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: oral features (lobulated tongue, tongue nodules, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities); facial features (widely spaced eyes, telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft of the upper lip, micrognathia); digital features (brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe); polycystic kidney disease; brain MRI findings (intracerebral cysts, agenesis of the corpus callosum, cerebellar agenesis with or without Dandy-Walker malformation); and intellectual disability (in approximately 50% of affected individuals).

Diagnosis/testing.

The diagnosis of OFD1 is established in a female proband with suggestive findings and a heterozygous OFD1 pathogenic variant identified by molecular genetic testing. The diagnosis of OFD1 is established in a male proband with suggestive findings and a hemizygous pathogenic variant in OFD1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Surgery for cleft lip/palate, tongue nodules, accessory frenulae, syndactyly, and polydactyly; speech therapy and aggressive treatment of otitis media as needed; removal of accessory teeth; orthodontia for malocclusion; routine treatment for seizures and renal disease; early intervention and individualized education plan as needed; standard treatments for attention-deficit/hyperactivity disorder and/or autistic features; hearing aids and community hearing services as needed.

Surveillance: Annual audiology evaluation and assessment of speech development in children with cleft lip and/or cleft palate; annual dental evaluation or as recommended by the dentist; assessment for new seizures or changes in seizures as recommended by neurologist in those with brain involvement. Annual blood pressure; serum creatinine; and renal, liver, pancreas, and ovarian ultrasound for cystic disease beginning at age ten years. Assess developmental progress, educational needs, and behavioral manifestations at each visit.

Evaluation of relatives at risk: It is appropriate to evaluate the genetic status of apparently asymptomatic female relatives (even in the absence of oral, facial, and digital anomalies) to determine if they are at risk for renal disease.

Pregnancy management: Careful monitoring of blood pressure and renal function during pregnancy is warranted.

Genetic counseling.

OFD1 is inherited in an X-linked manner with, typically, male lethality. The full OFD1 phenotype has not been described in males beyond the perinatal period. Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a de novo pathogenic variant; approximately 25% of females diagnosed with OFD1 have an affected mother (mildly affected females may be diagnosed after the identification of a severely affected individual). If the mother of the proband has an OFD1 pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%; however, most male conceptuses with the OFD1 pathogenic variant miscarry. It is possible for an affected male to be born alive, though this is exceedingly rare. Thus, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. Once the OFD1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

OFD1 should be suspected in females with typical oral, facial, and digital findings, polycystic kidney disease, and/or milia. The oral, facial, and digital findings are also found in other oral-facial-digital syndromes. OFD1 is characterized by renal cystic disease in approximately 50% of individuals and by the X-linked inheritance pattern in families with more than one affected individual. Almost all individuals with OFD1 are female; however, a few affected males have been reported. Most affected males are described as malformed fetuses delivered by an affected female.

Establishing the Diagnosis

Female proband. The diagnosis of OFD1 is established in a female proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in OFD1 identified by molecular genetic testing (see Table 1).

Male proband. The diagnosis of OFD1 is established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in OFD1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this section is understood to include any likely pathogenic variant. (2) Identification of a heterozygous or hemizygous OFD1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of OFD1 has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The diagnosis of oral-facial-digital syndrome type I (OFD1) is suspected 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. Most affected males are described as malformed fetuses delivered by a female with OFD1. To date, 234 individuals have been identified with a pathogenic variant in OFD1 [Pezzella et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

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. 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 (telecanthus) occurs in at least 33% of affected individuals. Hypoplasia of the alae nasi, median cleft lip, or pseudocleft of the 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.

Brain malformations. Structural brain abnormalities may occur in as many as 65% of individuals with OFD1 [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.

Kidney manifestations. 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 kidney disease has been reported in affected girls and women ranging in age from 11 to 70 years.

Intellectual disability and neurobehavioral manifestations. 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]. Rarely, behavioral issues (e.g., attention-deficit/hyperactivity disorder, autistic features) are observed.

Milia, small keratinizing cysts, occur in at least 10% of individuals, and are likely more common than reported. Milia most often appears on the scalp, ear pinnae, face, and dorsa of the hands. Milia are usually present in infancy and then resolve, but they can leave pitting scars.

Hair. 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 [Del C Boente et al 1999].

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

Other. Liver, pancreatic, and ovarian cysts may be observed [Macca & Franco 2009, Chetty-John et al 2010].

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.

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 1:50,000 to 1:250,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with OFD1, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

It is appropriate to evaluate the genetic status of 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 in the US and EU Clinical Trials Register in Europe 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 with, typically, male lethality. Almost all affected individuals with OFD1 are female.

