US Pharm. 2018;43(5):HS-2-HS-7.

ABSTRACT: Treacher Collins syndrome (TCS) is a rare genetic disease that affects craniofacial development. Researchers estimate that it occurs in approximately 1 in 50,000 live births. The disorder results in distinctive physical features including downward-slanting eyes, hypoplasia of the lower jaw, and malformed or missing ears. These physical anomalies may cause hearing, eating, vision, and breathing problems. There is no single treatment for TCS. Management is dependent upon the extent of the signs and symptoms and should be tailored to the specific needs of each patient. A multidisciplinary approach, ranging from speech therapy to reconstructive surgery, is generally needed.

Treacher Collins syndrome (TCS), also known as mandibulofacial dysostosis and Treacher Collins–Franceschetti syndrome, is a rare genetic disorder that affects craniofacial development.1 It is named after the eminent surgeon and ophthalmologist Edward Treacher Collins, who first described it in the medical literature in 1900.2 From time to time, TCS attracts media and public attention, most recently with the release of the film “Wonder” in late 2017 that was based on a best-selling children’s book by the same name.3 When awareness of TCS increases, pharmacists, as accessible healthcare professionals, may find that an understanding of the disease helps them better serve a curious public. Pharmacists may also encounter TCS patients when they undergo surgical treatment, as well as in the community.

Features of TCS

TCS affects the development of bones and tissues of the head and face, resulting in distinctive, bilaterally symmetrical physical characteristics.3 The hallmark features include downward-slanting eyes, a small, underdeveloped lower jaw, and malformed or missing ears.4 Additional characteristics may include notched lower eyelids, hypoplasia or absence of cheekbones, absence of the side and floor of the eye socket, a beaklike nose, and cleft palate.5 These clinical features are recognizable at birth and may be seen prenatally with an ultrasound.6 The signs and symptoms vary greatly, ranging from almost unnoticeable to severe. Unless there is a major abnormality affecting breathing, TCS has no effect on life expectancy, and most children with TCS have normal intelligence.4

TCS occurs in an estimated 1 in 50,000 live births.4 Forty percent of TCS patients inherit the disorder from a parent who carries the affected gene. The remaining cases result from a new mutation in a person with no family history of the disorder.4 Studies have shown that parents who carry the gene have a 50% chance of passing it on to a child.5,6 TCS has no predilection for race, and it occurs equally among males and females.7 Genetic counseling is recommended for people with a family history of the disease.2

Risk Factors

TCS abnormalities are caused by mutations in the TCOF1, POLR1C, or POLR1D genes, which are responsible for craniofacial development.8 The mutations are believed to reduce the production of ribosomal RNA (rRNA), causing premature death of cells involved in facial bone and tissue development and leading to the signs and symptoms of TCS.9 Mutations typically occur between the fifth and eighth week of embryonic progression.8,10 TCOF1 mutations are most common, occurring in 81% to 93% of cases.2 POLR1C and POLR1D account for approximately 9%.8 Ten to 15% of individuals with the classic features of TCS do not have mutations in these genes.8 Consequently, researchers believe that there are other genes associated with TCS that have yet to be identified.7

The three genes associated with TCS are responsible for craniofacial development.8 They are involved in the production of proteins that help make rRNA, which is an essential chemical for the production of new proteins that are necessary for normal cell function and survival.9 These gene mutations could potentially reduce the production of rRNA and cause premature death of cells involved in the development of facial bone and tissue ultimately leading to the signs and symptoms of TCS.9 However, it remains unclear why the effects of these mutations are generally limited to facial development.

Diagnosis

Diagnosis of TCS can be made by the presence of characteristic physical features, imaging, or genetic testing. When a patient has obvious symptoms, a diagnosis of TCS is easily made. A patient with diminished expression of facial features is more difficult to diagnose. In fact, some individuals have such a mild case that they are not diagnosed until later in life or sometimes not at all.9

TCS affects certain bones of the face, ears, and soft tissues around the eyes. People with affected eye tissue typically have a “saddened” appearance. The most common ocular symptom is a downward slant to the opening between the upper and lower eyelids. Additional symptoms may include a lower- eyelid notch or cleft of missing lid tissue, partial absence of eyelashes on the lower eyelid, crossed eyes, and narrowed tear ducts. Sometimes malformations of the globe are seen, including a notch or cleft of missing tissue in the iris or abnormally small eyes.7

