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Tetralogy of Fallot(TOF)

MedGen UID:
21498
Concept ID:
C0039685
Congenital Abnormality
Synonyms: Fallot tetralogy; TOF
SNOMED CT: TOF - Tetralogy of Fallot (86299006); Fallot's tetralogy (86299006); Tetralogy of Fallot (86299006); Subpulmonic stenosis, ventricular septal defect, overriding aorta, AND right ventricular hypertrophy (86299006)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Multifactorial inheritance
MedGen UID:
109109
Concept ID:
C0600599
Genetic Function
Source: Orphanet
A mode of inheritance that depends on a mixture of major and minor genetic determinants possibly together with environmental factors. Diseases inherited in this manner are termed complex diseases.
 
Genes (locations): GATA4 (8p23.1); GATA6 (18q11.2); JAG1 (20p12.2); NKX2-5 (5q35.1); TBX1 (22q11.21); ZFPM2 (8q23.1)
 
HPO: HP:0001636
Monarch Initiative: MONDO:0008542
OMIM®: 187500
Orphanet: ORPHA3303

Definition

People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.\n\nEach of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.\n\nSome people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.\n\nAlthough babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.\n\nCritical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth. [from MedlinePlus Genetics]

Clinical features

From HPO
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Tetralogy of Fallot
MedGen UID:
21498
Concept ID:
C0039685
Congenital Abnormality
People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.\n\nEach of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.\n\nSome people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.\n\nAlthough babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.\n\nCritical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Preauricular pit
MedGen UID:
120587
Concept ID:
C0266610
Congenital Abnormality
Small indentation anterior to the insertion of the ear.
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.

