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Orofaciodigital syndrome 6(OFD6)

MedGen UID:
411200
Concept ID:
C2745997
Disease or Syndrome
Synonyms: Central polydactyly cleft lip/palate or lingual lump and psychomotor retardation; Joubert syndrome with orofacialdigital anomalies; OFD6; OFDS VI; Oral-facial-digital syndrome type 6; Oral-Facial-Digital Syndrome Type VI; Orofaciodigital syndrome VI; POLYDACTYLY, CLEFT LIP/PALATE OR LINGUAL LUMP, AND PSYCHOMOTOR RETARDATION; VARADI SYNDROME; Varadi-Papp syndrome; Y-shaped central metacarpal and cerebellar defect
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
X-linked recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Joubert syndrome with orofaciodigital defect (721873007); Joubert syndrome with oro-facial-digital syndrome (721873007); Orofaciodigital syndrome type 6 (721873007); Varadi Papp syndrome (721873007); Varadi syndrome (721873007)
 
Gene (location): C5orf42 (5p13.2)
OMIM®: 277170
Orphanet: ORPHA2754

Definition

Orofaciodigital syndrome type VI (OFD6), or Varadi syndrome, is a rare autosomal recessive disorder distinguished from other orofaciodigital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities, including the molar tooth sign (summary by Doss et al., 1998 and Lopez et al., 2014). [from GTR]

Additional descriptions

From OMIM
Orofaciodigital syndrome type VI (OFD6), or Varadi syndrome, is a rare autosomal recessive disorder distinguished from other orofaciodigital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities, including the molar tooth sign (summary by Doss et al., 1998 and Lopez et al., 2014).  http://www.omim.org/entry/277170
From GHR
Oral-facial-digital syndrome is actually a group of related conditions that affect the development of the oral cavity (the mouth and teeth), facial features, and digits (fingers and toes).Researchers have identified at least 13 potential forms of oral-facial-digital syndrome. The different types are classified by their patterns of signs and symptoms. However, the features of the various types overlap significantly, and some types are not well defined. The classification system for oral-facial-digital syndrome continues to evolve as researchers find more affected individuals and learn more about this disorder.The signs and symptoms of oral-facial-digital syndrome vary widely. However, most forms of this disorder involve problems with development of the oral cavity, facial features, and digits. Most forms are also associated with brain abnormalities and some degree of intellectual disability.Abnormalities of the oral cavity that occur in many types of oral-facial-digital syndrome include a split (cleft) in the tongue, a tongue with an unusual lobed shape, and the growth of noncancerous tumors or nodules on the tongue. Affected individuals may also have extra, missing, or defective teeth. Another common feature is an opening in the roof of the mouth (a cleft palate). Some people with oral-facial-digital syndrome have bands of extra tissue (called hyperplastic frenula) that abnormally attach the lip to the gums.Distinctive facial features often associated with oral-facial-digital syndrome include a split in the lip (a cleft lip); a wide nose with a broad, flat nasal bridge; and widely spaced eyes (hypertelorism).Abnormalities of the digits can affect both the fingers and the toes in people with oral-facial-digital syndrome. These abnormalities include fusion of certain fingers or toes (syndactyly), digits that are shorter than usual (brachydactyly), or digits that are unusually curved (clinodactyly). The presence of extra digits (polydactyly) is also seen in most forms of oral-facial-digital syndrome.Other features occur in only one or a few types of oral-facial digital syndrome. These features help distinguish the different forms of the disorder. For example, the most common form of oral-facial-digital syndrome, type I, is associated with polycystic kidney disease. This kidney disease is characterized by the growth of fluid-filled sacs (cysts) that interfere with the kidneys' ability to filter waste products from the blood. Other forms of oral-facial-digital syndrome are characterized by neurological problems, particular changes in the structure of the brain, bone abnormalities, vision loss, and heart defects.  https://ghr.nlm.nih.gov/condition/oral-facial-digital-syndrome

