth, but without lissencephaly, pachygyria, or polymicrogyria. Clinically, patients present global developmental delay with motor development usually being more affected that speech. Variable features are abnormal eye movements including oculomotor apraxia, strabismus, seizures and behavioral problems.	Preferred (foundation metadata concept)
A rare genetic central nervous system malformation syndrome characterized by bilateral congenital cataracts and severe hemorrhagic destruction of the brain parenchyma with associated massive cystic degeneration, enlarged ventricles and subependymal calcification. Patients typically present generalized spasticity, increased deep tendon reflexes and seizures. Hepatomegaly and renal anomalies have also been reported. Caused by homozygous mutation in the JAM3 gene on chromosome 11q25.	Preferred (foundation metadata concept)
A rare genetic central nervous system malformation syndrome with characteristics of congenital progressive microcephaly, neonatal to infancy-onset of severe intractable seizures and diffuse cerebral cortex and cerebellar vermis atrophy with mild cerebellar hemisphere atrophy associated with profound global developmental delay. Hypotonia or hypertonia with brisk reflexes, variable dysmorphic facial features, ophthalmological signs (cortical visual impairment, nystagmus, eye deviation) and episodes of sudden extreme agitation caused by severe illness may also be associated. Caused by compound heterozygous mutation in the QARS gene on chromosome 3p21.	Preferred (foundation metadata concept)
A rare genetic central nervous system malformation syndrome with characteristics of early-onset progressive severe cerebellar ataxia associated with progressive moderate to severe intellectual disability, global developmental delay, progressively coarsening facial features, relative macrocephaly and absence of seizures. Sensorineural hearing loss may be associated. Neuroimaging reveals cerebellar atrophy/hypoplasia. There is evidence the disease is caused by homozygous mutation in the SNX14 gene on chromosome 6q14.	Preferred (foundation metadata concept)
A rare genetic central nervous system malformation syndrome with characteristics of marked prenatal-onset microcephaly, severe motor delay with hypotonia, bilateral polymicrogyria, corpus callosum agenesis, ventricular dilation, small cerebellum and early lethality.	Preferred (foundation metadata concept)
A rare genetic cerebral malformation characterized by the presence of cortical smoothening with loss of secondary and tertiary gyri, associated with an excessive number of small, irregular gyri with increased cortical thickness, located in the occipital lobes. Patients usually present with seizures (including myoclonic-astatic, absence, atypical absence, vision loss, myoclonic-atonic, generalized tonic-clonic) and variable (absent to moderate) developmental and/or intellectual delay. There is evidence the disease is caused by homozygous or compound heterozygous mutations in the LAMC3 gene on chromosome 9q34.	Preferred (foundation metadata concept)
A rare genetic cerebral malformation with characteristics of an intracerebral fluid-filled cyst or cavity with or without communication between the ventricle and subarachnoid space. Clinical manifestations depend on location and severity and may include hemiparesis, seizures, intellectual disability, and dystonia. Porencephaly may manifest before or after birth. The cysts or cavities can be located anywhere within the cerebral parenchyma and are typically lined by smooth walls and surrounded by an atrophic cortex. Mutations in the COL4A1 (13q34) and COL4A2 (13q34) genes have been identified in familial porencephaly and de novo cases. The pattern of inheritance for familial porencephaly is autosomal dominant.	Preferred (foundation metadata concept)
A rare genetic cerebral small vessel disease characterized by leukoencephalopathy and cerebral calcification and cysts due to diffuse cerebral microangiopathy resulting in microcystic and macrocystic parenchymal degeneration. The condition can present at any age from early childhood to late adulthood and manifests as a progressive cerebral degeneration. Symptoms are variable but restricted to the central nervous system and include among others slowing of cognitive performance, seizures and movement disorder with a combination of pyramidal, extrapyramidal and cerebellar features.	Preferred (foundation metadata concept)
A rare genetic cerebral small vessel disease characterized by recurrent ischemic strokes, often with a predilection for the pons, with typical onset in the fourth or fifth decade of life. Patients present progressive cognitive and motor impairment with pyramidal, bulbar and cerebellar symptoms among others. Brain imaging shows multiple lacunar infarcts, typically with involvement of the pons, as well as variable leukoencephalopathy of the cerebral hemispheres.	Preferred (foundation metadata concept)
A rare genetic cerebral small vessel disease characterized by subcortical ischemic events associated with cognitive decline and gait disturbance with an age of onset typically in the sixth or seventh decade of life. Imaging reveals white matter hyperintensities, status cribrosum, lacunar infarcts and sometimes microbleeds. Extra-neurological manifestations are absent.	Preferred (foundation metadata concept)
