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Imperforate anus

MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Synonyms: Anal atresia; Anorectal stenosis
SNOMED CT: Anal atresia (204712000); Aproctia (204712000); Atresia ani (204712000); Congenital atresia of anus (204712000); Imperforate anus (204712000); Congenital imperforate anus (204712000)
 
HPO: HP:0002023
Monarch Initiative: MONDO:0001046
OMIM®: 207500; 301800

Definition

Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract. [from HPO]

Clinical features

From HPO
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Imperforate anus
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.
Ectopic anus
MedGen UID:
75606
Concept ID:
C0266231
Congenital Abnormality
Abnormal displacement or malposition of the anus.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVImperforate anus

Conditions with this feature

Imperforate anus
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.
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.
Prune belly syndrome
MedGen UID:
18718
Concept ID:
C0033770
Disease or Syndrome
In its rare complete form, 'prune belly' syndrome (PBS) comprises megacystis (massively enlarged bladder) with disorganized detrusor muscle, cryptorchidism, and thin abdominal musculature with overlying lax skin (summary by Weber et al., 2011).
Asphyxiating thoracic dystrophy 3
MedGen UID:
19860
Concept ID:
C0036069
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). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).
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).
Fryns syndrome
MedGen UID:
65088
Concept ID:
C0220730
Disease or Syndrome
Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia, or agenesis); characteristic facial appearance (coarse facies, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, long philtrum, low-set and anomalous ears, tented vermilion of the upper lip, wide mouth, and a small jaw); short distal phalanges of the fingers and toes (the nails may also be small); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia). Survival beyond the neonatal period is rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common.
Pallister-Hall syndrome
MedGen UID:
120514
Concept ID:
C0265220
Disease or Syndrome
GLI3-related Pallister-Hall syndrome (GLI3-PHS) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild GLI3-PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with GLI3-PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Greig cephalopolysyndactyly syndrome
MedGen UID:
120531
Concept ID:
C0265306
Congenital Abnormality
Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by macrocephaly, widely spaced eyes associated with increased interpupillary distance, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GCPS and may be more common in individuals with large (>300-kb) deletions that encompass GLI3. Approximately 20% of individuals with GCPS have hypoplasia or agenesis of the corpus callosum.
Baller-Gerold syndrome
MedGen UID:
120532
Concept ID:
C0265308
Disease or Syndrome
Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.
CHARGE syndrome
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.
Pallister-Killian syndrome
MedGen UID:
120540
Concept ID:
C0265449
Disease or Syndrome
Pallister-Killian syndrome (PKS) is a dysmorphic condition involving most organ systems, but is also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).
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).
Dihydropyrimidinase deficiency
MedGen UID:
83353
Concept ID:
C0342803
Disease or Syndrome
Dihydropyrimidinase deficiency (DPYSD) is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder.
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).
Osteopathia striata with cranial sclerosis
MedGen UID:
96590
Concept ID:
C0432268
Disease or Syndrome
Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. Males can present with a mild or severe phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant. The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.
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.
Microphthalmia, syndromic 1
MedGen UID:
162898
Concept ID:
C0796016
Congenital Abnormality
Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.
Linear skin defects with multiple congenital anomalies 1
MedGen UID:
163210
Concept ID:
C0796070
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.
Renpenning syndrome
MedGen UID:
208670
Concept ID:
C0796135
Disease or Syndrome
Renpenning syndrome is an X-linked syndromic intellectual developmental disorder 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.
Acrocallosal syndrome
MedGen UID:
162915
Concept ID:
C0796147
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Simpson-Golabi-Behmel syndrome type 1
MedGen UID:
162917
Concept ID:
C0796154
Disease or Syndrome
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.
McKusick-Kaufman syndrome
MedGen UID:
184924
Concept ID:
C0948368
Disease or Syndrome
