PAPILLON-LEAGE AND PSAUME SYNDROME
ORAL-FACIAL-DIGITAL SYNDROME, TYPE I
OFDS I
OFD1
OFDI
OFDSI
Papillon-Léage-Psaume syndrome
Oral-facial-digital syndrome type 1
Orofaciodigital syndrome type I (OFD1) is characterized by malformations of the face, oral cavity, and digits and is transmitted as an X-linked dominant condition with lethality in males (Ferrante et al., 2001). Thickened alveolar ridges and abnormal dentition, ... Orofaciodigital syndrome type I (OFD1) is characterized by malformations of the face, oral cavity, and digits and is transmitted as an X-linked dominant condition with lethality in males (Ferrante et al., 2001). Thickened alveolar ridges and abnormal dentition, including absent lateral incisors, are additional characteristics of OFD1. The central nervous system may also be involved in as many as 40% of cases. Although these clinical features overlap those reported in other forms of orofaciodigital syndrome, OFD1 can be easily distinguished from among these by its X-linked dominant inheritance pattern and by polycystic kidney disease, which seems to be specific to type I. Since the CXORF5 gene localizes to the centrosome and basal body of primary cilia, OFD1 is considered to be a ciliopathy (Chetty-John et al., 2010).
Papillon-Leage and Psaume (1954) described 8 female patients with a hereditary syndrome involving abnormal oral frenula accompanied by alveolar and lingual clefting. They stated that there were only 3 previous reports of the syndrome, and all patients described ... Papillon-Leage and Psaume (1954) described 8 female patients with a hereditary syndrome involving abnormal oral frenula accompanied by alveolar and lingual clefting. They stated that there were only 3 previous reports of the syndrome, and all patients described to date were female. Radiography of the skull in the 8 patients of Papillon-Leage and Psaume (1954) showed asymmetry of the cranial vault, nasal fossae, and sometimes the mandible, with increased interorbital distance and a sella turcica that 'appeared abnormal.' Histologic examination of one of the oral adhesions revealed condensation of the conjunctival tissue around a narrow and deep epithelial invagination. The authors noted that although the phenotype varied in severity, ranging from simple hypertrophy of the frenula with mesialization of the lateral frenula to forms with more marked malpositioning of the teeth, the sites of involvement were always the same. The syndrome was frequently accompanied by a specific constellation of malformations, including cleft lip/palate, aplasia of the alar cartilages, digital malformations such as syndactyly or trident hand, familial tremor, and mental retardation. Papillon-Leage and Psaume (1954) included photographs and detailed clinical descriptions of each of their 8 patients. On the basis of a review of the clinical features in their patients and the patients they identified in the literature, Papillon-Leage and Psaume (1954) expanded the phenotype of OFD I to include a granular appearance of facial skin with diffuse alopecia and dry hair. They suggested that malpositioning of a single canine or premolar with hypertrophy of the lateral frenulum might represent a minimal form of the disorder, and reviewed the embryologic development of the affected region. Gorlin et al. (1961) first reported this condition in the English literature. Clefts of the jaw and tongue in the area of the lateral incisors and canines, other malformations of the face and skull, malformation of the hands (specifically syndactyly, clinodactyly, brachydactyly and occasionally postaxial polydactyly) and mental retardation are features. Others include small nostrils, lobulated tongue with hamartomas, peculiarly irregular and asymmetric clefts of the palate, aberrant hyperplastic oral frenula, transient multiple milia on pinnae, and spotty alopecia. The abnormal oral frenula appear to lead to the clefting of jaw, tongue, and upper lip. Harrod et al. (1976) observed bilateral polycystic kidneys and renal failure in an affected 48-year-old woman and noted