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Congenital vertical talus(CVT)

MedGen UID:
66821
Concept ID:
C0240912
Congenital Abnormality
Synonyms: Pes valgus, congenital convex; Rocker-bottom foot deformity
SNOMED CT: Congenital vertical talus (205082007); CVT - Congenital vertical talus (205082007); Rocker bottom foot (205082007); Convex pes valgus (205082007)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): HOXD10 (2q31.1)
 
HPO: HP:0001838
Monarch Initiative: MONDO:0008652
OMIM®: 192950
Orphanet: ORPHA178382

Definition

Congenital vertical talus (CVT), also known as 'rocker-bottom foot' deformity, is a dislocation of the talonavicular joint characterized by vertical orientation of the talus with a rigid dorsal dislocation of the navicular, equinus deformity of the calcaneus, abduction deformity of the forefoot, and contracture of the soft tissues of the hind- and mid-foot. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity with familial occurrence (summary by Levinsohn et al., 2004). The condition is transmitted in an autosomal dominant pattern of inheritance, and sometimes shows incomplete penetrance and variable expressivity. There may be a broad spectrum of deformities, including flatfoot, talipes equinovarus (TEV or clubfoot), cavus foot, metatarsus adductus, and even hypoplasia of the tibia (summary by Dobbs et al., 2006). [from OMIM]

Clinical features

From HPO
Congenital vertical talus
MedGen UID:
66821
Concept ID:
C0240912
Congenital Abnormality
Congenital vertical talus (CVT), also known as 'rocker-bottom foot' deformity, is a dislocation of the talonavicular joint characterized by vertical orientation of the talus with a rigid dorsal dislocation of the navicular, equinus deformity of the calcaneus, abduction deformity of the forefoot, and contracture of the soft tissues of the hind- and mid-foot. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity with familial occurrence (summary by Levinsohn et al., 2004). The condition is transmitted in an autosomal dominant pattern of inheritance, and sometimes shows incomplete penetrance and variable expressivity. There may be a broad spectrum of deformities, including flatfoot, talipes equinovarus (TEV or clubfoot), cavus foot, metatarsus adductus, and even hypoplasia of the tibia (summary by Dobbs et al., 2006).
Equinus calcaneus
MedGen UID:
395488
Concept ID:
C1860449
Finding
Abnormal plantar flexion of the calcaneus relative to the longitudinal axis of the tibia. This results in the angle between the long axis of the tibia and the long axis of the heel bone (calcaneus) being greater than 90 degrees.
Calcaneovalgus deformity
MedGen UID:
395489
Concept ID:
C1860450
Anatomical Abnormality
This is a postural deformity in which the foot is positioned up against the tibia. The heel (calcaneus) is positioned downward (that is, the ankle is flexed upward), and the heel is turned outward (valgus).
Arthritis
MedGen UID:
2043
Concept ID:
C0003864
Disease or Syndrome
Inflammation of a joint.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCongenital vertical talus
Follow this link to review classifications for Congenital vertical talus in Orphanet.