McKusick-Kaufman syndrome (MKS) is characterized by the combination of postaxial polydactyly (PAP), congenital heart disease (CHD), and hydrometrocolpos (HMC) in females and genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee). HMC in infants usually presents as a large cystic abdominal mass arising out of the pelvis, caused by dilatation of the vagina and uterus as a result of the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by failure of the distal third of the vagina to develop (vaginal agenesis), a transverse vaginal membrane, or an imperforate hymen. PAP is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot. A variety of congenital heart defects have been reported including atrioventricular canal, atrial septal defect, ventricular septal defect, or a complex congenital heart malformation.
Deficiency of beta-ureidopropionase
MedGen UID:
226944
Concept ID:
C1291512
Disease or Syndrome
Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (Yaplito-Lee et al., 2008).
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).
Currarino triad
MedGen UID:
323460
Concept ID:
C1531773
Disease or Syndrome
The Currarino syndrome is an autosomal dominant form of hereditary sacral dysgenesis that classically consists of the triad of sacral malformation, presacral mass, and anorectal malformations. However, other features include neonatal-onset bowel obstruction, chronic constipation, recurrent perianal sepsis, renal/urinary tract anomalies, female internal genital anomalies, tethered spinal cord, and anterior meningocele. There is marked inter- and intrafamilial variability, and up to 33% of patients are asymptomatic (summary by Wang et al., 2006).
Duane-radial ray syndrome
MedGen UID:
301647
Concept ID:
C1623209
Disease or Syndrome
SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).
Focal facial dermal dysplasia type III
MedGen UID:
315643
Concept ID:
C1744559
Disease or Syndrome
The focal dermal dysplasias (FFDDs) are a group of related developmental defects characterized by bitemporal or preauricular skin lesions resembling aplasia cutis congenita. FFFD3 is an autosomal recessive disorder characterized by bitemporal skin lesions with variable facial findings, including thin and puckered periorbital skin, distichiasis and/or absent eyelashes, upslanting palpebral fissures, a flat nasal bridge with a broad nasal tip, large lips, and redundant facial skin (summary by Slavotinek et al., 2013). FFDD2 (614973) is characterized by the same facial features as FFDD3, but the inheritance is autosomal dominant. For a classification and a discussion of genetic heterogeneity of FFDD, see FFDD1 (136500).
Cervical ribs, Sprengel anomaly, anal atresia, and urethral obstruction
MedGen UID:
318617
Concept ID:
C1832391
Disease or Syndrome
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.
Emanuel syndrome
MedGen UID:
323030
Concept ID:
C1836929
Disease or Syndrome
Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males.
CODAS syndrome
MedGen UID:
333031
Concept ID:
C1838180
Disease or Syndrome
CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015).
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.
Absent radius-anogenital anomalies syndrome
MedGen UID:
333312
Concept ID:
C1839410
Disease or Syndrome
A rare, genetic limb reduction defects syndrome characterized by bilateral radial aplasia/hypoplasia manifesting with absent/short forearms in association with anogenital abnormalities (e.g. hypospadias or imperforate anus). Additional features reported include hydrocephalus and absent preaxial digits. There have been no further descriptions in the literature since 1993.
Skeletal dysplasia-intellectual disability syndrome
MedGen UID:
326949
Concept ID:
C1839729
Disease or Syndrome
This syndrome combines skeletal anomalies (short stature, ridging of the metopic suture, fusion of cervical vertebrae, thoracic hemivertebrae, scoliosis, sacral hypoplasia and short middle phalanges) and mild intellectual deficit. It has been described in four male cousins in three sibships. Glucose intolerance was present in three cases, and imperforated anus in one case. Carrier females had minor manifestations (fusion of cervical vertebrae and glucose intolerance). Transmission seems to be X-linked.
Heterotaxy, visceral, 1, X-linked
MedGen UID:
336609
Concept ID:
C1844020
Disease or Syndrome
Heterotaxy Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. Multiple Types of Congenital Heart Defects Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011). Reviews Obler et al. (2008) reviewed published cases of double-outlet right ventricle and discussed etiology and associations. Genetic Heterogeneity of Visceral Heterotaxy See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22; HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q21; HTX7 (616749), caused by mutation in the MMP21 gene (608416) on chromosome 10q26; HTX8 (617205), caused by mutation in the PKD1L1 gene (609721) on chromosome 7p12; HTX9 (618948), caused by mutation in the MNS1 gene (610766) on chromosome 15q21; HTX10 (619607), caused by mutation in the CFAP52 gene (609804) on chromosome 17p13; HTX11 (619608), caused by mutation in the CFAP45 gene (605152) on chromosome 1q23; and HTX12 (619702), caused by mutation in the CIROP gene (619703) on chromosome 14q11. Genetic Heterogeneity of Multiple Types of Congenital Heart Defects An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26. CHTD2 (614980) is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q31. CHTD4 (615779) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26. CHTD5 (617912) is caused by mutation in the GATA5 gene (611496) on chromosome 20q13. CHTD6 (613854) is caused by mutation in the GDF1 gene (602880) on chromosome 19p13. CHTD7 (618780) is caused by mutation in the FLT4 gene (136352) on chromosome 5q35. CHTD8 (619657) is caused by mutation in the SMAD2 gene (601366) on chromosome 18q21. CHTD9 (620294) is caused by mutation in the PLXND1 gene (604282) on chromosome 3q22.