A rare genetic cerebral small vessel disease with characteristics of adult-onset primary microangiopathy with severe atherosclerosis of arterioles and secondary leukoencephalopathy. Patients may present with migraine, transient ischemic attacks, stroke with central facial palsy, cognitive dysfunction with impaired concentration, dementia, depression, movement disorder, vertigo, dysphagia, dysarthria, impaired REM sleep, and therapy-resistant hypertension, among others. Brain MRI typically shows a leukoencephalopathy that is disproportionately severe and extensive compared to the clinical disease.	Preferred (foundation metadata concept)
A rare genetic cerebral small vessel disease with 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.	Preferred (foundation metadata concept)
A rare genetic chromosomal anomaly syndrome resulting from a partial deletion of the long arm of chromosome 21. The disease has characteristics of pre and post-natal growth delay, short stature, intellectual disability, developmental delay with severe language impairment, thrombocytopenia and craniofacial dysmorphism which may include microcephaly, downslanted palpebral fissures, low-set ears, broad nose, thin upper vermillion and downturned corners of the mouth. Brain MRI abnormalities (such as agenesis of the corpus callosum) behavioral problems and seizures may be associated.	Preferred (foundation metadata concept)
A rare genetic chromosomal anomaly syndrome resulting from partial duplication of the long arm of chromosome 2 with characteristics of congenital pendular nystagmus associated with bilateral cutaneous syndactyly between the third and fourth fingers.	Preferred (foundation metadata concept)
A rare genetic chronic primary adrenal insufficiency disorder due to partial loss-of-function CYP11A1 mutations. The disease has characteristics of early-onset adrenal insufficiency without associated abnormal external male genitalia. Patients present with signs of adrenal crisis, including electrolyte abnormalities, severe weakness, recurrent vomiting and seizures. Ultrasound reveals absent (or very small) adrenal glands.	Preferred (foundation metadata concept)
A rare genetic chronic skeletal disorder with characteristics of peripheral osteolysis, interphalangeal joint erosions, subcutaneous fibrocollagenous nodules, facial dysmorphism, and a wide range of associated manifestations. The prevalence and incidence of MONA are not known. Fewer than 50 cases have been reported worldwide. MONA spectrum disorders are caused by mutations in the MMP2 gene (16q13-q21) or MMP14 gene (14q11-q12). Follows an autosomal recessive pattern of inheritance. Many cases are reported in children from consanguineous unions.	Preferred (foundation metadata concept)
A rare genetic coagulation disorder characterized by easy bruising (without hemarthrosis or spontaneous hematomas), epistaxis, menorrhagia, and excessive bleeding after minor trauma and surgical procedures. Patients present a prolonged prothrombin time and/or activated partial thromboplastin time, normal levels of all coagulation factors and normal protein C activity.	Preferred (foundation metadata concept)
A rare genetic coagulation disorder characterized by marked bleeding tendency and posttraumatic bleeding with easy bruising, soft tissue and muscle bleeding, hemarthroses and menorrhagia. Caused by an increase of soluble thrombomodulin in plasma with subsequent protein C activation and reduction of thrombin generation within a potential thrombus. Abnormal laboratory findings include markedly elevated plasma thrombomodulin, reduced prothrombin consumption and decreased thrombin generation.	Preferred (foundation metadata concept)
A rare genetic coagulation disorder characterized by the usually incidental laboratory finding of a prolonged activated partial thromboplastin time (aPTT) but normal prothrombin time, due to a deficiency of normal prekallikrein or the presence of nonfunctional prekallikrein. Most patients remain clinically asymptomatic, although an association with cardiovascular conditions (hypertension, myocardial infarction, other coronary artery diseases, and ischemic strokes) and venous thrombosis, as well as rare cases with increased bleeding tendency have been reported.	Preferred (foundation metadata concept)
A rare genetic coagulation disorder with characteristics of a tendency to develop thrombosis resulting from decreased histidine-rich glycoprotein (HRG) plasma levels. Manifestations are variable depending on location of thrombosis, but may include headaches, diplopia, progressive pain, limb swelling, itching or ulceration, and brownish skin discoloration, among others. There is evidence the disease is caused by heterozygous mutation in the HRG gene on chromosome 3q27.	Preferred (foundation metadata concept)
A rare genetic coagulation disorder with characteristics of mild to moderate bleeding tendency due to impaired platelet activation and aggregation in response to collagen, or impaired platelet-vessel wall interaction, resulting from a collagen receptor defect. Patients manifest with ecchymoses, epistaxis, menorrhagia, and/or post-traumatic and post-surgery bleeding complications. Laboratory analysis reveals prolonged bleeding time and occasionally mild thrombocytopenia.	Preferred (foundation metadata concept)
