Frantisek Grochal¹; Robert Dankovcik²; Jana Krsiakova³ Kathleen Comalli Dillon⁴; Milan Puskeiler⁵; Martin Gencik⁶, Martina Hikkelova⁶.

1 Femicare, Center of prenatal ultrasonographic diagnostics, Kollarova 17A, 036 01 Martin, Slovak republic; 2 Louis Pasteur University Hospital Kosice, 2nd Department of Gynecology and Obstetrics, Slovak Republic; 3 Genetic department, M-Genetik, s.r.o., Martin, Slovak republic; 4 RDMS, ComalliWrites Medical Writing, bluevireo55@yahoo.com, Petaluma, CA, USA; 5 Central Military Hospital Ruzomberok, Department of Obstetrics and Gynecology, Slovak republic; 6 Medgene, s.r.o, Bratislava, Slovak republic.


Abstract

Treacher Collins syndrome (mandibulofacial dysostosis) is a rare congenital anomaly whose more severe phenotypic variants can be recognized during prenatal 2D ultrasonographic examination. 3D/4D ultrasonographic imaging is an effective tool for detection of even the less striking features of the syndrome, such as downslanting palpebral fissures or macrostomia. We present a case of Treacher Collins syndrome of de novo origin in a fetus of a nonconsanguineous healthy couple. The fetus was diagnosed at 19 weeks, 1 day of pregnancy and the diagnosis subsequently confirmed by invasive genetic testing. The genetic etiology of Treacher Collins Syndrome, basic embryology, principal ultrasonographic features, the need of a multidisciplinary approach for diagnosis, and optimal case management are discussed.

Case report

Our patient was a 27-year-old woman, gravida 2, para1, from a nonconsanguineous couple with no family history of genetic disease.

She came to our center for the first time at 11 weeks, 4 days of pregnancy for first-trimester ultrasonographic screening. Her first child was a healthy 3-year-old female. No anomalies were seen in the first-trimester screening (a normal nasal bone and a nuchal translucency of 1.16 mm were noted), although retrospective analysis of the images revealed fetal micro/retrognathia.

The second-trimester ultrasonographic morphologic screening was performed at 19 weeks, 1 day; the examination revealed a male fetus with several anomalies, including retrognathia (the inferior facial angle was between 36.07°- 40.91°; cutoff of 50° for a normal angle is suggested in the Rotten et al study of 2002); microtia (ear length of only 8.4 mm) with auricular malformation; downslanting (“antimongoloid”) palpebral fissures; and macrostomia, the latter two demonstrated by 3D imaging. Paradoxically, although the mandible was severely retropositioned, the width of the mandible was greater than that of the maxilla (mandible width/maxilla width ratio was 1.14); therefore, retrognathia rather than micrognathia was present in our case. The findings suggested Treacher Collins syndrome.

The parents were sent to the geneticist; amniocentesis and gene sequencing revealed a causal mutation p.Lys643GlufsX38(c.1927dupG) in the TCOF1 gene, confirming the diagnosis of Treacher Collins syndrome.

The parents opted for termination of pregnancy at 24 weeks; autopsy findings were consistent with Treacher Collins syndrome.

Figures 1, 2, 3, and 4: 2D ultrasonographic features of Treacher Collins syndrome. Figure 1 is a sagittal scan of the fetal head at 11weeks, 4 days: retrognathia is seen (curved arrow), with normal nasal bone and nuchal translucency. Figure 2 is a sagittal scan of the fetal face at 19 weeks, 1 day showing an abnormally small inferior facial angle (36.07°) due to retrognathia. Figures 3 and 4 compare the sizes of the maxilla (Fig. 3) and mandible (Fig. 4). The mandibular width was paradoxically larger than that of the maxilla, indicating that retrognathia rather than micrognathia was present in our case.

Figures 5, 6, and 7: Comparison of the 3D scan of the fetal face obtained at 19 weeks, 4 days (Fig. 5) showing characteristic features of Treacher Collins syndrome with the postmortem appearance of the fetus, terminated at 24 weeks (Fig. 7). Figure 6 represents a fusion of the prenatal 3D scan with the postmortem image of the fetus, showing good correlation of the prenatal findings with the postmortem appearance. The typical features of Treacher Collins syndrome (downslanting palpebral fissures, retrognathia, and macrostomia) are well visualized both on the prenatal 3D scans and on the autopsy specimen.

