TREACHER COLLINS SYNDROME (MANDIBULOFACIAL DYSOSTOSIS )
Omamah Asif Jiman Demonstrator Department of Genetic Medicine Faculty of Medicine, KAU
09/01/2012 Paediatric Grand Round Case Presentation
History: 21m/o Pakistani boy, born to a healthy 26 yr-old mother at full-term by SVD in KAUH. B.wt = 2.4kg (5th centile) Lt = 52cm (>50th) HC = 33.5cm (>10th) Antenatal Hx: PROM Postnatal Hx: NICU admission Echo: ASD Referred to Genetics dept soon after birth. Family History
5 2 3 3 29yrs 27yrs
4yrs 21m What is Treacher Collins Syndrome (TCS) ?
It is a genetic condition in which cheek bones and jawbones are under-developed.
Named after Dr. Edward Treacher Collins, a British opthalomlogist, who described the condition in an affected individual in 1900.
Although Thompson reported the first case in 1846.
Franceschetti and Klein made extensive reports on the condition in 1940s and called it Mandibulofacial Dysostosis.
Overveiw of Treacher Collins Syndrome
Frequency between 1:10,000-50,000
Male= Female
Most of cases are the result of new mutation
Non-penetrance is rare
Variable expressivity
Mild cases may go undiagnosed
Mutation on the TCOF-1 gene
Affected structures are those derived from the first and second brachial arches Why TCS Happens ?
TCS is an Autosomal Dominant disorder.
40% of affected population are familial cases.
60% of cases represent de novo gene mutation associated with older paternal age.
Teratogenic dose of vitamin A and isotretinoin given in animal models produced malformations of the craniofacial skeleton that closely resemble the syndromic features of TCS.
A possible human phenocopy induced by vitamin A was reported by Lungarotti et al (1987). Three genes in which mutations are known to cause TCS:
1. TCOF1 (78%-93%) – chromosome 5q31-34 Protein: Treacle
2. POLR1D : Chr 13
3. POLR1C : Chr 6
How TCS Happens?
TCOF1gene encodes for a low complexity, serine/alanine-rich nucleolar phosphoprotein, Treacle.
The clinical phenotype of Treacher Collins syndrome suggests that the responsible gene plays a fundamental role in early embryonic development, particularly in development of the craniofacial complex. Mutation analysis of TCOF1 has resulted in the identification of over 120 mutations that are spread throughout the gene.
Mutations include splicing mutations, insertions and non-sense mutations, the majority are deletions.
Craniofacial External ear abnormalities Features • (77%) including absent, small, and malformed ears (microtia) or rotated ears
Lower eyelid abnormalities - Coloboma (notching) (69%) - Partially or totally absent medial lashes (53%) - Downslanting palpebral fissures
Hypoplasia of the zygomatic bones and mandible - Midface hypoplasia (89%) - Micrognathia and retrognathia (78%) Minor Clinical features
Ear abnormalities including atresia or stenosis of the external auditory canals (36%)
Conductive hearing loss (40%-50%) attributed mostly to hypoplasia, or absence of the ossicles and hypoplasia of the middle ear cavities.
Ophthalmologic defects Vision loss (37%), amblyopia (33%), refractive errors (58%), anisometropia (17%), strabismus (37%)
Minor Clinical features(contd.)
Cleft palate with or without cleft lip (28%)
Preauricular hair displacement (26%), in which hair growth extends in front of the ear to the lateral cheekbones
Airway abnormalities including the following: Tracheostoma Uni- or bilateral choanal stenosis or atresia
Congenital Heart defects
Cryptorchidism
Blind fistulas and skin tags between auricle and angle of mouth
Absence of parotid gland and dacrostenosis
Diagnosis
The diagnosis of Treacher Collins syndrome (TCS) is based upon a characteristic pattern of malformation and radiographic findings.
TCS is distinguished from the other genetically determined disorders with mandibulofacial dysostoses by the absence of limb anomalies. Testing Strategy
To confirm/establish the diagnosis in a proband. Sequence analysis of TCOF1 is performed first for: Those with a family history of TCS consistent with autosomal dominant inheritance; and Those who represent simplex cases (i.e., a single occurrence in a family). If a mutation in TCOF1 is not identified, POLR1D sequence analysis should be considered next. POLR1C sequence analysis should be considered: In families with multiple affected sibs and/or consanguinity; or In those who represent simplex cases who do not have a TCOF1 or POLR1D mutation. Prenatal Diagnosis
Ultrasound has allowed successful prenatal diagnosis and should help identify those infants with severe craniofacial involvement in the second trimester of pregnancy (18wks).
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies are available but require prior identification of the disease-causing mutation in the family.
