ß 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 143A:3314 – 3323 (2007)
Research Review
Oral–Facial–Digital Syndromes: Review and Diagnostic Guidelines Fiorella Gurrieri,1* Brunella Franco,2,4 Helga Toriello,3 and Giovanni Neri1 1
Istituto di Genetica Medica, Universita` Cattolica Facolta` di Medicina, Roma, Italy 2 TIGEM (Telethon Institute of Genetics and Medicine), Naples, Italy 3 Genetics Services, Spectrum Health Hospitals, Grand Rapids, MI, Italy 4 Medical Genetics, Federico II Secondo Universita` di Napoli, Napoli, Italy Received 30 May 2007; Accepted 5 August 2007
The oral–facial–digital syndromes (OFDS) result from the pleiotropic effect of a morphogenetic impairment affecting almost invariably the mouth, face and digits. Other organ systems can be involved, defining specific types of OFDS. To date, 13 types have been distinguished based on characteristic clinical manifestations. An updated list of these types is provided and recent molecular data are discussed. ß 2007 Wiley-Liss, Inc.
Key words: transitional phenotypes; overlapping phenotypes; syndrome delineation; phenotypic spectrum; autosomal dominant; autosomal recessive; X-linked dominant; oral clefting; alveolar ridge abnormalties; tongue anomalies; syndactyly; brachydactyly; clinodactyly; polydactyly; CNS malformations; renal anomalies; diagnostic approach; molecular genetics; OFD1 gene; animal model; ciliopathies
How to cite this article: Gurrieri F, Franco B, Toriello H, Neri G. 2007. Oral–facial–digital syndromes: Review and diagnostic guidelines. Am J Med Genet Part A 143A:3314–3323.
INTRODUCTION
The first description of an oral–facial–digital syndrome (OFDS) can be traced back 66 years ago when Mohr [1941] reported a family in which the propositus had oral, facial, and digital (OFD) findings, including highly arched palate, lobate tongue with papilliform outgrowths, a broad nasal root, and hypertelorism. Additional findings included syndactyly, brachydactyly, and polydactyly of the hands and feet. Mohr concluded that this condition was due to a sex-linked recessive sublethal gene. A later report of this same family [Claussen, 1946] identified a similarly affected individual born to consanguineous parents, thus leading to the conclusion that the syndrome was inherited as an autosomal recessive trait. A similar OFD phenotype was described by Papillon-Leage and Psaume [1954], who recognized that the condition was hereditary and affected exclusively females. Subsequent reports of only females with this OFD phenotype strengthened the hypothesis that it was inherited as an X-linked dominant trait. This hypothesis was confirmed almost 50 years later when the genetic basis was unraveled [Ferrante et al., 2001]. For some unknown reason, all subsequent literature reports referred to the X-linked dominant form
of Papillon-Leage and Psaume as OFDS type I, even if it was described after the recessive form of Mohr and Claussen, now referred to as OFDS type II. After the description of OFDS types I and II, the phenotypic spectrum was further expanded with extra-OFD manifestations [Sugarman et al., 1971], leading to the definition of new types, each being characterized either by distinctive clinical findings and/or by a specific mode of inheritance. The first review of the topic [Toriello, 1988] accounted for seven conditions which could be considered distinct OFDS. Subsequently, two new types of OFDS were added to the list, so that in the second and last review of the field, nine different types were listed [Toriello, 1993]. Later, further new types were suggested, that is, OFDS type X [Figuera et al., 1993] and OFDS type XI [Gabrielli et al., 1994], whereas one, that is, OFD VII, was withdrawn from the list because it was considered identical to OFD I [Nowaczyk et al., 2003]. A possibly
*Correspondence to: Fiorella Gurrieri, Istituto di Genetica Medica, Universita` Cattolica Facolta` di Medicina, L. go F. Vito 1, 00168 Roma, Italy. E-mail:
