• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Oral-Facial-Digital Syndrome Type I

Synonyms: OFD1, Orofaciodigital Syndrome I

, PhD and , MD.

Author Information
, PhD
Director, Genetics Services
Spectrum Health
Grand Rapids, Michigan
, MD
Principal Investigator, Telethon Institute of Genetics and Medicine
Associate Professor, Medical Genetics
Department of Translational Medical Sciences,
University of Naples Federico II
Naples, Italy

Initial Posting: ; Last Update: February 28, 2013.

Summary

Disease characteristics. Oral-facial-digital syndrome type I (OFD1) is associated with dysfunction of primary cilia and is characterized by the following abnormalities:

  • Oral (lobed tongue, hamartomas or lipomas of the tongue, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities)
  • Facial (widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia)
  • Digital (brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger; duplicated hallux [great toe]; preaxial or postaxial polydactyly of the hands)
  • Brain (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation)
  • Kidney (polycystic kidney disease)

As many as 50% of individuals with OFD1 have some degree of intellectual disability, which is usually mild. Almost all affected individuals are female. However, males with OFD1 have been described, mostly as malformed fetuses delivered by women with OFD1.

Diagnosis/testing. The diagnosis of OFD1 is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood. OFD1 is the only gene in which mutations are known to cause oral-facial-digital syndrome type I.

Management. Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulas, and syndactyly; removal of accessory teeth, and orthodontia for malocclusion. Routine treatment for renal disease and seizures. Speech therapy and special education may be warranted.

Surveillance: Annual monitoring of renal function; periodic screening for ovarian, pancreatic, and hepatic cystic disease; if cleft lip is present, regular speech and hearing assessment.

Genetic counseling. OFD1 is inherited in an X-linked dominant manner. Approximately 75% of affected individuals are simplex cases (i.e., with no family history of OFD1). A female proband with OFD1 may have the disorder as the result of a de novo gene mutation; the proportion of cases caused by de novo mutations is unknown. The risk that the unaffected mother of an affected female who is a simplex case will give birth to another female with OFD1 is less than 1%. At conception, the risk to the offspring of females with OFD1 of inheriting the disease-causing OFD1 allele is 50%; however, most male conceptuses with the disease-causing allele miscarry. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. Prenatal ultrasound examination may detect structural brain malformations and/or duplication of the hallux.

Diagnosis

Clinical Diagnosis

The diagnosis of oral-facial-digital syndrome type I (OFD1) is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood [Coll et al 1997]. The X-linked dominant male lethal pattern of inheritance may suggest the diagnosis in the presence of the characteristic clinical signs:

Oral. Oral findings affect primarily the tongue, palate, and teeth:

  • The tongue is lobed and often described as bifid or trifid. Tongue nodules, which are usually hamartomas or lipomas, also occur in at least one third of individuals with OFD1. Ankyloglossia attributable to a short lingual frenulum is common.
  • Cleft hard or soft palate, submucous cleft palate, or highly arched palate occurs in more than 50% of affected individuals. Trifurcation of the soft palate has been reported [al-Qattan 1998].
  • Alveolar clefts and accessory gingival frenulae are common. These fibrous bands are hyperplastic frenulae extending from the buccal mucous membrane to the alveolar ridge, resulting in notching of the alveolar ridges.
  • Dental abnormalities include missing teeth (most common), extra teeth, enamel dysplasia, and malocclusion.

Facial

  • Widely spaced eyes or telecanthus occurs in at least 33% of affected individuals.
  • Hypoplasia of the alae nasi, median cleft lip, or pseudocleft upper lip is common.
  • Micrognathia and downslanting palpebral fissures are common.

Digital

  • Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger are common.
  • The other fingers, particularly the third (i.e., middle finger) may show variable radial or ulnar deviation.
  • Duplicated hallux (great toe) occurs in fewer than 50% of affected individuals, and if present is usually unilateral.
  • Preaxial or postaxial polydactyly of the hands occurs in 1%-2% of affected individuals.
  • Radiographs of the hands often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges [al-Qattan & Hassanain 1997].