other reports of this feature. Donnai et al. (1987) reported a 3-generation family with OFD I in 5 females. Several family members were thought to suffer from autosomal dominant polycystic kidney disease, but examination of the proband led to the correct diagnosis. Connacher et al. (1987) reported a girl with OFD I who, by age 17 years, had established renal failure and bilaterally palpable renal masses. Her mother had less severe OFD I associated with polycystic kidneys, but her renal function was normal. The proband also had agenesis of the corpus callosum demonstrable by computerized tomography. Her IQ was about 70 and she had marked dysarthria and a clumsy gait from early childhood. Anneren et al. (1984) suggested that irregular mineralization of the bones of the hands and feet is an important feature of OFD I distinguishing it from OFD II (252100). Malformations of the brain were described in a severe case of OFD I. Towfighi et al. (1985) found reports of a variety of central nervous system malformations in OFD I and gave a description of the findings in a personally studied case. Goodship et al. (1991) described a 3-generation family in which 3 females showed minor features of OFD I and a severely affected male was born in the third generation. The male showed bilateral duplication of the halluces, a feature considered diagnostic of OFD II, and an atrioventricular septal defect. Heart defects had not previously been reported in OFD I but had been found in OFD II. Goodship et al. (1991) suggested that OFD I and OFD II are not phenotypically distinct and that the case for an autosomal recessive locus deserves reexamination. They urged that when a male neonate has features of OFD, his mother should be examined carefully before it is assumed that he has OFD II. Salinas et al. (1991) reported the variability in 6 affected black U.S. females and in 2 previously reported black patients. Only 2 of the 8 had cleft palate and none had midline of the upper lip; among whites, 80% have cleft palate and 45% have midline cleft of the upper lip. Half of the black patients showed polycystic kidneys. Lipp and Lubit (1990) reported the cases of an affected black mother and daughter followed over many years. Larralde de Luna et al. (1992) described an 11-month-old girl classified as having OFD I, whose features included cleft palate, bifid uvula, lingual cleft, numerous hypertrophic frenula, numerous milia on face, scalp, and ears, frontal bossing, hypertelorism, hypoplasia of the nasal alar cartilages, micrognathia, and bilateral brachydactyly of hands. She also had diffuse, nonscarring alopecia with wiry, dry hair. Radiographic and ultrasound studies were normal, and her psychomotor development was appropriate for her age. - Clinical Variability Additional forms of orofaciodigital syndrome have been described and numbered OFD2 through OFD11. Gurrieri et al. (2007) referred to 2 further possible forms: OFD12 with myelomeningocele, stenosis of the aqueduct of Sylvius, and cardiac anomalies (Moran-Barroso et al., 1998), and OFD13 with psychiatric symptoms, epilepsy, and brain MRI findings of leukoaraiosis (Degner et al., 1999). Toriello (2009) noted many phenotypic similarities between OFD syndromes and conditions known as ciliopathies, and suggested that many, if not all, OFD syndromes could be caused by mutations in ciliary proteins.
Thauvin-Robinet et al. (2006) reported 25 females with OFD I from 16 French and Belgian families. Eleven novel mutations in the CXORF5 gene were identified in 16 patients from 11 families. Renal cysts were associated with splice site ... Thauvin-Robinet et al. (2006) reported 25 females with OFD I from 16 French and Belgian families. Eleven novel mutations in the CXORF5 gene were identified in 16 patients from 11 families. Renal cysts were associated with splice site mutations, mental retardation was associated with mutations in exons 3, 8, 9, 13, and 16, and tooth abnormalities were associated with mutations in coiled-coil domains. Seven (30%) of 23 patients showed nonrandom X inactivation.
