Volume 4, Issue 3 , Pages 118-122, September 2009
Type VIII oral–facial–digital syndrome. A rare case series of a forgotten syndrome subtype
Article Outline
Summary
The oral–facial–digital (OFD) syndrome is a constellation of clinical syndromes having similar characteristics like involvement of cleft lip, cleft palate, tongue clefts or hamartomas, hypertelorism and limb abnormalities which include hand, foot malformations, and central abnormalities. OFD type VIII shares a special place in OFDS due to its X linked recessive nature of transmission and very few cases have been reported of this syndrome (only one series by Edward 1988). In view of very limited number of such reports in Otolaryngological literature, we intend to describe this rare case series of type VIII OFDS for recognition among pediatric otolaryngologists so that early diagnosis and intervention can be done. We describe three cases of OFD VIII to highlight their diverse manifestations, diagnostic workup and management issues.
Keywords: Oral–facial–digital syndrome, Type VIII OFDS, Tongue nodule, Polydactyly, Laryngeal hypoplasia
1. Introduction
The oral–facial–digital (OFD) syndrome is a constellation of clinical syndromes having similar characteristics like involvement of cleft lip, cleft palate, tongue clefts or hamartomas, hypertelorism and limb abnormalities which include hand, foot malformations, and central abnormalities. First description of OFDS is credited to Papillon–League and Psaume in 1954 who reported OFDS I [1]. Since then a total of 13 variants of OFD syndrome have been added in the literature, and all 13 subtypes have few extra or less features than the OFDS1 [2]. OFD syndromes intrigue otolaryngologist and the pediatrician both, a thorough knowledge of subtypes of OFDS helps in managing and prognosticating this clinical entity. Constellation of clinical presentation in OFDS is as follows: The malformations of the oral cavity consist of multiple hypertrophied frenula, clefts of the alveolar ridge and ankyloglossia, multilobulated tongue and tongue nodules, cleft lip-palate, supernumerary teeth, agenesis, poor dental position and bone hypoplasia. The malformations of face are aplasia of the alar cartilage, ocular hypertelorism, strabismus, seborrhic and granulose skin and alopecia. The digital malformations vary from syndactyly and brachydactyly which are commoner than polydactyly [3]. Miscellaneous abnormalities include brain malformations and mental retardation, conductive hearing loss and polycystic kidney disease.OFDS type VIII shares a special place in OFDS due to its X linked recessive nature of transmission and very few cases reported in this syndrome (only one series by Edward, 1988) [4]. In view of limited number of reports of such cases in Otolaryngological literature we intend to describe this rare case series of 3 cases of type VIII OFDS for recognition among pediatric otolaryngologists so that early diagnosis and intervention can be done.
2. Case report
2.1. Case 1
The case subject is a 5-year-old male who presented to pediatric ENT services of our institute with multiple lobulations on tongue, malocclusion of teeth, speech and hearing difficulty and multiple digits in upper and lower limbs. The child was short statured, and had skin eczema, alopecia and seborrhic dermatitis. He had difficulty in standing up and walking. The child was mentally subnormal without any gross retardation on IQ assessment. His perinatal history had evidence of intermittent stridor, feeding problems and associated aspiration pneumonia. Orthopedic evaluation revealed kyphosis of spine with short tibia and mid shaft bowing leading to equines deformity. Oral cavity examination showed severe malocclusion of teeth with supernumerary teeth. There was high arched palate but no cleft lip or cleft palate. Tongue showed large central cleft of tongue with multiple lobulations [Fig. 1]. Biopsy of these lobulations confirmed it to be hamartomas of tongue. Child had some degree of ankyloglossia due to hypertrophied frenulae. Direct laryngoscopy showed hypoplastic epiglottis. Skeletal survey showed post-axial six digits in each upper limb and both lower limbs had duplicated hallux in association with eight digits [Fig. 2]. CT scan of brain and ultrasound of abdomen were normal. BERA (Brain Stem Evoked Response Audiometry) revealed moderate hearing loss of 55 decibels in both ears. Chromosomal analysis showed normal 23 XY karyotype. There was family history of consanguineous marriage, however both parents were normal. With the above clinical picture this syndrome was grouped in to OFDS VIII [Fig. 3].
Fig. 1.
. Multiple digits in upper limbs, multiple hamartomas of tongue with clefting, bowing of legs, hypoplastic epiglottis, duplicated hallux.
Fig. 2.
