Balkan Journal of Medical Genetics

MISDIAGNOSIS OF TRACHER-COLLINS SYNDROME INITIALLY ATTRIBUTED TO DRUG TERATOGENICITY: A MOROCCAN CASE REPORT
Lamzouri A, EL Rherbi A, Ratbi I, Laarabi FZ, Chahboune R, Elalaoui SC, Hamdaoui H, Bencheikh RS, Sefiani
*Corresponding Author: Afaf Lamzouri (MD, Ass. Prof.): Department of Medical Genetics and Oncogenetics, Mohammed VI University Hospital, Faculty of Medicine and Pharmacy of Tangier, BP 365 km 15 Gzenaya Tangier, Morocco. Fax: 05.39.39.21.46. Phone number: 00 212 6 10 77 79 59. Email: lamzouriafaf@hotmail.com / lamzouriafaf82@gmail.com / a.lamzouri@uae.ac.ma
page: 69

DISCUSSION

Treacher Collins syndrome is named after the English surgeon Edward Treacher Collins, who initially described the syndrome’s traits in 1900. It is a rare congenital disorder of craniofacial development with an estimated prevalence of 1/50000 births [1]. Most TCS is inherited in an autoso- mal dominant manner; a small portion (~4%) is inherited in an autosomal recessive manner [4]. TCS is characterized by major clinical manifestations including hypoplasia of the zygomatic bones and mandible resulting in midface hypoplasia, micrognathia and retrognathia; lower eyelid abnormalities including coloboma and partially or totally absent lashes; external ear abnormalities comprising absent or malformed ears; and a family history consistent with autosomal dominant inheritance. Minor clinical features related to TCS are atresia or stenosis of the external au- ditory canals; conductive hearing loss; ophthalmologic defects; airway abnormalities comprising tracheostoma and choanal stenosis or atresia; cleft palate; preauricular hair displacement; and delayed motor or speech develop- ment. Da Silva Dalben et al. found dental anomalies in 60% of TCS patients, with one to eight anomalies per individual [5]. These anomalies consist in tooth agenesis, enamel deformities and malposition of the maxillary first molars. In some cases, dental anomalies in combination with mandible hypoplasia result in a malocclusion, thus possibly leading to problems with food intake and the ability to close the mouth [5]. Our patient has none of these dental anomalies. Less commonly, TCS has been associated with heart defects, malformed or absent thumbs and cryptorchidism [6]. To date, four genes have been identified in TCS whose diagnosis is established by detection of a heterozygous (au- tosomal dominant) pathogenic variant in TCOF1, POLR1D or POLR1B [7,8], or biallelic (autosomal recessive) patho- genic variants in POLR1C or POLR1D [7,9]. TCOF1, located on the 5q32-q33.1 region, is the major gene involved with heterozygous mutation in up to 93% of individuals with TCS [4]. TCOF1 encodes a nucleolar phosphoprotein called treacle, thought to play a central role in various cellular processes such as ribosome biogenesis, rRNA transcrip- tion, and potentially neural crest cell migration. Pathogenic variants in the TCOF1 gene lead to haploinsufficiency of treacle, disrupting its normal functions. This would af- fect nuclear localization signals and triggers apoptosis of cephalic neural crest cells during embryogenesis, thereby contributing to the symptoms observed in Treacher Collins Syndrome [10,11,12]. The specific variant identified in our patient, c.4372_4376del, results in a premature stop codon, producing a truncated protein. Already described in the literature, this variant is classified as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. In individuals with TCS, hundreds of pathogenic variants within TCOF1 have been documented [13], and while some have been observed more than once, our patient’s variant is noteworthy for its recurrence in 16% of cases [4]. The genes POLR1D, POLR1C, and POLR1B, located at 13q12.2, 6p21.1, and 2q14.1, respectively, exhibit limited mutations, being as- sociated with a small subset of TCS patients. These three genes are also expressed in neural crest cells, impacting ribogenesis and potentially disrupting cell division. POLR1D and POLR1C encode subunits that are integral to both the RNA polymerase I and RNA polymerase III complexes, critical for the synthesis of ribosomal RNA precursors and small RNA, and POLR1B encodes the RNA polymerase I subunit B [7,8]. Roughly 40% of individuals with autosomal domi- nant TCS have an affected parent [4], and this is the case of our patient, whose father exhibits a mild expression of TCS. The risk to the siblings is 50%, the specific mal- formations or their severity cannot be predicted because significant inter- and intrafamilial clinical variability is common in TCS. Treatment should be customized to meet the unique requirements of each person, ideally carried out by a com- prehensive craniofacial management team. Such a team typically includes a medical geneticist, plastic surgeon, head and neck surgeon, otolaryngologist, oral surgeon, orthodontist, audiologist, speech pathologist, and psychologist, ensuring a holistic approach to care.

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