Brain. Structural brain abnormalities may occur in as many as 65% of individuals with OFD1 [Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013]. Anomalies most commonly include intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation. Other reported anomalies include type 2 porencephaly (schizencephalic porencephaly), pachygyria and heterotopias, hydrocephalus, cerebral or cerebellar atrophy, and berry aneurysms, each of which has been described in a few affected individuals.

Intellect. It is estimated that as many as 50% of individuals with OFD1 have some degree of intellectual disability or learning disability. Intellectual disability depends in part on the presence of brain abnormalities, but no consistent correlation exists. When present, intellectual disability is usually mild. Severe intellectual disability in the absence of brain malformations appears to be rare.

Kidney. Renal cysts can develop from both tubules and glomeruli. Polycystic kidney disease occurs in at least 50% of individuals with OFD1 although the exact frequency is unknown. Recent data indicate that renal cystic disease is present in 60% of affected individuals older than age 18 years [Prattichizzo et al 2008]. The age of onset is most often in adulthood, but renal cysts in children as young as age two years have been described.

Molecular Genetic Testing

Gene. OFD1 is the only gene in which mutations are known to cause oral-facial-digital syndrome type I [Ferrante et al 2001].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected MalesAffected Females
OFD1Sequence analysisSequence variants 2, 3Not applicable (lethal in males)80%
Partial- and whole-gene deletions0% 4
Duplication / deletion analysis 5Partial- and whole-gene deletions 65%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. A variety of mutations have been identified, the majority of which predict premature protein truncation. The reported mutation detection rate is about 80% [Nowaczyk et al 2003, Thauvin-Robinet et al 2006, Prattichizzo et al 2008].

4. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in females.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. One study found that six of 131 individuals with OFDI had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a mutation identified on gene sequencing were found on qPCR to have an exonic or multiexonic deletion [Thauvin-Robinet et al 2009].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Gene sequencing followed by deletion/duplication analysis for detection of deletions identifies a mutation in approximately 85% of affected individuals.

Testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Females are heterozygotes for this X-linked male lethal disorder. (2) Identification of the disease-causing mutation in females requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected relative is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

In addition to the findings described in Clinical Diagnosis, the following may be present in oral-facial-digital syndrome type I (OFD1):

Brain. Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy.

Intellect. As many as 50% of individuals with OFD1 have some degree of intellectual disability, usually mild. Those with brain malformations are more likely to have intellectual disability, but the association is not consistent.

Oral manifestations. Hearing loss from recurrent otitis media, usually associated with cleft palate, has been reported. On occasion, speech and mastication can be affected.

Skin and hair. The hair is often described as dry, coarse, and brittle. Alopecia, usually partial, is an occasional finding. Alopecia has been described to follow the lines of Blaschko [Boente et al 1999]. Milia, small keratinizing cysts, occur in at least 10%, and likely more, most often appearing on the scalp, ear pinnae, face, and dorsa of the hands. Milia are usually present in infancy and then resolve, but can then leave pitting scars.

Kidney. Although renal cysts have been reported as a prenatal finding [Nishimura et al 1999], the diagnosis is doubtful in these cases. Typically, cysts appear no earlier than late childhood. End-stage renal disease has been reported in affected girls and women ranging in age from 11 to 70 years. Recently it has been emphasized that the risk for significant renal disease appears to be higher than 60% after age 18 years [Prattichizzo et al 2008, Saal et al 2009]. In addition, liver and pancreatic cysts may be observed, but only in those who have renal cysts as well.

Other. Rare manifestations include hearing impairment, cysts in pancreas, ovary and liver, short stature, choanal atresia, tibial pseudarthrosis, and berry aneurysms.