Conditions with this feature

DiGeorge syndrome
MedGen UID:
4297
Concept ID:
C0012236
Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.
Complete trisomy 21 syndrome
MedGen UID:
4385
Concept ID:
C0013080
Disease or Syndrome
Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.
Tetralogy of Fallot
MedGen UID:
21498
Concept ID:
C0039685
Congenital Abnormality
People with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.\n\nEach of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.\n\nSome people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.\n\nAlthough babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.\n\nCritical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.
Radial aplasia-thrombocytopenia syndrome
MedGen UID:
61235
Concept ID:
C0175703
Disease or Syndrome
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
Velocardiofacial syndrome
MedGen UID:
65085
Concept ID:
C0220704
Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.
Nager syndrome
MedGen UID:
120519
Concept ID:
C0265245
Disease or Syndrome
Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (263750), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by Bernier et al., 2012).
Distichiasis-lymphedema syndrome
MedGen UID:
75566
Concept ID:
C0265345
Disease or Syndrome
Lymphedema-distichiasis syndrome (referred to as LDS in this GeneReview) is characterized by lower-limb lymphedema, and distichiasis (aberrant eyelashes ranging from a full set of extra eyelashes to a single hair). Lymphedema typically appears in late childhood or puberty, is confined to the lower limbs with or without involvement of the external genitalia, and is often asymmetric; severity varies within families. Males develop edema at an earlier age and have more problems with cellulitis than females. Distichiasis, which may be present at birth, is observed in 94% of affected individuals. About 75% of affected individuals have ocular findings including corneal irritation, recurrent conjunctivitis, and photophobia; other common findings include varicose veins and ptosis.
CHARGE association
MedGen UID:
75567
Concept ID:
C0265354
Disease or Syndrome
CHD7 disorder encompasses the entire phenotypic spectrum of heterozygous CHD7 pathogenic variants that includes CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype. The mnemonic CHARGE syndrome, introduced in the premolecular era, stands for coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (including deafness). Following the identification of the genetic cause of CHD7 disorder, the phenotypic spectrum expanded to include cranial nerve anomalies, vestibular defects, cleft lip and/or palate, hypothyroidism, tracheoesophageal anomalies, brain anomalies, seizures, and renal anomalies. Life expectancy highly depends on the severity of manifestations; mortality can be high in the first few years when severe birth defects (particularly complex heart defects) are present and often complicated by airway and feeding issues. In childhood, adolescence, and adulthood, decreased life expectancy is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. Despite these complications, the life expectancy for many individuals can be normal.
Cat eye syndrome
MedGen UID:
120543
Concept ID:
C0265493
Disease or Syndrome
Cat eye syndrome (CES) is characterized clinically by the combination of coloboma of the iris and anal atresia with fistula, downslanting palpebral fissures, preauricular tags and/or pits, frequent occurrence of heart and renal malformations, and normal or near-normal mental development. A small supernumerary chromosome (smaller than chromosome 21) is present, frequently has 2 centromeres, is bisatellited, and represents an inv dup(22)(q11).
Beta-hydroxyisobutyryl-CoA deacylase deficiency
MedGen UID:
83349
Concept ID:
C0342738
Disease or Syndrome
3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by Ferdinandusse et al., 2013).
Asymmetric crying face
MedGen UID:
140911
Concept ID:
C0431406
Disease or Syndrome
Asymmetry observed in the face of a neonate or infant whose face appears symmetric at rest and asymmetric during crying as the mouth is pulled downward on one side while not moving on the other side.
Recombinant 8 syndrome
MedGen UID:
167070
Concept ID:
C0795822
Disease or Syndrome
Recombinant chromosome 8 syndrome (Rec8 syndrome) is a chromosomal disorder found among individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have impaired intellectual development, congenital heart defects, seizures, a characteristic facial appearance with hypertelorism, thin upper lip, anteverted nares, wide face, and abnormal hair whorl, and other manifestations (Sujansky et al., 1993, summary by Graw et al., 2000).
Renpenning syndrome
MedGen UID:
208670
Concept ID:
C0796135
Disease or Syndrome
Renpenning syndrome is an X-linked mental retardation syndrome with clinically recognizable features. Affected individuals have microcephaly, short stature, small testes, and dysmorphic facies, including tall narrow face, upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. Stevenson et al. (2005) proposed that the various X-linked mental retardation syndromes due to PQBP1 mutations be combined under the name of Renpenning syndrome.
Oculootoradial syndrome
MedGen UID:
233003
Concept ID:
C1327918
Disease or Syndrome
IVIC syndrome (IVIC) is an autosomal dominant disorder characterized by upper limb anomalies (radial ray defects, carpal bone fusion), extraocular motor disturbances, and congenital bilateral nonprogressive mixed hearing loss. More variable features include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation, and rectovaginal fistula (summary by Paradisi and Arias, 2007).
