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Cafe-au-lait spot

MedGen UID:
113157
Concept ID:
C0221263
Finding
Synonyms: Café au Lait; Café-au-lait spot
SNOMED CT: Café au lait spots (201281002); Café au lait spot (201281002); Cafe au lait spots (201281002); Cafe-au-lait spots (201281002)
 
HPO: HP:0000957

Definition

Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCafe-au-lait spot

Conditions with this feature

Ataxia-telangiectasia syndrome
MedGen UID:
439
Concept ID:
C0004135
Disease or Syndrome
Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.
Bloom syndrome
MedGen UID:
2685
Concept ID:
C0005859
Disease or Syndrome
Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include chronic obstructive pulmonary disease, diabetes mellitus as a result of insulin resistance, and cancer of a wide variety of types and anatomic sites.
Multiple endocrine neoplasia, type 1
MedGen UID:
9957
Concept ID:
C0025267
Neoplastic Process
Multiple endocrine neoplasia type 1 (MEN1) includes varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors become evident either by overproduction of hormones by the tumor or by growth of the tumor itself. Parathyroid tumors are the most common MEN1-associated endocrinopathy; onset in 90% of individuals is between ages 20 and 25 years with hypercalcemia evident by age 50 years; hypercalcemia causes lethargy, depression, confusion, anorexia, constipation, nausea, vomiting, diuresis, dehydration, hypercalciuria, kidney stones, increased bone resorption/fracture risk, hypertension, and shortened QT interval. Pituitary tumors include prolactinoma (the most common), which manifests as oligomenorrhea/amenorrhea and galactorrhea in females and sexual dysfunction in males. Well-differentiated endocrine tumors of the gastro-entero-pancreatic (GEP) tract can manifest as Zollinger-Ellison syndrome (gastrinoma); hypoglycemia (insulinoma); hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (glucagonoma); and watery diarrhea, hypokalemia, and achlorhydria syndrome (vasoactive intestinal peptide [VIP]-secreting tumor). Carcinoid tumors are non-hormone-secreting and can manifest as a large mass after age 50 years. Adrenocortical tumors can be associated with primary hypercortisolism or hyperaldosteronism. Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.
Neurofibromatosis, type 2
MedGen UID:
18014
Concept ID:
C0027832
Neoplastic Process
Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Johanson-Blizzard syndrome
MedGen UID:
59798
Concept ID:
C0175692
Disease or Syndrome
Johanson-Blizzard syndrome is an autosomal recessive disorder characterized by poor growth, mental retardation, and variable dysmorphic features, including aplasia or hypoplasia of the nasal alae, abnormal hair patterns or scalp defects, and oligodontia. Other features include hypothyroidism, sensorineural hearing loss, imperforate anus, and pancreatic exocrine insufficiency (summary by Al-Dosari et al., 2008).
Roberts-SC phocomelia syndrome
MedGen UID:
95931
Concept ID:
C0392475
Disease or Syndrome
ESCO2 spectrum disorder is characterized by mild-to-severe prenatal growth restriction, limb malformations (which can include bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening), hand anomalies (including oligodactyly, thumb aplasia or hypoplasia, and syndactyly), elbow and knee flexion contractures (involving elbows, wrists, knees, ankles, and feet [talipes equinovarus]), and craniofacial abnormalities (which can include bilateral cleft lip and/or cleft palate, micrognathia, widely spaced eyes, exophthalmos, downslanted palpebral fissures, malar flattening, and underdeveloped ala nasi), ear malformation, and corneal opacities. Intellectual disability (ranging from mild to severe) is common. Early mortality is common among severely affected pregnancies and newborns; mildly affected individuals may survive to adulthood.
Microcephaly, normal intelligence and immunodeficiency
MedGen UID:
140771
Concept ID:
C0398791
Disease or Syndrome
Nijmegen breakage syndrome (NBS) is characterized by progressive microcephaly, early growth deficiency that improves with age, recurrent respiratory infections, an increased risk for malignancy (primarily lymphoma), and premature ovarian failure in females. Developmental milestones are attained at the usual time during the first year; however, borderline delays in development and hyperactivity may be observed in early childhood. Intellectual abilities tend to decline over time. Recurrent pneumonia and bronchitis may result in respiratory failure and early death. Other reported malignancies include solid tumors (e.g., medulloblastoma, glioma, rhabdomyosarcoma).