Conditions with this feature

Arthrogryposis, distal, type 1A
MedGen UID:
113099
Concept ID:
C0220662
Congenital Abnormality
Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. The term "arthrogryposis" comes from the Greek words for joint (arthro-) and crooked or hooked (gryposis). The characteristic features of this condition include permanently bent fingers and toes (camptodactyly), overlapping fingers, and a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation). Clubfoot, which is an inward- and upward-turning foot, is also commonly seen with distal arthrogryposis type 1. The specific hand and foot abnormalities vary among affected individuals. However, this condition typically does not cause any signs and symptoms affecting other parts of the body.
Cerebrooculofacioskeletal syndrome 1
MedGen UID:
66320
Concept ID:
C0220722
Disease or Syndrome
Cerebrooculofacioskeletal syndrome is an autosomal recessive progressive neurodegenerative disorder characterized by microcephaly, congenital cataracts, severe mental retardation, facial dysmorphism, and arthrogryposis (summary by Jaakkola et al., 2010). Genetic Heterogeneity of Cerebrooculofacioskeletal Syndrome See also COFS2 (610756), caused by mutation in the ERCC2 gene (126340); COFS3 (616570), caused by mutation in the ERCC5 gene (133530); and COFS4 (610758), caused by mutation in the ERCC1 gene (126380).
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.
Congenital vertical talus
MedGen UID:
66821
Concept ID:
C0240912
Congenital Abnormality
Congenital vertical talus (CVT), also known as 'rocker-bottom foot' deformity, is a dislocation of the talonavicular joint characterized by vertical orientation of the talus with a rigid dorsal dislocation of the navicular, equinus deformity of the calcaneus, abduction deformity of the forefoot, and contracture of the soft tissues of the hind- and mid-foot. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity with familial occurrence (summary by Levinsohn et al., 2004). The condition is transmitted in an autosomal dominant pattern of inheritance, and sometimes shows incomplete penetrance and variable expressivity. There may be a broad spectrum of deformities, including flatfoot, talipes equinovarus (TEV or clubfoot), cavus foot, metatarsus adductus, and even hypoplasia of the tibia (summary by Dobbs et al., 2006).
Freeman-Sheldon syndrome
MedGen UID:
120516
Concept ID:
C0265224
Disease or Syndrome
Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Autosomal recessive multiple pterygium syndrome
MedGen UID:
82696
Concept ID:
C0265261
Congenital Abnormality
Multiple pterygium syndromes comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal (253290) and nonlethal (Escobar) types.
Deletion of long arm of chromosome 18
MedGen UID:
96605
Concept ID:
C0432443
Disease or Syndrome
Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.
Fine-Lubinsky syndrome
MedGen UID:
163198
Concept ID:
C0795941
Disease or Syndrome
Syndrome with characteristics of psychomotor delay, brachycephaly with flat face, small nose, microstomia, cleft palate, cataract, hearing loss, hypoplastic scrotum and digital anomalies. Less than 10 patients have been described in the literature so far. Although the majority of reported cases were sporadic, the syndrome has been reported in one pair of siblings (a brother and sister) with an apparently autosomal recessive inheritance pattern.
Fetal akinesia deformation sequence 1
MedGen UID:
220903
Concept ID:
C1276035
Disease or Syndrome
Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).
TARP syndrome
MedGen UID:
333324
Concept ID:
C1839463
Disease or Syndrome
The classic features of TARP syndrome are talipes equinovarus, atrial septal defect, Robin sequence (micrognathia, cleft palate, and glossoptosis), and persistent left superior vena cava. Not all patients have all classic features. Some patients have the additional features of central nervous system dysfunction, renal abnormalities, variable cardiac anomalies including hypertrophic obstructive cardiomyopathy, and variable distal limb defects including syndactyly. Most patients die in late prenatal or early postnatal stages (summary by Kaeppler et al., 2018).
Oto-palato-digital syndrome, type II
MedGen UID:
337064
Concept ID:
C1844696
Disease or Syndrome
The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.
Cree intellectual disability syndrome
MedGen UID:
335673
Concept ID:
C1847361
Disease or Syndrome
Teebi-Shaltout syndrome
MedGen UID:
376472
Concept ID:
C1848912
Disease or Syndrome
Teebi-Shaltout syndrome is characterized by slow hair growth, scaphocephaly with prominent forehead, bitemporal depression, absence of primary teeth, camptodactyly, and caudal appendage with sacral dimple (summary by Aldemir et al., 2013).
Cerebrooculofacioskeletal syndrome 3
MedGen UID:
342008
Concept ID:
C1851443
Disease or Syndrome
Cerebrooculofacioskeletal syndrome is a severe, progressive neurologic disorder characterized by prenatal onset of arthrogryposis, microcephaly, and growth failure. Postnatal features include severe developmental delay, congenital cataracts (in some), and marked UV sensitivity of the skin. Survival beyond 6 years of age is rare. COFS represents the severe end of the spectrum of disorders caused by mutations in nucleotide excision repair (NER) genes, with Cockayne syndrome and xeroderma pigmentosum being milder NER-related phenotypes (summary by Drury et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see COFS1 (214150).