Porencephaly-cerebellar hypoplasia-internal malformations syndrome
MedGen UID:
331296
Concept ID:
C1832472
Disease or Syndrome
Porencephaly-cerebellar hypoplasia-internal malformations syndrome is rare central nervous system malformation syndrome characterized by bilateral porencephaly, absence of the septum pellucidum and cerebellar hypoplasia with absent vermis. Additionally, dysmorphic facial features (hypertelorism, epicanthic folds, high arched palate, prominent metopic suture), macrocephaly, corneal clouding, situs inversus, tetralogy of Fallot, atrial septal defects and/or seizures have been observed.
Matthew-Wood syndrome
MedGen UID:
318679
Concept ID:
C1832661
Disease or Syndrome
Syndromic microphthalmia-9, also referred to as pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect, is characterized by bilateral clinical anophthalmia, pulmonary hypoplasia/aplasia, cardiac malformations, and diaphragmatic defects. The phenotype is variable, ranging from isolated clinical anophthalmia or microphthalmia to complex presentations involving the cardiac, pulmonary, diaphragmatic, and renal systems. At its most severe, infants are born without pulmonary structures and die soon after birth (Marcadier et al., 2015).
Fallot complex-intellectual disability-growth delay syndrome
MedGen UID:
322025
Concept ID:
C1832735
Disease or Syndrome
A rare disorder characterised by tetralogy of Fallot, minor facial anomalies, and severe intellectual deficiency and growth delay. Dysmorphic features include large, protruding, abnormally modelled ears and broad nasal root. Microcephaly and syndactyly of second and third toes have also been recorded. All patients have severe intellectual deficiency. The condition is transmitted as an autosomal recessive trait.
Timothy syndrome
MedGen UID:
331395
Concept ID:
C1832916
Disease or Syndrome
The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes: Timothy syndrome with or without syndactyly. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval. These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C: QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current). Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current).
Meacham syndrome
MedGen UID:
373234
Concept ID:
C1837026
Disease or Syndrome
WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past, those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful.
Acrocardiofacial syndrome
MedGen UID:
324947
Concept ID:
C1838121
Disease or Syndrome
A rare genetic disorder characterised by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and intellectual deficit.
Atrioventricular defect-blepharophimosis-radial and anal defect syndrome
MedGen UID:
374010
Concept ID:
C1838606
Disease or Syndrome
A rare, genetic multiple congenital anomalies syndrome characterized by atrioventricular septal defects and blepharophimosis, in addition to radial (e.g. aplastic radius, shortened ulna, fifth finger clinodactyly, absent first metacarpal and thumb) and anal (e.g. imperforate or anteriorly place anus, rectovaginal fistula) defects.
TARP syndrome
MedGen UID:
333324
Concept ID:
C1839463
Disease or Syndrome
The classic features of TARP syndrome are talipes equinovarus, atrial septal defect, Robin sequence (micrognathia, cleft palate, and glossoptosis), and persistent left superior vena cava. Not all patients have all classic features. Some patients have the additional features of central nervous system dysfunction, renal abnormalities, variable cardiac anomalies including hypertrophic obstructive cardiomyopathy, and variable distal limb defects including syndactyly. Most patients die in late prenatal or early postnatal stages (summary by Kaeppler et al., 2018).
Chromosome 1p36 deletion syndrome
MedGen UID:
334629
Concept ID:
C1842870
Disease or Syndrome
The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36. See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features.
CHIME syndrome
MedGen UID:
341214
Concept ID:
C1848392
Disease or Syndrome
CHIME syndrome, also known as Zunich neuroectodermal syndrome, is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (summary by Ng et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Thakker-Donnai syndrome
MedGen UID:
346465
Concept ID:
C1856892
Disease or Syndrome
Thakker-Donnai syndrome is a rare, genetic, lethal, multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphism (including long, downward slanting palpebral fissures, hypertelorism, posteriorly rotated ears, broad nasal bridge, short nose with a bulbous tip and anteverted nares, downturned corners of the mouth) as well as vertebral (occult spina bifida, hemivertebrae), brain (ventricular dilatation, agenesis of corpus callosum), cardiac (tetralogy of Fallot, ventricular septal defect) and gastrointestinal (short esophagus with intrathoracic stomach, small intestine, spleen and pancreas, anal atresia) malformations. There have been no further descriptions in the literature since 1991.
Yunis-Varon syndrome
MedGen UID:
341818
Concept ID:
C1857663
Disease or Syndrome
Yunis-Varon syndrome is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013).
Alagille syndrome due to a NOTCH2 point mutation
MedGen UID:
341844
Concept ID:
C1857761
Disease or Syndrome
Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability; this variability is seen even among individuals from the same family. The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects (primarily involving the pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Renal abnormalities, growth failure, developmental delays, splenomegaly, and vascular abnormalities may also occur.
Osteodysplastic primordial dwarfism, type 1
MedGen UID:
347149
Concept ID:
C1859452
Congenital Abnormality