[email protected] DOI 10.1002/ajmg.a.32032
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ORAL–FACIAL–DIGITAL SYNDROMES
new type of OFDS is characterized by myelomeningocele and heart defects and it has been designated OFD XII [Moran-Barroso et al., 1998], and an additional new form, OFD XIII, has been described, with neuropsychiatric findings [Degner et al., 1999]. Still, if one wants to keep on splitting, any further OFD condition with previously undescribed findings, it will add to the official list of OFDS types. TYPES OF ORAL–FACIAL–DIGITAL SYNDROMES OFDS I—Papillon-Leage–Psaume Syndrome (OMIM 311200)
Clinical description. OFDS I was first reported by Papillon-Leage and Psaume [1954] and further defined by Gorlin and Psaume [1962]. It has an estimated incidence of 1:50,000–250,000 live births [Wahrman et al., 1966] and it has been described in different ethnic backgrounds [Salinas et al., 1991]. This syndrome is transmitted as an X-linked dominant trait with embryonic male lethality, which usually occurs in the first and second trimester of pregnancy [Doege et al., 1964; Wettke Scha¨fer et al., 1983]. However, 75% of the cases have an apparently sporadic presentation. OFDS I is characterized by anomalies of the face, oral cavity, and digits with a high degree of phenotypic variability even within the same family, possibly due to different degrees of somatic mosaicism resulting from random X inactivation [ThauvinRobinet et al., 2006]. Abnormalities of the oral cavity include median pseudoclefting of the upper lip, clefts of the palate, hamartomas of the tongue, bifid tongue,
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and hyperplastic oral frenula (Fig. 1a–c). Thickened alveolar ridges and abnormal dentition are possible additional manifastations [Gorlin et al., 2001; Thauvin-Robinet et al., 2006], as well as irregular margin of the lips (Fig. 1c). Morphological abnormalities affecting the head and face include facial asymmetry, hypertelorism, micrognathia, broadened nasal ridge, hypoplasia of the malar bones and nasal alar cartilages, and frontal bossing [Gorlin et al., 2001; Thauvin-Robinet et al., 2006]. Vanishing milia of the face and ears, which usually disappear before the third year of life [Habib et al., 1992] are commonly found in association with dryness, brittleness, and/or alopecia of the scalp hair (Fig. 1d) [Reinwein et al., 1966]. The digital abnormalities, which seem to affect the hands more often than the feet, are very common (about 65% of cases) and include syndactyly, brachydactyly, clinodactyly, unilateral duplication of the hallux, and more rarely, pre- or postaxial polydactyly (Fig. 2a–e) [Gorlin et al., 2001; ThauvinRobinet et al., 2006]. CNS malformations are relatively common and comprise a variable spectrum of defects, including agenesis of the corpus callosum, intracerebral single or multiple epithelial or arachnoid cysts and porencephaly, heterotopia of gray matter, cerebellar malformations, abnormal gyrations, and microcephaly [Towfighi et al., 1985; Connacher et al., 1987; Coll et al., 1997; Odent et al., 1998; Holub et al., 2005]. Mild mental retardation has been observed in about 50% of cases [Holub et al., 2005]. Polycystic kidney disease is commonly associated with OFDS I [Connacher et al., 1987; Donnai et al., 1987], with reports of patients in whom renal involvement
FIG. 1. Oral findings in OFDS I: (a) bifid tongue; (b) bifid and hamartomatous tongue; (c) puckered lips (from L. Garavelli) and multiple frenula; (d) miliary skin lesions (from G. Cocchi). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
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FIG. 2. Digital anomalies in OFDS: (a,b) brachysyndactyly and clinodactyly of fingers and toes; (c,d) pre- and postaxial enlargement of the distal phalanx (bifid on X-ray not shown) of fingers (from L. Garavelli); (e) hallux duplication (from G. Cocchi). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