Figures 8, 9: Prenatal 3D scans of the fetal face obtained at 19 weeks, 4 days, showing Treacher Collins syndrome. Typical features of Treacher Collins syndrome (downslanting palpebral fissures, retrognathia, macrostomia – figure 8; and microtia with dysplastic malformed auricles – figure 9) are clearly visible.

Figure 10, 11: Autopsy images showing the appearance of the aborted fetus at 24 weeks with typical features of Treacher Collins syndrome: downslanting palpebral fissures, retrognathia, macrostomia, and microtia with dysplastic malformed auricles.

Discussion

Treacher Collins syndrome, also known as mandibulofacial dysostosis or Franceschetti-Zwahlen-Klein syndrome, is an autosomal dominant disorder caused by mutations in the TCOF1 gene mapped to chromosome 5q32-q33.1, which encodes a nucleolar phosphoprotein called treacle [2,3].

Treacle plays a role in ribosome maturation; treacle deficiency leads to nucleolar stress activation of p53 (protein 53) with consequent activation of numerous proapoptotic genes, resulting in extensive neuroepithelial apoptosis of neural crest cells [2,3,4].

The neural crest cells migrate into many locations in the embryonic body and differentiate into a great variety of structures, including the pharyngeal (branchial) arches which contribute to formation of facial, neck, laryngeal, and pharyngeal structures [5,6]. 

A decreased amount of cell migration into the first and second pharyngeal branches due to the abovementioned neuroepithelial apoptosis is responsible for malformations in the mandibulofacial and auricular structures in Treacher Collins syndrome [2,3,4].

The incidence of Treacher Collins syndrome is about 1:50,000 live births; about 40% of cases have a previous family history, while the remaining 60% represent de novo mutations of the TCOF1 gene [7].

Characteristic features of the disease include mandibular and malar hypoplasia with or without cleft zygoma; multiple abnormalities of the ears (microtia; dysplastic ears often associated with atresia of the external auditory canals and anomalies of the middle ear ossicles leading to conductive hearing loss); downslanting (“antimongoloid”) palpebral fissures with colobomas of the lower eyelids and partial or total absence of the lower eyelashes; macrostomia; cleft palate; choanal atresia or stenosis; and vision loss [8,9].

Additional findings are more rarely described in the literature, including encephalocele, ocular malformations, and extracraniofacial anomalies involving thyroid, thymus, heart, splenules, ectopic adrenal gland tissue, and hypoplastic external genitalia [10].

The spectrum of phenotypic findings in Treacher Collins syndrome varies from mild forms, clinically almost undetectable, to severe cases resulting in perinatal death or requiring emergent tracheostomy due to breathing problems from micrognathia and lingual obstruction of the hypopharynx [2].

Developmental delays were reported in only 5% of cases [9], usually as sequelae of hearing loss; thus early diagnosis and treatment can prevent associated developmental and educational disability.

Ultrasonographic examination plays a crucial role especially in detection of de novo Treacher Collins cases, and is very important in assessment of the severity of the findings in both de novo cases and cases with a positive family history. 3D ultrasonography adds information to the assessment of facial dysmorphism and more clearly illustrates some of the more subtle findings, such as downslanting palpebral fissures or macrostomia. The combination of retrognathia, microtia (with dysplastic, malformed pinnae), downslanting palpebral fissures, and macrostomia were the most significant findings in our case, leading to the suspicion of Treacher Collins syndrome at 19 weeks, 1 day of pregnancy, observed using both 2D and 3D imaging. Retrospective views of the first-trimester images also revealed micrognathia/retrognathia of the fetus, but unfortunately we did not note this important finding at that time.


The differential diagnosis includes other phenotypically similar entities, especially:

• Retinoid acid embryopathy (in addition to microtia, cardiovascular and central nervous system anomalies are present) [11];

• Nager syndrome (here, there are also preaxial limb abnormalities and the mandible is considerably more hypoplastic) [2,12];

• Miller syndrome (a cleft lip is more frequently seen; postaxial limb anomalies are present, such as incomplete development of the fifth digital ray of all limbs; also, occasionally, heart defects are present) [2, 13];

• Goldenhar syndrome (usually featuring unilateral facial abnormalities – microtia; malar, maxillary or mandibular hypoplasia; hemi- or hypoplastic vertebrae, most commonly of the cervical region) [14];
  
• Pierre Robin syndrome (micrognathia, but with normal ears) [15]; and other anomalies, usually distinguishable by extrafacial features.

References