VACTERL with hydrocephalus
MedGen UID:
376400
Concept ID:
C1848599
Disease or Syndrome
VACTERL describes a constellation of congenital anomalies, including vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects; see 192350. Cases of familial VACTERL with hydrocephalus (H) have been reported with suggestion of autosomal recessive or X-linked inheritance (see 314390). Other patients thought to have VACTERL-H, including 2 unrelated infants reported by Porteous et al. (1992), had been found to have Fanconi anemia (see 227650). Porteous et al. (1992) suggested that chromosomal breakage studies should be performed in all cases of VACTERL/VACTERL-H to rule out Fanconi anemia. Alter et al. (2007) noted that a VATER phenotype had been reported in Fanconi anemia of complementation groups A (227650), C (227645), D1 (605724), E (600901), F (603467), and G (614082). X-linked VACTERL-H is also associated with mutations in the FANCB gene (300515).
Thymic-renal-anal-lung dysplasia
MedGen UID:
336425
Concept ID:
C1848812
Congenital Abnormality
This syndrome has characteristics of intrauterine growth retardation, renal dysgenesis and a unilobed or absent thymus. It has been described in three girls born to a nonconsanguineous couple.
Spondylocostal dysostosis-anal and genitourinary malformations syndrome
MedGen UID:
341373
Concept ID:
C1849069
Congenital Abnormality
Spondylocostal dysostosis-anal and genitourinary malformations syndrome is characterized by the association of spondylocostal dysostosis with anal and genitourinary malformations (anal atresia and agenesis of external and internal genitalia). To date, only four cases have been described in the literature. Autosomal recessive inheritance has been suggested.
Holoprosencephaly-postaxial polydactyly syndrome
MedGen UID:
340382
Concept ID:
C1849649
Disease or Syndrome
Holoprosencephaly-postaxial polydactyly syndrome associates, in chromosomally normal neonates, holoprosencephaly, severe facial dysmorphism, postaxial polydactyly and other congenital abnormalities, suggestive of trisomy 13. Incidence is unknown. Dysmorphic features include hypotelorism, severe eye anomalies such as microphthalmia or anophthalmia, premaxillary region aplasia and cleft lip and palate. Congenital cardiac anomalies are common. The condition seems to be inherited as an autosomal recessive trait. Prognosis is poor.
Bartsocas-Papas syndrome 1
MedGen UID:
337894
Concept ID:
C1849718
Disease or Syndrome
Bartsocas-Papas syndrome-1 (BPS1) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by Mitchell et al., 2012). Genetic Heterogeneity of Bartsocas-Papas Syndrome Bartsocas-Papas syndrome-2 (BPS2) is caused by mutation in the CHUK gene (600664). A less severe form of popliteal pterygium syndrome (PPS; 119500) is caused by mutation in the IRF6 gene (607199).
Exstrophy-epispadias complex
MedGen UID:
338020
Concept ID:
C1850321
Disease or Syndrome
Carey et al. (1978) gave the name OEIS complex to a combination of defects comprising omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. This rare complex is thought to represent the most severe end of a spectrum of birth defects, the exstrophy-epispadias sequence, which, in order of increasing severity, includes phallic separation with epispadias, pubic diastasis, exstrophy of the bladder (600057), cloacal exstrophy, and OEIS complex. Very few instances of recurrence of anomalies in this cluster have been reported.
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 1
MedGen UID:
343663
Concept ID:
C1851841
Disease or Syndrome
An EEC syndrome characterized by autosomal dominant inheritance that has material basis in variation in the chromosome region 7q11.2-q21.3.
Genitopatellar syndrome
MedGen UID:
381208
Concept ID:
C1853566
Disease or Syndrome
KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype.
Absence deformity of leg-cataract syndrome
MedGen UID:
343374
Concept ID:
C1855523
Disease or Syndrome
A very rare congenital limb malformation syndrome characterized by absence deformity of one leg, progressive scoliosis, short stature, and congenital cataract associated with dysplasia of the optic nerve. No intellectual deficit has been reported. There have been no further descriptions in the literature since 1968.
Hirschsprung disease-nail hypoplasia-dysmorphism syndrome
MedGen UID:
344653
Concept ID:
C1856110
Disease or Syndrome
A fatal malformative disorder with characteristics of Hirschsprung disease, hypoplastic nails, distal limb hypoplasia and minor craniofacial dysmorphic features (flat facies, upward slanting palpebral fissures, narrow philtrum, narrow, high arched palate, micrognathia, low set ears with abnormal helices). Hydronephrosis has also been reported. There have been no further descriptions in the literature since 1988.