To identify the gene responsible for OFD I, Ferrante et al. (2001) analyzed several transcripts mapping to the critical region on Xp22 and found mutations in the CXORF5 gene (see 300170.0001-300170.0003). They analyzed 3 familial and 4 sporadic ... To identify the gene responsible for OFD I, Ferrante et al. (2001) analyzed several transcripts mapping to the critical region on Xp22 and found mutations in the CXORF5 gene (see 300170.0001-300170.0003). They analyzed 3 familial and 4 sporadic cases of OFD I. Analysis of the familial cases revealed a missense mutation, a 19-bp deletion, and a single basepair deletion leading to a frameshift. In the sporadic cases, they found a missense (de novo), a nonsense, a splice site, and a frameshift mutation. RNA in situ studies on mouse embryo tissue sections showed that Ofd1 is developmentally regulated and is expressed in all tissues affected in OFD I syndrome. Thus, the involvement of CXORF5 in this specific disorder demonstrates an important role of the gene in human development.
The diagnosis of oral-facial-digital syndrome type I (OFD1) is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood [Coll et al 1997]. The X-linked dominant male lethal pattern of inheritance may suggest the diagnosis in the presence of the characteristic clinical signs:...
DiagnosisClinical DiagnosisThe diagnosis of oral-facial-digital syndrome type I (OFD1) is established at birth in some infants on the basis of characteristic oral, facial, and digital anomalies; in other instances, the diagnosis is suspected only after polycystic kidney disease is identified in later childhood or adulthood [Coll et al 1997]. The X-linked dominant male lethal pattern of inheritance may suggest the diagnosis in the presence of the characteristic clinical signs:Oral. Oral findings affect primarily the tongue, palate, and teeth: The tongue is lobed and often described as bifid or trifid. Tongue nodules, which are usually hamartomas or lipomas, also occur in at least one third of individuals with OFD1. Ankyloglossia attributable to a short lingual frenulum is common. Cleft hard or soft palate, submucous cleft palate, or highly arched palate occurs in more than 50% of affected individuals. Trifurcation of the soft palate has been reported [al-Qattan 1998]. Alveolar clefts and accessory gingival frenulae are common. These fibrous bands are hyperplastic frenulae extending from the buccal mucous membrane to the alveolar ridge, resulting in notching of the alveolar ridges. Dental abnormalities include missing teeth (most common), extra teeth, enamel dysplasia, and malocclusion. Facial Widely spaced eyes or telecanthus occurs in at least 33% of affected individuals. Hypoplasia of the alae nasi, median cleft lip, or pseudocleft upper lip is common. Micrognathia and downslanting palpebral fissures are common. Digital Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger are common. The other fingers, particularly the third (i.e., middle finger) may show variable radial or ulnar deviation. Duplicated hallux (great toe) occurs in fewer than 50% of affected individuals, and if present is usually unilateral. Preaxial or postaxial polydactyly of the hands occurs in 1%-2% of affected individuals. Radiographs of the hands often demonstrate fine reticular radiolucencies, described as irregular mineralization of the bone, with or without spicule formation of the phalanges [al-Qattan & Hassanain 1997]. Brain. Structural brain abnormalities may occur in as many as 65% of individuals with OFD1 [Thauvin-Robinet et al 2006, Macca & Franco 2009, Bisschoff et al 2013]. Anomalies most commonly include intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation. Other reported anomalies include type 2 porencephaly (schizencephalic porencephaly), pachygyria and heterotopias, hydrocephalus, cerebral or cerebellar atrophy, and berry aneurysms, each of which has been described in a few affected individuals. Intellect. It is estimated that as many as 50% of individuals with OFD1 have some degree of intellectual disability or learning disability. Intellectual disability depends in part on the presence of brain abnormalities, but no consistent correlation exists. When present, intellectual disability is usually mild. Severe intellectual disability in the absence of brain malformations appears to be rare. Kidney. Renal cysts can develop from both tubules and glomeruli. Polycystic kidney disease occurs in at least 50% of individuals with OFD1 although the exact frequency is unknown. Recent data indicate that renal cystic disease is present in 60% of affected individuals older than age 18 years [Prattichizzo et al 2008]. The age of onset is most often in adulthood, but renal cysts in children as young as age two years have been described. Molecular Genetic TestingGene. OFD1 is the only gene in which mutations are known to cause oral-facial-digital syndrome type I [Ferrante et al 2001]. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Oral-Facial-Digital Syndrome Type IView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesAffected FemalesOFD1Sequence analysisSequence variants 2, 3Not applicable (lethal in males)80%ClinicalPartial- and whole-gene deletions0% 4Duplication / deletion analysis 5Partial- and whole-gene deletions 65%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. A variety of mutations have been identified, the majority of which predict premature protein truncation. The reported mutation detection rate is about 80% [Nowaczyk et al 2003, Thauvin-Robinet et al 2006, Prattichizzo et al 2008].4. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in females.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. One study found that six of 131 individuals with OFDI had a deletion ranging in size from one to 14 exons. None had the same deletion. Within this group, 23% of those who did not have a mutation identified on gene sequencing were found on qPCR to have an exonic or multiexonic deletion [Thauvin-Robinet et al 2009]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. Gene sequencing followed by deletion/duplication analysis for detection of deletions identifies a mutation in approximately 85% of affected individuals. Testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Females are heterozygotes for this X-linked male lethal disorder. (2) Identification of the disease-causing mutation in females requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected relative is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by deletion/duplication analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersOFD7, which includes unilateral cleft lip and hydronephrosis, has only been described in one mother-daughter pair, who were later found to have a mutation in OFD1; thus, this condition is either allelic to OFD1 or demonstrates variable expression of OFD1 [Nowaczyk et al 2003]. Similarly, in a family in which males had a lethal congenital malformation syndrome characterized by oral, facial, digital, cerebral, and renal anomalies and in utero lethality, disease was found to be caused by a novel splicing mutation (c.2388+1G>C) in intron 17 of OFD1. Carrier females were described to have hyperplastic frenulae and tooth anomalies only [Tsurusaki et al 2013]. Several reports of individuals with Joubert syndrome associated with mutations in OFD1 have been reported [Coene et al 2009, Field et al 2012, Juric-Sekhar et al 2012]. An X-linked recessive syndrome associated with cognitive impairment, macrocephaly, and ciliary dysfunction is associated with a four-nucleotide duplication within OFD1, which led to a premature stop codon in exon 16 [Budny et al 2006].Males with retinitis pigmentosa and an intronic mutation (IVS9+706A.G) in OFD1 have been described [Webb et al 2012].
In addition to the findings described in Clinical Diagnosis, the following may be present in oral-facial-digital syndrome type I (OFD1):...
Natural HistoryIn addition to the findings described in Clinical Diagnosis, the following may be present in oral-facial-digital syndrome type I (OFD1):Brain. Structural brain abnormalities may be accompanied by seizures and ataxia, especially in those with cerebellar atrophy. Intellect. As many as 50% of individuals with OFD1 have some degree of intellectual disability, usually mild. Those with brain malformations are more likely to have intellectual disability, but the association is not consistent. Oral manifestations. Hearing loss from recurrent otitis media, usually associated with cleft palate, has been reported. On occasion, speech and mastication can be affected. Skin and hair. The hair is often described as dry, coarse, and brittle. Alopecia, usually partial, is an occasional finding. Alopecia has been described to follow the lines of Blaschko [Boente et al 1999]. Milia, small keratinizing cysts, occur in at least 10%, and likely more, most often appearing on the scalp, ear pinnae, face, and dorsa of the hands. Milia are usually present in infancy and then resolve, but can then leave pitting scars. Kidney. Although renal cysts have been reported as a prenatal finding [Nishimura et al 1999], the diagnosis is doubtful in these cases. Typically, cysts appear no earlier than late childhood. End-stage renal disease has been reported in affected girls and women ranging in age from 11 to 70 years. Recently it has been emphasized that the risk for significant renal disease appears to be higher than 60% after age 18 years [Prattichizzo et al 2008, Saal et al 2009]. In addition, liver and pancreatic cysts may be observed, but only in those who have renal cysts as well.Other. Rare manifestations include hearing impairment, cysts in pancreas, ovary and liver, short stature, choanal atresia, tibial pseudarthrosis, and berry aneurysms. Almost all affected individuals with classic OFD1 are female; however, a few affected males have been reported. In most cases, these males are described as malformed fetuses delivered by women with OFD1; however, a male described by Goodship et al [1991] survived to term and expired on the first day of life. Virtually all reported males are simplex cases (i.e., a single occurrence in a family); the certainty of the diagnosis is thus unknown. Some of the other reported males with suspected OFD1 may in fact have other diagnoses, such as another OFD or Meckel-Gruber syndrome. It is theoretically possible (though highly unlikely) for an affected male to survive birth. Phenotypic variability is often seen in affected females, possibly as a result of random X-chromosome inactivation [Morleo & Franco 2008].