Clinical features

Esotropia
MedGen UID:
4550
Concept ID:
C0014877
Disease or Syndrome
A form of ocular misalignment characterized by an excessive convergence of the visual axes, resulting in a "cross-eye" appearance. An example of this condition occurs when paralysis of the lateral rectus muscle causes an abnormal inward deviation of one eye on attempted gaze.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Hamartoma of hypothalamus
MedGen UID:
137970
Concept ID:
C0342418
Finding
The presence of a hamartoma of the hypothalamus.
Renal agenesis
MedGen UID:
154237
Concept ID:
C0542519
Congenital Abnormality
A congenital abnormality characterized by the absence of one or both kidneys.
Renal dysplasia
MedGen UID:
760690
Concept ID:
C3536714
Congenital Abnormality
A developmental defect characterized by absence or poor development of proximal renal tubules.
Postaxial polydactyly type A1
MedGen UID:
67394
Concept ID:
C0220697
Disease or Syndrome
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012). Genetic Heterogeneity of Postaxial Polydactyly Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; and PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Congenital anomaly of abnormally short fingers or toes.
Clinodactyly
MedGen UID:
120550
Concept ID:
C0265610
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Toe syndactyly
MedGen UID:
75581
Concept ID:
C0265660
Congenital Abnormality
Webbing or fusion of the toes, involving soft parts only or including bone structure. Bony fusions are revered to as \
Preaxial hand polydactyly
MedGen UID:
237235
Concept ID:
C1395852
Congenital Abnormality
Supernumerary digits located at the radial side of the hand. Polydactyly (supernumerary digits) involving the thumb occurs in many distinct forms of high variability and severity. Ranging from fleshy nubbins over varying degrees of partial duplication/splitting to completely duplicated or even triplicated thumbs or preaxial (on the radial side of the hand) supernumerary digits.
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Central Y-shaped metacarpal
MedGen UID:
338504
Concept ID:
C1848597
Finding
A central Y-shaped metacarpal is the result of a partial fusion of two central metacarpals (i.e., metacarpals 2-4) of the hand, with the two arms of the Y pointing in the distal direction. Central Y-shaped metacarpals may be seen as a result of a central polydactyly with partial fusion of the duplicated metacarpal.
Preaxial foot polydactyly
MedGen UID:
389171
Concept ID:
C2112942
Finding
Duplication of all or part of the first ray.
Mesoaxial hand polydactyly
MedGen UID:
866528
Concept ID:
C4020820
The presence of a supernumerary finger (not a thumb) involving the third or fourth metacarpal with associated osseous syndactyly.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to \
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Hamartoma of hypothalamus
MedGen UID:
137970
Concept ID:
C0342418
Finding
The presence of a hamartoma of the hypothalamus.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Molar tooth sign on MRI
MedGen UID:
400670
Concept ID:
C1865060
Finding
An abnormal appearance of the midbrain in axial magnetic resonance imaging in which the elongated superior cerebellar peduncles give the midbrain an appearance reminiscent of a molar or wisdom tooth.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Renal agenesis
MedGen UID:
154237
Concept ID:
C0542519
Congenital Abnormality
A congenital abnormality characterized by the absence of one or both kidneys.
Renal dysplasia
MedGen UID:
760690
Concept ID:
C3536714
Congenital Abnormality
A developmental defect characterized by absence or poor development of proximal renal tubules.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
A congenital abnormality of the jaws (particularly the mandible) in which they are unusually small. This condition is not always pathological and may correct itself as the patient matures; however, it may also present as a birth defect in multiple syndromes.
Postaxial polydactyly type A1
MedGen UID:
67394
Concept ID:
C0220697
Disease or Syndrome
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012). Genetic Heterogeneity of Postaxial Polydactyly Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; and PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Congenital anomaly of abnormally short fingers or toes.
Clinodactyly
MedGen UID:
120550
Concept ID:
C0265610
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Toe syndactyly
MedGen UID:
75581
Concept ID:
C0265660
Congenital Abnormality
Webbing or fusion of the toes, involving soft parts only or including bone structure. Bony fusions are revered to as \
Preaxial hand polydactyly
MedGen UID:
237235
Concept ID:
C1395852
Congenital Abnormality
Supernumerary digits located at the radial side of the hand. Polydactyly (supernumerary digits) involving the thumb occurs in many distinct forms of high variability and severity. Ranging from fleshy nubbins over varying degrees of partial duplication/splitting to completely duplicated or even triplicated thumbs or preaxial (on the radial side of the hand) supernumerary digits.
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Central Y-shaped metacarpal
MedGen UID:
338504
Concept ID:
C1848597
Finding
A central Y-shaped metacarpal is the result of a partial fusion of two central metacarpals (i.e., metacarpals 2-4) of the hand, with the two arms of the Y pointing in the distal direction. Central Y-shaped metacarpals may be seen as a result of a central polydactyly with partial fusion of the duplicated metacarpal.
Preaxial foot polydactyly
MedGen UID:
389171
Concept ID:
C2112942
Finding
Duplication of all or part of the first ray.
Mesoaxial hand polydactyly
MedGen UID:
866528
Concept ID:
C4020820
The presence of a supernumerary finger (not a thumb) involving the third or fourth metacarpal with associated osseous syndactyly.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
A congenital abnormality of the jaws (particularly the mandible) in which they are unusually small. This condition is not always pathological and may correct itself as the patient matures; however, it may also present as a birth defect in multiple syndromes.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Broad nasal tip
MedGen UID:
98424
Concept ID:
C0426429
Finding
Increase in width of the nasal tip.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Cleft secondary palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Cleft upper lip
MedGen UID:
892653
Concept ID:
C4020893
A gap in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Accessory oral frenulum
MedGen UID:
867439
Concept ID:
C4021814
Anatomical Abnormality
Extra fold of tissue extending from the alveolar ridge to the inner surface of the upper or lower lip.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVOrofaciodigital syndrome 6
Follow this link to review classifications for Orofaciodigital syndrome 6 in Orphanet.