Almost all affected individuals with classic OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by women with OFD1; however, a male described by Goodship et al [1991] survived to term and expired on the first day of life. Virtually all reported males are simplex cases (i.e., a single occurrence in a family); the certainty of the diagnosis is thus unknown. Some of the other reported males with suspected OFD1 may in fact have other diagnoses, such as another OFD or Meckel-Gruber syndrome. It is theoretically possible (though highly unlikely) for an affected male to survive birth. Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [Morleo & Franco 2008].

Genotype-Phenotype Correlations

There is some evidence that genotype-phenotype correlation exists:

  • According to Thauvin-Robinet et al [2006], renal cysts appear to be correlated with splice mutations. Saal et al [2009], however, did not find this correlation.
  • High-arched/cleft palate was found most frequently with missense and splice site mutations [Prattichizzo et al 2008].
  • Intellectual disability is more often associated with mutations in exons 3, 8, 9, 13, and 16.
  • Anomalous teeth are more often found in those with mutations in coiled coil domains.

Penetrance

OFD1 appears to be highly penetrant, although highly variable in expression. In some reports, renal cysts are the only apparent manifestation in affected women [McLaughlin et al 2000].

Anticipation

No evidence for anticipation exists.

Nomenclature

OFD1 was previously called Papillon-Léage-Psaume syndrome.

Prevalence

Prevalence estimates range from 1:250,000 to 1:50,000.

Differential Diagnosis

The differential diagnosis includes the other oral-facial-digital syndromes and disorders, including cystic renal disease.

Oral-facial-digital syndromes. See Table 2 (pdf).

  • OFD2, Mohr syndrome, is primarily distinguished by polydactyly. Other manifestations include bifid nasal tip. Affected individuals do not have milia or polycystic kidney disease.
  • OFD3 is characterized by seesaw winking (alternate winking of the eyes) and polydactyly. Myoclonic jerks, profound intellectual disability, bulbous nose, and apparently low-set ears also occur.
  • OFD4 has tibial involvement and polydactyly as the primary manifestations. Other findings include pectus excavatum and short stature.
  • OFD5 includes polydactyly and median cleft lip only. Hyperplastic frenula have been reported in one affected individual.
  • OFD6 is distinguished by polydactyly (particularly central) and cerebellar malformations. Renal agenesis and dysplasia have been described.
  • OFD8, apparently inherited as an X-linked recessive trait, is characterized by the combination of polydactyly, tibial and radial defects, and epiglottal abnormalities, none of which is seen in the classic form of OFD1.
  • OFD9 includes retinal abnormalities and non-median cleft lip.

Cystic renal disease. Autosomal dominant polycystic kidney disease (ADPKD) should be considered in the differential diagnosis of OFD1. The diagnosis of ADPKD has been made in some individuals who later were found to have OFD1 [Scolari et al 1997]. In ADPKD, cysts develop from tubules, whereas in OFD1 cysts develop from both tubules and glomeruli; however, imaging studies cannot always distinguish the renal cystic disease of OFD1 from that of ADPKD and other cystic renal disorders. The cysts are said to be smaller and more uniform in size in OFD1 than in ADPKD, and the kidneys are not as enlarged or malformed in OFD1. Hepatic cysts and berry aneurysms have been observed in OFD1. Other distinguishing features are mode of inheritance and the absence of oral, facial, digital, or brain abnormalities in ADPKD.

Meckel-Gruber syndrome is characterized by CNS malformation (posterior encephalocele, cerebral and cerebellar hypoplasia), polycystic or hypoplastic kidneys, preaxial or postaxial polydactyly, and early demise. Additional findings include cleft lip and palate, ambiguous genitalia, microcephaly, and microphthalmia. Ocular histopathology reveals retinal dysplasia, coloboma, cataract, and corneal dysgenesis. Two loci have been mapped and one gene, MKS3, identified. Inheritance is autosomal recessive.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with oral-facial-digital syndrome type I (OFD1), the following evaluations are recommended:

  • Examination of the face, especially the mouth, and the hands for characteristic anomalies
  • Formal, age-appropriate assessment of development
  • Blood pressure and serum creatinine concentration
  • Urinalysis, serum chemistries, and ultrasound evaluation of the kidneys, liver, and pancreas for cysts if the individual is age ten years or older
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Cosmetic or reconstructive surgery for clefts of the lip and/or palate, tongue nodules, and accessory frenulae; treatment as for isolated cleft palate, including speech therapy and assessment for and aggressive treatment of otitis media
  • Removal of accessory teeth
  • Orthodontia for malocclusion
  • Surgery to repair syndactyly, if present
  • Routine management of renal disease, which may require hemodialysis or peritoneal dialysis and renal transplantation
  • Routine management of seizures
  • Special educational evaluation and input to address learning disabilities and other cognitive impairments

Surveillance

Surveillance includes the following:

  • Regular follow-up for assessment of speech and ear infections/hearing loss if cleft lip is present
  • Annual determination of blood pressure and serum creatinine concentration to monitor renal function
  • Annual assessment of renal function with follow-up by renal ultrasound evaluation to assess cyst development if abnormalities are detected
  • Periodic screening for ovarian, pancreatic, and hepatic cystic disease

Evaluation of Relatives at Risk

Molecular testing of daughters of known mutation carriers, even in the absence of oral, facial, and digital anomalies, may be reasonable.

Similarly, mothers of affected daughters could benefit from testing to determine if they are at risk for renal disease.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected pregnant women should undergo careful monitoring of their blood pressure and renal function during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Oral-facial-digital syndrome type I (OFD1) is inherited in an X-linked dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the mother.
  • When the mother of an affected female is also affected, the risk to sibs of inheriting the disease-causing OFD1 allele at conception is 50%; however, most male conceptuses with the disease-causing OFD1 allele miscarry [Macca & Franco 2009]. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.
  • If no family history of OFD1 exists, the risk that the unaffected mother of an affected female will give birth to another female with OFD1 is less than 1%. Two possibilities account for this small increased risk: (1) a new mutation in a second child or (2) germline mosaicism in a parent [Nishimura et al 1999]. Although germline mosaicism has not been reported, it remains a possibility.

Offspring of a proband. The risk to the offspring of females with OFD1 must take into consideration the presumed lethality to affected males during gestation. At conception, the risk that the disease-causing OFD1 allele will be transmitted is 50%; however, most male conceptuses with the disease-causing OFD1 allele miscarry. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.

Other family members of a proband. The risk to other family members depends on the status of the proband's mother. If the mother is affected, her family members could be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Specific risk issues. Males described as having OFD1 have been reported. As virtually all are simplex cases (i.e., a single occurrence in a family), the certainty of the diagnosis is unknown. It is theoretically possible for an affected male to be born alive, though this would be exceedingly rare.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

Ascertainment of affected individuals. Often, mildly affected female relatives are diagnosed only after the identification of a severely affected individual [Thauvin-Robinet et al 2001].

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination

  • High-risk pregnancies. In pregnancies of a female with OFD1, which are at 50% risk, prenatal ultrasound examination may detect structural brain malformations (e.g., porencephaly) [Shipp et al 2000, Thauvin-Robinet et al 2001] and/or duplicated hallux.
  • Low-risk pregnancies. In pregnancies not known to be at increased risk for OFD1, the findings of structural brain anomalies and unilateral polydactyly of the great toe (duplicated hallux) should lead to consideration of OFD1. In such instances, it is appropriate to evaluate the mother for manifestations of OFD1.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
    Phone: 800-242-5338 (toll-free); 919-933-9044
    Fax: 919-933-9604
    Email: info@cleftline.org
  • Kidney Foundation of Canada
    1599 Hurontario Street
    Suite 201
    Mississauga Ontario L5G 4S1
    Canada
    Phone: 800-387-4474 (toll-free); 905-278-3003
    Fax: 905-271-4990
    Email: kidney@kidney.on.ca
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Fax: 212-689-9261
    Email: info@kidney.org
  • National Renal Resource Centre
    Sydney Dialysis Centre
    37 Darling Point road
    Darling Point New South Wales 2027
    Australia
    Phone: 61 2 9362 3995; 61 2 9362 3121; 1 800 257 189 (toll-free)
    Fax: 61 2 9362 4354
    Email: renalresource@nsccahs.health.nsw.gov.au

