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.

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.

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].

• Female proband. The diagnosis of OFD1 is established by identification of a heterozygous pathogenic variant in OFD1 by molecular genetic testing (see Table 1).
• Male proband. The diagnosis of OFD1 is established by identification of a hemizygous pathogenic variant in OFD1 by molecular genetic testing (see Table 1).

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 an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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.

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.

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

• Approximately 25% of females diagnosed with OFD1 have an affected mother.
• Approximately 75% of affected females are simplex cases (i.e., occurrence of OFD1 in a single family member) and have a de novo pathogenic variant [Feather et al 1997, Macca & Franco 2009].
• Recommendations for the evaluation of the mother of a proband with an apparent de novo pathogenic variant include clinical evaluation and molecular genetic testing if the pathogenic variant in the proband has been identified. If the mother meets the diagnostic criteria for OFD1 or if she has another affected relative, she is an obligate heterozygote.

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.

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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.
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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