Microcephalic osteodysplastic primordial dwarfism type I is a severe autosomal recessive skeletal dysplasia characterized by dwarfism, microcephaly, and neurologic abnormalities, including mental retardation, brain malformations, and ocular/auditory sensory deficits. Patients often die in early childhood (summary by Pierce and Morse, 2012).
Tetralogy of fallot and glaucoma
MedGen UID:
396086
Concept ID:
C1861234
Disease or Syndrome
Progeroid facial appearance with hand anomalies
MedGen UID:
356343
Concept ID:
C1865699
Disease or Syndrome
Deafness, congenital heart defects, and posterior embryotoxon
MedGen UID:
355614
Concept ID:
C1866053
Disease or Syndrome
Orofaciodigital syndrome V
MedGen UID:
358131
Concept ID:
C1868118
Disease or Syndrome
Orofaciodigital syndrome V (OFD5) is an autosomal recessive disorder characterized by cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (summary by Faily et al., 2017).
Alagille syndrome due to a JAG1 point mutation
MedGen UID:
365434
Concept ID:
C1956125
Disease or Syndrome
Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability; this variability is seen even among individuals from the same family. The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects (primarily involving the pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Renal abnormalities, growth failure, developmental delays, splenomegaly, and vascular abnormalities may also occur.
Chromosome 6pter-p24 deletion syndrome
MedGen UID:
393396
Concept ID:
C2675486
Disease or Syndrome
Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.
Diamond-Blackfan anemia 7
MedGen UID:
436451
Concept ID:
C2675512
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
Microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type
MedGen UID:
414129
Concept ID:
C2751878
Disease or Syndrome
A rare syndrome with characteristics of pre-natal onset growth retardation (low birth weight and short stature), hypotonia, developmental delay and intellectual disability associated with microcephaly and craniofacial (low anterior hairline, hypotelorism, thick lips with carp-shaped mouth, high-arched palate, low-set ears), cardiac (conotruncal heart malformations such as tetralogy of Fallot) and skeletal (hypoplastic thumbs and first metacarpals) abnormalities.
Diamond-Blackfan anemia 6
MedGen UID:
419918
Concept ID:
C2931850
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia or no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
Alveolar capillary dysplasia with pulmonary venous misalignment
MedGen UID:
755478
Concept ID:
C2960310
Congenital Abnormality
Congenital alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is characterized histologically by failure of formation and ingrowth of alveolar capillaries that then do not make contact with alveolar epithelium, medial muscular thickening of small pulmonary arterioles with muscularization of the intraacinar arterioles, thickened alveolar walls, and anomalously situated pulmonary veins running alongside pulmonary arterioles and sharing the same adventitial sheath. Less common features include a reduced number of alveoli and a patchy distribution of the histopathologic changes. The disorder is associated with persistent pulmonary hypertension of the neonate and shows varying degrees of lability and severity (Boggs et al., 1994). Affected infants present with respiratory distress resulting from pulmonary hypertension in the early postnatal period, and the disease is uniformly fatal within the newborn period (Vassal et al., 1998). Additional features of ACDMPV include multiple congenital anomalies affecting the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems, as well as disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs (Sen et al., 2004).
Warsaw breakage syndrome
MedGen UID:
462008
Concept ID:
C3150658
Disease or Syndrome
Warsaw syndrome is characterized by the clinical triad of severe congenital microcephaly, growth restriction, and sensorineural hearing loss due to cochlear hypoplasia. Intellectual disability is typically in the mild-to-moderate range. Severe speech delay is common. Gross and fine motor milestones are usually attained at the usual time, although a few individuals have mild delays. Additional common features include skeletal anomalies and cardiovascular anomalies. Abnormal skin pigmentation and genitourinary malformations have also been reported. Some individuals have had increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane and mitomycin C.
Chromosome 16p13.3 duplication syndrome
MedGen UID:
462058
Concept ID:
C3150708
Disease or Syndrome
16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.
Cocoon syndrome
MedGen UID:
462241
Concept ID:
C3150891
Disease or Syndrome
A rare lethal developmental defect during embryogenesis with characteristics of severe fetal malformations. These malformations include craniofacial dysmorphism (abnormal cyst in the cranial region, hypoplastic eyeballs, two orifices in the nasal region separated by a nasal septum, abnormal orifice replacing the mouth), omphalocele and immotile hypoplastic limbs encased under an abnormal, transparent membrane-like skin. Additional features include absence of adnexal structures of the skin on the outer aspect of the limbs, as well as underdeveloped skeletal muscles and bones. Association with tetralogy of Fallot, horseshoe kidneys, diaphragm and lung lobulation defects is reported.
LEOPARD syndrome 3
MedGen UID:
462321
Concept ID:
C3150971
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.
Congenital heart defects, multiple types, 6
MedGen UID:
462571
Concept ID:
C3151221
Congenital Abnormality