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Oral-Facial-Digital Syndrome Type I: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
OFD1Xp22​.2Oral-facial-digital syndrome 1 proteinOFD1 @ LOVDOFD1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Oral-Facial-Digital Syndrome Type I (View All in OMIM)

300170OFD1 GENE; OFD1
311200OROFACIODIGITAL SYNDROME I; OFD1

Normal allelic variants. OFD1 has 23 exons (reference sequence NM_003611.2) and is located on a region of the X chromosome where transcripts frequently escape X-chromosome inactivation. See Table 3 (pdf) for normal allelic variants.

Pathologic allelic variants. To date, more than 120 different mutations (including large genomic rearrangements) have been identified [Ferrante et al 2001, Rakkolainen et al 2002, Stoll & Sauvage 2002, Romio et al 2003, Morisawa et al 2004, Thauvin Robinet et al 2006, Prattichizzo et al 2008, Thauvin-Robinet et al 2009, Bisschoff et al 2013]. See Table 3.

Both exonic and intronic pathologic allelic variants have been described. Point mutations in exons include single base-pair changes, frameshifts, and deletions. To date, these changes have been identified in exons 2 through 17. Abnormal splicing has also been reported in introns 2, 3, 4, 5, 6, 7, 10, 11, 12, 16 [Macca & Franco 2009, Bisschoff et al 2013].

Nine different genomic deletions involving exons 1 through 23 or the entire transcript have been reported [Thauvin-Robinet et al 2009, Bisschoff et al 2013].

Normal gene product. Oral-facial-digital syndrome 1 protein occurs in two forms, OFD1-1 (Cxorf5-1) and OFD1-2 (Cxorf5-2), which are differentiated by the use of an alternative splice site. OFD1-1 is a 1012-amino acid protein (reference sequence NP_003602.1); OFD1-2 is a 367-amino acid protein. The two proteins share the first 351 amino acids; OFD1-2 then has a C-terminal region of 16 amino acids. OFD1 was expressed in all adult tissues that were examined by de Conciliis et al [1998]. However, during early development, expression is exclusively in the genital ridges, soon followed by expression in craniofacial structures and nervous system [Ferrante et al 2001]. The function of the protein is as yet unknown, although characterization of a mouse model bearing ubiquitous inactivation of the Ofd1 transcript from early stages of development demonstrated that Ofd1 is required for formation of primary cilia and determination of left-right asymmetry [Ferrante et al 2006]. In vitro studies demonstrate that Ofd1 regulates the length and distal structures of centrioles [Singla et al 2010].

Abnormal gene product. Most of the mutations predict a premature truncation of the protein and apparent loss of function, which is further supported by the OFD1 intragenic deletion alleles. Since OFD1 is on the portion of the X chromosome that escapes X-chromosome inactivation, the truncated protein may theoretically interact with the wild-type product to produce a dominant-negative effect.

