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Oral-Facial-Digital Syndrome Type I

Synonyms: OFD1, Orofaciodigital Syndrome I

, PhD, , MD, , PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: August 4, 2016.

Summary

Clinical characteristics.

Oral-facial-digital syndrome type I (OFD1) is usually male lethal during gestation and predominantly affects females. OFD1 is characterized by the following features:

  • Oral (lobulated tongue, tongue nodules, 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, clinodactyly of the fifth finger; duplicated hallux [great toe])
  • Kidney (polycystic kidney disease)
  • Brain (e.g., intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation)
  • Intellectual disability (in ~50% of individuals)

Diagnosis/testing.

The diagnosis of OFD1 is established in a proband by identification of an OFD1 pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulae, 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 audiology evaluation and assessment of speech development in children if cleft lip and/or cleft palate is present. Individuals age ten years and older: annual blood pressure examination, serum creatinine, annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease.

Genetic counseling.

OFD1 is inherited in an X-linked manner. Approximately 75% of affected individuals represent 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 pathogenic variant; the proportion of cases caused by de novo pathogenic variants 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 pathogenic variant is 50%; however, most male conceptuses with the pathogenic variant 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 pathogenic variant in the family is known. Prenatal ultrasound examination may detect structural brain malformations and/or duplication of the hallux.

Diagnosis

Suggestive Findings

Oral-facial-digital syndrome type I (OFD1) should be suspected in females with typical oral-facial-digital findings, milia, and/or polycystic kidney disease. The oral-facial-digital findings are also found in other OFDs. OFD1 is characterized by renal cystic disease in approximately 50% of individuals and by the X-linked inheritance pattern in familial cases; see Table 2 (pdf). Almost all individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by an affected female.

Clinical Features

Oral

  • Tongue anomalies (e.g., lobulated, nodules, ankyloglossia)
  • Cleft palate
  • Alveolar clefts and accessory gingival frenulae
  • Dental anomalies (e.g., missing teeth, extra teeth)

Facial

  • Widely spaced eyes, telecanthus, downslanting palpebral fissures
  • Hypoplasia of the alae nasi
  • Median cleft lip, pseudocleft upper lip
  • Micrognathia

Digital

  • Brachydactyly, syndactyly
  • Clinodactyly of the fifth finger
  • Radial or ulnar deviation of the other fingers, particularly the third
  • Unilateral duplicated hallux (great toe)

Other

Radiographic Features

Hand x-rays often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges.

Renal ultrasound examination shows renal cysts in at least 50% of individuals.

Brain MRI most commonly shows intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation.

Establishing the Diagnosis

No formal diagnostic criteria are available. Because of the extensive genetic heterogeneity observed in OFD syndromes, OFD1 molecular genetic testing is recommended to establish the diagnosis [Franco & Thauvin-Robinet 2016].

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of OFD1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes OFD1 and other genes of interest (see Differential Diagnosis) is recommended if no pathogenic variant is identified on single-gene testing.
    Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing is recommended if serial single-gene testing (and/or use of a multi-gene panel that includes OFD1) fails to confirm a diagnosis in an individual with features of OFD1. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For more information on comprehensive genome sequencing click here.

Table 1.

Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type I

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
OFD1Sequence analysis 3, 480% 5
Gene-targeted deletion/duplication analysis 65% 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

5.

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

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

One study found that six of 131 individuals with OFD1 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 pathogenic variant identified on gene sequencing were found on qPCR to have an exon or multiexon deletion [Thauvin-Robinet et al 2009].

Clinical Characteristics

Clinical Description

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. Almost all affected individuals with OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by a female with OFD1.

Oral manifestations. The tongue is lobulated. 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 features. 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 anomalies. 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].

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 leave pitting scars.

Kidney. Renal cysts can develop from both tubules and glomeruli. The age of onset is most often in adulthood, but renal cysts in children as young as age two years have been described. Although renal cysts have been reported as a prenatal finding [Nishimura et al 1999], the diagnosis is doubtful in these cases. The risk for significant renal disease appears to be higher than 60% after age 18 years [Prattichizzo et al 2008, Saal et al 2010]. End-stage renal disease has been reported in affected girls and women ranging in age from 11 to 70 years.

Intellectual disability. 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 [Del Giudice et al 2014].

Brain malformations. 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, Del Giudice et al 2014]. 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, hypothalamic hamartomas, and berry aneurysms, each of which has been described in a few affected individuals.

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

Other

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

The hair is often described as dry, coarse, and brittle. Alopecia, usually partial, is an occasional finding. Alopecia following the lines of Blaschko has been described [Boente et al 1999].

Liver, pancreatic, and ovarian cysts may be observed, but only in those who have renal cysts as well.

Short stature, choanal atresia, and tibial pseudarthrosis have been reported.

Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [Morleo & Franco 2008].

Genotype-Phenotype Correlations

No convincing genotype-phenotype correlations have been reported. The majority of OFD1 pathogenic variants are localized within exon 16 of the OFD1 transcript.