The full OFD1 phenotype has not been described in males beyond the perinatal period. Males with a hemizygous OFD1 pathogenic variant who survive present a phenotype characterized by only some of the clinical features of OFD1, Joubert syndrome, retinitis pigmentosa, or primary ciliary dyskinesia, or with a clinical phenotype that is a combination of the different disorders [Sakakibara et al 2019, Sharma et al 2016, Zhang et al 2020, Pezzella et al 2022].

Risk to Family Members

Parents of a female proband

• A female proband may have inherited the OFD1 pathogenic variant from her mother or the pathogenic variant may be de novo. (Theoretically, a female proband may have inherited an OFD1 pathogenic variant from a father with germline mosaicism; however, this has not been reported to date.)
  • Approximately 75% of affected females represent simplex cases (i.e., the occurrence of OFD1 in a single family member) and have a de novo pathogenic variant [Pezzella et al 2022].
  • Approximately 25% of females diagnosed with OFD1 have an affected mother. (Mildly affected females may be diagnosed after the identification of a severely affected individual.)
• Recommendations for the evaluation of the mother of a proband with an apparent de novo pathogenic variant include clinical evaluation and molecular genetic testing for the pathogenic variant in the proband. (Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.)

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents.

• If the mother of the proband has an OFD1 pathogenic variant, the chance of transmitting the causative OFD1 pathogenic variant in each pregnancy is 50%; however, most male conceptuses with the OFD1 pathogenic variant miscarry [Macca & Franco 2009]. It is possible for an affected male to be born alive, though this is exceedingly rare. 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 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 because of the possibility of parental germline mosaicism. Maternal mosaicism for an OFD1 pathogenic variant has been reported [Wentzensen et al 2016, Gangaram et al 2022]. Paternal germline mosaicism has not been reported to date but remains a possibility.

Offspring of a female proband. Women with an OFD1 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy; however, the expected sex ratio of offspring at delivery is 33% unaffected females, 33% affected females, and 33% unaffected males because of the presumed lethality to affected males during gestation (most male conceptuses with an OFD1 pathogenic variant miscarry).

Other family members. The risk to other family members depends on the status of the proband's mother: if the mother has an OFD1 pathogenic variant, the mother's family members may 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 having an OFD1 pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the OFD1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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) [Carss et al 2014, Alamillo et al 2015] and/or skeletal defects.
• 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Oral-facial-digital syndrome 1 protein (also called centriole and centriolar satellite protein OFD1) 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 1,012-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 the nervous system [Ferrante et al 2001]. Functional in vivo and in vitro studies have demonstrated that OFD1 is required for ciliogenesis and determination of left-right asymmetry [Ferrante et al 2006, Singla et al 2010]. Recent studies reviewed in Morleo & Franco [2020] demonstrated that OFD1 has a role in microtubule organization and cell cycle progression [Alfieri et al 2020] and protein quality balance [Iaconis et al 2017, Morleo et al 2021]. A more recent report also indicated that OFD1 acts as a class II nucleation-promoting factor to promote Arp2/3 complex-mediated actin branching [Cao et al 2023].

Mechanism of disease causation. Most OFD1 pathogenic variants predict a premature truncation of the protein and apparent loss of function, which is further supported by OFD1 intragenic deletions causing the phenotype. However, the OFD1 transcript escapes X-chromosome inactivation; thus, the abnormal protein may theoretically interact with the wild type product to produce a dominant-negative effect.

OFD1-specific laboratory technical considerations. In females without a pathogenic variant identified on OFD1 sequence analysis, gene-targeted deletion/duplication analysis should be done, as the deletion could be masked by the wild type allele.

Acknowledgments

We thank the Italian Fondazione telethon for continuous support of our research and the patients and their families for participating in research activities. We also thank all the researchers who have contributed to the understanding of this disorder.

Author History

Ange-Line Bruel, PhD (2016-present)
Brunella Franco, MD (2010-present)
Danilo Moretti-Ferreira, PhD; São Paulo State University (2002-2010)
Izolda Nunes Guimaraes, PhD; São Paulo State University (2002-2010)
Christel Thauvin-Robinet, MD, PhD (2016-present)
Helga V Toriello, PhD; Genetics Services Spectrum Health (2002-2023)

Revision History

• 11 May 2023 (sw) Comprehensive update posted live
• 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 live
• 29 June 2004 (me) Comprehensive update posted live
• 24 July 2002 (me) Review posted live
• 27 February 2002 (ht) Original submission

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