Digitotalar dysmorphism; ulnar drift, hereditary
MedGen UID:
342156
Concept ID:
C1852085
Disease or Syndrome
Cerebrooculofacioskeletal syndrome 4
MedGen UID:
342798
Concept ID:
C1853100
Disease or Syndrome
Cerebrooculofacioskeletal syndrome-4 is a severe autosomal recessive disorder characterized by growth retardation, dysmorphic facial features, arthrogryposis, and neurologic abnormalities. Cellular studies show a defect in both transcription-coupled and global genome nucleotide excision repair (TC-NER and GG-NER) (summary by Jaspers et al., 2007 and Kashiyama et al., 2013). For a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see 214150.
Cerebrooculofacioskeletal syndrome 2
MedGen UID:
342799
Concept ID:
C1853102
Disease or Syndrome
Any COFS syndrome in which the cause of the disease is a mutation in the ERCC2 gene.
Bowen-Conradi syndrome
MedGen UID:
349160
Concept ID:
C1859405
Disease or Syndrome
Bowen-Conradi syndrome is a disorder that affects many parts of the body and is usually fatal in infancy. Affected individuals have a low birth weight, experience feeding problems, and grow very slowly. Their head is unusually small overall (microcephaly), but is longer than expected compared with its width (dolichocephaly). Characteristic facial features include a prominent, high-bridged nose and an unusually small jaw (micrognathia) and chin. Affected individuals typically have pinky fingers that are curved toward or away from the ring finger (fifth finger clinodactyly) or permanently flexed (camptodactyly), feet with soles that are rounded outward (rocker-bottom feet), and restricted joint movement.\n\nOther features that occur in some affected individuals include seizures; structural abnormalities of the kidneys, heart, brain, or other organs; and an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate). Affected males may have the opening of the urethra on the underside of the penis (hypospadias) or undescended testes (cryptorchidism).\n\nBabies with Bowen-Conradi syndrome do not achieve developmental milestones such as smiling or sitting, and they usually do not survive more than 6 months.
H syndrome
MedGen UID:
400532
Concept ID:
C1864445
Disease or Syndrome
The histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC described an autosomal recessive disease involving joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes (summary by Morgan et al., 2010). SHML, or familial Rosai-Dorfman disease, was described as a rare cause of lymph node enlargement in children, consisting of chronic massive enlargement of cervical lymph nodes frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal sites were involved in approximately 25% of patients, including salivary glands, orbit, eyelid, spleen, and testes. The involvement of retropharyngeal lymphoid tissue sometimes caused snoring and sleep apnea (summary by Kismet et al., 2005). H syndrome was characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss was also found in about half of patients, and many had short stature. PHID was characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome, with hepatosplenomegaly occurring in about half of patients (Cliffe et al., 2009). Bolze et al. (2012) noted that mutations in the SLC29A3 gene (612373) had been implicated in H syndrome, PHID, FHC, and SHML, and that some patients presented a combination of features from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' Bolze et al. (2012) suggested that the histologic features of the lesions seemed to be the most uniform phenotype in these patients. In addition, the immunophenotype of infiltrating cells in H syndrome patients was shown to be the same as that seen in patients with the familial form of Rosai-Dorfman disease, further supporting the relationship between these disorders (Avitan-Hersh et al., 2011; Colmenero et al., 2012).
External auditory canal atresia-vertical talus-hypertelorism syndrome
MedGen UID:
361813
Concept ID:
C1876181
Disease or Syndrome
A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad: congenital, bilateral, symmetrical, subtotal, external auditory canal atresia, bilateral vertical talus and increased interocular distance.
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.
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.
Chromosome 16p13.3 duplication syndrome
MedGen UID:
462058
Concept ID:
C3150708
Disease or Syndrome
16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1
MedGen UID:
477906
Concept ID:
C3276276
Disease or Syndrome