According to the National Organization for Rare Disorders, “Infants with TCS exhibit underdeveloped or absent cheekbones, causing this area of the face to appear flat or sunken. The bone of the lower jaw is incompletely developed, causing the chin and the lower jaw to appear abnormally small. Certain bony structures that anchor portions of the lower jaw bone to muscle can be unusually flat or absent.”7 In addition to facial and jaw problems, people with TCS may have underdevelopment of the throat, a retropositioned tongue, and even a cleft palate, which can make it difficult for infants to feed and breathe at birth.9 Often the facial symptoms are accompanied by visual and/or hearing problems owing to the underdeveloped structures.9

If physical findings give reason to suspect TCS, specialized imaging tests, such as x-rays and CT scans, may be performed to confirm bone structure abnormalities in the craniofacial area. TCS has several physical features that are similar to those  of other disorders, such as Nager syndrome; Miller syndrome; acrofacial dysostosis, Cincinnati type; and hemifacial macrosomia.7 Nager syndrome is a rare genetic disorder characterized by craniofacial malformations in addition to small or absent thumbs.11 Miller syndrome is a rare genetic disorder characterized by craniofacial malformations in addition to abnormalities of the pinky finger or fusion of the fingers.11 Acrofacial dysostosis, Cincinnati type, is a rare genetic disorder characterized by underdevelopment of the jaw with or without skeletal limb defects that include pelvic and digit anomalies.7 Hemifacial microsomia is a rare disorder characterized by craniofacial abnormalities involving the jaws, mouth, and ears in addition to extracranial anomalies of the cardiac, skeletal, and renal systems, and the extremities.7 Follow-up with genetic testing is recommended to rule out other conditions.7,10

Molecular genetic testing is done as a confirmatory method to detect mutations in the TCOF1, POLR1C, and/or POLR1D genes. If suspicion of TCS arises prior to birth, possibly because of findings on ultrasound or family history, genetic testing may be done by amniocentesis and chorionic villus sampling.7

Treatment

Although there is no cure for TCS,7,12,13 a variety of treatment options are available to meet the specific needs of patients. The type of treatment required is dictated by the severity of patient symptoms, so each case is different.6,7,12-14 Treatment often requires assistance from a team of craniofacial specialists, including orthodontists, plastic surgeons, speech pathologists, and ophthalmologists.4,6,7,12 With proper treatment, children with TCS can grow to become functioning adults.6

The approach to therapy is often specific to the patient’s age.6 In patients from birth to age 2 years, management focuses on airway and feeding difficulties. A sleep or nap study may be performed to help physicians diagnose and determine the severity of airway obstruction.7 The repair plan may include special anatomical positioning and craniofacial reconstruction to improve respiratory function, restore patency of the nostrils, allow distraction of the mandible, and repair a cleft palate.4,6,12 Early craniofacial reconstruction may also prevent the progression of facial asymmetry.6 If feeding difficulties are noted, a gastrostomy may be required to ensure adequate caloric intake.6

From ages 3 to 12 years, management focuses on speech therapy and integrating the child into the educational system.6 It is critical to assess the child’s auditory perception early on, as the treatment of hearing loss ensures better academic performance.7,15 A diagnostic hearing test should be performed before the age of 1 year, and then annually in order to ensure proper speech development.7 Methods of treating hearing loss include bone- conduction amplification, speech therapy, and educational intervention.4,6,12 Bone-anchored hearing aids, which transmit sound directly through bone into the inner ear, are an alternative for individuals with ear anomalies.6,7 External ear reconstruction is typically performed after the age of 6 years for patients with bilateral underdevelopment of the external ear and/or narrow ear canals, before reconstruction of the external auditory canal or middle ear.6

From ages 13 to 18 years, management focuses on corrective jaw surgery. This process may require orthodontia, dentures, dental implants, braces, dental surgery, and/or other corrective procedures.6,7 Plastic surgery may be required to correct changes to the facial structure, such as a receding chin.15 If visual impairments associated with TCS are noted upon examination with an ophthalmoscope, corrective glasses, contact lenses, surgery, and/or other supportive techniques may be used to help improve vision.7 Nasal reconstruction is also considered a part of this stage, if needed.6

Investigative Treatment

Although there is no cure for TCS, some potential treatments are being investigated for safety and efficacy.12 Researchers are looking for ways to inhibit p53, a protein that promotes damaged-cell death. This protein is mutated in individuals with TCS, causing an overgrowth of damaged cells and the features of TCS.12 Researchers are also investigating the use of fat-tissue stem cells to stimulate the regrowth of bone and cartilage to improve surgical outcomes when treating abnormalities of the skull and face.4,12 Genetic counseling may be suggested for affected individuals and their families in order to learn more about the outlook regarding the disorder and their chances of passing the condition on.4