completely dominates the clinical course of the disease [Coll et al., 1997; Feather et al., 1997]. Pancreatic, ovarian and liver cysts have also been described in OFDS I patients [Doege et al., 1964; Feather et al., 1997; Sabato et al., 1998; Ferrante et al., 2001]. The clinical features described above overlap with those reported in the other forms of OFDS [Toriello, 1993], although OFDS I can be easily distinguished because of its X-linked dominant inheritance with male lethality and the presence of cystic kidneys, which are not found in other forms. Molecular genetics. The gene responsible for this disorder, OFD1, was identified by Ferrante et al. [2001] and comprises 23 exons encoding a 1011 amino acid protein (OFD1) that shares no sequence homologies with other proteins of known function. Subcellular localization experiments showed that this protein is centrosomal and localized in the basal body of primary cilia [Romio et al., 2003, 2004]. RT-PCR, Northern blot and RNA in situ hybridization studies indicate that OFD1 is widely expressed from the early stages of development in all the tissues affected in the syndrome in both humans and mice [de Conciliis et al., 1998; Ferrante et al., 2003; Romio et al., 2003]. Interestingly, the OFD1 gene has been found to escape X-inactivation in humans while the murine counterpart is subject to X-inactivation [Ferrante et al., 2003]. A total of 26 different mutations have been reported to date. The vast majority are frameshift mutations resulting in premature protein truncation and are therefore predicted to act by a loss-of-function
mechanism [Ferrante et al., 2001; Rakkolainen et al., 2002; Romio et al., 2003; Thauvin-Robinet et al., 2006]. However, the possibility that truncated forms of the OFD1 protein may have a dominant-negative effect on the wild type protein has not been formally ruled out. Animal model. Ofd1-knockout mice have been recently generated. Heterozygous females reproduce the main features of the human syndrome and display severe craniofacial abnormalities (shortened skull, cleft palate, lobulate tongue), limb and skeletal defects (shortened long bones and polydactyly or polysyndactyly) and cystic kidneys of glomerular origin [Ferrante et al., 2006]. Immunofluorescence analysis with an antibody that preferentially labels the ciliary axoneme of primary cilia showed the absence of cilia on the luminal surfaces of cells that line the cysts, thus implicating a defect in ciliogenesis as a mechanism underlying cyst development in OFDS 1. Complete inactivation of Ofd1 in hemizygous males causes male embryonic lethality and early developmental defects, mainly neural tube and laterality defects. Some Ofd1 male embryos display situs inversus and abnormal expression of markers involved in molecular asymmetry. Electron microscopy analysis demonstrated absence of primary cilia in the embryonic node of these embryos. These results are consistent with the subcellular localization of OFD1 and indicate that Ofd1 is required for primary cilia formation and left-right axis specification [Ferrante et al., 2006].
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ORAL–FACIAL–DIGITAL SYNDROMES
Interestingly, the effects of Ofd1 disruption in the mouse proved to be more severe than in humans: newborn females do not survive beyond birth, display cystic kidney, and cleft palate in 100% of cases and have additional features rarely or never observed in OFDS I patients, such as skeletal and laterality defects. Moreover, polydactyly is invariably present, whereas in humans it is less frequent than brachydactyly or syndactyly. Obvious differences between H. sapiens and M. musculus could account for this discrepancy, although a possible explanation could be related to the difference of the X-inactivation status for the OFD1/Ofd1 genes in the two species [Ferrante et al., 2003; Franco and Ballabio 2006]. Is OFDS I a Ciliopathy?
