Oral-Facial-Digital Syndrome Type I

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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 1 (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

  • Milia
  • Polycystic kidney disease (50%)
  • Intellectual disability
  • X-linked dominant inheritance pattern in familial cases

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].

  • Female proband. The diagnosis of OFD1 is established by identification of a heterozygous pathogenic variant in OFD1 by molecular genetic testing (see Table 2).
  • Male proband. The diagnosis of OFD1 is established by identification of a hemizygous pathogenic variant in OFD1 by molecular genetic testing (see Table 2).

Molecular testing approaches can include single-gene testing, use of a multigene 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 multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing is recommended if single-gene testing (and/or use of a multigene 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.

Table 2.

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

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

See Table A. Genes and Databases for chromosome locus and protein.

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. 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 used may 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 1 (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 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.