TCS in the Media

Although TCS is a rare disorder, it is not uncommon for it to enter the public awareness through news articles, television, and movies. In addition to the recent film, in 1977 the New York Times published an article about the TCS diagnosis and treatment of a young man from Guyana; in 2015 a television documentary, “Born Without a Face,” aired, featuring a woman with severe TCS, and in late 2017 a television news magazine ran a story that discussed the challenges of raising a child with TCS.16-18

Conclusion

Although pharmacotherapy is not a major component of TCS treatment, familiarity with the disease, its management, and available resources (Sidebar 1) may help pharmacists serve affected patients, their families, and the public.

 

REFERENCES

1. National Institutes of Health. United States National Library of Medicine Genetics Home Reference. Treacher Collins syndrome. https://ghr.nlm.nih.gov/condition/treacher-collins-syndrome#sourcesforpage. Accessed February 23, 2018.
2. Sharma R, Sharma B, Babber M, et al. Treacher Collins syndrome: a case report and review of ophthalmic features. Taiwan J Ophth. 2016;6(4):206-209.
3. Wonder. Story. http://wonder.movie/?story. Accessed February 5, 2018.
4. Silva JC. What is Treacher Collins syndrome? Medical News Today. www.medicalnewstoday.com/articles/320306.php. Accessed February 7, 2018.
5. Faces: The National Craniofacial Association. Treacher Collins syndrome. www.faces-cranio.org/Disord/Treacher.htm. Accessed February 13, 2018.
6. Katsanis SH, Jabs EW. NCBI GeneReviews. Treacher Collins syndrome. www.ncbi.nlm.nih.gov/books/NBK1532/. Accessed February 8, 2018.
7. National Organization for Rare Disorders. Treacher Collins syndrome. https://rarediseases.org/rare-diseases/treacher-collins-syndrome/. Accessed February 10, 2018.
8. Schlump J, Stein A, Hehr U, et al. Treacher Collins syndrome: clinical implications for the paediatrician—a new mutation in a severely affected newborn and comparison with three further patients with the same mutation, and review of the literature. Eur J Pediatr. 2012;171(11):1611-1618.
9. Genetic and Rare Diseases Information Center (GARD). Treacher Collins syndrome. https://rarediseases.info.nih.gov/diseases/9124/treacher-collins-syndrome. Accessed February 12, 2018.
10. Tolarova M, Wong G, Varma S, Rohena L. Medscape. Mandibulofacial dysostosis (Treacher Collins syndrome). https://emedicine.medscape.com/article/946143-overview. Accessed February 12, 2018.
11. Johns Hopkins All Children’s Hospital. Treacher Collins syndrome, Nager syndrome and Miller syndrome. www.hopkinsallchildrens.org/services/cleft-and-craniofacial-center/conditions-we-treat/treacher-collins-syndrome. Accessed February 26, 2018.
12. MedicineNet. Treacher Collins syndrome. www.medicinenet.com/treacher_collins_syndrome/article.htm#what_are_the_treatment_and_management_guidelines_for_this_syndrome. Accessed February 2, 2018.
13. WebMD. What is Treacher Collins syndrome? www.webmd.com/children/treacher-collins-syndrome#2. Accessed February 2, 2018.
14. Seattle Children’s Hospital. Treacher Collins syndrome. www.seattlechildrens.org/medical-conditions/chromosomal-genetic-conditions/treacher-collins/. Accessed February 2, 2018.
15. Medline Plus. Treacher Collins syndrome. https://medlineplus.gov/ency/article/001659.htm. Accessed February 2, 2018.
16. McNeil DG. Surgical teamwork gives disease victims a new life. New York Times. July 26, 1977, page L31.
17. Blaylock J. Girl born without a face has undergone 45 surgeries. USA Today. www.usatoday.com/story/news/nation-now/2015/06/30/girl-born-without-face-surgeries-florida/29504043/. Accessed February 5, 2018.
18. Real E. ‘20/20’ features real-life “wonder boy” with Treacher Collins syndrome ahead of ‘Wonder’ premiere. InTouch. www.intouchweekly.com/posts/wonder-boy-abc-146997. Accessed February 5, 2018.

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