Orofaciodigital Syndrome Vi
A number sign (#) is used with this entry because orofaciodigital syndrome VI (OFD6) is caused by homozygous or compound heterozygous mutation in the C5ORF42 gene (CPLANE1; 614571) on chromosome 5p13.
Mutation in the C5ORF42 gene can also cause Joubert syndrome-17 (JBTS17; 614615), a disorder with overlapping features.
DescriptionOrofaciodigital syndrome type VI (OFD6), or Varadi syndrome, is a rare autosomal recessive disorder distinguished from other orofaciodigital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities, including the molar tooth sign (summary by Doss et al., 1998 and Lopez et al., 2014).
Clinical FeaturesIn 7 children in an inbred Gypsy group, Varadi et al. (1980) delineated a 'new' syndrome of reduplicated big toes, hexadactyly, cleft lip/palate or lingual nodule, and somatic and psychomotor retardation. Some showed absent olfactory bulbs and tracts, cryptorchidism, inguinal hernia, and congenital heart disease. Four of the 6 died within 2 weeks, 1 at 3 years, 1 at 6 years, and the seventh was alive at 3 years. The authors pointed out phenotypic similarities to trisomy 13 but the karyotype was normal and the pedigrees suggested autosomal recessive inheritance. Papp and Varadi (1985) found another case in a sibship of 12 children; a deceased member also had the syndrome.
Munke et al. (1990) presented evidence on the basis of 3 unrelated patients that hypoplastic cerebellar vermis, as demonstrated by magnetic resonance imaging (MRI) as well as by clinical signs of cerebellar defect, is a consistent finding in patients with this disorder, which they referred to as the oral-facial-digital syndrome type VI. Polydactyly of the hands is characterized by a Y-shaped central metacarpal. 'Central polydactyly' of the hands must be the most specific feature of this disorder. Clinically, recurrent episodes of tachypnea and hyperpnea were remarkable features of the cerebellar vermis. Their 3 patients had short stature. In contrast to reported patients who were all severely mentally retarded, 1 of the 3 was of normal intelligence. Munke et al. (1990) proposed that OFD VI was the disorder present in the families reported by Gustavson et al. (1971), Egger et al. (1982), Gencik and Gencikova (1983), Haumont and Pelc (1983), Mattei and Ayme (1983) and Silengo et al. (1987).
Muenke et al. (1991) described detailed studies of a fetus with clinical findings overlapping this disorder, the hydrolethalus syndrome (236680), and the Pallister-Hall syndrome (PHS; 146510). The fetus had many manifestations in common with the twin fetuses reported by Hingorani et al. (1991).
Cleper et al. (1993) reported the cases of 2 male cousins, both the offspring of consanguineous matings, with multiple congenital anomalies. They had an unusual facial appearance. Multiple buccoalveolar frenula and notched inferior alveolar ridges were present at birth. Both had congenital heart anomalies, micropenis, and cryptorchidism. Persistence of Mullerian structures was documented at necropsy in one patient. The surviving patient was mentally retarded and had a unilateral central extra digit with partially formed metacarpal, as well as partial agenesis of the corpus callosum. Bulimia and episodic hyperthermia were attributed to hypothalamic dysfunction. Cleper et al. (1993) pictured a metopic ridge in the forehead of the surviving patient and in the ear an accessory fold between a prominent crus helix and the external meatus. Cleper et al. (1993) suggested that the findings overlapped with those of the Varadi syndrome and Opitz trigonocephaly syndrome (211750). Stephan et al. (1994) suggested that hypothalamic hamartoma is an occasional manifestation of Varadi syndrome.
Toriello (1993) reviewed the clinical overlap observed with the 9 described types of OFD syndromes and with other entities such as Pallister-Hall syndrome and the hydrolethalus syndrome. Shashi et al. (1995) reported 2 brothers with findings overlapping OFD II (252100), OFD VI, and Pallister-Hall syndrome, both of whom had congenital absence of the pituitary gland. Shashi et al. (1995) raised the possibility that this represented a new type of OFD syndrome.
