Orofaciodigital Syndrome I

A number sign (#) is used with this entry because orofaciodigital syndrome I (OFD1) is caused by mutation in the OFD1 gene (300170) on chromosome Xp22.

Mutations in the CXORF5 gene also cause Simpson-Golabi-Behmel syndrome type 2 (GBS2; 300209) and Joubert syndrome-10 (JBTS10; 300804).

Description

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. 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 (summary by Ferrante et al., 2001).

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).

Clinical Features

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 clinical 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). Additional forms of OFD (e.g., OFD14-OFD18) were numbered based on genotype.

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.

Bruel et al. (2017) reviewed 155 index OFD cases from an international cohort, and noted that although OFD syndromes were initially classified into 13 clinical subtypes, that initial classification appeared to be obsolete given the wide clinical and molecular heterogeneity, as well as multiple overlapping ciliopathies such as Joubert syndrome (see 213300), Meckel syndrome (see 249000), Bardet-Biedl syndrome (see 209900), short-rib polydactyly syndrome (see 208500), and nephronophthisis (see 256100). Bruel et al. (2017) proposed an OFD classification restricted to the 3 most common and well-delineated subtypes, involving the clinical features of kidney disease/corpus callosum agenesis, tibial dysplasia, and molar tooth sign, with further classification based on genotype; however, they stated that detailed classification is extremely complex and of little use in such diseases with high clinical and genetic heterogeneity.

Other Features

Chetty-John et al. (2010) emphasized that patients with OFD1 can develop fibrocystic disease of the liver and pancreas, in addition to polycystic kidneys. They reported 2 unrelated women with OFD1 diagnosed at birth, who presented as adults with visceral involvement. The first patient presented at age 29 years with severe hypertension and was found to have mildly increased liver enzymes at age 35. Abdominal ultrasound showed multiple cystic intrahepatic bile duct dilatations, pancreatic cysts, and numerous macrocysts in both kidneys. She had no evidence of pancreatic insufficiency. The second patient presented at age 25 years with abdominal pain associated with cystic kidneys, and developed hypertension in her early thirties. At age 37, she had mild hepatomegaly, dilation and beading of the intrahepatic bile ducts, and evidence of hepatic fibrosis. She also had significant proteinuria. In a review of 35 OFD1 patients reported in the literature, Chetty-John et al. (2010) found that all had polycystic kidney disease, 9 (45%) of 20 evaluated had multiple liver macrocysts, and 5 (29%) of 17 evaluated had pancreatic macrocysts. The ages of the patients with cysts ranged from 15 to 38 years. The findings were consistent with OFD1 being a ciliopathy, affecting the development and maintenance of bile ducts and renal tubules. Chetty-John et al. (2010) suggested that patients with OFD1 be routinely monitored for visceral involvement.

Inheritance

All cases (with the exception mentioned below) are female. A male reported as presumed OFD I syndrome (Kushnick et al., 1963) probably had OFD II or the XXY Klinefelter syndrome. Doege et al. (1964) reported a kindred with 15 affected females. Chromosome studies of 8 of them did not uncover any abnormality. Wahrman et al. (1966) described the condition in an XXY male. This greatly strengthens the idea that inheritance is male-lethal X-linked dominant. Incontinentia pigmenti (308300) and focal dermal hypoplasia (305600) have the same inheritance. Melnick and Shields (1975) suggested that there is some female lethality due to lyonization in heterozygotes.

Fuhrmann and Vogel (1960) described cleft lip-palate and syndactyly in a female infant and partial manifestation (syndactyly, finger deformity and split in tip of tongue) in the mother. The lip cleft was median. They cited other cases of this syndrome and suggested autosomal dominant inheritance. Subsequently Fuhrmann et al. (1966) concluded that this was a case of OFD syndrome and that inheritance is X-linked dominant with lethality in males. Vaillaud et al. (1968) described a remarkable pedigree in which 10 females had OFD. The grandmother and 9 of her granddaughters through 3 unaffected sons had OFD. The 9 affected included all daughters of the 3 carrier males. The authors accepted the interpretation of X-linked dominance with lethality in the hemizygous males, which has been applied to previously published pedigrees. In addition, however, to explain the findings in this specific family, they postulated that the OFD gene is on a terminal segment of the X chromosome homologous with a segment of the Y chromosome and that the 3 carrier males had inherited a Y chromosome which in some way masked expression of the OFD gene.

Cohen et al. (1981) reported the occurrence of OFD I in a 47,XXX female.