Microcephalic osteodysplastic primordial dwarfism type II
MedGen UID:
96587
Concept ID:
C0432246
Disease or Syndrome
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities.
Kabuki syndrome
MedGen UID:
162897
Concept ID:
C0796004
Congenital Abnormality
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Nicolaides-Baraitser syndrome
MedGen UID:
220983
Concept ID:
C1303073
Disease or Syndrome
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay / intellectual disability. Seizures are of various types and can be difficult to manage. Developmental delay / intellectual disability (ID) is severe in nearly a half, moderate in a third, and mild in the remainder. Nearly a third never develop speech or language skills.
Neurofibromatosis, familial spinal
MedGen UID:
320296
Concept ID:
C1834235
Disease or Syndrome
Spinal neurofibromatosis is an autosomal dominant disorder characterized by a high load of spinal tumors. These tumors may be asymptomatic or result in neurologic symptoms, including back pain, difficulty walking, and paresthesias. Spinal NF is considered to be a subtype of neurofibromatosis type I (NF1; 162200), which is an allelic disorder. Patients with spinal NF may or may not have the classic cutaneous cafe-au-lait pigmentary macules or ocular Lisch nodules typically observed in patients with classic NF1. Patients with spinal NF should be followed closely for spinal sequelae (summary by Burkitt Wright et al., 2013).
Fanconi anemia complementation group N
MedGen UID:
372133
Concept ID:
C1835817
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group I
MedGen UID:
323016
Concept ID:
C1836861
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Intellectual disability-brachydactyly-Pierre Robin syndrome
MedGen UID:
325196
Concept ID:
C1837564
Disease or Syndrome
Intellectual disability-brachydactyly-Pierre Robin syndrome is a rare developmental defect during embryogenesis syndrome characterized by mild to moderate intellectual disability and phsychomotor delay, Robin sequence (incl. severe micrognathia and soft palate cleft) and distinct dysmorphic facial features (e.g. synophris, short palpebral fissures, hypertelorism, small, low-set, and posteriorly angulated ears, bulbous nose, long/flat philtrum, and bow-shaped upper lip). Skeletal anomalies, such as brachydactyly, clinodactyly, small hands and feet, and oral manifestations (e.g. bifid, short tongue, oligodontia) are also associated. Additional features reported include microcephaly, capillary hemangiomas on face and scalp, ventricular septal defect, corneal clouding, nystagmus and profound sensorineural deafness.
Fanconi anemia complementation group D1
MedGen UID:
325420
Concept ID:
C1838457
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Hyperpigmentation with or without hypopigmentation, familial progressive
MedGen UID:
333550
Concept ID:
C1840392
Disease or Syndrome
Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is characterized by diffuse hyperpigmentation of variable intensity sometimes associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules. These features, which involve the face, neck, trunk, and limbs, are seen at birth or develop early in infancy (summary by Wang et al., 2009 and Amyere et al., 2011). Also see familial progressive hyperpigmentation (FPH1; 614233).
Gastrocutaneous syndrome
MedGen UID:
338154
Concept ID:
C1850899
Disease or Syndrome
A rare syndromic hyperpigmentation of the skin with characteristics of multiple lentigines and cafe-au-lait spots associated with hiatal hernia and peptic ulcer, hypertelorism and myopia. There have been no further descriptions in the literature since 1982.
Tuberous sclerosis 1
MedGen UID:
344288
Concept ID:
C1854465
Disease or Syndrome
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical tubers, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Noonan syndrome 2
MedGen UID:
344290
Concept ID:
C1854469
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Metaphyseal chondrodysplasia-retinitis pigmentosa syndrome
MedGen UID:
381579
Concept ID:
C1855188
Disease or Syndrome