Doss et al. (1998) described the neuropathologic findings in a stillborn, 21-week estimated gestational age, male fetus diagnosed antenatally. Autopsy findings included facial abnormalities, postaxial central polydactyly of the right hand, bilateral bifid toes, and absence of cerebellar vermis with hypoplasia of the hemispheric cortex. Microscopic analysis of the cerebellum demonstrated absence of the subpial granular cell layer and disruption or dysgenesis of the glial architecture. These histopathologic findings suggested that a primary neuronal or glial cell defect, rather than an associated Dandy-Walker malformation, may account for the cerebellar abnormalities in this form of OFD syndrome.
Panigrahi et al. (2013) reported 2 patients with overlapping features of OFD type II and type VI. Y-shaped metacarpal, central polydactyly, and renal disease were characteristic of type VI, whereas face and hand abnormalities and cardiac defect were suggestive of type II. Panigrahi et al. (2013) suggested that types II and VI are part of the same phenotypic spectrum with serious intracranial abnormalities at the more severe end of the spectrum.
Darmency-Stamboul et al. (2013) reported 6 unrelated girls with OFD6. All patients presented with one or more oral malformations, including lobulated tongue, lingual hamartoma, multiple frenula, cleft lip/palate, and upper lip notch. Four patients had pre- or postaxial polydactyly of the hands and/or feet. All had delayed psychomotor development with moderate to severe mental retardation. Other common neurologic abnormalities included ataxia, fine motor difficulties, poor or absent speech, orofacial dyspraxia, and oculomotor apraxia. Four patients had ventilatory disorders. Brain imaging showed cerebellar malformations, brainstem malformations, and cystic dilatation of the posterior fossa; all had the molar tooth sign. These findings indicated that OFD6 should be included among the 'Joubert syndrome-related disorders' (JSRDs). Twin sisters (patients 3 and 4) reported by Darmency-Stamboul et al. (2013), born of consanguineous Turkish parents, were found by Lambacher et al. (2016) to have a homozygous mutation in the TMEM107 gene (E45G; 616183.0003).
Lopez et al. (2014) reported 12 patients, including 8 fetuses, from 9 unrelated families with OFD6. All patients had the molar tooth sign with cerebellar vermis hypoplasia, verified either by brain imaging or neuropathologic examination. Other common features included tongue hamartoma and/or additional frenula and/or upper lip notch, mesoaxial or preaxial polydactyly of the hands or feet, Y-shaped metacarpals, and hypothalamic hamartoma. All 4 surviving patients, including 1 reported by Darmency-Stamboul et al. (2013), had intellectual disability. Atypical features observed in 1 patient each included short femurs, occipital meningocele, and tibial bowing and fibular agenesis. Features common to other ciliopathies, such as polycystic kidney disease or retinal disease, were not present.
InheritanceBecause of the consanguinity in the family reported by Varadi et al. (1980) and because of the involvement of multiple sibs in that and other families, Munke et al. (1990) suggested that OFDS VI is an autosomal recessive disorder.
Molecular GeneticsValente et al. (2010) reported 2 unrelated Ashkenazi Jewish patients, a 4-year-old boy and a male fetus, with Joubert syndrome-2 (JBTS2; 608091) caused by the same homozygous mutation in the TMEM216 gene (R73L; 613277.0001). In addition to molar tooth sign on brain imaging and polydactyly, the 2 patients had tongue tumors or multiple oral frenula, reminiscent of OFD6.
In 12 patients from 9 of 11 unrelated families with OFD6, Lopez et al. (2014) identified 14 different homozygous or compound heterozygous mutations in the C5ORF42 gene (see, e.g., 614571.0007-614571.0011). Mutations in the first 6 families were found by exome sequencing; in the remaining 3 families, they were found by direct sequencing of the C5ORF42 gene in 9 additional probands with a clinical diagnosis of OFD6 or a similar disorder. Four frameshift, 3 nonsense, 5 missense, and 2 splice site mutations were identified, suggesting that at least 1 truncating mutation is necessary to cause the phenotype. However, functional studies of the variants were not performed.
HistoryMunke et al. (1990) provided a classification of orofaciodigital syndrome into 7 varieties, following in part the classification of Toriello (1988).