Case 1 shows tibial bowing, duplicated hallux, polydactyly of upper limbs with y shaped metacarpal. Case 2 shows tibial bowing, polydactyly of upper limbs with y shaped metacarpal and hypoplastic maxilla.
Fig. 3.
Patient with normal facial profile having hamartoma of tongue, bilateral polydactyly in upper limbs and normal lower limbs.
2.2. Case 2
This 6-month-old girl child, younger sibling of case 1, presented with multiple nodules of tongue since birth. However her manifestations of this syndrome were much milder. She had 6 digits in both upper limbs post-axially and bowing of tibia in lower limbs. She had no hearing loss, kyphosis or rudimentary epiglottis. Her milestones were also not delayed. Rest of the examinations including skeletal survey, CT scan, chromosomal analysis were normal for this child. Excision biopsy of the tongue nodules revealed hamartomas of the tongue. She had clinical picture consistent with type VIII OFDS as described by Edward.
2.3. Case 3
The eldest male sibling of the same family died 3rd day post-natally in a peripheral hospital. This child had severe stridor and died of respiratory distress. Mother remembers that he had nodules in tongue and polydactyly in all limbs. No autopsy was done on this child. No hospital records are available to ascertain the cause of death and other congenital abnormalities.
3. Discussion
The oral–facial–digital syndromes (OFDS) are a constellation of clinical syndromes with common minor facial and oral anomalies (including tongue lobulations and or hamartomas, accessory frenulae, and alveolar anomalies) and variable digital defects such as polydactyly. Their underlying pathogenesis remains unclear, and it is possible that complex abnormal developmental pathways controlled by several genes are involved. The total number of genetically distinct types of OFDS is controversial but to date, 13 different types of OFDS have been identified [2]. According to Gorlin (1973), the incidence of Oro-Facial–Digital syndrome is 1:250,000 births [3]. Incidence of type VIII OFDS is extremely rare. Our review of OFDS VIII cases points out to only one series of first reported OFDS VIII by Edward et al. [4]. Although Gurrieri described a case of two brothers with retinal involvement and clinical picture similar to type VIII OFDS [5]. Some authors like Toriello consider it to be type IX OFDS due to retinal involvement and insufficient evidence to prove X linked recessive inheritance [6]. In our series, all three cases can be grouped into OFDS VIII (X linked recessive) based on their clinical picture and mode of inheritance (Table 1).
Table 1. Illustration of the findings present in our case and type VIII OFDS.
| Features | Our case 1 | Our case 2 | Our case 3 | Edwards (1988) type VIII OFDS |
|---|---|---|---|---|
| Inheritance | X linked R | X linked R | X linked R | X linked R |
| Tongue nodules | + | + | + | + |
| Thick frenulae | + | + | NA | + |
| High arched palate | + | + | NA | + |
| Hypertelorism | + | − | NA | + |
| Polydactyly | + | + | + | + |
| Syndactyly | + | − | + | + |
| Tibial deformity | + | + | NA | + |
| CNS abnormality | − | − | NA | − |
| Hearing loss | + | − | NA | + |
| Laryngeal hypoplasia | + | − | + | + |
| Skin Manifestations | + | − | − | + |
| Affected females | − | Mild | − | Mild |
=This syndrome first described by Edward et al. in family of seven included clinical features of hypertelorism, broad, bifid nasal tip, median cleft lip, tongue lobulations and hamartomas, skin miliae, oral frenulae, high arched palate, bilateral polydactyly and duplicated hallux. Other variations had abnormal tibia, short stature, and hypoplasia of the epiglottis [4]. This type of syndrome primarily affects males and has milder manifestations in females.
In our series, cases 1–3 belonged to the same family and had most of the manifestations of OFDS present. Female case 2 in our series had milder manifestations than her male sibling case 1. The possible cause of this disparity can be related to X linked recessive nature of the transmission which causes milder manifestations in affected females. However, we admit that this assumption of X linked inheritance is not flawless. It is complicated by the fact that both the parents have normal phenotypes and the female daughter is affected. Since no cytogenetic studies or any linkage data of candidate genes is available to us for confirming X linked recessive nature of inheritance, we would like to explain this plausible discrepancy on the basis of random X chromosome inactivation (XCI). X chromosome inactivation (XCI) is the process by which one of the two X chromosomes becomes transcriptionally inactive in each somatic cell of mammalian females. Inactivation is complete random process in which any one of the two X chromosomes can be inactivated and is further propagated in all cells. This phenomenon can modulate the expression of disease manifestations of X-linked recessive disorders in females [7]. Skewed Inactivation of normal X chromosome may manifest the other affected X chromosome and there by manifest disease (as seen in daughter) and also skewed inactivation of affected allele may present with normal phenotypic female (as seen in mother). Authors like Brunella Franco have explained a similar heterogeneity of OFD1 females in their phenotypic expression of mutated X chromosome on the basis of skewed X Chromosome Inactivation (XCI) [7].