A rare genetic cobblestone lissencephaly disease with characteristics of the presence of a constellation of brain malformations, including cortical gyral and sulcus anomalies, white matter signal abnormalities, cerebellar dysplasia and brainstem hypoplasia, existing alone or in conjunction with minimal muscular and ocular abnormalities, typically manifesting with severe developmental delay, increased head circumference, hydrocephalus and seizures. There is evidence the disease is caused by homozygous or compound heterozygous mutation in the LAMB1 gene on chromosome 7q31.	Preferred (foundation metadata concept)
A rare genetic coenzyme Q10 deficiency with characteristics of sensorineural deafness and severe progressive nephrotic syndrome not responding to steroid treatment. Clinical manifestations include early onset proteinuria, hypoalbuminemia and edema, leading to end-stage renal disease. Renal biopsy reveals focal segmental glomerulosclerosis and diffuse mesangial sclerosis. Rarely seizures, ataxia and dysmorphic features have been described.	Preferred (foundation metadata concept)
A rare genetic combined T and B cell immunodeficiency characterized by T- and B-cell lymphopenia, hypergammaglobulinemia and intermittent neutropenia. It presents with recurrent opportunistic viral, bacterial and fungal infections involving skin (cutaneous papillomatosis, molluscum contagiosum, skin abscesses, mucocutaneous candidiasis), upper and lower respiratory tract or septicemia. Other clinical features include autoimmune manifestations (autoimmune hemolytic anemia) and congenital heart defects (atrial septal defects, patent foramen ovale, mitral, tricuspid and pulmonary valve insufficiency). Caused by homozygous mutation in the STK4 gene on chromosome 20q13.	Preferred (foundation metadata concept)
A rare genetic combined T and B cell immunodeficiency characterized by life-threatening infections due to disrupted transferrin receptor 1 endocytosis, resulting in defective cellular iron transport and impaired T and B cell function. Patients present with early-onset chronic diarrhea, severe recurrent infections and failure to thrive. Laboratory studies reveal hypo or agammaglobulinemia, normal lymphocyte counts but decreased numbers of memory B cells, intermittent neutropenia and thrombocytopenia, and mild anemia (resistant to iron supplementation) with low mean corpuscular volume.	Preferred (foundation metadata concept)
A rare genetic complex cerebral cortical malformation characterized by generalized or focal dysgyria (also named polymicrogyria-like cortical dysplasia) or alternatively by microlissencephaly with dysmorphic basal ganglia and dysgenesis of the corpus callosum. Clinical manifestations are variable and include microcephaly, seizures, hypotonia, developmental delay, severe psychomotor delay, ataxia, spastic diplegia or tetraplegia, and ocular abnormalities (strabismus, ptosis or optic atrophy).	Preferred (foundation metadata concept)
A rare genetic complex hereditary spastic paraplegia disorder with characteristics of adulthood-onset of slowly progressive, bilateral, mainly lower limb spasticity and distal weakness associated with lower limb pain, hyperreflexia, and reduced vibration sense. Axonal neuropathy is frequently observed on electromyography and nerve conduction examination.	Preferred (foundation metadata concept)
A rare genetic complex spastic paraplegia disorder with characteristics of infantile-onset of psychomotor developmental delay with severe intellectual disability and poor speech acquisition, associated with seizures (mostly myoclonic), muscular hypotonia which may be noted at birth and slowly progressive spasticity in the lower limbs leading to severe gait disturbances. Ocular abnormalities and incontinence are commonly associated. Other symptoms may include verbal dyspraxia, hypogenitalism, macrocephaly and sensorineural hearing loss, as well as dystonic movements and ataxia with upper limb involvement.	Preferred (foundation metadata concept)
A rare genetic congenital anomalies/dysmorphic syndrome characterized by growth failure, global developmental delay, profound intellectual disability, autistic behavior, acquired second-degree heart block with bradycardia and vasomotor instability. Hands and feet present with long fusiform fingers, campto-clinodactyly and crowded toes while craniofacial dysmorphism includes microcephaly, broad forehead, thin eyebrows, upslanting palpebral fissures, large ears with prominent antihelix, prominent nose, long philtrum, thin upper lip vermillion and prominent lower lip. Neurological signs include hypotonia, brisk reflexes, dystonic-like movements and truncal ataxia and imaging shows cerebellar hypoplasia and simplified gyral pattern.	Preferred (foundation metadata concept)
A rare genetic congenital disorder of glycosylation and glycogen storage disease with characteristics of a wide range of clinical manifestations, most commonly presenting with bifid uvula with or without cleft palate at birth, associated with growth delay, hepatopathy with elevated aminotransferase serum levels, myopathy (including exercise-related fatigue, exercise intolerance, muscle weakness), intermittent hypoglycemia, and dilated cardiomyopathy and/or cardiac arrest, due to decreased phosphoglucomutase 1 enzyme activity. Less common manifestations include malignant hyperthermia, rhabdomyolysis, and hypogonadotropic hypogonadism with delayed puberty. Caused by homozygous or compound heterozygous mutation in the PGM1 gene on chromosome 1p31.	Preferred (foundation metadata concept)
