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Choanal atresia

MedGen UID:
3395
Concept ID:
C0008297
Congenital Abnormality
Synonyms: Atresia, Choanal; Atresias, Choanal; Choanal Atresia; Choanal Atresias
SNOMED CT: Choanal atresia (204508009); Atresia of posterior naris (204508009); Congenital atresia of choana (204508009); Congenital atresia of posterior nares (204508009); Atresia of posterior nares (204508009)
Modes of inheritance:
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
HPO: HP:0000453
Monarch Initiative: MONDO:0012155
Orphanet: ORPHA137914

Definition

Absence or abnormal closure of the choana (the posterior nasal aperture). Most embryologists believe that posterior choanal atresia results from a failure of rupture between the 35th and 38th day of fetal life of the partition which separates the bucconasal or buccopharyngeal membranes. The resultant choanal atresia may be unilateral or bilateral, bony or membranous, complete or incomplete. In over 90 per cent of cases the obstruction is bony, while in the remainder it is membranous. The bony type of atresia is commonly located 1-2 mm. anterior to the posterior edge of the hard palate, and the osseous septum varies in thickness from 1 to 10 mm. In the membranous form of choanal atresia the obstruction usually occurs further posteriorly. In approximately one third of cases the atresia is bilateral. [from HPO]

Term Hierarchy

Conditions with this feature

Acrocephalosyndactyly type I
MedGen UID:
7858
Concept ID:
C0001193
Congenital Abnormality
Apert syndrome is characterized by the presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails. Almost all affected individuals have coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures. The midface in Apert syndrome is underdeveloped as well as retruded; a subset of affected individuals have cleft palate. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger are sometimes also involved. Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae) are also common. Multilevel airway obstruction may be present and can be due to narrowing of the nasal passages, tongue-based airway obstruction, and/or tracheal anomalies. Nonprogressive ventriculomegaly is present in a majority of individuals, with a small subset having true hydrocephalus. Most individuals with Apert syndrome have normal intelligence or mild intellectual disability; moderate-to-severe intellectual disability has been reported in some individuals. A minority of affected individuals have structural cardiac abnormalities, true gastrointestinal malformations, and anomalies of the genitourinary tract.
Pfeiffer syndrome
MedGen UID:
67390
Concept ID:
C0220658
Disease or Syndrome
Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome with characteristic anomalies of the hands and feet. Three clinical subtypes, which have important diagnostic and prognostic implications, have been identified. Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly. Type 2 consists of cloverleaf skull with Pfeiffer hands and feet, together with ankylosis of the elbows. Type 3 is similar to type 2 but without cloverleaf skull. Ocular proptosis is severe, and the anterior cranial base is markedly short. Various visceral malformations have been found in association with type 3. Early demise is characteristic of types 2 and 3 (Cohen, 1993). Cohen and Barone (1994) further tabulated the findings in the 3 types of Pfeiffer syndrome.
FG syndrome 1
MedGen UID:
113106
Concept ID:
C0220769
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.
Marshall-Smith syndrome
MedGen UID:
75551
Concept ID:
C0265211
Disease or Syndrome
The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).
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.
Miller syndrome
MedGen UID:
120522
Concept ID:
C0265257
Disease or Syndrome
Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by Ng et al., 2010).
Metaphyseal chondrodysplasia, Jansen type
MedGen UID:
120529
Concept ID:
C0265295
Disease or Syndrome
The Murk Jansen type of metaphyseal chondrodysplasia is characterized by severe short stature, short bowed limbs, clinodactyly, prominent upper face, and small mandible. Hypercalcemia and hypophosphatemia occur despite the lack of parathyroid abnormalities (summary by Cohen, 2002).
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.
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).
Lenz-Majewski hyperostosis syndrome
MedGen UID:
98483
Concept ID:
C0432269
Congenital Abnormality
Lenz-Majewski hyperostotic dwarfism is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, distinct craniofacial and dental anomalies, loose skin, and distal limb anomalies, particularly brachydactyly and symphalangism. Patients have multiple radiographic abnormalities due to progressive generalized hyperostosis that affects the cranium, vertebrae, and diaphyses of tubular bones, leading to severe growth retardation (summary by Sousa et al., 2014).