Multiple types of congenital heart defects are associated with mutation in the GDF1 gene, including tetralogy of fallot (TOF), transposition of the great arteries (TGA), double-outlet right ventricle (DORV), total anomalous pulmonary venous return (TAPVR), pulmonary stenosis or atresia, atrioventricular canal, ventricular septal defect (VSD), and hypoplastic left or right ventricle (Jin et al., 2017). For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.
Right atrial isomerism
MedGen UID:
465274
Concept ID:
C3178806
Congenital Abnormality
Right atrial isomerism (RAI) is a severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries. Affected individuals present at birth with severe cardiac failure. Other associated abnormalities include bilateral trilobed lungs, midline liver, and asplenia, as well as situs inversus affecting other organs. Left atrial isomerism (LAI) is a related disorder with a somewhat better prognosis. LAI is characterized by bilateral superior vena cava, interruption of the intrahepatic portion of the inferior vena cava, partial anomalous pulmonary venous drainage, and ventricular septal defect. Patients with LAI may have polysplenia and bilateral bilobed lungs, as well as situs inversus affecting other organs. Both RAI and LAI malformation complexes have classically been referred to as Ivemark syndrome (summary by Eronen et al., 2004 and Kaasinen et al., 2010).
Atrial septal defect 7
MedGen UID:
477726
Concept ID:
C3276096
Disease or Syndrome
An extremely rare genetic congenital heart disease characterized by the presence of atrial septal defect, mostly of the ostium secundum type, associated with conduction anomalies like atrioventricular block, atrial fibrillation or right bundle branch block.
Ventricular septal defect 1
MedGen UID:
482407
Concept ID:
C3280777
Disease or Syndrome
Ventricular septal defect (VSD) is the most common form of congenital cardiovascular anomaly, occurring in nearly 50% of all infants with a congenital heart defect and accounting for 14 to 16% of cardiac defects that require invasive treatment within the first year of life. Congenital VSDs may occur alone or in combination with other cardiac malformations. Large VSDs that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death (summary by Wang et al., 2011, 2011). Other congenital cardiac defects caused by mutation in the GATA4 gene include atrial septal defect (ASD2; 607941), tetralogy of Fallot (see TOF, 187500), and endocardial cushion defects (AVSD4; 614430). Genetic Heterogeneity of Ventricular Septal Defect VSD2 (614431) is caused by mutation in the CITED2 gene (602937) on chromosome 6q24; VSD3 (614432) is caused by mutation in the NKX2-5 gene (600584) on chromosome 5q34. Somatic mutations in the HAND1 gene (602406) have been identified in tissue samples from patients with VSD.
Coffin-Siris syndrome 1
MedGen UID:
482831
Concept ID:
C3281201
Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Goldenhar syndrome
MedGen UID:
501171
Concept ID:
C3495417
Congenital Abnormality
Craniofacial microsomia (CFM) is an autosomal dominant disorder characterized by mandibular hypoplasia, microtia, facial and preauricular skin tags, epibulbar dermoids, and lateral oral clefts, in addition to skeletal and cardiac abnormalities. Inter- and intrafamilial variability has been observed (Timberlake et al., 2021). Hemifacial microsomia is a common birth defect involving the first and second branchial arch derivatives. It typically affects the external ear, middle ear, mandible and temporomandibular joint, muscles of mastication and facial muscles, and other facial soft tissues on the affected side. In some cases, other facial structures, such as the orbit, eye, nose, cranium, or neck, may be involved. Involvement is usually limited to one side, but bilateral involvement is known. In addition to craniofacial anomalies, there may be cardiac, vertebral, and central nervous system defects. The phenotype is highly variable. Most cases are sporadic, but there are rare familial cases that exhibit autosomal dominant inheritance (summary by Poole, 1989 and Hennekam et al., 2010). See also hemifacial microsomia with radial defects (141400) and oculoauriculofrontonasal dysplasia (OAFNS; 601452), which may be part of the OAV spectrum. Another disorder that overlaps clinically with CFM is Townes-Brocks syndrome (TBS; 107480).
Linear skin defects with multiple congenital anomalies 2
MedGen UID:
763835
Concept ID:
C3550921
Disease or Syndrome
Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, usually involving the face and neck, which are present at birth and heal with age, leaving minimal residual scarring. Other findings can include a wide variety of other ocular abnormalities (e.g., corneal anomalies, orbital cysts, cataracts), central nervous system involvement (e.g., structural anomalies, developmental delay, infantile seizures), cardiac concerns (e.g., hypertrophic or oncocytic cardiomyopathy, atrial or ventricular septal defects, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, hearing impairment, and genitourinary malformations. Inter- and intrafamilial variability is described.
Cornelia de Lange syndrome 4
MedGen UID:
766431
Concept ID:
C3553517
Disease or Syndrome
Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.
Congenital heart defects, multiple types, 3
MedGen UID:
767108
Concept ID:
C3554194
Disease or Syndrome
Multiple types of congenital heart defects-3 (CHTD3) is an autosomal dominant condition characterized by various types of congenital heart defects and low atrial rhythm (van de Meerakker et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of multiple types of congenital heart defects, see 306955.
Congenital heart defects, multiple types, 2
MedGen UID:
767193
Concept ID:
C3554279
Disease or Syndrome
Multiple types of congenital heart defects-2 (CHTD2) is characterized by variable congenital heart defects, primarily involving the valves, but also including septal defects or aneurysms, and complex defects such as tetralogy of Fallot. Dilated cardiomyopathy and myocardial noncompaction have been reported in some patients. In addition, some affected individuals exhibit facial dysmorphism and features of connective tissue disease (Thienpont et al., 2010; Ackerman et al., 2016; Ritelli et al., 2018). For a discussion of genetic heterogeneity of CHTD, see 306955.
Testicular anomalies with or without congenital heart disease
MedGen UID:
816188
Concept ID:
C3809858
Disease or Syndrome
Aortic valve disease 1
MedGen UID:
854610
Concept ID:
C3887892
Disease or Syndrome
Any aortic valve disease in which the cause of the disease is a mutation in the NOTCH1 gene.
Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
MedGen UID:
860891
Concept ID:
C4012454
Disease or Syndrome
A rare, syndromic diabetes mellitus characterized by partial pancreatic agenesis, diabetes mellitus, and heart anomalies (including transposition of the great vessels, ventricular or atrial septal defects, pulmonary stenosis, or patent ductus arteriosis).
Congenital heart defects, multiple types, 4
MedGen UID:
862747
Concept ID:
C4014310
Disease or Syndrome
The multiple types of congenital heart defects observed in CHTD4 include atrial, ventricular, and atrioventricular septal defects, double-outlet right ventricle, tetralogy of Fallot, hypoplastic left heart syndrome, aortic stenosis, and coarctation of the aorta. Intrafamilial variability and incomplete penetrance has been reported (Al Turki et al., 2014; Qiao et al., 2018). Some patients exhibit syndromic features such as developmental delay, congenital diaphragmatic hernia, and severe gastroesophageal reflux (High et al., 2016; Upadia et al., 2018). For a discussion of genetic heterogeneity of multiple types of congenital heart defects, see CHTD1 (306955).
VATER association
MedGen UID:
902479
Concept ID:
C4225671
Disease or Syndrome
VATER is a mnemonically useful acronym for the nonrandom association of vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R). This combination of associated defects was pointed out by Quan and Smith (1972). Nearly all cases have been sporadic. VACTERL is an acronym for an expanded definition of the association that includes cardiac malformations (C) and limb anomalies (L). The VACTERL association is a spectrum of various combinations of its 6 components, which can be a manifestation of several recognized disorders rather than a distinct anatomic or etiologic entity (Khoury et al., 1983). Also see VATER/VACTERL association with hydrocephalus (VACTERL-H; 276950) and VACTERL with or without hydrocephalus (VACTERLX; 314390).
Sifrim-Hitz-Weiss syndrome
MedGen UID:
934655
Concept ID:
C4310688
Disease or Syndrome
CHD4 neurodevelopmental disorder (CHD4-NDD) is associated with developmental delay, speech delay, and usually mild-to-moderate intellectual disability. Variability between individuals with CHD4-NDD is significant, and a few have normal intelligence. Other manifestations can include brain anomalies, heart defects, and skeletal abnormalities; less common features are hypogonadism in males, hearing impairment, and ophthalmic abnormalities. Most affected individuals have mild nonspecific dysmorphic facial features with or without macrocephaly.
Structural heart defects and renal anomalies syndrome
MedGen UID:
1387412
Concept ID:
C4479549
Disease or Syndrome
Townes-Brocks syndrome 1
MedGen UID:
1635275
Concept ID:
C4551481
Disease or Syndrome
Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (84%), dysplastic ears (87%; overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment [65%]), and thumb malformations (89%; triphalangeal thumbs, duplication of the thumb [preaxial polydactyly], and rarely hypoplasia of the thumbs). Renal impairment (42%), including end-stage renal disease (ESRD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%; flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of individuals. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.
Adams-Oliver syndrome 1
MedGen UID:
1635567
Concept ID:
C4551482
Disease or Syndrome
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
RAB23-related Carpenter syndrome
MedGen UID:
1644017
Concept ID:
C4551510
Disease or Syndrome
Carpenter syndrome is a rare autosomal recessive disorder with the cardinal features of acrocephaly with variable synostosis of the sagittal, lambdoid, and coronal sutures; peculiar facies; brachydactyly of the hands with syndactyly; preaxial polydactyly and syndactyly of the feet; congenital heart defects; growth retardation; mental retardation; hypogenitalism; and obesity. In addition, cerebral malformations, oral and dental abnormalities, coxa valga, genu valgum, hydronephrosis, precocious puberty, and hearing loss may be observed (summary by Altunhan et al., 2011). Genetic Heterogeneity of Carpenter Syndrome Carpenter syndrome-2 (CRPT2; 614976), in which the features of Carpenter syndrome are sometimes associated with defective lateralization, is caused by mutation in the MEGF8 gene (604267).
Ritscher-Schinzel syndrome 1
MedGen UID:
1634646
Concept ID:
C4551776
Disease or Syndrome