Craniosynostosis-anal anomalies-porokeratosis syndrome
MedGen UID:
351066
Concept ID:
C1864186
Disease or Syndrome
CDAGS syndrome is characterized by craniosynostosis and clavicular hypoplasia, delayed closure of the fontanel, anal and genitourinary anomalies, and skin eruption of porokeratotic lesions (Mendoza-Londono et al., 2005).
Omphalocele syndrome, Shprintzen-Goldberg type
MedGen UID:
356653
Concept ID:
C1866958
Disease or Syndrome
A very rare inherited malformation syndrome with characteristics of omphalocele, scoliosis, mild dysmorphic features (downslanted palpebral fissures, s-shaped eyelids and thin upper lip), laryngeal and pharyngeal hypoplasia and learning disabilities.
Ulnar-mammary syndrome
MedGen UID:
357886
Concept ID:
C1866994
Disease or Syndrome
Ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (Bamshad et al., 1996).
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.
Syndactyly-telecanthus-anogenital and renal malformations syndrome
MedGen UID:
394424
Concept ID:
C2678045
Disease or Syndrome
Syndrome with the association of toe syndactyly, facial dysmorphism including telecanthus and a broad nasal tip, urogenital malformations and anal atresia. Around ten cases have been reported so far. The syndrome is caused by mutations in the FAM58A gene (located on the X chromosome) encoding a protein of unknown function.
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.
46,XY sex reversal 4
MedGen UID:
416704
Concept ID:
C2752149
Congenital Abnormality
Sex reversal in an individual associated with a 9p24.3 deletion.
VACTERL association, X-linked, with or without hydrocephalus
MedGen UID:
419019
Concept ID:
C2931228
Disease or Syndrome
VACTERL is an acronym for vertebral anomalies (similar to those of spondylocostal dysplasia), anal atresia, cardiac malformations, tracheoesophageal fistula, renal anomalies (urethral atresia with hydronephrosis), and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia, and proximally placed thumb; see 192350). Some patients may have hydrocephalus, which is referred to as VACTERL-H (Briard et al., 1984).
X-linked Opitz G/BBB syndrome
MedGen UID:
424842
Concept ID:
C2936904
Disease or Syndrome
X-linked Opitz G/BBB syndrome (X-OS) is a multiple-congenital-anomaly disorder characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations (present in <50% of individuals) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only.
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).
Fanconi anemia complementation group O
MedGen UID:
462003
Concept ID:
C3150653
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.
Multiple congenital anomalies-hypotonia-seizures syndrome 1
MedGen UID:
481405
Concept ID:
C3279775
Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome MCAHS2 (300868) is caused by mutation in the PIGA gene (311770) on chromosome Xp22, MCAHS3 (615398) is caused by mutation in the PIGT gene (610272) on chromosome 20q13, and MCAHS4 (618548) is caused by mutation in the PIGQ gene (605754) on chromosome 16p13. Knaus et al. (2018) provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between MCAHS and HPMRS1 (239300), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).
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.
Anorectal anomaly
MedGen UID:
501217
Concept ID:
C3495676
Anatomical Abnormality
An abnormality of the anus or rectum.
Hyperphosphatasia with intellectual disability syndrome 2
MedGen UID:
766551
Concept ID:
C3553637
Disease or Syndrome
Hyperphosphatasia with impaired intellectual development syndrome-2 (HPMRS2) is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with impaired intellectual development syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Meckel syndrome, type 1
MedGen UID:
811346
Concept ID:
C3714506
Disease or Syndrome
Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. There is extensive clinical variability and controversy as to the minimum diagnostic criteria. Early reports, including that of Opitz and Howe (1969) and Wright et al. (1994), stated that the classic triad of Meckel syndrome comprises (1) cystic renal disease; (2) a central nervous system malformation, most commonly occipital encephalocele; and (3) polydactyly, most often postaxial. However, based on a study of 67 patients, Salonen (1984) concluded that the minimum diagnostic criteria are (1) cystic renal disease; (2) CNS malformation, and (3) hepatic abnormalities, including portal fibrosis or ductal proliferation. In a review of Meckel syndrome, Logan et al. (2011) stated that the classic triad first described by Meckel (1822) included occipital encephalocele, cystic kidneys, and fibrotic changes to the liver. Genetic Heterogeneity of Meckel Syndrome See also MKS2 (603194), caused by mutation in the TMEM216 gene (613277) on chromosome 11q12; MKS3 (607361), caused by mutation in the TMEM67 gene (609884) on chromosome 8q; MKS4 (611134), caused by mutation in the CEP290 gene (610142) on chromosome 12q; MKS5 (611561), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; MKS6 (612284), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; MKS7 (267010), caused by mutation in the NPHP3 (608002) gene on chromosome 3q22; MKS8 (613885), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; MKS9 (614209), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; MKS10 (614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; MKS11 (615397), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; MKS12 (616258), caused by mutation in the KIF14 gene (611279) on chromosome 1q32; MKS13 (617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; and MKS14 (619879), caused by mutation in the TXNDC15 gene (617778) on chromosome 5q31.