References

Literature Cited

  1. al-Qattan MM. Cone-shaped epiphyses in the toes and trifurcation of the soft palate in oral-facial-digital syndrome type-I. Br J Plast Surg. 1998;51:476–9. [PubMed: 9849370]
  2. al-Qattan MM, Hassanain JM. Classification of limb anomalies in oral-facial-digital syndromes. J Hand Surg Br. 1997;22:250–2. [PubMed: 9149999]
  3. Bisschoff IJ, Zeschnigk C, Horn D, Wellek B, Rieß A, Wessels M, Willems P, Jensen P, Busche A, Bekkebraten J, Chopra M, Hove HD, Evers C, Heimdal K, Kaiser AS, Kunstmann E, Robinson KL, Linné M, Martin P, McGrath J, Pradel W, Prescott KE, Roesler B, Rudolf G, Siebers-Renelt U, Tyshchenko N, Wieczorek D, Wolff G, Dobyns WB, Morris-Rosendahl DJ. Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability. Hum Mutat. 2013;34:237–47. [PubMed: 23033313]
  4. Boente M, Primc N, Veliche H, Rosales S, Carrero-Valenzuela R, Saleme C, Asial R. A mosaic pattern of alopecia in the oral-facial-digital syndrome type I (Papillon-Léage and psaume syndrome). Pediatr Dermatol. 1999;16:367–70. [PubMed: 10571835]
  5. Budny B, Chen W, Omran H, Friegauf M, Tzschach A, Wisniewska M, Jensen LR, Raynaud M, Shoichet SA, Badura M, Lenzner S, Latos-Bielenska A, Ropers HH. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006;120:171–8. [PubMed: 16783569]
  6. Coene KLM, Roepman R, Doherty D. OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5- encoded lebercilin. Am J Hum Genet. 2009;85:465–81. [PMC free article: PMC2756557] [PubMed: 19800048]
  7. Coll E, Torra R, Pascual J, Botey A, Ara J, Perez L, Ballesta F, Darnell A. Sporadic orofaciodigital syndrome type I presenting as end-stage renal disease. Nephrol Dial Transplant. 1997;12:1040–2. [PubMed: 9175067]
  8. de Conciliis L, Marchitiello A, Wapenaar MC, Borsani G, Giglio S, Mariani M, Consalez GG, Zuffardi O, Franco B, Ballabio A, Banfi S. Characterization of Cxorf5 (71-7A), a novel human cDNA mapping to Xp22 and encoding a protein containing coiled-coil alpha-helical domains. Genomics. 1998;51:243–50. [PubMed: 9722947]
  9. Feather SA, Winyard PJ, Dodd S, Woolf AS. Oral-facial-digital syndrome type 1 is another dominant polycystic kidney disease: clinical, radiological and histopathological features of a new kindred. Nephrol Dial Transplant. 1997;12:1354–61. [PubMed: 9249769]
  10. Ferrante MI, Giorgio G, Feather SA, Bulfone A, Wright V, Ghiani M, Selicorni A, Gammaro L, Scolari F, Woolf AS, Sylvie O, Bernard L, Malcolm S, Winter R, Ballabio A, Franco B. Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet. 2001;68:569–76. [PMC free article: PMC1274470] [PubMed: 11179005]
  11. Ferrante MI, Zullo A, Barra A, Bimonte S, Messaddeq N, Studer M, Dolle P, Franco B. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet. 2006;38:112–7. [PubMed: 16311594]
  12. Field M, Scheffer IE, Gill D, Wilson M, Christie L, Shaw M, Gardner A, Glubb G, Hobson L, Corbett M, Friend K, Willis-Owen S, Gecz J. Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations. Eur J Hum Genet. 2012;20:806–9. [PMC free article: PMC3376274] [PubMed: 22353940]
  13. Goodship J, Platt J, Smith R, Burn J. A male with type I orofaciodigital syndrome. J Med Genet. 1991;28:691–4. [PMC free article: PMC1017056] [PubMed: 1941964]
  14. Juric-Sekhar G, Adkins J, Doherty D, Hevner RF. Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia. Acta Neuropathol. 2012;123:695–709. [PubMed: 22331178]
  15. Macca M, Franco B. The molecular basis of oral-facial-digital syndrome, type 1. Am J Med Genet C Semin Med Genet. 2009;151C:318–25. [PubMed: 19876934]
  16. McLaughlin K, Neilly JB, Fox JG, Boulton-Jones JM. The hypertensive young lady with renal cysts--it is not always polycystic kidney disease. Nephrol Dial Transplant. 2000;15:1245–7. [PubMed: 10910455]
  17. Morisawa T, Yagi M, Surono A, Yokoyama N, Ohmori M, Terashi H, Matsuo M. Novel double-deletion mutations of the Ofd1 gene creating multiple novel transcripts. Hum Genet. 2004;115:97–103. [PubMed: 15221448]