Both the cases were managed by excision of the tongue nodules and repair of the tongue cleft. Speech and feeding difficulty improved after surgical excision of nodules. Hearing aid and speech therapy was provided to case 1, and he is still under follow-up. Orthopedic intervention for tibial bowing included corrective osteotomies and vitamin D supplementation. Hypoplasia of epiglottis in our case did not need any surgical intervention as the symptoms were mild and occasional. Aspiration symptoms in male child improved with age and currently he has no swallowing or aspiration problems.
OFDS usually presents to an otolaryngologist for Orofacial anomalies including tongue nodule. The specific findings of tongue hamartomas in any combination of digital and facial abnormalities should raise strong suspicion of OFDS. Literature search in (OMIM) online Mendelian inheritance reveals only one more syndrome, i.e. Cowden syndrome with tongue hamartomas [8]. It can be easily differentiated by presence of multi-organ hamartomas as seen Cowden syndrome where as OFDS contains only tongue hamartomas/nodule. Otolaryngological intervention may be also required for cleft lip/palate, epiglottis hypoplasia and hearing loss.
Although the clinical subtype of OFDS is best decided by dymorphologist, preliminary work up by otolaryngologist must include but not necessarily limited to biopsy of the nodules, CT scan of head, skeletal X-ray work up, renal ultra sound and hearing assessment. A recent review on diagnosis of OFDS suggests Karyotyping and array CGH analysis be performed where feasible to detect any chromosomal rearrangements and identification of new candidate gene loci for research purposes.[2] This genetic work up enables to determine the possible mode of inheritance and prognosticating the affected individuals. We performed Karyotyping for both the live cases and it was normal. To our knowledge only type OFD 1 gene has been elucidated to X chromosome. The OFD1 gene encodes a 1011 amino acid protein, which is expressed during development and in adult tissues in all the structures affected in this syndrome. Most of the OFD1 mutations identified to date in patients lead to a premature truncation of the protein in its N-terminal region and are therefore predicted to act with a loss-of-function mechanism [9].
The treatment of OFDS is a multidisciplinary team approach involving the professionals of otolaryngology, orthopedics, dentistry and health care professional of appropriate fields as and when required. The present series confirms more cases of type VIII OFDS which have not been reported yet after its initial identification by Edward in 1988. Further this report will increase the recognition of this group of syndromes among otolaryngologists and lead to earlier diagnosis and treatment.
Acknowledgements
Special thanks to Dr. Tatavarty Giridhar, Dr. T. Veda, Dr. Sapna Jain, Dr. Shakuntala for helping in the collection of articles, clinical photographs and tables.
References
- . Une malformation hereditaire de la muquese buccale: Brides et freins anomaux. Rev. Stomatol. 1954;55:209–227
- . Oral–facial–digital syndromes: review and diagnostic guidelines. Am. J. Med. Genet. Part A. 2007;143A(24):3314–3323
- . Oro-Digito-Facial dysostosis—a new syndrome. J. Pediatr. 1962;61:520–530
- . X-linked recessive inheritance of an orofacial digital syndrome with partial expression in females and survival of affected males. Clin. Genet. 1988;34:325–332
- . Possible new type of Oral–Facial–Digital Syndrome with retinal abnormalities: OFDS Type (VIII). Am. J. Med. Genet. 1992;42:789–792
- . Oral–Facial–Digital syndromes. Clin. Dysmorphol. 1993;2:95–105
- . X-inactivation and human disease: X-linked dominant male-lethal disorders. Curr. Opin. Genet. Dev. 2006;16(3):254–259
- . Otolaryngologic aspects of oral–facial–digital syndrome. Int. J. Pediatr. Otorhinolaryngol. 2000;53(1):39–44Jun 9
- Clinical, molecular, and genotype–phenotype correlation studies from 25 cases of oral–facial–digital syndrome type 1: A French and Belgian collaborative study. J. Med. Genet. 2006;43:54–61
PII: S1871-4048(08)00068-3
doi:10.1016/j.pedex.2008.09.005
© 2008 Elsevier Ireland Ltd. All rights reserved.
Volume 4, Issue 3 , Pages 118-122, September 2009