Professional guidelines

PubMed

Valente EM, Brancati F, Boltshauser E, Dallapiccola B
Eur J Hum Genet 2011 Sep;19(9) Epub 2011 Mar 30 doi: 10.1038/ejhg.2011.49. PMID: 21448235Free PMC Article

Recent clinical studies

Etiology

Roosing S, Romani M, Isrie M, Rosti RO, Micalizzi A, Musaev D, Mazza T, Al-Gazali L, Altunoglu U, Boltshauser E, D'Arrigo S, De Keersmaecker B, Kayserili H, Brandenberger S, Kraoua I, Mark PR, McKanna T, Van Keirsbilck J, Moerman P, Poretti A, Puri R, Van Esch H, Gleeson JG, Valente EM
J Med Genet 2016 Sep;53(9):608-15. Epub 2016 May 6 doi: 10.1136/jmedgenet-2016-103832. PMID: 27208211Free PMC Article
Romani M, Mancini F, Micalizzi A, Poretti A, Miccinilli E, Accorsi P, Avola E, Bertini E, Borgatti R, Romaniello R, Ceylaner S, Coppola G, D'Arrigo S, Giordano L, Janecke AR, Lituania M, Ludwig K, Martorell L, Mazza T, Odent S, Pinelli L, Poo P, Santucci M, Signorini S, Simonati A, Spiegel R, Stanzial F, Steinlin M, Tabarki B, Wolf NI, Zibordi F, Boltshauser E, Valente EM
Hum Genet 2015 Jan;134(1):123-6. Epub 2014 Nov 19 doi: 10.1007/s00439-014-1508-3. PMID: 25407461Free PMC Article
Sattar S, Gleeson JG
Dev Med Child Neurol 2011 Sep;53(9):793-8. Epub 2011 Jun 17 doi: 10.1111/j.1469-8749.2011.04021.x. PMID: 21679365Free PMC Article