  18. Morleo M, Franco B. Dosage compensation of the mammalian X-chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders. J Med Genet. 2008;45:401–8. [PubMed: 18463129]
  19. Nishimura G, Kuwashima S, Kohno T, Teramoto C, Watanabe H, Kubota T. Fetal polycystic kidney disease in oro-facio-digital syndrome type I. Pediatr Radiol. 1999;29:506–8. [PubMed: 10398784]
  20. Nowaczyk MJ, Zeesman S, Whelan DT, Wright V, Feather SA. Oral-facial-digital syndrome VII is oral-facial-digital syndrome I: a clarification. Am J Med Genet. 2003;123A:179–82. [PubMed: 14598343]
  21. Prattichizzo C, Macca M, Novelli V, Giorgio G, Barra A, Franco B. Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients. Hum Mutat. 2008;29:1237–46. [PubMed: 18546297]
  22. Rakkolainen A, Ala-Mello S, Kristo P, Orpana A, Jarvela I. Four novel mutations in the OFD1 (Cxorf5) gene in Finnish patients with oral-facial-digital syndrome 1. J Med Genet. 2002;39:292–6. [PMC free article: PMC1735103] [PubMed: 11950863]
  23. Romio L, Wright V, Price K, Winyard PJ, Donnai D, Porteous ME, Franco B, Giorgio G, Malcolm S, Woolf AS, Feather SA. OFD1, the gene mutated in oral-facial-digital syndrome type 1, is expressed in the metanephros and in human embryonic renal mesenchymal cells. J Am Soc Nephrol. 2003;14:680–9. [PubMed: 12595504]
  24. Saal S, Faivre L, Aral B. Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I. Clin Genet. 2009;77:258–65. [PubMed: 19817772]
  25. Scolari F, Valzorio B, Carli O, Vizzardi V, Costantino E, Grazioli L, Bondioni MP, Savoldi S, Maiorca R. Oral-facial-digital syndrome type I: an unusual cause of hereditary cystic kidney disease. Nephrol Dial Transplant. 1997;12:1247–50. [PubMed: 9198060]
  26. Shipp TD, Chu GC, Benacerraf B. Prenatal diagnosis of oral-facial-digital syndrome, type I. J Ultrasound Med. 2000;19:491–4. [PubMed: 10898304]
  27. Singla V, Romaguera-Ros M, Garcia-Verdugo JM, Reiter JF. Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev Cell. 2010;18:410–24. [PMC free article: PMC2841064] [PubMed: 20230748]
  28. Stoll C, Sauvage P. Long-term follow-up of a girl with oro-facio-digital syndrome type I due to a mutation in the OFD 1 gene. Ann Genet. 2002;45:59–62. [PubMed: 12119212]
  29. Thauvin-Robinet C, Cossee M, Cormier-Daire V, Van Maldergem L, Toutain A, Alembik Y, Bieth E, Layet V, Parent P, David A, Goldenberg A, Mortier G, Heron D, Sagot P, Bouvier AM, Huet F, Cusin V, Donzel A, Devys D, Teyssier JR, Faivre L. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J Med Genet. 2006;43:54–61. [PMC free article: PMC2564504] [PubMed: 16397067]
  30. Thauvin-Robinet C, Franco B, Saugier-Veber P, Aral B, Gigot N, Donzel A, Van Maldergem L, Bieth E, Layet V, Mathieu M, Teebi A, Lespinasse J, Callier P, Mugneret F, Lasurel-Paulet A, Gautier E, Huet F, Teyssier JR, Tosi M, Frebourg T, Faivre L. Genomic deletions of OFD1 account for 23% of oral-facial-digital type 1 syndrome after negative DNA sequencing. Hum Mutat. 2009;30:E320–9. [PubMed: 19023858]
  31. Thauvin-Robinet C, Rousseau T, Durand C, Laurent N, Maingueneau C, Faivre L, Sagot P, Nivelon-Chevallier A. Familial orofaciodigital syndrome type I revealed by ultrasound prenatal diagnosis of porencephaly. Prenat Diagn. 2001;21:466–70. [PubMed: 11438951]
  32. Tsurusaki Y, Kosho T, Hatasaki K, Narumi Y, Wakui K, Fukushima Y, Doi H, Saitsu H, Miyake N, Matsumoto N. Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients. Clin Genet. 2013;83:135–44. [PubMed: 22548404]
  33. Webb TR, Parfitt DA, Gardner JC, Martinez A, Bevilacqua D, Davidson AE, Zito I, Thiselton DL, Ressa JH, Apergi M, Schwarz N, Kanuga N, Michaelides M, Cheetham ME, Gorin MB, Hardcastle AJ. Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). Hum Mol Genet. 2012;21:3647–54. [PMC free article: PMC3406759] [PubMed: 22619378]