Isolated congenital breast hypoplasia/aplasia
MedGen UID:
98489
Concept ID:
C0432357
Congenital Abnormality
A rare breast malformation characterized by congenital absence of breast and nipple (amastia), or nipple or mammary gland (athelia or amazia, respectively). It can be unilateral or bilateral and may occur as an isolated malformation or be associated with a syndrome or cluster of other anomalies.
Chromosome 9p deletion syndrome
MedGen UID:
167073
Concept ID:
C0795830
Disease or Syndrome
A rare chromosomal anomaly with characteristics of psychomotor developmental delay, facial dysmorphism (trigonocephaly, midface hypoplasia, upslanting palpebral fissures, dysplastic small ears, flat nasal bridge with anteverted nostrils and long philtrum, micrognathia, choanal atresia, short neck), single umbilical artery, omphalocele, inguinal or umbilical hernia, genital abnormalities (hypospadia, cryptorchidism), muscular hypotonia and scoliosis.
Phosphoribosylaminoimidazole carboxylase deficiency
MedGen UID:
713858
Concept ID:
C1291561
Disease or Syndrome
Phosphoribosylaminoimidazole carboxylase deficiency (PAICSD) is an autosomal recessive disorder characterized by multiple congenital anomalies and early neonatal death (Pelet et al., 2019).
Hypogonadotropic hypogonadism 2 with or without anosmia
MedGen UID:
289648
Concept ID:
C1563720
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
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).
Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome
MedGen UID:
325265
Concept ID:
C1837822
Disease or Syndrome
TXNL4A-related craniofacial disorders comprise a range of phenotypes that includes: isolated choanal atresia; choanal atresia with minor anomalies; and Burn-McKeown syndrome (BMKS), which is characterized by typical craniofacial features (bilateral choanal atresia/stenosis, short palpebral fissures, coloboma of the lower eyelids, prominent nasal bridge with widely spaced eyes, short philtrum, thin vermilion of the upper lip, and prominent ears). Hearing loss is common and cardiac defects and short stature have been reported. Intellectual disability is rare.
Solitary median maxillary central incisor
MedGen UID:
326686
Concept ID:
C1840235
Congenital Abnormality
A single maxillary central incisor positioned in the midline with morphological symmetry of the crown and bordered by lateral incisors.
Microphthalmia with cyst, bilateral facial clefts, and limb anomalies
MedGen UID:
375210
Concept ID:
C1843492
Disease or Syndrome
Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome
MedGen UID:
335185
Concept ID:
C1845446
Disease or Syndrome
Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome is a developmental anomalies syndrome characterized by coloboma of the iris and optic nerve, facial dysmorphism (high forehead, microretrognathia, low-set ears), intellectual deficit, agenesis of the corpus callosum (ACC), sensorineural hearing loss, skeletal anomalies and short stature.
Lethal osteosclerotic bone dysplasia
MedGen UID:
342416
Concept ID:
C1850106
Disease or Syndrome
Raine syndrome (RNS) is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009). Some patients survive infancy (Simpson et al., 2009; Fradin et al., 2011).
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.
Beare-Stevenson cutis gyrata syndrome
MedGen UID:
377668
Concept ID:
C1852406
Disease or Syndrome
Beare-Stevenson cutis gyrata syndrome (BSTVS) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death (summary by Przylepa et al., 1996).
Bamforth-Lazarus syndrome
MedGen UID:
343420
Concept ID:
C1855794
Disease or Syndrome
A very rare syndrome of congenital hypothyroidism with characteristics of thyroid dysgenesis, cleft palate and spiky hair, with or without choanal atresia, and bifid epiglottis. Facial dysmorphism and porencephaly have been reported in isolated cases. Only 8 patients from 6 families have been reported to date. Newborns present at birth with thyroid dysgenesis (in most cases athyreosis) leading to congenital hypothyroidism that manifests with lethargy, poor feeding, macroglossia, cold or mottled skin, persistent jaundice and umbilical hernia. All newborns have a cleft palate and spiky hair. The syndrome is due to homozygous loss-of-function missense mutations located within the forkhead domain of the FOXE1 gene (9q22), encoding thyroid transcription factor 2 (TTF-2). TTF-2 is expressed in the thyroid gland (as well as elsewhere like the tongue, epiglottis and palate) and is thought to play a crucial role in thyroid morphogenesis. The disease is inherited autosomal recessively.