Diagnosis

Bayram Y, Aydin H, Gambin T, Akdemir ZC, Atik MM, Karaca E, Karaman A, Pehlivan D, Jhangiani SN, Gibbs RA, Lupski JR
Am J Med Genet A 2015 Sep;167A(9):2132-7. Epub 2015 Apr 6 doi: 10.1002/ajmg.a.37092. PMID: 25846457Free PMC Article
Lopez E, Thauvin-Robinet C, Reversade B, Khartoufi NE, Devisme L, Holder M, Ansart-Franquet H, Avila M, Lacombe D, Kleinfinger P, Kaori I, Takanashi J, Le Merrer M, Martinovic J, Noël C, Shboul M, Ho L, Güven Y, Razavi F, Burglen L, Gigot N, Darmency-Stamboul V, Thevenon J, Aral B, Kayserili H, Huet F, Lyonnet S, Le Caignec C, Franco B, Rivière JB, Faivre L, Attié-Bitach T
Hum Genet 2014 Mar;133(3):367-77. Epub 2013 Nov 1 doi: 10.1007/s00439-013-1385-1. PMID: 24178751
Darmency-Stamboul V, Burglen L, Lopez E, Mejean N, Dean J, Franco B, Rodriguez D, Lacombe D, Desguerres I, Cormier-Daire V, Doray B, Pasquier L, Gonzales M, Pastore M, Crenshaw ML, Huet F, Gigot N, Aral B, Callier P, Faivre L, Attié-Bitach T, Thauvin-Robinet C
Eur J Med Genet 2013 Jun;56(6):301-8. Epub 2013 Mar 21 doi: 10.1016/j.ejmg.2013.03.004. PMID: 23523602
Poretti A, Vitiello G, Hennekam RC, Arrigoni F, Bertini E, Borgatti R, Brancati F, D'Arrigo S, Faravelli F, Giordano L, Huisman TA, Iannicelli M, Kluger G, Kyllerman M, Landgren M, Lees MM, Pinelli L, Romaniello R, Scheer I, Schwarz CE, Spiegel R, Tibussek D, Valente EM, Boltshauser E
Orphanet J Rare Dis 2012 Jan 11;7:4. doi: 10.1186/1750-1172-7-4. PMID: 22236771Free PMC Article
Sattar S, Gleeson JG
Dev Med Child Neurol 2011 Sep;53(9):793-8. Epub 2011 Jun 17 doi: 10.1111/j.1469-8749.2011.04021.x. PMID: 21679365Free PMC Article

Prognosis

Bayram Y, Aydin H, Gambin T, Akdemir ZC, Atik MM, Karaca E, Karaman A, Pehlivan D, Jhangiani SN, Gibbs RA, Lupski JR
Am J Med Genet A 2015 Sep;167A(9):2132-7. Epub 2015 Apr 6 doi: 10.1002/ajmg.a.37092. PMID: 25846457Free PMC Article
Romani M, Mancini F, Micalizzi A, Poretti A, Miccinilli E, Accorsi P, Avola E, Bertini E, Borgatti R, Romaniello R, Ceylaner S, Coppola G, D'Arrigo S, Giordano L, Janecke AR, Lituania M, Ludwig K, Martorell L, Mazza T, Odent S, Pinelli L, Poo P, Santucci M, Signorini S, Simonati A, Spiegel R, Stanzial F, Steinlin M, Tabarki B, Wolf NI, Zibordi F, Boltshauser E, Valente EM
Hum Genet 2015 Jan;134(1):123-6. Epub 2014 Nov 19 doi: 10.1007/s00439-014-1508-3. PMID: 25407461Free PMC Article

Clinical prediction guides

Bayram Y, Aydin H, Gambin T, Akdemir ZC, Atik MM, Karaca E, Karaman A, Pehlivan D, Jhangiani SN, Gibbs RA, Lupski JR
Am J Med Genet A 2015 Sep;167A(9):2132-7. Epub 2015 Apr 6 doi: 10.1002/ajmg.a.37092. PMID: 25846457Free PMC Article
Romani M, Mancini F, Micalizzi A, Poretti A, Miccinilli E, Accorsi P, Avola E, Bertini E, Borgatti R, Romaniello R, Ceylaner S, Coppola G, D'Arrigo S, Giordano L, Janecke AR, Lituania M, Ludwig K, Martorell L, Mazza T, Odent S, Pinelli L, Poo P, Santucci M, Signorini S, Simonati A, Spiegel R, Stanzial F, Steinlin M, Tabarki B, Wolf NI, Zibordi F, Boltshauser E, Valente EM
Hum Genet 2015 Jan;134(1):123-6. Epub 2014 Nov 19 doi: 10.1007/s00439-014-1508-3. PMID: 25407461Free PMC Article

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