Axenfeld-Rieger syndrome type 1
MedGen UID:
811487
Concept ID:
C3714873
Disease or Syndrome
Axenfeld-Rieger syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals (Fitch and Kaback, 1978). Systemic anomalies are associated, including dental hypoplasia, failure of involution of periumbilical skin, and maxillary hypoplasia (Alkemade, 1969). Genetic Heterogeneity of Axenfeld-Rieger Syndrome Linkage studies indicate that a second type of Axenfeld-Rieger syndrome maps to chromosome 13q14 (RIEG2; 601499). A third form of Axenfeld-Rieger syndrome (RIEG3; 602482) is caused by mutation in the FOXC1 gene (601090) on chromosome 6p25. See 109120 for a form of Axenfeld-Rieger syndrome associated with partially absent eye muscles, hydrocephalus, and skeletal abnormalities.
Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome
MedGen UID:
816673
Concept ID:
C3810343
Disease or Syndrome
Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome is a rare, genetic, neural tube defect malformation syndrome characterized by sacral agenesis and abnormal vertebral body ossification with normal vertebral arches associated with notochord canal persistence on ultrasonography. Additional findings include bilateral clubfoot, oligohydramnios, single umbilical artery and, in some, increased nuchal translucency.
Hermansky-Pudlak syndrome 6
MedGen UID:
854714
Concept ID:
C3888007
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Tetraamelia syndrome 1
MedGen UID:
860705
Concept ID:
C4012268
Disease or Syndrome
Tetraamelia syndrome-1 (TETAMS1) is characterized by complete limb agenesis without defects of scapulae or clavicles. Other features include bilateral cleft lip/palate, diaphragmatic defect with bilobar right lung, renal and adrenal agenesis, pelvic hypoplasia, and urogenital defects (Niemann et al., 2004). Genetic Heterogeneity of tetraamelia syndrome Tetraamelia syndrome-2 (TETAMS2; 618021) is caused by mutation in the RSPO2 gene (610575) on chromosome 8q23.
Cerebellar atrophy, visual impairment, and psychomotor retardation;
MedGen UID:
905041
Concept ID:
C4225172
Disease or Syndrome
Even-plus syndrome
MedGen UID:
904613
Concept ID:
C4225180
Disease or Syndrome
EVEN-plus syndrome (EVPLS) is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (600373; Royer-Bertrand et al., 2015).
Short-rib thoracic dysplasia 13 with or without polydactyly
MedGen UID:
898712
Concept ID:
C4225378
Disease or Syndrome
An asphyxiating thoracic dystrophy that has material basis in homozygous mutation in the CEP120 gene on chromosome 5q23.
Intellectual disability, X-linked 99, syndromic, female-restricted
MedGen UID:
899839
Concept ID:
C4225416
Disease or Syndrome
Female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F) is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development and mild to moderate intellectual disability. Affected females can have a wide range of additional congenital anomalies, including scoliosis, postaxial polydactyly, mild cardiac or urogenital anomalies, dysmorphic facial features, and mild structural brain abnormalities (summary by Reijnders et al., 2016).
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).
Polydactyly, postaxial, type A1
MedGen UID:
924305
Concept ID:
C4282400
Congenital Abnormality
Fanconi anemia complementation group R
MedGen UID:
924579
Concept ID:
C4284093
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.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
MedGen UID:
924974
Concept ID:
C4284790
Disease or Syndrome
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (Dobyns et al., 1989). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A) Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (613150), caused by mutation in the POMT2 gene (607439); MDDGA3 (253280), caused by mutation in the POMGNT1 gene (606822); MDDGA4 (253800), caused by mutation in the FKTN gene (607440); MDDGA5 (613153), caused by mutation in the FKRP gene (606596); MDDGA6 (613154), caused by mutation in the LARGE gene (603590); MDDGA7 (614643), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGA8 (614830) caused by mutation in the GTDC2 gene (POMGNT2; 614828); MDDGA9 (616538), caused by mutation in the DAG1 gene (128239); MDDGA10 (615041), caused by mutation in the TMEM5 gene (RXYLT1; 605862); MDDGA11 (615181), caused by mutation in the B3GALNT2 gene (610194); MDDGA12 (615249), caused by mutation in the SGK196 gene (POMK; 615247); MDDGA13 (615287), caused by mutation in the B3GNT1 gene (B4GAT1; 605517); and MDDGA14 (615350), caused by mutation in the GMPPB gene (615320).
Meier-Gorlin syndrome 7
MedGen UID:
934705
Concept ID:
C4310738
Disease or Syndrome
Any Meier-Gorlin syndrome in which the cause of the disease is a mutation in the CDC45 gene.