Neonatal diabetes mellitus with congenital hypothyroidism
MedGen UID:
347541
Concept ID:
C1857775
Disease or Syndrome
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015).
Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3
MedGen UID:
347666
Concept ID:
C1858562
Disease or Syndrome
The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.
Arrhinia with choanal atresia and microphthalmia syndrome
MedGen UID:
355084
Concept ID:
C1863878
Disease or Syndrome
Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence (summary by Graham and Lee, 2006). Also see absence of nasal bones (161480).
Mandibulofacial dysostosis-microcephaly syndrome
MedGen UID:
355264
Concept ID:
C1864652
Disease or Syndrome
Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia, microcephaly (congenital or postnatal onset), intellectual disability (mild, moderate, or severe), malformations of the external ear, and hearing loss that is typically conductive. Associated craniofacial malformations may include cleft palate, choanal atresia, zygomatic arch cleft (identified on cranial CT scan), and facial asymmetry. Other relatively common findings (present in 25%-35% of individuals) can include cardiac anomalies, thumb anomalies, esophageal atresia/tracheoesophageal fistula, short stature, spine anomalies, and epilepsy.
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.
Crouzon syndrome-acanthosis nigricans syndrome
MedGen UID:
394201
Concept ID:
C2677099
Disease or Syndrome
Crouzon syndrome with acanthosis nigricans is considered to be a distinct disorder from classic Crouzon syndrome (123500), which is caused by mutation in the FGFR2 gene (176943). Cohen (1999) argued that this condition is separate from Crouzon syndrome for 2 main reasons: it is caused by a highly specific mutation of the FGFR3 gene, whereas multiple different FGFR2 mutations result in Crouzon syndrome, and the phenotypes are different.
X-linked intellectual disability-craniofacioskeletal syndrome
MedGen UID:
394716
Concept ID:
C2678036
Disease or Syndrome
X-linked intellectual disability-craniofacioskeletal syndrome is a rare, hereditary, syndromic intellectual disability characterized by craniofacial and skeletal abnormalities in association with mild intellectual disability in females and early postnatal lethality in males. In addition to mild cognitive impairment, females present with microcephaly, short stature, skeletal features and extra temporal lobe gyrus. In males, intrauterine growth impairment, cardiac and urogenital anomalies have been reported.
Diamond-Blackfan anemia 10
MedGen UID:
412873
Concept ID:
C2750080
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.
Choanal atresia with radial ray hypoplasia
MedGen UID:
419083
Concept ID:
C2931464
Disease or Syndrome
An extremely rare syndrome with characteristics of radial ray hypoplasia, choanal atresia and convergent strabismus. It has been reported in a father and his two daughters. The radial ray involvement varies from absent radius, first metacarpal and thumb to hypoplastic thumb or triphalangeal thumb. Transmitted as an autosomal dominant trait.
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
MedGen UID:
422448
Concept ID:
C2936791
Disease or Syndrome
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
MedGen UID:
461449
Concept ID:
C3150099
Disease or Syndrome
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking.
Syndromic multisystem autoimmune disease due to ITCH deficiency
MedGen UID:
461999
Concept ID:
C3150649
Disease or Syndrome
Syndromic multisystem autoimmune disease due to Itch deficiency is a rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland.
Lymphedema-posterior choanal atresia syndrome
MedGen UID:
462225
Concept ID:
C3150875
Disease or Syndrome
A rare genetic disease characterized by choanal atresia and early onset of lymphedema of the lower extremities. Additional reported features include facial dysmorphism (hypertelorism, broad forehead, smooth philtrum, unilateral low-set ear and high-arched palate), hypoplastic nipples and pectus excavatum.
Treacher Collins syndrome 2
MedGen UID:
462333
Concept ID:
C3150983
Disease or Syndrome
Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal.
Intellectual disability, autosomal dominant 6
MedGen UID:
462761
Concept ID:
C3151411
Mental or Behavioral Dysfunction
GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common. Other infantile- or childhood-onset findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. Brain MRI reveals a malformation of cortical development in a minority of affected individuals. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported.
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.