Differential Dagnosis
1. Nager syndrome: Preaxial acrofacial dysostosis Similar craniofacial malformations as TCS Radial limb reduction defects varying from mild thenar hypoplasia to absent radius with a radial club hand AD and AR inheritance reported Differential Dx (contd.)
2. Miller syndrome: Postaxial acrofacial dysostosis Similar craniofacial anomalies as TCS Ulnar limb reduction defects, usually absence of the fifth finger and metacarpal Syndactyly may occur Lower extremities are often involved Probably AR inheritance Differential Dx (contd.)
3. Oculo-auriculo-vertebral spectrum (Goldenhar syndrome):
Over 50% have abnormalities outside of the craniofacial area
Craniofacial involvement is always asymmetric and maybe bilateral
Upper eye-lid colobomas
Epibulbar dermoids and lipodermoids do not occur in TCS
Differential Dx (contd.)
4. Autosomal dominant mandibulofacial dysostosis (Bauru type): similar but no eyelid coloboma or zygomatic arch hypolasia
5. Autosomal dominant mandibulofacial dysostosis (Hedera type): Similar features but linkage to TCS locus was excluded
What problems can be expected?
The most common difficulties involve:
Breathing
Hearing
Vision
Causes of breathing problems
Micrognathia
Cleft palate
Choanal atresia/stenosis
Glossoptosis
Pharyngeal hypoplasia
Airway (evaluation and treatment)
Intubation maybe difficult due to abnormal anatomy of the airway… may need long-term tracheostomy.
Observe all neonates in a supine sleep position to assess for lesser degrees of obstruction.
Monitor O2 saturation if signs or symptoms of hypoxia develop.
A formal sleep study may be necessary. Ophthalmologic
Evaluate the adequacy of lid closure in the newborn period (large lower lid colobomas and zygomatic deficency corneal exposure)
Referral to ophthalmologist
Rarely , an affected child will need surgery early in life to provide adequate coverage of the eye closure ENT & Hearing
All neonates with TCS need formal ENT and hearing assessment
CT scan of the petrous temporal bone to evaluate middle ear and adjacent structures if hearing loss is bilateral Early amplification is essential
Bone-anchored hearing aides have been used successfully Early intervention programs are critical External ear reconstruction Craniofacial
Craniofacial malformations in TCS are stable over time and non-progressive.
Cleft palate repair, typically at less than a year of age.
Distraction osteogenesis to lengthen the mandible.
Zygomatic and orbital reconstruction. Growth and feeding
Growth potential is normal
Feeding difficulty secondary to craniofacial malformation
Gastroesophageal reflux occurs in TCS
Management:
Soft squeeze devices for isolated clefts, gavage-assisted feeding and gastrostomy tube can be considered
Feeding specialist or occupational therapist should be involved in the care of a child with feeding difficulty Development and behaviour
Majority are cognitively normal
With proper attention to the hearing loss, language development should be normal.
Evaluation: Longitudinal monitoring of speech is critical.
Treatment: Augmentative systems for communication such as sign and picture exchange should be implemented early in those with long term tracheostomies. Anaesthesia
The craniofacial structural alterations in TCS present a variety of challenges for which the anaesthesiologists need to be prepared.
Laryngeal mask airways and fiberoptic devices have been advocated.
Postoperative airway obstruction should be anticipated. Learning points
. Patients with auricular and facial abnormalities need to be carefully evaluated for skeletal and visceral anomalies.
. Early intervention and recognition of hearing has paramount importance
. Family support and counselling References
Management of Genetic Syndromes, Second Edition, edited by Suzanne B. Cassidy and Judith E. Allanson (2005) th Gorlin’s Syndromes of the heaqd and neck, 5 edition, edited by Raoul Hennekam, Ian Krantz and Judith Allanson (2010)
GeneReviews, Pagon RA, Bird TD, Dolan CR, et al., editors. : http://www.ncbi.nlm.nih.gov/books/NBK1532/
OMIM-Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim th Smith’s Recognizable Patterns of Human Malformation, Jones, 6 edition, 2010
Dixon J., Trainor P. and Dixon M. (2007), Treacher Collins Syndrome. Orthodontics & Craniofacial Research, 10:88-95.
Thompson A. Notic of several cases of malformation of the external ear, together with experiments on the state of hearing in such persons. Monthly J Med Sci 1846 ; 7:420
Treacher Collins E. Cases with symmetrical congenital notches in the outer part of each lid and defective development of the malar bones. Trans Ophthalmol Soc UK 1900; 20:190-2
Franceschetti A, KleinD. Mandibulo-facial dysostosis: new hereditary syndrome. Acta Ophthalmol 1949; 27:143-224
THANK YOU !
Special Thanks to the parents of our patient for their cooperation