Brachydactyly-short stature-retinitis pigmentosa syndrome is a rare, genetic, congenital limb malformation syndrome characterized by mild to severe short stature, brachydactyly, and retinal degeneration (usually retinitis pigmentosa), associated with variable intellectual disability, developmental delays, and craniofacial anomalies.
Frank-Ter Haar syndrome
MedGen UID:
383652
Concept ID:
C1855305
Disease or Syndrome
The primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).
Tuberous sclerosis 2
MedGen UID:
348170
Concept ID:
C1860707
Disease or Syndrome
Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical tubers, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.
Pheochromocytoma-islet cell tumor syndrome
MedGen UID:
401431
Concept ID:
C1868392
Neoplastic Process
LEOPARD syndrome 2
MedGen UID:
370588
Concept ID:
C1969056
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Noonan syndrome 5
MedGen UID:
370589
Concept ID:
C1969057
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Legius syndrome
MedGen UID:
370709
Concept ID:
C1969623
Disease or Syndrome
Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.
Waardenburg syndrome type 2E
MedGen UID:
398476
Concept ID:
C2700405
Disease or Syndrome
Waardenburg syndrome type 2 (WS2) is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the inner canthus of each eye, which is seen in some other forms of WS (review by Read and Newton, 1997). Individuals with WS type 2E (WS2E) may have neurologic abnormalities, including mental impairment, myelination defects, and ataxia. Waardenburg syndrome type 2 is genetically heterogeneous (see WS2A, 193510). For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS3 (148820), and WS4 (277580).
Noonan syndrome 6
MedGen UID:
413028
Concept ID:
C2750732
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
CBL-related disorder
MedGen UID:
462153
Concept ID:
C3150803
Disease or Syndrome
Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; 163950) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by Martinelli et al., 2010). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as also seen in patients with Noonan syndrome (summary by Niemeyer et al., 2010).
Fanconi anemia complementation group D2
MedGen UID:
463627
Concept ID:
C3160738
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group E
MedGen UID:
463628
Concept ID:
C3160739
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Mosaic variegated aneuploidy syndrome 2
MedGen UID:
481473
Concept ID:
C3279843
Disease or Syndrome
Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (summary by Snape et al., 2011). See also MVA1 (257300), caused by mutation in the BUB1B gene (602860) on chromosome 15q15.
Fanconi anemia complementation group C
MedGen UID:
483324
Concept ID:
C3468041
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group A
MedGen UID:
483333
Concept ID:
C3469521
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group F
MedGen UID:
854016
Concept ID:
C3469526
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group L
MedGen UID:
854018
Concept ID:
C3469528
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia complementation group P
MedGen UID:
854020
Concept ID:
C3469542
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.
17q11.2 microduplication syndrome
MedGen UID:
501218
Concept ID:
C3495679
Disease or Syndrome
Syndrome that has characteristics of dysmorphic features and intellectual deficit. It has been described in seven patients within one family. 17q11.2 microduplication encompasses the NF1 region. The underlying mechanism may be non-allelic homologous recombination. The study of pedigree suggests that this microduplication segregates within the family for at least two generations. Two patients displayed a normal clinical presentation, suggesting an autosomal dominant pattern of inheritance with incomplete penetrance.
Blepharophimosis - intellectual disability syndrome, MKB type
MedGen UID:
785805
Concept ID:
C3698541
Disease or Syndrome
MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.
Severe congenital hypochromic anemia with ringed sideroblasts
MedGen UID:
815250
Concept ID:
C3808920
Disease or Syndrome
STEAP3/TSAP6-related sideroblastic anemia is a very rare severe non-syndromic hypochromic anemia, which is characterized by transfusion-dependent hypochromic, poorly regenerative anemia, iron overload, resembling non-syndromic sideroblastic anemia (see this term) except for increased erythrocyte protoporphyrin levels.