Immunoskeletal dysplasia with neurodevelopmental abnormalities
MedGen UID:
1381460
Concept ID:
C4479452
Disease or Syndrome
Townes-Brocks syndrome 2
MedGen UID:
1381939
Concept ID:
C4479534
Disease or Syndrome
Congenital heart defects and skeletal malformations syndrome
MedGen UID:
1618340
Concept ID:
C4539857
Disease or Syndrome
Congenital heart defects and skeletal malformations syndrome (CHDSKM) is characterized by atrial and ventricular septal defects, with aortic root dilation in adulthood. Skeletal defects are variable and include pectus excavatum, scoliosis, and finger contractures, and some patients exhibit joint laxity. Failure to thrive is observed during infancy and early childhood (Wang et al., 2017).
Fraser syndrome 2
MedGen UID:
1624349
Concept ID:
C4540036
Disease or Syndrome
Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (summary by van Haelst et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of Fraser syndrome, see 219000.
Pontocerebellar hypoplasia, type 11
MedGen UID:
1627627
Concept ID:
C4540164
Congenital Abnormality
Pontocerebellar hypoplasia type 11 (PCH11) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with impaired intellectual development and poor speech, microcephaly, dysmorphic features, and pontocerebellar hypoplasia on brain imaging. Additional features are more variable (summary by Marin-Valencia et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Sweeney-Cox syndrome
MedGen UID:
1625659
Concept ID:
C4540299
Disease or Syndrome
Sweeney-Cox syndrome (SWCOS) is characterized by striking facial dysostosis, including hypertelorism, deficiencies of the eyelids and facial bones, cleft palate/velopharyngeal insufficiency, and low-set cupped ears (Kim et al., 2017).
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.
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.
Van Maldergem syndrome 1
MedGen UID:
1644627
Concept ID:
C4551950
Disease or Syndrome
Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013). Genetic Heterogeneity of Van Maldergem Syndrome See also VMLDS2 (615546), caused by mutation in the FAT4 gene (612411) on chromosome 4q28.
Blepharocheilodontic syndrome 1
MedGen UID:
1632198
Concept ID:
C4551988
Disease or Syndrome
The blepharocheilodontic syndrome is a rare autosomal dominant disorder characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. An additional rare manifestation is imperforate anus (summary by Weaver et al., 2010).
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).
3p- syndrome
MedGen UID:
1643555
Concept ID:
C4706503
Disease or Syndrome
Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features. Although intellectual deficits are almost invariably associated with cytogenetically visible 3p deletions, rare patients with a 3p26-p25 deletion and normal intelligence or only mild abnormalities have been described (summary by Shuib et al., 2009).
Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy
MedGen UID:
1679397
Concept ID:
C5193085
Disease or Syndrome
Myoectodermal gonadal dysgenesis syndrome (MEGD) is characterized by 46,XY complete or partial gonadal dysgenesis, or 46,XX gonadal dysgenesis, in association with extragonadal anomalies, including low birth weight, typical facies, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. Dysmorphic facial features along with muscular habitus are the hallmarks of the syndrome. Abnormal hair patterning with frontal upsweep and additional whorls, eyebrow abnormalities comprising broad, arched, and sparse or thick eyebrows, underdeveloped alae nasi, smooth philtrum, and low-set ears with overfolded helices facilitate a gestalt diagnosis. (Guran et al., 2019; Altunoglu et al., 2022).
FG syndrome 1
MedGen UID:
1768809
Concept ID:
C5399762
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.
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).
Congenital secretory sodium diarrhea 3
MedGen UID:
1778108
Concept ID:
C5441927
Disease or Syndrome
Any secretory diarrhea in which the cause of the disease is a mutation in the SPINT2 gene.
Global developmental delay with speech and behavioral abnormalities
MedGen UID:
1787991
Concept ID:
C5543226
Disease or Syndrome
Global developmental delay with speech and behavioral abnormalities (GDSBA) is characterized by developmental delay apparent from infancy or early childhood. Affected individuals have mildly delayed fine and motor skills with walking by 3 years of age, mildly impaired intellectual development, speech and language delay, and variable behavioral abnormalities, mostly autism and ADHD. Some patients may have additional nonspecific features, such as facial dysmorphism, myopia or strabismus, and skeletal defects, including joint hypermobility, pes planus, or slender fingers (summary by Granadillo et al., 2020).
Oculogastrointestinal-neurodevelopmental syndrome
MedGen UID:
1779113
Concept ID:
C5543355
Disease or Syndrome
Oculogastrointestinal neurodevelopmental syndrome (OGIN) is characterized by microphthalmia and/or coloboma in association with other congenital anomalies, including imperforate anus, horseshoe kidney, and structural cardiac defects. Hearing loss and severe developmental delay are also observed in most patients (Zha et al., 2020; Mor-Shaked et al., 2021).