Microcephalic primordial dwarfism due to ZNF335 deficiency
MedGen UID:
767413
Concept ID:
C3554499
Disease or Syndrome
Primary microcephaly-10 (MCPH10) is an autosomal recessive disorder characterized by extremely small head size (-9 SD) at birth and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation (summary by Yang et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Tetraamelia syndrome 1
MedGen UID:
860705
Concept ID:
C4012268
Disease or Syndrome
Tetraamelia syndrome-1 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.
Acrofacial dysostosis Cincinnati type
MedGen UID:
903483
Concept ID:
C4225317
Disease or Syndrome
The Cincinnati type of acrofacial dysostosis is a ribosomopathy characterized by a spectrum of mandibulofacial dysostosis phenotypes, with or without extrafacial skeletal defects (Weaver et al., 2015).
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).
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.
Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart
MedGen UID:
934739
Concept ID:
C4310772
Disease or Syndrome
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.
Sweeney-Cox syndrome
MedGen UID:
1625659
Concept ID:
C4540299
Disease or Syndrome
Sweeney-Cox syndrome 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.
Cornelia de Lange syndrome 1
MedGen UID:
1645760
Concept ID:
C4551851
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.
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).
Developmental and epileptic encephalopathy, 85, with or without midline brain defects
MedGen UID:
1708832
Concept ID:
C5393312
Disease or Syndrome
Developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is an X-linked neurologic disorder characterized by onset of severe refractory seizures in the first year of life, global developmental delay with impaired intellectual development and poor or absent speech, and dysmorphic facial features. The seizures tend to show a cyclic pattern with clustering. Many patients have midline brain defects on brain imaging, including thin corpus callosum and/or variable forms of holoprosencephaly (HPE). The severity and clinical manifestations are variable. Almost all reported patients are females with de novo mutations predicted to result in a loss of function (LOF). However, some patients may show skewed X inactivation, and the pathogenic mechanism may be due to a dominant-negative effect. The SMC1A protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; DEE85 can thus be classified as a 'cohesinopathy' (summary by Symonds et al., 2017 and Kruszka et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Kilquist syndrome
MedGen UID:
1742639
Concept ID:
C5436756
Disease or Syndrome
Kilquist syndrome (KILQS) is an autosomal recessive multisystem disorder characterized by neurologic, gastrointestinal, and secretory dysfunction. Affected individuals present at birth with hypotonia, feeding difficulties, mild dysmorphic features, and sensorineural hearing loss. They show poor overall growth associated with gastrointestinal anomalies such as gastroesophageal reflux or midgut malrotation, as well as profound global developmental delay with inability to sit or speak. Tear, sweat, and saliva production is also impaired, causing dry mouth and recurrent bronchial mucus plugging. Some of the clinical features are reminiscent of cystic fibrosis (CF; 219700) (summary by Stodberg et al., 2020).
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.
Vertebral, cardiac, tracheoesophageal, renal, and limb defects
MedGen UID:
1788069
Concept ID:
C5543189
Disease or Syndrome
VCTERL syndrome is characterized by anomalies of the vertebrae, heart, trachea, esophagus, kidneys, and limbs. Some patients also exhibit craniofacial abnormalities. Incomplete penetrance and markedly variable disease expression have been observed, including intrafamilial variability (Martin et al., 2020).
Treacher Collins syndrome 1
MedGen UID:
1800828
Concept ID:
C5574871
Disease or Syndrome
Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal.
Lethal tight skin contracture syndrome
MedGen UID:
1812447
Concept ID:
C5676878
Disease or Syndrome
Restrictive dermopathy is a rare, lethal genodermatosis with characteristic manifestations that are easily recognizable at birth: thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, and generalized joint ankylosis. Prenatal signs can include intrauterine growth retardation, reduced fetal movements, polyhydramnios, and premature rupture of the membranes. Most infants die within the first week of life (summary by Smigiel et al., 2010). Genetic Heterogeneity of Restrictive Dermopathy See also RSMD2 (619793), caused by mutation in the LMNA gene (150330) on chromosome 1q22.