Functional studies have recently placed OFDS I in the increasing number of genetic disorders caused by primary ciliary dysfunction (for a recent review on this topic see References [Badano et al., 2006; Bisgrove and Yost, 2006]). Primary cilia have been implicated in different molecular pathways fundamental for normal development such as Hedgehog (Hh) and Wnt signaling, and preliminary data indicate that Ofd1 might also be involved in Hh signaling [Ferrante et al., 2006 and Franco, unpublished results]. Although we have accumulated a vast amount of information from the characterization of the mouse model for OFDS I, we still do not know the function of the OFD1 protein. Further insights into the developmental pathways impaired in OFDS I will be obtained by conditional inactivation of the Ofd1 gene in different organs. OFDS II—Mohr Syndrome (OMIM 252100)
This form shares many component manifestations with OFDS I, such as nodules of the tongue, midline clefts of the lip, thick frenula, dystopia canthorum, clinobrachydactyly, syndactyly, and polydactyly [Rimoin and Edgerton, 1967]. However, subtle clinical differences between types I and II have been noted, such as greater thickness of the alveolar ridge that in type I, which is normal in type II; and the presence of hair and skin abnormalities in type I, but the presence of bilateral polysyndactyly of the halluces in type II rather unilateral polysyndactyly, which is usually found in type I [Rimoin and Edgerton, 1967; Muenke et al., 1990; Toriello, 1993]. In addition, conductive hearing impairment may occur in type II [Rimoin and Edgerton, 1967; Prpic et al., 1995]. The central nervous system can also be affected in this form mainly with porencephaly and hydrocephaly [Muenke et al., 1990; Toriello, 1993]. However, what clearly makes the difference is the mode of
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inheritance: OFDS type II is, in fact, caused by mutations of an as yet unidentified autosomal recessive gene. Heart malformations, such as atrioventricular canal and endocardial cushion defects have been repeatedly been found in OFDS II [Digilio et al., 1996; Hsieh and Hou, 1999], thus expanding its phenotypic spectrum. A Y-shaped central metacarpal, which is usually considered typical of OFDS type VI, has also been reported in patients with clinical characteristics falling within the OFDS II spectrum [Hsieh and Hou, 1999]. This finding suggests the existence of transitional OFDS types that may turn out to be allelic forms once the genetic defects of all OFDSs are discovered. OFDS III—Sugarman Syndrome (OMIM 258850)
There are only two reports of this condition. Besides oral, facial, and digital abnormalities, additional findings include ceaseless seesaw winking of the eyes and/or myoclonic jerks [Sugarman et al., 1971; McKusick, 1990]. In OFDS III, polydactyly is postaxial and the mode of inheritance is autosomal recessive. Two sibs were subsequently reported as being affected with OFDS III [Smith and GardnerMedwin, 1993], but the finding of a hypoplastic cerebellar vermis makes them more likely affected with OFDS type VI. OFDS IV—Baraitser-Burn Syndrome (OMIM 258860)
A fourth type of OFDS was recognized in two sisters with the typical oral, facial, and digital involvement and, as a distinctive clinical finding, severe tibial dysplasia [Burn et al., 1984; Baraitser, 1986]. OFDS IV is inherited as an autosomal recessive trait. The phenotypic spectrum has been subsequently expanded to include occipitoschisis, brain malformation, ocular colobomas, intrahepatic cyst, renal cysts [Ade`s et al., 1994], anal atresia, and joint dislocations [Digilio et al., 1995]. OFDS V—Thurston Syndrome (OMIM 174300)
This type represents the mildest form within the OFDS group. It is characterized by midline cleft lip and postaxial polydactyly, and it has been reported exclusively in individuals of Indian ethnicity [Thurston, 1909; Khoo and Saad, 1980; Gopalakrishna and Thatte, 1982; Valiathan et al., 2006]. OFDS VI—Varadi–Papp Syndrome (OMIM 277170)
The first report of OFDS VI can be traced back to Varadi et al. [1980], who reported oral, facial, and
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digital findings associated with cerebral and/or cerebellar anomalies in endogamic gypsies. Inheritance is autosomal recessive. The cerebellar findings (vermis hypoplasia/aplasia, Dandy–Walker anomaly) and the recurrence of Y-shaped metacarpals (indicating central polydactyly) represent distinctive features of OFDS VI. Subsequent reports have further delineated this condition [Muenke et al., 1990] and subsequent reported findings include penile agenesis, abnormal clavicles [Yildirim et al., 2002], absent pituitary gland [Al-Gazali et al., 1999], and hypothalamic hamartoma with precocious puberty [Sthephan et al., 1994]. This latter finding is almost constantly found in Pallister–Hall syndrome, an autosomal dominant condition characterized by postaxial polydactyly, imperforate anus, and hypothalamic hamartoma. The phenotypic overlap between OFDS VI and Pallister–Hall syndrome has been noted and lumping of the two conditions as the same entity has been proposed [Muenke et al., 1991]. The identified GLI3 mutations in Pallister–Hall syndrome suggest that GLI3 analysis should also be carried out in patients with OFDS VI to find out if these two conditions are allelic. A single report of neuropathologic findings in OFDS VI showed disruption or dysgenesis of glial architecture, suggesting a primary glial cell defect [Doss et al., 1998]. This observation is interesting in light of the recent discovery that OFDS I is caused by a failure of the ciliary system, which is involved in cellular migration during embryogenesis.