There is some evidence that genotype-phenotype correlation exists:...
Genotype-Phenotype CorrelationsThere is some evidence that genotype-phenotype correlation exists:According to Thauvin-Robinet et al [2006], renal cysts appear to be correlated with splice mutations. Saal et al [2009], however, did not find this correlation. High-arched/cleft palate was found most frequently with missense and splice site mutations [Prattichizzo et al 2008].Intellectual disability is more often associated with mutations in exons 3, 8, 9, 13, and 16. Anomalous teeth are more often found in those with mutations in coiled coil domains.
The differential diagnosis includes the other oral-facial-digital syndromes and disorders, including cystic renal disease....
Differential DiagnosisThe differential diagnosis includes the other oral-facial-digital syndromes and disorders, including cystic renal disease.Oral-facial-digital syndromes. See Table 2 (pdf). OFD2, Mohr syndrome, is primarily distinguished by polydactyly. Other manifestations include bifid nasal tip. Affected individuals do not have milia or polycystic kidney disease. OFD3 is characterized by seesaw winking (alternate winking of the eyes) and polydactyly. Myoclonic jerks, profound intellectual disability, bulbous nose, and apparently low-set ears also occur. OFD4 has tibial involvement and polydactyly as the primary manifestations. Other findings include pectus excavatum and short stature. OFD5 includes polydactyly and median cleft lip only. Hyperplastic frenula have been reported in one affected individual. OFD6 is distinguished by polydactyly (particularly central) and cerebellar malformations. Renal agenesis and dysplasia have been described. OFD8, apparently inherited as an X-linked recessive trait, is characterized by the combination of polydactyly, tibial and radial defects, and epiglottal abnormalities, none of which is seen in the classic form of OFD1. OFD9 includes retinal abnormalities and non-median cleft lip. Cystic renal disease. Autosomal dominant polycystic kidney disease (ADPKD) should be considered in the differential diagnosis of OFD1. The diagnosis of ADPKD has been made in some individuals who later were found to have OFD1 [Scolari et al 1997]. In ADPKD, cysts develop from tubules, whereas in OFD1 cysts develop from both tubules and glomeruli; however, imaging studies cannot always distinguish the renal cystic disease of OFD1 from that of ADPKD and other cystic renal disorders. The cysts are said to be smaller and more uniform in size in OFD1 than in ADPKD, and the kidneys are not as enlarged or malformed in OFD1. Hepatic cysts and berry aneurysms have been observed in OFD1. Other distinguishing features are mode of inheritance and the absence of oral, facial, digital, or brain abnormalities in ADPKD. Meckel-Gruber syndrome is characterized by CNS malformation (posterior encephalocele, cerebral and cerebellar hypoplasia), polycystic or hypoplastic kidneys, preaxial or postaxial polydactyly, and early demise. Additional findings include cleft lip and palate, ambiguous genitalia, microcephaly, and microphthalmia. Ocular histopathology reveals retinal dysplasia, coloboma, cataract, and corneal dysgenesis. Two loci have been mapped and one gene, MKS3, identified. Inheritance is autosomal recessive. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