Shotelersuk et al. (1999) reported monozygotic twin girls who were discordant for OFD I. Monozygosity was supported by placental pathology (monochorionic diamniotic) and molecular studies which yielded a probability of dizygosity less than 1 x 10(-6). The affected twin had oral cavity abnormalities including median cleft lip, cleft palate, lobulated hamartomatous tongue, aberrant hyperplastic oral frenula, alveolar notches, and absent lateral incisors. Facial manifestations included telecanthus, hypoplastic alae nasi, and transient neonatal facial milia. The patient also had short and deviated fingers with partial cutaneous syndactyly. At 10 years, she had not had central nervous system or kidney problems. X-inactivation study revealed similar X-inactivation patterns in the lymphoblasts of both twins. Shotelersuk et al. (1999) concluded that skewed X-inactivation is an unlikely cause for the discordance, which in their view was more likely due to a postzygotic mutation in the affected twin.

Mapping

Feather et al. (1997) performed linkage studies in 2 kindreds with OFD I in which the clinical course was dominated by polycystic kidney disease requiring dialysis and transplantation. They were able to map the disorder to a region on the short arm of the X chromosome (Xp22.3-p22.2) spanning 19.8 cM and flanked by crossovers with the markers DXS996 and DX7S105. There was a maximum lod score of 3.32 (theta = 0.0) in an 'affecteds only' analysis using a marker within the KAL1 gene (300836), thereby confirming the location of the gene for OFD1 on Xp/Xp. The remainder of the X chromosome was excluded by recombinants in affected individuals. The importance of the findings included the definitive assignment of this male-lethal disorder to the X chromosome and the mapping of a further locus for human polycystic kidney disease (see also 173900). Furthermore, this mapping suggested that a possible mouse model for OFD1 is the X-linked dominant Xpl mutant, in which polydactyly and renal cystic disease occurs. Xpl maps to the homologous region of the mouse X chromosome (Sweet and Lane, 1980). The full clinical details of one of the families were reported by Feather et al. (1997); the other family had been described by Donnai et al. (1987).

By linkage analysis, Malcolm et al. (1997) demonstrated that the OFD1 locus is situated at Xp22.3-p22.2. A maximum lod score of 3.32 at theta = 0.0 was obtained using a marker within the KAL1 gene. They suggested the Xpl mouse as a possible model; that mutation maps to a homologous region of the mouse X chromosome.

By linkage studies, Gedeon et al. (1999) narrowed the physical interval containing the OFD1 gene to 12 Mb. They suggested that the flanking markers defined in their study could be used for prenatal diagnosis in female fetuses in families with clinically classic OFD type I.

Molecular Genetics

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.

In 8 affected female members of 4 Finnish families with OFD1, Rakkolainen et al. (2002) identified heterozygosity for 4 different mutations in the OFD1 gene (see, e.g., 300170.0004 and 300170.0005).

In a Japanese woman with sporadic OFD1, Morisawa et al. (2004) identified 2 deletions on the same allele of the OFD1 gene (300170.0006). The most likely cause of the double deletion was considered to be 2 unequal recombinations between homologous sequences.

Bruel et al. (2017) reported that 59 (51%) of 115 index OFD cases from an international cohort had causative SNVs or CNVs involving the OFD1 gene.

Genotype/Phenotype Correlations

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.

Animal Model

Ferrante et al. (2009) studied Ofd1 function during zebrafish embryonic development. In wildtype embryos, Ofd1 mRNA was widely expressed and Ofd1-green fluorescent protein (GFP) fusion localized to the centrosome/basal body. Disrupting Ofd1 using antisense morpholinos led to bent body axes, hydrocephalus, and edema. Laterality was randomized in the brain, heart, and viscera, likely a consequence of shorter cilia with disrupted axonemes and perturbed intravesicular fluid flow in Kupffer vesicle. Embryos injected with Ofd1 antisense morpholinos also displayed convergent extension defects, which were enhanced by loss of Slb/Wnt11 (603699) or Tri/Vangl2 (600533), 2 proteins functioning in a noncanonic Wnt/planar cell polarity pathway. Pronephric glomerular midline fusion was compromised in Vangl2 and Ofd1 loss-of-function embryos. The authors concluded that Ofd1 is required for ciliary motility and function in zebrafish, supporting data showing that Ofd1 is essential for primary cilia function in mice. In addition, Ofd1 is important for convergent extension during gastrulation, consistent with data linking primary cilia and noncanonic Wnt/planar cell polarity signaling.

Zullo et al. (2010) generated a mouse line with kidney-specific inactivation of the Ofd1 gene, which resulted in a viable animal model for renal cystic disease and progressive impairment of renal function. Primary cilia initially formed and then disappeared after the development of cysts, suggesting that the absence of primary cilia may be a consequence rather than the primary cause of renal cystic disease. Immunofluorescence and Western blot analysis revealed upregulation of the mammalian target of rapamycin (mTOR; 601231) pathway in both dilated and nondilated renal structures. Treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction in the number and size of renal cysts and a decrease in the cystic index compared with untreated mutant mice. The authors concluded that dysregulation of this pathway in the model is mTOR-dependent.