1992] in addition to the core oral, facial, and digital findings. The digital anomalies usually consist of hallucal duplication detectable radiologically. The first report was of two brothers; thus, the mode of inheritance could have been either X-linked or autosomal recessive. Subsequent reports have confirmed this specific type of OFDS and established autosomal recessive inheritance [Nevin et al., 1994; Sigaudy et al., 1996; Nagai et al., 1998]. OFDS X—Figuera Syndrome (OMIM 165590)
This type is characterized by mesomelic limb shortening, specifically due to radial hypoplasia and fibular agenesis in association with oral, facial, and digital findings. The digital anomalies comprise oligodactyly and preaxial polydactyly [Figuera et al., 1993]. To date, there have been no further reports. OFDS XI—Gabrielli Syndrome
This type is specified by the presence of craniovertebral anomalies in association with the oral, facial, and digital anomalies. Findings include midline cleft involving the palate, vomer, ethmoid, and crista galli; apophysis and vertebral malformations including fusion of vertebral arches in C1, C2, and C3, and clefts of vertebral bodies in a sporadic male patient [Gabrielli et al., 1994]. A subsequent report of OFDS with vertebral anomalies in a female patient confirmed the existence of this variant [Ferrero et al., 2002].
OFDS VII—Whelan Syndrome (OMIM 608518)
There has been a single report of mother and daughter with oral, facial, and digital findings associated with hydronephrosis and facial asymmetry [Whelan et al., 1975]. Later, it was suggested that this type is the same as OFDS I, since both the mother and the daughter developed cystic kidney disease. However, mutational analysis of the OFD1 gene in this family performed by WAVE heteroduplex analysis and direct sequencing of exons failed to detect a pathogenic mutation [Nowaczyk et al., 2003]. The approach used for mutational analysis, however, cannot completely exclude a pathogenic mutation of OFD1. Thus, the issue of whether or not these are two entities are separate has not yet been solved. OFDS VIII—Edwards Syndrome (OMIM 300484)
This condition clinically overlaps with OFDS II but it can be distinguished by its X-linked recessive inheritance [Edwards et al., 1988]. OFDS IX—Gurrieri Syndrome (OMIM 258865)
OFDS IX is characterized by the presence of retinal colobomata as a distinctive feature [Gurrieri et al.,
OFDS XII—Moran-Barroso Syndrome
A new variant of OFDS was suggested by a report of OFD findings in a male patient who additionally had myelomeningocele, stenosis of the acqueduct of Sylvius, and cardiac anomalies [Moran-Barroso et al., 1998]. OFDS XIII—Degner Syndrome
This form is characterized by the presence of psychiatric symptoms (major depression), epilepsy, and brain MRI findings of leukoaraiosis (patched loss of white matter of unknown pathogenetic origin, possibly of ischemic nature, considered to increase the risk of stroke) in association with core oral, facial, and digital findings [Degner et al., 1999]. Diagnostic approach. Once the clinician has ascertained a patient with oral, facial, and digital findings, it should be determined whether there is a positive family history and whether a mode of inheritance can be established. In patients with clear X-linked dominant transmission and even in sporadic female patients, it is necessary to rule out mutations in the OFD1 gene. Given the fragmentary nosology of OFDS and the urgent need to strengthen the
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delineation of the various types by collecting more clinical data, it is recommended to perform a brain MRI, an abdominal ultrasound, a skeletal survey, an ophthalmologic evaluation, and an audiometric test in all consenting patients. For research purposes, it may be helpful to perform chromosome analysis and to search for submicroscopic rearrangements by array-CGH analysis to obtain clues towards the identification of new candidate gene loci. ‘‘TRANSITIONAL’’ OFD (PHENO) TYPES AND OTHER CONDITIONS OVERLAPPING WITH OFDS