A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by Mayr et al., 2010). Genetic Heterogeneity of Mitochondrial Complex V Deficiency Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (614052), caused by mutation in the TMEM70 gene (612418) on chromosome 8q21; MC5DN3 (614053), caused by mutation in the ATP5E gene (ATP5F1E; 606153) on chromosome 20q13; MC5DN4A (620358) and MC5DN4B (615228), both caused by mutation in the ATP5A1 gene (ATP5F1A; 164360) on chromosome 18q; MC5DN5 (618120), caused by mutation in the ATP5D gene (ATP5F1D; 603150) on chromosome 19p13; MC5DN6 (618683), caused by mutation in the USMG5 gene (ATP5MD; 615204) on chromosome 10q24; and MC5DN7 (620359), caused by mutation in the ATP5PO gene (600828) on chromosome 21q22. Mutations in the mitochondrial-encoded MTATP6 (516060) and MTATP8 (516070) genes can also cause mitochondrial complex V deficiency (see, e.g., 500015).
Arthrogryposis, distal, type 1B
MedGen UID:
482156
Concept ID:
C3280526
Disease or Syndrome
Neu-Laxova syndrome 2
MedGen UID:
863456
Concept ID:
C4015019
Disease or Syndrome
Neu-Laxova syndrome-2 is a rare autosomal recessive disorder characterized by a recognizable pattern of severe congenital malformations leading to prenatal or early postnatal lethality. Affected patients have abnormal craniofacial features, microcephaly, intrauterine growth retardation, ichthyosis, flexion deformities, limb malformations, and edema of the hands and feet. Some patients have malformations of the central nervous system, such as abnormal gyration (summary by Acuna-Hidalgo et al., 2014). For a discussion of genetic heterogeneity of Neu-Laxova syndrome, see NLS1 (256520).
Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
MedGen UID:
864138
Concept ID:
C4015701
Disease or Syndrome
A rare genetic developmental defect during embryogenesis malformation syndrome with characteristics of intrauterine growth restriction, flexion arthrogryposis of all joints, severe microcephaly, renal cystic dysplasia/agenesis/hypoplasia and complex malformations of the brain (cerebral and cerebellar hypoplasia, vermis, corpus callosum and/or occipital lobe agenesis, with or without arhinencephaly), as well as of the genitourinary tract (ureteral agenesis/hypoplasia, uterine hypoplasia and/or vaginal atresia), leading to fetal demise.
Developmental and epileptic encephalopathy, 29
MedGen UID:
908570
Concept ID:
C4225361
Disease or Syndrome
Developmental and epileptic encephalopathy-29 (DEE29) is an autosomal recessive neurologic disorder characterized by the onset of refractory myoclonic seizures in the first months of life. Affected individuals have poor overall growth, congenital microcephaly with cerebral atrophy and impaired myelination on brain imaging, spasticity with abnormal movements, peripheral neuropathy, and poor visual fixation (summary by Simons et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
MIRAGE syndrome
MedGen UID:
924576
Concept ID:
C4284088
Disease or Syndrome
MIRAGE syndrome is an acronym for the major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. Cytopenias are typically seen soon after birth; thrombocytopenia is the most common followed by anemia and pancytopenia. Recurrent infections from early infancy include pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. Reported genital phenotypes in those with 46,XY karyotype included hypospadias, microphallus, bifid shawl scrotum, ambiguous genitalia, or complete female genitalia. Hypoplastic or dysgenetic ovaries have been reported in females. Gastrointestinal complications include chronic diarrhea and esophageal dysfunction. Moderate-to-severe developmental delay is reported in most affected individuals. Autonomic dysfunction and renal dysfunction are also reported.
Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies
MedGen UID:
1380260
Concept ID:
C4479631
Disease or Syndrome
NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy. Some patients die in early childhood (summary by Falik Zaccai et al., 2017 and Hall et al., 2017).
Neu-Laxova syndrome 1
MedGen UID:
1633287
Concept ID:
C4551478
Disease or Syndrome
Any Neu-Laxova syndrome in which the cause of the disease is a mutation in the PHGDH gene.
Peroxisome biogenesis disorder 1A (Zellweger)
MedGen UID:
1648474
Concept ID:
C4721541
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Pontocerebellar hypoplasia, type 12
MedGen UID:
1648343
Concept ID:
C4748873
Disease or Syndrome
Fetal akinesia deformation sequence 4
MedGen UID:
1675450
Concept ID:
C4760578
Disease or Syndrome
Fetal akinesia deformation sequence-4 (FADS4) is an autosomal recessive disorder characterized by decreased fetal movements due to impaired neuromuscular function, resulting in significant congenital contractures and death in utero or soon after birth (summary by Bonnin et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of FADS, see 208150.
Coffin-Siris syndrome 10
MedGen UID:
1683634
Concept ID:
C4760583
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.
Fetal akinesia deformation sequence 3
MedGen UID:
1680087
Concept ID:
C4760599
Disease or Syndrome
The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome (see 253290). For a general phenotypic description and a discussion of genetic heterogeneity of FADS, see 208150.
Distal arthrogryposis type 2B1
MedGen UID:
1676961
Concept ID:
C5193014
Disease or Syndrome