Recent clinical studies

Etiology

Tonello C, Martins DANDP, Baptista MAFB, Mondelli F, Kokitsu Nakata NM, Feitosa LB, Alonso N
Cleft Palate Craniofac J 2022 Oct;59(10):1228-1232. Epub 2021 Sep 13 doi: 10.1177/10556656211042172. PMID: 34514882
Wang PP, Tang LX, Zhang J, Yang XJ, Zhang W, Han Y, Xiao X, Ni X, Ge WT
J Otolaryngol Head Neck Surg 2021 Aug 12;50(1):51. doi: 10.1186/s40463-021-00535-9. PMID: 34384505Free PMC Article
Paradis J, Dzioba A, El-Hakim H, Hong P, Kozak FK, Nguyen LHP, Perera D, Propst EJ, Siu JM, Wojtera M, Husein M; National Choanal Atresia Study Working Group.
J Otolaryngol Head Neck Surg 2021 Jul 13;50(1):46. doi: 10.1186/s40463-021-00503-3. PMID: 34256864Free PMC Article
Šebová I, Vyrvová I, Barkociová J
Medicina (Kaunas) 2021 Jan 21;57(2) doi: 10.3390/medicina57020093. PMID: 33494264Free PMC Article
Oh MS, Kadom N, Abramowicz S, Todd NW Jr
Am J Otolaryngol 2021 Jan - Feb;42(1):102824. Epub 2020 Nov 12 doi: 10.1016/j.amjoto.2020.102824. PMID: 33221635

Diagnosis

Tonello C, Martins DANDP, Baptista MAFB, Mondelli F, Kokitsu Nakata NM, Feitosa LB, Alonso N
Cleft Palate Craniofac J 2022 Oct;59(10):1228-1232. Epub 2021 Sep 13 doi: 10.1177/10556656211042172. PMID: 34514882
Wang PP, Tang LX, Zhang J, Yang XJ, Zhang W, Han Y, Xiao X, Ni X, Ge WT
J Otolaryngol Head Neck Surg 2021 Aug 12;50(1):51. doi: 10.1186/s40463-021-00535-9. PMID: 34384505Free PMC Article
Paradis J, Dzioba A, El-Hakim H, Hong P, Kozak FK, Nguyen LHP, Perera D, Propst EJ, Siu JM, Wojtera M, Husein M; National Choanal Atresia Study Working Group.
J Otolaryngol Head Neck Surg 2021 Jul 13;50(1):46. doi: 10.1186/s40463-021-00503-3. PMID: 34256864Free PMC Article
Koppen T, Bartmann D, Jakob M, Bootz F, Müller A, Dresbach T, Send T
J Neonatal Perinatal Med 2021;14(1):67-74. doi: 10.3233/NPM-200450. PMID: 32741782
Childs AJ, Mabin DC, Turnpenny PD
Am J Med Genet A 2020 Aug;182(8):1939-1943. Epub 2020 May 31 doi: 10.1002/ajmg.a.61628. PMID: 32476291

Therapy

Gundle L, Ojha S, Hendry J, Rosen H
Int J Pediatr Otorhinolaryngol 2021 Dec;151:110926. Epub 2021 Oct 1 doi: 10.1016/j.ijporl.2021.110926. PMID: 34624631
Wilcox LJ, Smith MM, de Alarcon A, Epperson M, Born H, Hart CK
Ann Otol Rhinol Laryngol 2020 Oct;129(10):1003-1010. Epub 2020 May 29 doi: 10.1177/0003489420928374. PMID: 32468891
Marston AP, Patel T, Nguyen SA, White DR
Ann Otol Rhinol Laryngol 2019 Sep;128(9):855-861. Epub 2019 May 8 doi: 10.1177/0003489419848457. PMID: 31067984
Kita M, Kuwata Y, Usui T
Auris Nasus Larynx 2019 Oct;46(5):808-812. Epub 2018 Nov 2 doi: 10.1016/j.anl.2018.10.005. PMID: 30396722
Moreddu E, Rossi ME, Nicollas R, Triglia JM
J Pediatr 2019 Jan;204:234-239.e1. Epub 2018 Oct 2 doi: 10.1016/j.jpeds.2018.08.074. PMID: 30291020