There have been a few reports about the observation of patients who, in addition to oral, facial, and digital anomalies, also have findings that are considered specific of more than one OFDS type. These are defined as transitional types. One example is the report by Camera et al. [1994] of a patient with oral, facial, and digital findings including central polydactyly, typical of OFDS VI, but without cerebellar abnormalities, thus making it more likely a diagnosis of OFDS II. The authors concluded that, for the purpose of genetic counseling, it did not matter whether the patient was affected with OFDS type II or VI given that both conditions have autosomal recessive inheritance. Still, the existence of transitional types blurs the nosology of OFDS and weakens their distinction into several subtypes. Is it possible that OFDS II and VI are allelic forms? This question can be extended to all the OFDS with autosomal recessive inheritance, that is, types II, III, IV, V, VI, VII, IX, and perhaps even the new entries X, XI, XII, and XIII. A clarification of this complex nosological issue can only come from a better understanding of the molecular bases of OFDS, that is, from the discovery of the causal genes. It is possible that the discovery of the molecular basis for just one of the recessive forms will tell us that they should all be lumped under the same genetic cause. The present classification (Table I), updated with the OFDS reported after the last review on this topic [Toriello, 1993], is based on clinical findings only, with the exception of OFDS I. This classification is meant to be a useful guide when one either wants to assign a patient with oral, facial, and digital findings to the proper type or wants to describe a new OFDS type. Another important issue is that of distinguishing OFDS from other genetic conditions with oral, facial, and digital anomalies in addition to other major signs that seem to define distinct clinical entities. For instance, it has been suggested that OFDS VI, Pallister–Hall syndrome, and Hydrolethalus syndrome share so many features that could in fact be considered as the same entity [Muenke et al., 1991; Hingorani et al., 1992; Sharma et al., 1992; Genuardi et al., 1995; Unsinn et al., 1995; Hsieh and Hou, 1999]. However, a genetic cause has now been established
both for Pallister–Hall syndrome and Hydrolethalus syndrome [Kang et al., 1997; Mee et al., 2005], thus ruling out the hypothesis of a common genetic cause for at least two of the three conditions that were initially lumped together. In the most recent review [Toriello, 1992], 14 conditions were considered in the differential diagnosis of OFDS: Ellis-van Creveld syndrome; C syndrome; acrocallosal syndrome; Majewski syndrome and the other short rib-polydactyly syndromes; Carpenter syndrome; Pallister–Hall syndrome; acro–fronto– facio–nasal syndrome; craniofrontonasal dysplasia; holoprosencephaly–polydactyly syndrome; Grix syndrome; Smith-Lemli-Opitz syndrome; Beemer-Langer syndrome; and Egger-Joubat syndrome. For the majority of these conditions, except for Ellis-van Creveld syndrome, Jeune syndrome, Pallister–Hall syndrome, and Smith-Lemli-Opitz syndrome, the responsible genes have not been identified as yet and it is therefore impossible to make predictions as to whether some of them will end up being allelic forms. It is of interest to note that the gene responsible for Jeune syndrome turned out to be another piece of the cilioma mosaic. The gene, IFT80, encodes an intraflagellar transport protein and causes absence of cilia when knocked down in Tetrahymena [Beales et al., 2007]. This finding further suggests a common pathogenetic pathway for at least some of these phenotypically related conditions. In addition to the above listed conditions, for which there is phenotypic overlap with OFDS, other conditions, which share pathogenetic pathways with OFDS I, should be considered. In fact, the identification of the function of the OFD I gene led to the discovery that the corresponding phenotype is caused by an impaired ciliary functioning, thus including it in the chapter of ciliopathies together with a number of conditions such as Kartagener syndrome, Meckel syndrome, Alstrom syndrome, Bardet-Biedl syndrome, and Kaufman-McKusick syndrome, as well as Joubert syndrome [Inglis et al., 2006]. Beside these rare conditions, more common human disorders, such as renal cystic disease and nephronophthisis, retinal degeneration and retinitis pigmentosa, situs inversus, anosmia, hydrocephalus, diabetes, and even obesity are likely to be due, at least to some extent, to ciliary impairment. These observations seem to suggest that the developmental mechanisms determining the rare OFD phenotypes may be shared by common disorders like the ones listed above. CONCLUSION
Since the discovery that numerous proteins involved in human diseases localize to the basal bodies of cilia, these organelles have emerged from relative obscurity to the center of intense experimental work and scientific speculation. A relevant number of human diseases, including OFDS I, have contributed to underline the importance of cilia
Trembling
XLD
Inheritance
—
Miscellaneous
Other skeletal anomalies
Kidney defects Adult-onset polycystic Cerebral Callosal agenesis anomalies porencephaly
AR
—
—
Porencephaly hydrocephaly
—
Rare
Heart defects
—
Pre- or postaxial polydactyly
Clino-brachysyn-dactyly pre/postaxial polydactyly
Foot anomalies Preaxial polydactyly
Hand anomalies
Alopecia military skin lesions Clino-brachysyndactyly
Skin and hair
Coarse hair
Median cleft lip bifid nose tip
Telcanthus, hypertelorism median cleft lip alar hypoplasia
Facial anomalies
OFDS II Mohr
Cleft palate frenula tongue nodules tongue clefts
OFDS I PapillonLeage–Psaume
Oral anomalies Missing teeth tongue clefts frenula
Finding
AR
Hyperconvex nails
Short sternum
See-saw winking myoclonic jerks
—
—
Postaxial poly-dactyly
Postaxial poly-dactyly
—
AR
Short stature
Pectus excavatum tibial defects
Porencephaly cerebral atrophy
—
Pre- or postaxial polydactyly clino-brachysyn-dactyly Pre- and postaxial poly-dactyly —
—
Epicanthal folds micrognathia lowest ears
Frenula (rare)
Cleft palate lobed tongue, tongue nodules frenula
Cleft uvula tongue nodules tongue clefts extra small teeth Hypertelorism bulbous nose lowset ears
OFDS VI Varadi
AR
—
—
—
—
AR
—
—
Agenesis/ dysplasia Cerebellar anomalies
Preaxial poly-syndactyly Rare
Postaxial poly-dactyly —
Brachy-clinosyn-dactyly central polydactyly
—
Postaxial poly-dactyly
—
Cleft palate, lobed tongue, tongue nodules frenula Median cleft lip Hypertelorism cleft lip broad nasal tip
OFDS V Thurston
OFDS IV Baraitser-Burn
OFDS III Sugarman
AR
Preauricular skin tag
—
Hydronephrosis —
—
—
Clinodactyly
—
XLR
Hypoplastic epiglottis
Tibial and radial defects
—
—
—
Preaxial polydatcyly
Pre- and postaxial polydactyly
AR
Radial shortening, fibular agenesis —
—
—
—
—
AR/XLR
—
AR
—
Cranio-vertebral anomalies
Dilated ventricles
Hypertrophic septum —
Postaxial polydactyly
Oligodactyly, Postaxial polydactyly preaxial polydactyly
—
—
Retinal anomalies short stature
Cleft palate, frenula
OFDS XI Gabrielli
Telecanthus, Hypertelorism median flat nasal cleft lip alar bridge, hypoplasia retrognathia
Cleft palate, vestibular frenula
OFDS X Figuera
—
—
—
Bifid toes
Brachysyn-dactyly
Cleft lip Median synophrys cleft lip telecanthus broad/bifid nose — —
Hypertelorism cleft lip asymmetry