Ritscher-Schinzel syndrome (RSS) is a clinically recognizable condition that includes the cardinal findings of craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome. Dysmorphic facial features may include brachycephaly, hypotonic face with protruding tongue, flat appearance of the face on profile view, short midface, widely spaced eyes, downslanted palpebral fissures, low-set ears with overfolding of the upper helix, smooth or short philtrum, and high or cleft palate. Affected individuals also typically have a characteristic metacarpal phalangeal profile showing a consistent wavy pattern on hand radiographs. RSS is associated with variable degrees of developmental delay and intellectual disability. Eye anomalies and hypercholesterolemia may be variably present.
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.
Congenital heart defects, multiple types, 5
MedGen UID:
1636547
Concept ID:
C4693563
Disease or Syndrome
Short-rib thoracic dysplasia 20 with polydactyly
MedGen UID:
1634931
Concept ID:
C4693616
Disease or Syndrome
Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330).
Orofaciodigital syndrome 17
MedGen UID:
1644516
Concept ID:
C4693640
Disease or Syndrome
Cardiac-urogenital syndrome
MedGen UID:
1648333
Concept ID:
C4748946
Disease or Syndrome
Cardiac-urogenital syndrome is characterized by partial anomalous pulmonary venous return in association with tracheal anomalies, pulmonary hypoplasia, congenital diaphragmatic hernia, thyroid fibrosis, thymic involution, cleft spleen, penoscrotal hypospadias, and cryptorchidism (Pinz et al., 2018).
Intellectual developmental disorder with cardiac defects and dysmorphic facies
MedGen UID:
1675627
Concept ID:
C5193024
Disease or Syndrome
IDDCDF is an autosomal recessive syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Additional features, such as distal skeletal anomalies, may also be observed (Stephen et al., 2018).
Noonan syndrome 12
MedGen UID:
1684730
Concept ID:
C5231432
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.
Intellectual developmental disorder with hypotonia and behavioral abnormalities
MedGen UID:
1684709
Concept ID:
C5231489
Disease or Syndrome
Intellectual developmental disorder with hypotonia and behavioral abnormalities (IDDHBA) is a neurodevelopmental disorder characterized by onset of hypotonia and variably impaired global developmental delay in infancy. Affected individuals tend to have learning disability, usually requiring special schooling, as well as behavioral abnormalities, such as autistic features and attention deficit-hyperactivity disorder (ADHD). Additional more variable features may include nonspecific dysmorphic facial features, congenital heart defects, visual or ocular movement anomalies, and poor feeding and/or gastroesophageal reflux (summary by Calpena et al., 2019).
Congenital heart defects, multiple types, 7
MedGen UID:
1714491
Concept ID:
C5394062
Congenital Abnormality
Multiple types of congenital heart defects-7 (CHTD7) is an autosomal dominant disorder with incomplete penetrance characterized mainly by tetralogy of Fallot but also including right-sided aortic arch, absent pulmonary valve, and other cardiac abnormalities (Jin et al., 2017, Reuter et al., 2019).
Coffin-Siris syndrome 12
MedGen UID:
1782096
Concept ID:
C5444111
Disease or Syndrome
Coffin-Siris syndrome-12 (CSS12) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, speech and language delay, and behavioral abnormalities, such as autism or hyperactivity. Affected individuals may have hypotonia and poor feeding in infancy. There are variable dysmorphic facial features, although most patients do not have the classic hypoplastic fifth digit/nail abnormalities that are often observed in other forms of CSS (Barish et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
WHIM syndrome 2
MedGen UID:
1785594
Concept ID:
C5543622
Disease or Syndrome
WHIM syndrome-2 (WHIMS2) is an autosomal recessive immunologic disorder characterized by chronic neutropenia and myelokathexis, which is impaired neutrophil mobilization from the bone marrow. Affected individuals have recurrent infections, usually bacterial (summary by Auer et al., 2014). In a review of WHIMS, Heusinkveld et al. (2019) noted that there is significant phenotypic variation among patients, such that some individuals may have an 'incomplete' form of the disorder in which 1 or more of the classic tetrad features are not present. In general, the WHIMS phenotype comprises a spectrum of manifestations with variable expressivity. For a discussion of genetic heterogeneity of WHIMS, see 193670.
Congenital disorder of glycosylation, type IIw
MedGen UID:
1794196
Concept ID:
C5561986
Disease or Syndrome
Congenital disorder of glycosylation type IIw (CDG2W) is an autosomal dominant metabolic disorder characterized by liver dysfunction, coagulation deficiencies, and profound abnormalities in N-glycosylation of serum specific proteins. All reported patients carry the same mutation (602671.0017) (summary by Ng et al., 2021). For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).
Frontorhiny
MedGen UID:
1803615
Concept ID:
C5574965
Congenital Abnormality
A distinct syndromic type of frontonasal malformation with characteristics of hypertelorism, wide nasal bridge, broad columella, widened philtrum, widely separated narrow nares, poor development of nasal tip, midline notch of the upper alveolus, columella base swellings and a low hairline. Additional features reported in some include upper eyelid ptosis and midline dermoid cysts of craniofacial structures and philtral pits or rugose folding behind the ears.
Neurocardiofaciodigital syndrome
MedGen UID:
1804193
Concept ID:
C5677020
Disease or Syndrome
Neurocardiofaciodigital syndrome (NCFD) is characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with a supernumerary hypoplastic digit between the fourth and fifth digits of the hands and/or feet. Other features include eye abnormalities, hearing impairment, and electroencephalogram anomalies (summary by Horn et al., 2021).