Prognosis

Godse NR, Lu N, Shaffer AD, Stapleton AL
J Craniofac Surg 2022 Jul-Aug 01;33(5):1409-1412. Epub 2022 Mar 11 doi: 10.1097/SCS.0000000000008604. PMID: 35275859
De Vincentiis GC, Panatta ML, De Corso E, Marini G, Bianchi A, Giuliani M, Sitzia E, Tucci FM
Acta Otorhinolaryngol Ital 2020 Feb;40(1):44-49. doi: 10.14639/0392-100X-1567. PMID: 32275648Free PMC Article
Marston AP, Patel T, Nguyen SA, White DR
Ann Otol Rhinol Laryngol 2019 Sep;128(9):855-861. Epub 2019 May 8 doi: 10.1177/0003489419848457. PMID: 31067984
Moreddu E, Rossi ME, Nicollas R, Triglia JM
J Pediatr 2019 Jan;204:234-239.e1. Epub 2018 Oct 2 doi: 10.1016/j.jpeds.2018.08.074. PMID: 30291020
Bronshtein M, Leibovitz Z, Laham G, Egenburg S, Wolman I, Bardin R
J Ultrasound Med 2018 Oct;37(10):2439-2444. Epub 2018 Feb 26 doi: 10.1002/jum.14586. PMID: 29480518

Clinical prediction guides

van Schaik CGR, Paasch S, Albrecht T, Becker S
Int J Pediatr Otorhinolaryngol 2022 Sep;160:111240. Epub 2022 Jul 14 doi: 10.1016/j.ijporl.2022.111240. PMID: 35868110
Aydemir L, Sen C, Kara H, Pamuk S, Kesimli MC, Comoglu S, Keles Turel MN
Int J Pediatr Otorhinolaryngol 2021 Dec;151:110929. Epub 2021 Sep 27 doi: 10.1016/j.ijporl.2021.110929. PMID: 34600192
Kalentakis Z, Stamataki S, Chalkiadakis V, Papapetropoulos N
J Craniofac Surg 2021 Sep 1;32(6):e535-e539. doi: 10.1097/SCS.0000000000007490. PMID: 33770044
Oh MS, Kadom N, Abramowicz S, Todd NW Jr
Am J Otolaryngol 2021 Jan - Feb;42(1):102824. Epub 2020 Nov 12 doi: 10.1016/j.amjoto.2020.102824. PMID: 33221635
Saraniti C, Santangelo M, Salvago P
Braz J Otorhinolaryngol 2017 Mar - Apr;83(2):183-189. Epub 2016 Apr 22 doi: 10.1016/j.bjorl.2016.03.009. PMID: 27174773Free PMC Article

Recent systematic reviews

Thomas AT, Waite J, Williams CA, Kirk J, Oliver C, Richards C
J Neurodev Disord 2022 Aug 31;14(1):49. doi: 10.1186/s11689-022-09459-5. PMID: 36045324Free PMC Article
Gundle L, Ojha S, Hendry J, Rosen H
Int J Pediatr Otorhinolaryngol 2021 Dec;151:110926. Epub 2021 Oct 1 doi: 10.1016/j.ijporl.2021.110926. PMID: 34624631
Murray S, Luo L, Quimby A, Barrowman N, Vaccani JP, Caulley L
Int J Pediatr Otorhinolaryngol 2019 Apr;119:47-53. Epub 2019 Jan 4 doi: 10.1016/j.ijporl.2019.01.001. PMID: 30665176
Strychowsky JE, Kawai K, Moritz E, Rahbar R, Adil EA
Laryngoscope 2016 Jan;126(1):218-27. Epub 2015 May 25 doi: 10.1002/lary.25393. PMID: 26014684
Cedin AC, Atallah AN, Andriolo RB, Cruz OL, Pignatari SN
Cochrane Database Syst Rev 2012 Feb 15;(2):CD008993. doi: 10.1002/14651858.CD008993.pub2. PMID: 22336856

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