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

27yrs 29yrs

21m 4yrs

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).

1. TCOF1 (78%-93%) – chromosome 5q31-34

Protein: Treacle

2. POLR1D : Chr 13

3. POLR1C : Chr 6

Three genes in which mutations are known to cause TCS:

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

Features

Lower eyelid abnormalities

- Coloboma (notching) (69%)

- Partially or totally absent

medial lashes (53%)

- Downslanting palpebral

fissures

External ear abnormalities

• (77%) including absent, small,

and malformed ears (microtia) or

rotated ears

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.

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

Learning points

References

Management of Genetic Syndromes, Second Edition, edited by Suzanne B. Cassidy and Judith E. Allanson (2005)

Gorlin’s Syndromes of the heaqd and neck, 5th 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

Smith’s Recognizable Patterns of Human Malformation, Jones, 6th 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