Recent clinical studies

Etiology

Pascal FNB, Anusa B, Chikumbanje S, Pollach G
Malawi Med J 2022 Sep;34(3):201-203. doi: 10.4314/mmj.v34i3.9. PMID: 36406090Free PMC Article
Sugimoto A, Tachimori H, Hirata Y, Sakamoto K, Ota N, Shiraishi S, Tsuchida M, Motomura N
Gen Thorac Cardiovasc Surg 2022 Oct;70(10):835-841. Epub 2022 Mar 25 doi: 10.1007/s11748-022-01809-3. PMID: 35332445
Chungsomprasong P, Somkittithum P, Chanthong P, Vijarnsorn C, Durongpisitkul K, Soongswang J, Subtaweesin T, Sriyodchartti S
Asian Cardiovasc Thorac Ann 2022 May;30(4):433-440. Epub 2021 Aug 23 doi: 10.1177/02184923211039795. PMID: 34424057
Alsaied T, Geva T, Graf JA, Sleeper LA, Marie Valente A
Circ Cardiovasc Imaging 2021 Aug;14(8):e012519. Epub 2021 Aug 13 doi: 10.1161/CIRCIMAGING.121.012519. PMID: 34387102
Ravndal MEH, Borgwardt L, Juul K, Nielsen J, Borgwardt L, Henriksen BM, Willemoe GL, Jensen AS, Christensen VB, Kjær MS
Cardiol Young 2021 Nov;31(11):1796-1806. Epub 2021 Mar 15 doi: 10.1017/S1047951121000901. PMID: 33719984

Diagnosis

Sugimoto A, Tachimori H, Hirata Y, Sakamoto K, Ota N, Shiraishi S, Tsuchida M, Motomura N
Gen Thorac Cardiovasc Surg 2022 Oct;70(10):835-841. Epub 2022 Mar 25 doi: 10.1007/s11748-022-01809-3. PMID: 35332445
Alsaied T, Geva T, Graf JA, Sleeper LA, Marie Valente A
Circ Cardiovasc Imaging 2021 Aug;14(8):e012519. Epub 2021 Aug 13 doi: 10.1161/CIRCIMAGING.121.012519. PMID: 34387102
Sharma P, Samal S, Saha D, Naqvi SEH, Aggarwal S, Geelani MA
J Card Surg 2021 Oct;36(10):3901-3904. Epub 2021 Jul 9 doi: 10.1111/jocs.15792. PMID: 34241915
Yang JN, Zhang XM, Ma LY, Lu ZJ, Zheng SQ, Hamzah AW, Shao YF, Liu H, Liu GL
BMC Cardiovasc Disord 2021 Apr 26;21(1):210. doi: 10.1186/s12872-021-02033-2. PMID: 33902450Free PMC Article
Lowisz J, Alenghat FJ, Li Y, Roberson D, Penk J, Gandhi R
Cardiol Young 2021 Nov;31(11):1781-1787. Epub 2021 Mar 9 doi: 10.1017/S1047951121000871. PMID: 33685532

Therapy

Qureshi AM, Caldarone CA, Romano JC, Chai PJ, Mascio CE, Glatz AC, Petit CJ, McCracken CE, Kelleman MS, Nicholson GT, Meadows JJ, Zampi JD, Shahanavaz S, Law MA, Batlivala SP, Goldstein BH; Congenital Cardiac Research Collaborative Investigators.
J Thorac Cardiovasc Surg 2022 Jan;163(1):192-207.e3. Epub 2021 Feb 3 doi: 10.1016/j.jtcvs.2021.01.100. PMID: 33726912
Alsaied T, Geva T, Graf JA, Sleeper LA, Marie Valente A
Circ Cardiovasc Imaging 2021 Aug;14(8):e012519. Epub 2021 Aug 13 doi: 10.1161/CIRCIMAGING.121.012519. PMID: 34387102
Yang JN, Zhang XM, Ma LY, Lu ZJ, Zheng SQ, Hamzah AW, Shao YF, Liu H, Liu GL
BMC Cardiovasc Disord 2021 Apr 26;21(1):210. doi: 10.1186/s12872-021-02033-2. PMID: 33902450Free PMC Article
Apandi PR, Sukardi R, Djer MM, Yanuarso PB, Wardoyo S
Cardiol Young 2020 Dec;30(12):1917-1922. Epub 2020 Nov 13 doi: 10.1017/S1047951120003170. PMID: 33185178
Borodinova O, Mykychak Y, Yemets I
Semin Thorac Cardiovasc Surg 2020 Summer;32(2):282-289. Epub 2019 Sep 24 doi: 10.1053/j.semtcvs.2019.09.011. PMID: 31560970

Prognosis

Alsaied T, Geva T, Graf JA, Sleeper LA, Marie Valente A
Circ Cardiovasc Imaging 2021 Aug;14(8):e012519. Epub 2021 Aug 13 doi: 10.1161/CIRCIMAGING.121.012519. PMID: 34387102
Sharma P, Samal S, Saha D, Naqvi SEH, Aggarwal S, Geelani MA
J Card Surg 2021 Oct;36(10):3901-3904. Epub 2021 Jul 9 doi: 10.1111/jocs.15792. PMID: 34241915
Hosseinpour AR, González-Calle A, Adsuar-Gómez A, Ho SY
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