Distal arthrogryposis is a clinically and genetically heterogeneous disorder characterized by clenched fist, overlapping fingers, camptodactyly, ulnar deviation, and positional foot deformities from birth. It is a disorder of primary limb malformation without primary neurologic or muscle disease. DA1 is not associated with other abnormalities, whereas other forms of DA have additional phenotypic features (Bamshad et al., 1996). The congenital contractures in DA2B (Sheldon-Hall syndrome, SHS) are similar to those observed in DA1, but affected individuals tend to have more prominent nasolabial folds, downslanting palpebral fissures, and a small mouth. DA2B is thought to be the most common of the distal arthrogryposis disorders (summary by Bamshad et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
Lethal arthrogryposis-anterior horn cell disease syndrome
MedGen UID:
1677784
Concept ID:
C5193016
Disease or Syndrome
Congenital arthrogryposis with anterior horn cell disease (CAAHD) is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by Smith et al., 2017 and Tan et al., 2017). Distinction from Lethal Congenital Contracture Syndrome 1 Biallelic mutation in the GLE1 gene can also cause LCCS1, which is lethal in utero. However, distinguishing between LCCS1 and CAAHD is controversial. Smith et al. (2017) suggested that differentiating between the 2 disorders has limited utility, and that they may represent a genotype/phenotype correlation rather than 2 different disease entities. In contrast, Said et al. (2017) concluded that LCCS1 represents a distinct clinical entity in which all affected individuals die prenatally and exhibit no fetal movements. Vuopala et al. (1995) differentiated CAAHD from LCCS1, noting that both are prevalent in Finland. LCCS1 is always fatal during the fetal period, presenting with severe hydrops and intrauterine growth retardation. In LCCS1, the spinal cord is macroscopically thinned because of an early reduction of the anterior horn and a paucity of anterior horn cells. The skeletal muscles are extremely hypoplastic, even difficult to locate. Infants with CAAHD survive longer than those with LCCS1, and when present, hydrops and intrauterine growth retardation are mild. The macroscopic findings of the central nervous system and skeletal muscles are closer to normal, although microscopic analysis also shows degeneration of anterior horn cells. In addition, birthplaces of ancestors of affected individuals do not show clustering in the northeast part of Finland, as is the case with LCCS1.
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
MedGen UID:
1684840
Concept ID:
C5231431
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA) is an autosomal recessive disorder characterized by severe global developmental delay, usually with hypotonia and absence of spontaneous movements other than head control, impaired intellectual development with absent speech, distal contractures, progressive microcephaly, dysmorphic features, and distal skeletal abnormalities, such as rocker-bottom feet and clenched hands with camptodactyly. Brain imaging tends to show a simplified gyral pattern of the cerebral cortex, delayed myelination, thin corpus callosum, and hypoplasia of the brainstem and cerebellum. The disorder may be complicated by feeding and/or breathing difficulties, often resulting in death in infancy (summary by Magini et al., 2019).
Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum
MedGen UID:
1684706
Concept ID:
C5231494
Disease or Syndrome
Neurogenic arthrogryposis multiplex congenita-4 with agenesis of the corpus callosum (AMC4) is a severe neurologic disorder with onset in utero. Affected individuals show little or no fetal movements and are born with significant contractures affecting the upper and lower limbs, as well as dysmorphic facial features. Other abnormalities include globally impaired development, optic atrophy, agenesis of the corpus callosum, seizures, and peripheral neuropathy. Many patients die in early childhood (summary by Seidahmed et al., 2020).
Wieacker-Wolff syndrome, female-restricted
MedGen UID:
1715791
Concept ID:
C5393303
Disease or Syndrome
Female-restricted Wieacker-Wolff syndrome (WRWFFR) is an X-linked dominant syndromic form of neurogenic arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Affected individuals have decreased fetal movements causing the development of contractures in utero and resulting in AMC and diffuse contractures involving the large and small joints apparent at birth. There is global developmental delay with difficulty walking or inability to walk, hypotonia that often evolves to spasticity, and variably impaired intellectual development with poor or absent speech and language. Dysmorphic facial features, including hypotonic facies, ptosis, microretrognathia, and small mouth, are seen in most patients. Seizures are uncommon; some patients have evidence of a peripheral motor neuropathy with distal muscle weakness. The level of X inactivation in lymphocytes and fibroblasts is often skewed, but may not predict the severity of the phenotype. Most cases occur sporadically; rare X-linked dominant inheritance has been reported in families (summary by Frints et al., 2019).
Sandestig-stefanova syndrome
MedGen UID:
1718072
Concept ID:
C5394118
Disease or Syndrome