Suggested Reading

  1. Franco B. The molecular basis of oral-facial-digital type 1 (OFD1) syndrome. In: Epstein JC, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2 ed. Vol 1. New York, NY: Oxford University Press; 2008:1379-86.
  2. Odent S, Le Marec B, Toutain A, David A, Vigneron J, Treguier C, Jouan H, Milon J, Fryns JP, Verloes A. Central nervous system malformations and early end-stage renal disease in oro-facio-digital syndrome type I: a review. Am J Med Genet. 1998;75:389–94. [PubMed: 9482645]

Chapter Notes

Author History

Brunella Franco, MD (2010-present)
Danilo Moretti-Ferreira, PhD; São Paulo State University, Brazil (2002-2010)
Izolda Nunes Guimaraes, PhD; São Paulo State University, Brazil (2002-2010)
Helga V Toriello, PhD (2002-present)

Revision History

  • 28 February 2013 (me) Comprehensive update posted live
  • 14 October 2010 (me) Comprehensive update posted live
  • 9 March 2007 (ht, cd) Revision: sequence analysis and prenatal diagnosis clinically available
  • 14 August 2006 (me) Comprehensive update posted to live Web site
  • 29 June 2004 (me) Comprehensive update posted to live Web site
  • 24 July 2002 (me) Review posted to live Web site
  • 27 February 2002 (ht) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1188PMID: 20301367
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

  • X-Linked Opitz G/BBB Syndrome[GeneReviews<sup>®</sup>. 1993]
    X-Linked Opitz G/BBB Syndrome
    Meroni G. GeneReviews<sup>®</sup>. 1993
  • Focal Dermal Hypoplasia[GeneReviews<sup>®</sup>. 1993]
    Focal Dermal Hypoplasia
    Sutton VR, Van den Veyver IB. GeneReviews<sup>®</sup>. 1993
  • 22q11.2 Deletion Syndrome[GeneReviews<sup>®</sup>. 1993]
    22q11.2 Deletion Syndrome
    McDonald-McGinn DM, Emanuel BS, Zackai EH. GeneReviews<sup>®</sup>. 1993
  • Roberts Syndrome[GeneReviews<sup>®</sup>. 1993]
    Roberts Syndrome
    Gordillo M, Vega H, Jabs EW. GeneReviews<sup>®</sup>. 1993
  • Review The molecular basis of oral-facial-digital syndrome, type 1.[Am J Med Genet C Semin Med Genet. 2009]
    Review The molecular basis of oral-facial-digital syndrome, type 1.
    Macca M, Franco B. Am J Med Genet C Semin Med Genet. 2009 Nov 15; 151C(4):318-25.
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...