Professional guidelines

PubMed

Lee T, Weiss D, Roth E, Bortnick E, Jarosz S, Eftekharzadeh S, Groth T, Shukla A, Kryger JV, Lee RS, Canning DA, Mitchell ME, Borer JG
Urology 2023 Feb;172:174-177. Epub 2022 Nov 30 doi: 10.1016/j.urology.2022.11.020. PMID: 36460061
Schindewolf E, Moldenhauer JS
Curr Opin Obstet Gynecol 2020 Apr;32(2):134-139. doi: 10.1097/GCO.0000000000000613. PMID: 32039977
Ihn K, Na Y, Ho IG, Oh JT
J Pediatr Surg 2020 Aug;55(8):1507-1510. Epub 2019 Aug 13 doi: 10.1016/j.jpedsurg.2019.07.017. PMID: 31443920

Recent clinical studies

Etiology

Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article
Girard C, Bigorre M, Guillot B, Bessis D
Arch Dermatol 2006 Jul;142(7):884-8. doi: 10.1001/archderm.142.7.884. PMID: 16847205
Kulkarni B, Oak SN, Karmarkar SJ, Desai AP, Deshmukh SS
J Postgrad Med 1995 Apr-Jun;41(2):49-51. PMID: 10707712
Okonkwo JE, Crocker KM
Obstet Gynecol 1977 Jul;50(1):97-101. PMID: 876530
Adkins JC, Kiesewetter WB
Surg Clin North Am 1976 Apr;56(2):379-94. doi: 10.1016/s0039-6109(16)40884-4. PMID: 1265603

Diagnosis

Schindewolf E, Moldenhauer JS
Curr Opin Obstet Gynecol 2020 Apr;32(2):134-139. doi: 10.1097/GCO.0000000000000613. PMID: 32039977
Lohsiriwat V
World J Gastroenterol 2016 Jul 14;22(26):5867-78. doi: 10.3748/wjg.v22.i26.5867. PMID: 27468181Free PMC Article
Godbole K, Maja S, Leena H, Martin Z
Indian Pediatr 2013 May 8;50(5):510-2. PMID: 23778732
Herman RS, Teitelbaum DH
Clin Perinatol 2012 Jun;39(2):403-22. doi: 10.1016/j.clp.2012.04.001. PMID: 22682388
Adkins JC, Kiesewetter WB
Surg Clin North Am 1976 Apr;56(2):379-94. doi: 10.1016/s0039-6109(16)40884-4. PMID: 1265603