Cardiofaciocutaneous syndrome 4
MedGen UID:
815337
Concept ID:
C3809007
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
MedGen UID:
899689
Concept ID:
C4225259
Disease or Syndrome
Smith-Kingsmore syndrome (SKS) is a rare autosomal dominant syndromic intellectual disability syndrome characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features including frontal bossing, midface hypoplasia, small chin, hypertelorism with downslanting palpebral fissures, depressed nasal bridge, smooth philtrum, and thin upper lip (Smith et al., 2013; Baynam et al., 2015).
Noonan syndrome 10
MedGen UID:
902892
Concept ID:
C4225280
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Lichtenstein-Knorr syndrome
MedGen UID:
898996
Concept ID:
C4225383
Disease or Syndrome
Lichtenstein-Knorr syndrome is an autosomal recessive neurologic disorder characterized by postnatal onset of severe progressive sensorineural hearing loss and progressive cerebellar ataxia. Features usually develop in childhood or young adulthood (summary by Guissart et al., 2015). Some patients with SLC9A1 mutations may not have deafness (Iwama et al., 2018)
Maternal uniparental disomy of chromosome 20
MedGen UID:
909388
Concept ID:
C4275029
Congenital Abnormality
The Mulchandani-Bhoj-Conlin syndrome (MBCS) is characterized by prenatal growth restriction, severe short stature with proportional head circumference, and profound feeding difficulty (Mulchandani et al., 2016).
Noonan syndrome-like disorder with loose anagen hair 1
MedGen UID:
1379805
Concept ID:
C4478716
Disease or Syndrome
Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017). Reviews Komatsuzaki et al. (2010) reviewed the clinical manifestations of patients with Noonan syndrome, Costello syndrome (218040), and cardiofaciocutaneous syndrome (CFC; see 115150) compared to patients with mutations in the SHOC2 gene. They noted that although there is phenotypic overlap among the disorders, loose anagen/easily pluckable hair had not been reported in mutation-positive patients with Noonan, CFC, or Costello syndrome, and appeared to be a distinctive feature of SHOC2 mutation-positive patients. Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23.
Noonan syndrome-like disorder with loose anagen hair 2
MedGen UID:
1376945
Concept ID:
C4479577
Disease or Syndrome
An inherited condition caused by autosomal dominant mutation(s) in the PPP1CB gene, encoding serine/threonine-protein phosphatase PP1-beta catalytic subunit. The condition is characterized by facial features similar to those seen in Noonan syndrome but may also include short stature, cognitive deficits, relative macrocephaly, small posterior fossa resulting in Chiari I malformation, hypernasal voice, cardiac defects, and ectodermal abnormalities, which typically presents as slow-growing, sparse, and/or unruly hair.
Neurodevelopmental disorder with severe motor impairment and absent language
MedGen UID:
1622162
Concept ID:
C4540496
Mental or Behavioral Dysfunction
NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017 and Mannucci et al., 2021).
LEOPARD syndrome 1
MedGen UID:
1631694
Concept ID:
C4551484
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Noonan syndrome 1
MedGen UID:
1638960
Concept ID:
C4551602
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Rubinstein-Taybi syndrome due to CREBBP mutations
MedGen UID:
1639327
Concept ID:
C4551859
Disease or Syndrome
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.
Trichohepatoenteric syndrome 1
MedGen UID:
1644087
Concept ID:
C4551982
Disease or Syndrome
Trichohepatoenteric syndrome (THES), generally considered to be a neonatal enteropathy, is characterized by intractable diarrhea (seen in almost all affected children), woolly hair (seen in all), intrauterine growth restriction, facial dysmorphism, and short stature. Additional findings include poorly characterized immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies. To date 52 affected individuals have been reported.
PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome
MedGen UID:
1641154
Concept ID:
C4693860
Disease or Syndrome
Chung-Jansen syndrome (CHUJANS) is characterized by global developmental delay apparent from infancy, impaired intellectual development or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity. The severity of the phenotype and additional features are variable (summary by Jansen et al., 2018).