A rare genetic congenital disorder of glycosylation with characteristics of severe pre and post-natal short stature, joint hyperlaxity with multiple dislocations (elbows, fingers, hips, knees), and facial dysmorphism (round flat face, high forehead, hypertelorism, prominent bulging eyes with under-eye shadows, hypoplastic midface, microstomia, protruding lips). Other associated features may include cutaneous hyperextensibility, learning difficulties and ocular abnormalities. Advanced carpal ossification, widened metaphyses, and, occasionally, radioulnar synostosis, scoliosis and a Swedish key appearance of the proximal femora is observed on imaging.	Preferred (foundation metadata concept)
A rare genetic congenital hypothyroidism disorder with characteristics of mild global developmental delay in childhood, short stature, delayed bone age and abnormal thyroid and selenium levels in serum (high total and free T4 concentrations, low T3, high reverse T3, normal to high TSH, decreased selenium). Intellectual disability, primary infertility, hypotonia, muscle weakness and impaired hearing have also been reported. The disease can be caused by homozygous or compound heterozygous mutation in the SECISBP2 gene on chromosome 9q22.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation disorder with characteristics of bilateral medial displacement of the hallux and preaxial polysyndactyly of the first toes. Radiographs show broad, shortened, misshapen first metatarsals and may associate incomplete or complete duplication of proximal phalanges and duplication or triplication of distal phalanges. There have been no further descriptions in the literature since 1980.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation disorder with characteristics of hypoplasia or absence of central digital rays of the hands and/or feet and the presence of one or more, unilateral or bilateral, supernumerary digits on postaxial rays, ranging from hypoplastic digits devoid of osseous structures to complete duplication of a digit. Cutaneous syndactyly, symphalangism and clinodactyly have also been reported. There have been no further descriptions in the literature since 1982.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation disorder with characteristics of hypoplasia/aplasia of distal and/or middle phalanges in fingers and toes II-V (frequently severe in fingers/toes IV-V, milder in fingers/toes II-III) in association with proximal, and occasionally distal, symphalangism, fusion of carpal/tarsal bones and partial cutaneous syndactyly. Additional reported features include proximal placement of thumbs, sensorineural hearing loss and farsightedness. There is evidence this disease is caused by mutations in the bone morphogenetic protein antagonist Noggin (NOG).	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation disorder with characteristics of isolated, postaxial oligodactyly in all four extremities. Patients present a consistent pattern of malformation ranging from complete absence of the 5th metacarpals, metatarsals and phalanges to complete absence of the 5th metacarpals and metatarsals, with some residual distal 5th phalanges. There have been no further descriptions in the literature since 1993.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation disorder with characteristics of the presence of a single digit on all four extremities. The malformation is typically isolated however, aplastic and hypoplastic defects in the remaining skeletal parts of hands and feet have been reported. There have been no further descriptions in the literature since 1992.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation disorder with characteristics of unilateral or bilateral postaxial polydactyly in the hands and preaxial polydactyly in the feet, associated with bilateral cutaneous syndactyly of first, second and third toes. Cutaneous syndactyly in hands has also been reported in some patients. There have been no further descriptions in the literature since 1994.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation syndrome with characteristics of a unique combination of bilateral, symmetrical camptodactyly and clinodactyly of fifth fingers, mesoaxial camptodactyly of toes and ulnar deviation of third fingers. Additional variable manifestations include bifid toes and severe syndactyly or synpolydactyly involving all digits of hands and feet.	Preferred (foundation metadata concept)
A rare genetic congenital limb malformation syndrome with characteristics of complete cutaneous syndactyly between toes 1-2, ulnar polydactyly (ranging from nubbins to an almost complete additional finger) and earlobe malformations. Additionally, abnormalities along the medial border of the foot are observed on X-ray imaging. There have been no further descriptions in the literature since 1976.	Preferred (foundation metadata concept)

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Reference Sets

Reference set descriptor

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Id	Description	Lang	Type	Status	Case?	Module
900000000001115012	United States of America English language reference set	en	Synonym (core metadata concept)	Active	Entire term case sensitive (core metadata concept)	SNOMED CT model component module (core metadata concept)
900000000001116013	US English	en	Synonym (core metadata concept)	Active	Entire term case sensitive (core metadata concept)	SNOMED CT model component module (core metadata concept)
900000000001117016	United States of America English language reference set (foundation metadata concept)	en	Fully specified name	Active	Entire term case sensitive (core metadata concept)	SNOMED CT model component module (core metadata concept)