Penetrance

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

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 (OFD) syndromes. See also Table 2 (pdf).

  • OFD2 (Mohr syndrome; OMIM 252100) is primarily distinguished by polydactyly. Other manifestations include bifid nasal tip. Affected individuals do not have milia or polycystic kidney disease.
  • OFD3 (OMIM 258850) 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 (OMIM 258860) has tibial involvement and polydactyly as the primary manifestations. Other findings include pectus excavatum and short stature.
  • OFD5 (OMIM 174300) includes polydactyly and median cleft lip only. Hyperplastic frenula have been reported in one affected individual.
  • OFD6 (OMIM 277170) is distinguished by polydactyly (particularly central) and cerebellar malformations. Renal agenesis and dysplasia have been described. Brain MRI may show a molar tooth sign leading some to consider OFD6 a Joubert syndrome-related disorder.
  • OFD8 (OMIM 300484), apparently inherited as an X-linked trait, is characterized by the combination of polydactyly, tibial and radial defects, and epiglottal abnormalities, none of which are seen in the classic form of OFD1.
  • OFD9 (OMIM 258865) includes retinal abnormalities and non-median cleft lip.
  • OFD10 (OMIM 165590) includes short limbs with bilateral radial shortening and fibular agenesis.
  • OFD11 (OMIM 612913) includes odontoid and vertebral abnormalities.
  • OFD12 is described in only one individual with brain malformations, myelomeningocele, short tibiae and central Y-shaped metacarpal [Gurrieri et al 2007].
  • OFD13 is described in only one individual with neuropsychiatric disturbances and leukokaraiosis [Gurrieri et al 2007].
  • OFD14 (OMIM 615948) includes severe microcephaly and intellectual disability. Brain MRI shows vermis hypoplasia and molar tooth sign.

Cystic renal disease

  • Autosomal dominant polycystic kidney disease (ADPKD). 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. The two genes in which pathogenic variants are known to cause ADPKD are PKD1 and PKD2.
  • 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. Inheritance is autosomal recessive. See Meckel Syndrome: OMIM Phenotypic Series for associated genes.

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 and behavior
  • Evaluation of CNS involvement
  • Blood pressure and serum creatinine concentration
  • Urinalysis, serum chemistries, and ultrasound examination of the kidneys, liver, ovary and pancreas for cysts if the individual is age ten years or older
  • Audiology evaluation if cleft palate is present
  • Consultation with a clinical geneticist and/or genetic counselor

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:

  • Annual audiology evaluation and assessment of speech development and frequency of ear infections in children if cleft lip and/or cleft palate is present
  • Annual blood pressure examination and serum creatinine concentration to monitor renal function in individuals age ten years or older
  • Annual ultrasound examination for renal, hepatic, pancreatic, and ovarian cystic disease in individuals age ten years and older

Evaluation of Relatives at Risk

If an OFD1 pathogenic variant has been identified in an affected family member, it is appropriate to evaluate apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) 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 manner. Almost all affected individuals are female. A few affected males have been reported; in most cases, these males are described as malformed fetuses delivered by females with OFD1.

Risk to Family Members

Parents of a female proband

Sibs of a female 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 OFD1 pathogenic variant miscarry [Macca & Franco 2009]. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the OFD1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. Although germline mosaicism has not been reported, it remains a possibility.

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

Other family members. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the OFD1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.

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.

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
  • Friendly Faces
    Email: smile@friendlyfaces.org
  • Kidney Foundation of Canada
    310-5160 Decarie Blvd.
    Montreal Ontario H3X 2H9
    Canada
    Phone: 800-361-7494 (toll-free); 514-369-4806
    Fax: 514-369-2472
    Email: info@kidney.ca
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    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

GeneChromosome LocusProteinLocus SpecificHGMD
OFD1Xp22​.2Oral-facial-digital syndrome 1 proteinOFD1 @ LOVDOFD1

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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

Gene structure. 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 A, Gene for a detailed summary of gene and protein information.

Benign variants. See Table 3 (pdf) for benign variants.

Pathogenic variants. To date, more than 120 different pathogenic variants (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, Franco & Thauvin-Robinet 2016]. See Table 3.

Both exonic and intronic pathogenic variants have been described throughout the gene. Nucleotide variants in exons include single base-pair changes, frameshifts, and deletions [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 pathogenic variants 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

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  • al-Qattan MM, Hassanain JM. Classification of limb anomalies in oral-facial-digital syndromes. J Hand Surg Br. 1997;22:250–2. [PubMed: 9149999]
  • 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. [PMC free article: PMC5497464] [PubMed: 23033313]
  • 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]
  • 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]
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  • 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]
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  • 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]
  • 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]
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  • 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]
  • 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]
  • 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]
  • 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

  • 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.
  • 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

Ange-Line Bruel, PhD (2016-present)
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)
Christel Thauvin-Robinet, MD, PhD (2016-present)
Helga V Toriello, PhD (2002-present)

Revision History

  • 4 August 2016 (sw) Comprehensive update posted live
  • 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
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