Sandestig-Stefanova syndrome (SANDSTEF) is an autosomal recessive developmental syndrome characterized by pre- and postnatal microcephaly, trigonocephaly, congenital cataract, microphthalmia, facial gestalt, camptodactyly, loss of periventricular white matter, thin corpus callosum, delayed myelinization, and poor prognosis (Sandestig et al., 2019).
Arthrogryposis multiplex congenita 5
MedGen UID:
1731112
Concept ID:
C5436453
Disease or Syndrome
Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by Kariminejad et al., 2017).
Neurodevelopmental disorder with seizures and brain atrophy
MedGen UID:
1748227
Concept ID:
C5436732
Disease or Syndrome
Neurodevelopmental disorder with seizures and brain atrophy (NEDSEBA) is an autosomal recessive disorder with highly variable manifestations and severity of these core features. The most severely affected individuals develop symptoms in utero, which may lead to spontaneous abortion or planned termination. Those that survive may present with severe seizures at birth, have poor overall growth with small head circumference, achieve no developmental progress, and show significant brain atrophy and other brain abnormalities. Patients at the mildest end of the phenotypic spectrum have onset of seizures later in childhood and show developmental delay with mildly impaired intellectual development and minimal brain atrophy (summary by Coulter et al., 2020).
Arthrogryposis, distal, type 1C
MedGen UID:
1722257
Concept ID:
C5436834
Disease or Syndrome
Distal arthrogryposis type 1C (DA1C) is characterized by multiple congenital contractures, scoliosis, and short stature. Contractures involving the proximal joints appear to be more common in MYLPF-associated DA than in other forms of DA, and segmental amyoplasia has been observed (Chong et al., 2020).
Multiple congenital anomalies-neurodevelopmental syndrome, X-linked
MedGen UID:
1788942
Concept ID:
C5542341
Disease or Syndrome
X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade. Pathogenetically, the disorder results from disrupted gene expression and signaling during embryogenesis, thus affecting multiple systems (summary by Tripolszki et al., 2021 and Beck et al., 2021). Beck et al. (2021) referred to the disorder as LINKED syndrome (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects).
VISS syndrome
MedGen UID:
1794165
Concept ID:
C5561955
Disease or Syndrome
VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).
Schaaf-Yang syndrome
MedGen UID:
1807366
Concept ID:
C5575066
Disease or Syndrome
Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related Prader-Willi syndrome. It usually manifests at birth with muscular hypotonia in all and distal joint contractures in a majority of affected individuals. Gastrointestinal/feeding problems are particularly pronounced in infancy and childhood, but can transition to hyperphagia and obesity in adulthood. Respiratory distress is present in many individuals at birth, with approximately half requiring intubation and mechanical ventilation, and approximately 20% requiring tracheostomy. Skeletal manifestations such as joint contractures, scoliosis, and decreased bone mineral density are frequently observed. All affected individuals show developmental delay, resulting in intellectual disability of variable degree, from low-normal intelligence to severe intellectual disability. Other findings may include short stature, seizures, eye anomalies, and hypogonadism.
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.
Kury-Isidor syndrome
MedGen UID:
1807460
Concept ID:
C5676925
Disease or Syndrome
Kury-Isidor syndrome (KURIS) is a neurodevelopmental disorder with a highly variable phenotype. It is characterized mainly by mild global developmental delay apparent from infancy or early childhood with walking delayed by a few years and speech delay, often with language deficits. Intellectual development may be mildly delayed, borderline, or even normal; most patients have behavioral problems, including autism. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal anomalies, seizures, and nonspecific dysmorphic facial features (summary by Kury et al., 2022).
Tessadori-Van Haaften neurodevelopmental syndrome 4
MedGen UID:
1804234
Concept ID:
C5677016
Disease or Syndrome
Tessadori-Bicknell-van Haaften neurodevelopmental syndrome-4 (TEBIVANED4) is characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The severity and manifestations of the disorder are highly variable (Tessadori et al., 2022). For a discussion of genetic heterogeneity of TEBIVANED, see TEBIVANED1 (619758).
Arthrogryposis, distal, IIa 11
MedGen UID:
1823978
Concept ID:
C5774205
Disease or Syndrome
Distal arthrogryposis type 11 (DA11) is an autosomal dominant disorder characterized mainly by camptodactyly. Other features include absent flexion creases and limited forearm supination (Zhou et al., 2019).
Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties
MedGen UID:
1824001
Concept ID:
C5774228
Disease or Syndrome
Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (NEDSFF) is an autosomal recessive disorder characterized by distinct craniofacial features, multisystem dysfunction, profound neurodevelopmental delays, and neonatal death (Shankar et al., 2022).