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:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with oral-facial-digital syndrome type I (OFD1), the following evaluations are recommended:Examination of the face, especially the mouth, and the hands for characteristic anomalies Formal, age-appropriate assessment of development Blood pressure and serum creatinine concentration Urinalysis, serum chemistries, and ultrasound evaluation of the kidneys, liver, and pancreas for cysts if the individual is age ten years or older Medical genetics consultationTreatment of ManifestationsThe 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 SurveillanceSurveillance includes the following:Regular follow-up for assessment of speech and ear infections/hearing loss if cleft lip is present Annual determination of blood pressure and serum creatinine concentration to monitor renal function Annual assessment of renal function with follow-up by renal ultrasound evaluation to assess cyst development if abnormalities are detected Periodic screening for ovarian, pancreatic, and hepatic cystic diseaseEvaluation of Relatives at RiskMolecular testing of daughters of known mutation carriers, even in the absence of oral, facial, and digital anomalies, may be reasonable.Similarly, mothers of affected daughters could benefit from testing to determine if they are at risk for renal disease.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Affected pregnant women should undergo careful monitoring of their blood pressure and renal function during pregnancy. Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDOFD1Xp22.2Oral-facial-digital syndrome 1 proteinOFD1 @ LOVDOFD1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Oral-Facial-Digital Syndrome Type I (View All in OMIM) View in own window 300170OFD1 GENE; OFD1 311200OROFACIODIGITAL SYNDROME I; OFD1Normal allelic variants. OFD1 has 23 exons (reference sequence NM_003611.2) and is located on a region of the X chromosome where transcripts frequently escape X-chromosome inactivation. See Table 3 (pdf) for normal allelic variants. Pathologic allelic variants. To date, more than 120 different mutations (including large genomic rearrangements) have been identified [Ferrante et al 2001, Rakkolainen et al 2002, Stoll & Sauvage 2002, Romio et al 2003, Morisawa et al 2004, Thauvin Robinet et al 2006, Prattichizzo et al 2008, Thauvin-Robinet et al 2009, Bisschoff et al 2013]. See Table 3. Both exonic and intronic pathologic allelic variants have been described. Point mutations in exons include single base-pair changes, frameshifts, and deletions. To date, these changes have been identified in exons 2 through 17. Abnormal splicing has also been reported in introns 2, 3, 4, 5, 6, 7, 10, 11, 12, 16 [Macca & Franco 2009, Bisschoff et al 2013]. Nine different genomic deletions involving exons 1 through 23 or the entire transcript have been reported [Thauvin-Robinet et al 2009, Bisschoff et al 2013]. Normal gene product. Oral-facial-digital syndrome 1 protein occurs in two forms, OFD1-1 (Cxorf5-1) and OFD1-2 (Cxorf5-2), which are differentiated by the use of an alternative splice site. OFD1-1 is a 1012-amino acid protein (reference sequence NP_003602.1); OFD1-2 is a 367-amino acid protein. The two proteins share the first 351 amino acids; OFD1-2 then has a C-terminal region of 16 amino acids. OFD1 was expressed in all adult tissues that were examined by de Conciliis et al [1998]. However, during early development, expression is exclusively in the genital ridges, soon followed by expression in craniofacial structures and nervous system [Ferrante et al 2001]. The function of the protein is as yet unknown, although characterization of a mouse model bearing ubiquitous inactivation of the Ofd1 transcript from early stages of development demonstrated that Ofd1 is required for formation of primary cilia and determination of left-right asymmetry [Ferrante et al 2006]. In vitro studies demonstrate that Ofd1 regulates the length and distal structures of centrioles [Singla et al 2010]. Abnormal gene product. Most of the mutations predict a premature truncation of the protein and apparent loss of function, which is further supported by the OFD1 intragenic deletion alleles. Since OFD1 is on the portion of the X chromosome that escapes X-chromosome inactivation, the truncated protein may theoretically interact with the wild-type product to produce a dominant-negative effect.