Therapy

Singh S, Kayastha A, Thapa A, Thapa B, Dahal S
JNMA J Nepal Med Assoc 2023 Apr 1;61(260):375-378. doi: 10.31729/jnma.8048. PMID: 37208890Free PMC Article
Divarci E, Ergun O
Pediatr Surg Int 2020 Apr;36(4):431-445. Epub 2020 Feb 21 doi: 10.1007/s00383-020-04629-9. PMID: 32086570
Gupta S, Tiwari P, Gupta N, Nunia V, Saxena AK, Simlot A, Kothari SL, Suravajhala P, Medicherla KM, Mathur P
Curr Pediatr Rev 2019;15(4):259-264. doi: 10.2174/1573396315666190829155930. PMID: 31465285Free PMC Article
Gariepy CE, Mousa H
Semin Pediatr Surg 2009 Nov;18(4):224-38. doi: 10.1053/j.sempedsurg.2009.07.004. PMID: 19782304
Harrington S, Simmons K, Thomas C, Scully S
AORN J 2008 Aug;88(2):211-36; quiz 237-40. doi: 10.1016/j.aorn.2008.04.002. PMID: 18782939

Prognosis

Schindewolf E, Moldenhauer JS
Curr Opin Obstet Gynecol 2020 Apr;32(2):134-139. doi: 10.1097/GCO.0000000000000613. PMID: 32039977
Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article
Solomon BD
Orphanet J Rare Dis 2011 Aug 16;6:56. doi: 10.1186/1750-1172-6-56. PMID: 21846383Free PMC Article
Ebert AK, Reutter H, Ludwig M, Rösch WH
Orphanet J Rare Dis 2009 Oct 30;4:23. doi: 10.1186/1750-1172-4-23. PMID: 19878548Free PMC Article
Adkins JC, Kiesewetter WB
Surg Clin North Am 1976 Apr;56(2):379-94. doi: 10.1016/s0039-6109(16)40884-4. PMID: 1265603

Clinical prediction guides

Thakur S, Chaddha V, Gupta R, Singh C, Dagar S, Shastri A, Tiwari B, Kavitha, Sethia V, Malik M, Jain P, Kapoor A, Kapoor A, Kapoor T, Kapoor A, Kapoor R, Kumar M, Uppal R
J Clin Ultrasound 2023 Jan;51(1):96-106. Epub 2022 Aug 10 doi: 10.1002/jcu.23273. PMID: 36639848
Prefumo F, Izzi C
Best Pract Res Clin Obstet Gynaecol 2014 Apr;28(3):391-402. Epub 2013 Dec 3 doi: 10.1016/j.bpobgyn.2013.10.003. PMID: 24342556
Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article
Almashraki N, Abdulnabee MZ, Sukalo M, Alrajoudi A, Sharafadeen I, Zenker M
World J Gastroenterol 2011 Oct 7;17(37):4247-50. doi: 10.3748/wjg.v17.i37.4247. PMID: 22072859Free PMC Article
Girard C, Bigorre M, Guillot B, Bessis D
Arch Dermatol 2006 Jul;142(7):884-8. doi: 10.1001/archderm.142.7.884. PMID: 16847205

Recent systematic reviews

Hosokawa T, Yamada Y, Tanami Y, Hattori S, Sato Y, Tanaka Y, Kawashima H, Hsokawa M, Oguma E
J Ultrasound Med 2017 Sep;36(9):1747-1758. Epub 2017 May 8 doi: 10.1002/jum.14228. PMID: 28480580
Yang G, Wang Y, Jiang X
BMC Pediatr 2016 May 13;16:65. doi: 10.1186/s12887-016-0604-z. PMID: 27176040Free PMC Article
Wijers CH, van Rooij IA, Marcelis CL, Brunner HG, de Blaauw I, Roeleveld N
Birth Defects Res C Embryo Today 2014 Dec;102(4):382-400. doi: 10.1002/bdrc.21068. PMID: 25546370
van den Hondel D, Sloots C, Meeussen C, Wijnen R
Eur J Pediatr Surg 2014 Feb;24(1):61-9. Epub 2013 Aug 5 doi: 10.1055/s-0033-1351663. PMID: 23918670
Zwink N, Jenetzky E, Brenner H
Orphanet J Rare Dis 2011 May 17;6:25. doi: 10.1186/1750-1172-6-25. PMID: 21586115Free PMC Article

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