Professional guidelines

PubMed

Xiu Y, Wang Y, He F, Zhang Y, Wang Y, Sun W, Wang B, Chen L
J Matern Fetal Neonatal Med 2023 Dec;36(1):2192323. doi: 10.1080/14767058.2023.2192323. PMID: 36948222
Winfeld MJ, Winfeld BE
Pediatr Radiol 2019 Nov;49(12):1678-1690. Epub 2019 Nov 4 doi: 10.1007/s00247-019-04503-4. PMID: 31686173
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Orthop Nurs 2005 Sep-Oct;24(5):313-21; quiz 322-3. doi: 10.1097/00006416-200509000-00004. PMID: 16272908

Recent clinical studies

Etiology

Xiu Y, Wang Y, He F, Zhang Y, Wang Y, Sun W, Wang B, Chen L
J Matern Fetal Neonatal Med 2023 Dec;36(1):2192323. doi: 10.1080/14767058.2023.2192323. PMID: 36948222
Rampal V, Giuliano F
Orthop Traumatol Surg Res 2020 Feb;106(1S):S115-S123. Epub 2019 Oct 21 doi: 10.1016/j.otsr.2019.03.021. PMID: 31648997
Rubio EI, Mehta N, Blask AR, Bulas DI
Pediatr Radiol 2017 Dec;47(13):1793-1799. Epub 2017 Sep 6 doi: 10.1007/s00247-017-3957-z. PMID: 28879597
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Diagnosis

Wirth T
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Therapy

Cummings JL, Rivera AE, Tippabhatla A, Hosseinzadeh P
J Pediatr Orthop 2023 May-Jun 01;43(5):317-325. Epub 2023 Feb 20 doi: 10.1097/BPO.0000000000002369. PMID: 36808104
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J Pediatr Orthop 2022 May-Jun 01;42(5):e448-e452. doi: 10.1097/BPO.0000000000002134. PMID: 35405728
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Prognosis

Tayebi N, Charng WL, Dickson PI, Dobbs MB, Gurnett CA
Eur J Med Genet 2022 Jun;65(6):104514. Epub 2022 Apr 27 doi: 10.1016/j.ejmg.2022.104514. PMID: 35487415Free PMC Article
Rampal V, Giuliano F
Orthop Traumatol Surg Res 2020 Feb;106(1S):S115-S123. Epub 2019 Oct 21 doi: 10.1016/j.otsr.2019.03.021. PMID: 31648997
Rubio EI, Mehta N, Blask AR, Bulas DI
Pediatr Radiol 2017 Dec;47(13):1793-1799. Epub 2017 Sep 6 doi: 10.1007/s00247-017-3957-z. PMID: 28879597
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Clinical prediction guides

Tayebi N, Charng WL, Dickson PI, Dobbs MB, Gurnett CA
Eur J Med Genet 2022 Jun;65(6):104514. Epub 2022 Apr 27 doi: 10.1016/j.ejmg.2022.104514. PMID: 35487415Free PMC Article
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Recent systematic reviews

Cummings JL, Rivera AE, Tippabhatla A, Hosseinzadeh P
J Pediatr Orthop 2023 May-Jun 01;43(5):317-325. Epub 2023 Feb 20 doi: 10.1097/BPO.0000000000002369. PMID: 36808104

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