Microcephaly, growth restriction, and increased sister chromatid exchange 2
MedGen UID:
1648384
Concept ID:
C4748176
Disease or Syndrome
MGRISCE2 is an autosomal recessive disorder characterized by intrauterine growth restriction, poor postnatal growth with short stature and microcephaly, and increased sister chromatid exchange on cell studies. The disorder results from defective DNA decatenation. The pathogenesis of the disorder is similar to that of Bloom syndrome (BLM; 210900), but patients with mutations in the TOP3A gene do not have a malar rash (summary by Martin et al., 2018). For a discussion of genetic heterogeneity of MGRISCE, see Bloom syndrome (BLM; MGRISCE1; 210900)
Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
MedGen UID:
1684464
Concept ID:
C5193036
Disease or Syndrome
IMAGEI is an autosomal recessive disorder characterized by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency. Patients exhibit distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency (Logan et al., 2018). An autosomal dominant form of the disorder, without immunodeficiency (IMAGE; 614732), is caused by mutation in the CDKN1C gene (600856) on chromosome 11p15.
Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
MedGen UID:
1682403
Concept ID:
C5193134
Disease or Syndrome
Stolerman neurodevelopmental syndrome (NEDSST) is characterized by mildly impaired global development apparent from infancy, poor speech acquisition, hypotonia with early feeding difficulties, mildly delayed walking, and variable behavioral abnormalities, such as autistic features, hyperactivity, or attention deficits. Most individuals have coarse facial features, including prominent forehead, large ears, and wide mouth. Other features may include wide hands, thickened fingers, and cutaneous toe syndactyly, as well as joint hyperlaxity. Mutations occur de novo, such that the disorder occurs sporadically in patients with no family history of a similar disorder (Stolerman et al., 2019).
Hypopigmentation, organomegaly, and delayed myelination and development
MedGen UID:
1684826
Concept ID:
C5203300
Disease or Syndrome
Hypopigmentation, organomegaly, and delayed myelination and development (HOD) is characterized by hypopigmented skin and hair with normally pigmented irides; organomegaly including enlargement of liver, kidney, and spleen; and delayed myelination on brain MRI accompanied by developmental delay in both gross and fine motor skills. Biopsy findings from skin and other organs are consistent with a lysosomal storage disorder (Nicoli et al., 2019).
Rothmund-Thomson syndrome type 1
MedGen UID:
1684764
Concept ID:
C5231433
Disease or Syndrome
Rothmund-Thomson syndrome (RTS) is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; skeletal and dental abnormalities; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age two years) as erythema, swelling, and blistering on the face, subsequently spreading to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, telangiectasias, and punctate atrophy (collectively known as poikiloderma) that persist throughout life. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities can include radial ray defects, ulnar defects, absent or hypoplastic patella, and osteopenia.
Neurodevelopmental disorder with absent language and variable seizures
MedGen UID:
1684803
Concept ID:
C5231469
Disease or Syndrome
Silver-Russell syndrome 1
MedGen UID:
1718472
Concept ID:
C5393125
Disease or Syndrome
Silver-Russell Syndrome (SRS) is typically characterized by asymmetric gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference =1.5 SD above birth weight and/or length), prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure, and in some cases progressive limb length discrepancy and feeding difficulties. Additional clinical features include triangular facies, fifth-finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, the growth failure is proportionate and head growth normal. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean. The Netchine-Harbison Clinical Scoring System (NH-CSS) is a sensitive diagnostic scoring system. Clinical diagnosis can be established in an individual who meets at least four of the NH-CSS clinical criteria – prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings – and in whom other disorders have been ruled out.
Chromosome 17q11.2 deletion syndrome, 1.4Mb
MedGen UID:
1726802
Concept ID:
C5401456
Disease or Syndrome
Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).
Noonan syndrome 13
MedGen UID:
1761918
Concept ID:
C5436773
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Chromosome 13q33-q34 deletion syndrome
MedGen UID:
1744234
Concept ID:
C5436890
Disease or Syndrome
Chromosome 13q33-q34 deletion syndrome is associated with developmental delay and/or impaired intellectual development, facial dysmorphism, and an increased risk for epilepsy, cardiac defects and additional anatomic anomalies (summary by Sagi-Dain et al., 2019).
Vertebral, cardiac, tracheoesophageal, renal, and limb defects
MedGen UID:
1788069
Concept ID:
C5543189
Disease or Syndrome
VCTERL syndrome is characterized by anomalies of the vertebrae, heart, trachea, esophagus, kidneys, and limbs. Some patients also exhibit craniofacial abnormalities. Incomplete penetrance and markedly variable disease expression have been observed, including intrafamilial variability (Martin et al., 2020).
Baralle-Macken syndrome
MedGen UID:
1778777
Concept ID:
C5543241
Disease or Syndrome
Baralle-Macken syndrome (BARMACS) is an autosomal recessive disorder characterized by global developmental delay apparent from infancy, difficulty walking or inability to walk, and impaired intellectual development with poor or absent speech. Affected individuals develop early-onset cataracts; some may have microcephaly. Additional more variable features may include dysmorphic facial features, metabolic abnormalities, spasticity, and lymphopenia (summary by Macken et al., 2021).
Intellectual disability and myopathy syndrome
MedGen UID:
1808193
Concept ID:
C5676904
Disease or Syndrome
Intellectual disability and myopathy syndrome (IDMYS) is an autosomal recessive developmental disorder characterized by global developmental delay with mildly impaired intellectual development, hypotonia, muscle weakness and fatigue, and white matter abnormalities on brain imaging. Variable additional features may include sensorineural hearing loss, dysmorphic facies, and progressive heart disease (summary by Smeland et al., 2019).
Waardenburg syndrome, IIa 2F
MedGen UID:
1809587
Concept ID:
C5677013
Disease or Syndrome
Waardenburg syndrome type 2F (WS2F) is characterized by congenital or neonatal-onset sensorineural hearing loss and altered pigmentation of the iris, hair, and skin. Variable expressivity has been reported, even among patients with the same mutation (Ogawa et al., 2017; Vona et al., 2022). For a general phenotypic description and discussion of genetic heterogeneity of WS2, as well as a brief description of other clinical variants of Waardenburg syndrome (WS1, 193500; WS3, 148820; and WS4, 277580), see WS2A (193510).
Microcephaly 30, primary, autosomal recessive
MedGen UID:
1824053
Concept ID:
C5774280
Disease or Syndrome
Autosomal recessive primary microcephaly-30 (MCPH30) is characterized by small head circumference, poor overall growth, and global developmental delay with variably impaired intellectual development. Affected individuals have been reported to have variable additional congenital anomalies, including atrial septal defect, dysmorphic facial features, tracheal stenosis, and anomalies of the skin and teeth (Carvalhal et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Atelis syndrome 1
MedGen UID:
1824054
Concept ID:
C5774281
Disease or Syndrome
Atelis syndrome-1 (ATELS1) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay with learning difficulties and poor overall growth with short stature and microcephaly. Most patients have anemia, some have immunologic defects, and some have congenital heart septal defects. More variable features may include hypotonia, dysmorphic facial features, skin pigmentary anomalies, and mild skeletal defects. Patient cells show multiple chromosomal abnormalities due to impaired DNA replication and disrupted mitosis (Grange et al., 2022). See also ATELS2 (620185), caused by mutation in the SMC5 gene (609386) on chromosome 9q21. For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).
Tessadori-Van Haaften neurodevelopmental syndrome 3
MedGen UID:
1824083
Concept ID:
C5774310
Disease or Syndrome
Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-3 (TEBIVANED3) is characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of Tessadori-Bicknell-van Haaften neurodevelopmental disorder, see TEBIVANED1 (619758).