Lobed tongue, tongue nodules, frenula
OFDS IX Gurrieri
Lobed tongue, frenula absent teeth tongue nodules
OFDS VIII Edwards
Cleft palate tongue nodules frenula
OFDS VII Whelan
TABLE I. Summary of Clinical Findings in OFDS Types
AR
Myelomeningocele Stenosis of acqueduct of Sylvius —
Heart anomalies —
Brachy-clino -syn-dactyly
Brachyclino-syndactyly
—
—
Lobed tongue, frenula
OFDS XII Moran-Barroso
Neuropsychiatric findings, epilepsy AR
—
Leukoaraiosis
—
—
Brachy-clinosyn-dactyly
Brachy-clinosyn-dactyly
—
Cleft lip
Tongue nodules
OFDS XIII Degner
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a
American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a ORAL–FACIAL–DIGITAL SYNDROMES
under various perspectives: developmental patterning, pathogenesis of cystic and non-cystic pathology of different organs, and even evolutionary implications. In fact, it is notable that the cytoskelethon in its basic structure 9 þ 2 is conserved even in the most simple cell (according to the symbiotic model likely it derives from a symbiotic spirochete that attached to a primitive eukaryote or archaebacterium like organelle [Ibanez-Tallon et al., 2003]) and its maintenance throughout evolution has enabled the eukaryotic cells to achieve complex organizational and structural tasks such as cellular polarization, migration, and even molecular signaling [Benzing and Walz, 2006]. Such a crucial role of the ciliary apparatus is well proved by its involvement in almost all of the physiological processes and in many of the pathogenetic pathways in humans. OFDS I and many related conditions have so far contributed to widen the knowledge of the function of cilia: it is likely that the discovery of the genetic causes for the other OFDS will shed further light on this topic. REFERENCES Ade`s LC, Clapton WK, Morphett A, Morris LL, Haan EA. 1994. Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation in a fetus of consanguineous parents: A new multiple malformation syndrome, or a severe form of oral–facial–digital syndrome type I. Am J Med Genet 49:211–217. Al-Gazali LI, Sztriha L, Punnose J, Shather W, Nork M. 1999. Absent pituitary gland and hypoplasia of the cerebellar vermis associated with partial ophtalmoplegia and postaxial polydactyly: A variant of orofaciodigital syndrome type VI or a new syndrome? J Med Genet 36:161–166. Badano JL, Mitsuma N, Beales PL, Katsanis N. 2006. The Ciliopathies: An Emerging Class of Human Genetic Disorders. Annu Rev Genomics Hum Genet 7:125–148. Baraitser M. 1986. The orofaciodigital (OFD) syndromes. J Med Genet 23:116–119. Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, Pearson CG, Kai M, Hartley J, Johnson C, Irving M, Elcioglu N, Winey M, Tada M, Scambler PJ. 2007. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune ashyxiating thoracic dystrophy. Nat Genet 39:727–729. Benzing T, Walz G. 2006. Cilium-generated signalling: A cellular GPS? Curr Opin Nephrol Hypertens 15:245– 249. Bisgrove BW, Yost HJ. 2006. The roles of cilia in developmental disorders and disease. Development 133:4131–4143. Burn J, Dezateux C, Hall CM, Baraitser M. 1984. Orofaciodigital syndrome with mesomelic limb shortening. J Med Genet 21: 189–192. Camera G, Marasini M, Pozzolo S, Camera A. 1994. Oral–facial– digital syndrome: Report of a transitional type between Mohr and Varadi syndromes in a fetus. Am J Med Genet 53:196– 198. Claussen O. 1946. Et arvelig syndrome omfattende tungemisdannelse og polydaktyli. Nord Med Tidskr 30:1147. Coll E, Torra R, Pascual J, Botey A, Ara J, Perez L, Ballesta F, Darnell A. 1997. Sporadic orofaciodigital syndrome type 1 presenting as end-stage renal disease. Nephrol Dial Transplant 12:1040–1042. Connacher AA, Forsyth CC, Stewart WK. 1987. Orofaciodigital syndrome type 1 associated with polycystic kidneys and
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