Professional guidelines

PubMed

Kehrer-Sawatzki H, Cooper DN
Hum Genet 2022 Feb;141(2):177-191. Epub 2021 Dec 20 doi: 10.1007/s00439-021-02410-z. PMID: 34928431Free PMC Article
Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC), Huson SM, Evans DG, Plotkin SR
Genet Med 2021 Aug;23(8):1506-1513. Epub 2021 May 19 doi: 10.1038/s41436-021-01170-5. PMID: 34012067Free PMC Article
Plensdorf S, Livieratos M, Dada N
Am Fam Physician 2017 Dec 15;96(12):797-804. PMID: 29431372

Recent clinical studies

Etiology

Jamshidi K, Motaghi P, Bagherifard A, Eigi M, Al-Baseesee HH, Mirzaei A
J Orthop Sci 2021 Jul;26(4):655-659. Epub 2020 Aug 17 doi: 10.1016/j.jos.2020.06.010. PMID: 32819790
Zhang B, Chu Y, Xu Z, Sun Y, Li L, Han X, Wang C, Wei L, Liu Y, Ma L
Lasers Surg Med 2019 Oct;51(8):694-700. Epub 2019 May 25 doi: 10.1002/lsm.23097. PMID: 31129919Free PMC Article
Wimmer K, Rosenbaum T, Messiaen L
Clin Genet 2017 Apr;91(4):507-519. Epub 2017 Jan 10 doi: 10.1111/cge.12904. PMID: 27779754
Dragieva G, Stahel HU, Meyer M, Kempf W, Häffner A, Burg G, Hafner J
Vasa 2003 Aug;32(3):159-63. doi: 10.1024/0301-1526.32.3.159. PMID: 14524037
Gerritsen MJ, Steijlen PM, Brunner HG, Rieu P
Br J Dermatol 2000 Feb;142(2):366-9. doi: 10.1046/j.1365-2133.2000.03311.x. PMID: 10730777

Diagnosis

Garcia Neto V, de Almeida HL Jr, Lorea CF, Jorge VM, de Almeida AL
An Bras Dermatol 2022 Jan-Feb;97(1):58-62. Epub 2021 Nov 25 doi: 10.1016/j.abd.2021.09.002. PMID: 34839987Free PMC Article
Neri I, Lambertini M, Tengattini V, Rivalta B, Patrizi A
Pediatr Dermatol 2017 May;34(3):e152-e153. doi: 10.1111/pde.13126. PMID: 28523880
Wimmer K, Rosenbaum T, Messiaen L
Clin Genet 2017 Apr;91(4):507-519. Epub 2017 Jan 10 doi: 10.1111/cge.12904. PMID: 27779754
Dragieva G, Stahel HU, Meyer M, Kempf W, Häffner A, Burg G, Hafner J
Vasa 2003 Aug;32(3):159-63. doi: 10.1024/0301-1526.32.3.159. PMID: 14524037
Brownstein MH, Rabinowitz AD
J Am Acad Dermatol 1983 Apr;8(4):579-88. doi: 10.1016/s0190-9622(83)80078-4. PMID: 6853792

Therapy

Zhang B, Chu Y, Xu Z, Sun Y, Li L, Han X, Wang C, Wei L, Liu Y, Ma L
Lasers Surg Med 2019 Oct;51(8):694-700. Epub 2019 May 25 doi: 10.1002/lsm.23097. PMID: 31129919Free PMC Article
Gillbro JM, Olsson MJ
Int J Cosmet Sci 2011 Jun;33(3):210-21. Epub 2011 Jan 25 doi: 10.1111/j.1468-2494.2010.00616.x. PMID: 21265866
Endo M, Yamada Y, Matsuura N, Niikawa N
Am J Med Genet 1991 Nov 1;41(2):216-20. doi: 10.1002/ajmg.1320410217. PMID: 1838461

Prognosis

Zhang B, Chu Y, Xu Z, Sun Y, Li L, Han X, Wang C, Wei L, Liu Y, Ma L
Lasers Surg Med 2019 Oct;51(8):694-700. Epub 2019 May 25 doi: 10.1002/lsm.23097. PMID: 31129919Free PMC Article
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Mastrangelo MJ, Goepp CE, Patel YA, Clark WH Jr
Arch Dermatol 1979 Jul;115(7):864-5. PMID: 110269

Clinical prediction guides

Zhang B, Chu Y, Xu Z, Sun Y, Li L, Han X, Wang C, Wei L, Liu Y, Ma L
Lasers Surg Med 2019 Oct;51(8):694-700. Epub 2019 May 25 doi: 10.1002/lsm.23097. PMID: 31129919Free PMC Article
Gerritsen MJ, Steijlen PM, Brunner HG, Rieu P
Br J Dermatol 2000 Feb;142(2):366-9. doi: 10.1046/j.1365-2133.2000.03311.x. PMID: 10730777
Yamamoto T, Ozono K, Kasayama S, Yoh K, Hiroshima K, Takagi M, Matsumoto S, Michigami T, Yamaoka K, Kishimoto T, Okada S
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Hannan MA, Smith BP, Sigut D, Sackey K
Cancer Genet Cytogenet 1990 Jul 15;47(2):191-6. doi: 10.1016/0165-4608(90)90029-a. PMID: 2113426
Mastrangelo MJ, Goepp CE, Patel YA, Clark WH Jr
Arch Dermatol 1979 Jul;115(7):864-5. PMID: 110269

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