Talk:Head Development - Abnormalities

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Cite this page: Hill, M.A. (2019, September 17) Embryology Head Development - Abnormalities. Retrieved from


The ontogeny of Robin sequence

Am J Med Genet A. 2018 Jun;176(6):1349-1368. doi: 10.1002/ajmg.a.38718. Epub 2018 Apr 25.

Logjes RJH1, Breugem CC1, Van Haaften G2, Paes EC1, Sperber GH3, van den Boogaard MH2, Farlie PG4.

Abstract The triad of micrognathia, glossoptosis, and concomitant airway obstruction defined as "Robin sequence" (RS) is caused by oropharyngeal developmental events constrained by a reduced stomadeal space. This sequence of abnormal embryonic development also results in an anatomical configuration that might predispose the fetus to a cleft palate. RS is heterogeneous and many different etiologies have been described including syndromic, RS-plus, and isolated forms. For an optimal diagnosis, subsequent treatment and prognosis, a thorough understanding of the embryology and pathogenesis is necessary. This manuscript provides an update about our current understanding of the development of the mandible, tongue, and palate and possible mechanisms involved in the development of RS. Additionally, we provide the reader with an up-to-date summary of the different etiologies of this phenotype and link this to the embryologic, developmental, and genetic mechanisms. KEYWORDS: Pierre Robin sequence; Robin sequence; cleft palate; embryology; genetics; glossoptosis; micrognathia PMID: 29696787 DOI: 10.1002/ajmg.a.38718


Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Genet Med. 2016 Jan;18(1):49-56. doi: 10.1038/gim.2015.29. Epub 2015 Mar 19.

Vincent M1,2, Geneviève D2, Ostertag A3, Marlin S4, Lacombe D5, Martin-Coignard D6, Coubes C2, David A1, Lyonnet S7,8,9, Vilain C10, Dieux-Coeslier A11, Manouvrier S11, Isidor B1, Jacquemont ML12, Julia S13, Layet V14, Naudion S5, Odent S15, Pasquier L15, Pelras S5, Philip N16, Pierquin G17, Prieur F18, Aboussair N19, Attie-Bitach T8,9, Baujat G7, Blanchet P2, Blanchet C20, Dollfus H21, Doray B21, Schaefer E21, Edery P22, Giuliano F23, Goldenberg A24, Goizet C5, Guichet A25, Herlin C26, Lambert L27, Leheup B28, Martinovic J29, Mercier S1, Mignot C30, Moutard ML31, Perez MJ2, Pinson L2, Puechberty J2, Willems M2, Randrianaivo H12, Szakszon K, Toutain A33, Verloes A34, Vigneron J28, Sanchez E2, Sarda P2, Laplanche JL35, Collet C35. Author information Erratum in CORRIGENDUM: Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. [Genet Med. 2015] Abstract PURPOSE: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. METHODS: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. RESULTS: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature. CONCLUSION: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.

PMID 25790162 DOI: 10.1038/gim.2015.29


Fishing the molecular bases of Treacher Collins syndrome

PLoS One. 2012;7(1):e29574. Epub 2012 Jan 25.

Weiner AM, Scampoli NL, Calcaterra NB. Source Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Área Biología General, Departamento de Ciencias Biológicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.


Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, and mutations in the TCOF1 gene are responsible for over 90% of TCS cases. The knowledge about the molecular mechanisms responsible for this syndrome is relatively scant, probably due to the difficulty of reproducing the pathology in experimental animals. Zebrafish is an emerging model for human disease studies, and we therefore assessed it as a model for studying TCS. We identified in silico the putative zebrafish TCOF1 ortholog and cloned the corresponding cDNA. The derived polypeptide shares the main structural domains found in mammals and amphibians. Tcof1 expression is restricted to the anterior-most regions of zebrafish developing embryos, similar to what happens in mouse embryos. Tcof1 loss-of-function resulted in fish showing phenotypes similar to those observed in TCS patients, and enabled a further characterization of the mechanisms underlying craniofacial malformation. Besides, we initiated the identification of potential molecular targets of treacle in zebrafish. We found that Tcof1 loss-of-function led to a decrease in the expression of cellular proliferation and craniofacial development. Together, results presented here strongly suggest that it is possible to achieve fish with TCS-like phenotype by knocking down the expression of the TCOF1 ortholog in zebrafish. This experimental condition may facilitate the study of the disease etiology during embryonic development.

PMID 22295061


Role of multislice computed tomography and local contrast in the diagnosis and characterization of choanal atresia

Int J Pediatr. 2011;2011:280763. Epub 2011 May 22.

Al-Noury K, Lotfy A. Source Department of Otolaryngology, King Abdulaziz University, P.O. Box 35135, Jeddah 21488, Saudi Arabia.


Objective. To illustrate the role of multislice computed tomography and local contrast instillation in the diagnosis and characterization of choanal atresia. To review the common associated radiological findings. Methods. We analyzed 9 pediatric patients (5 males and 4 females) with suspected choanal atresia by multislice computed tomography. We recorded the type of atresia plate and other congenital malformations of the skull. Results. Multislice computed tomography with local contrast installed delineated the posterior choanae. Three patients had unilateral mixed membranous and bony atresia. Three patients had unilateral pure bony atresia. Only 1 of 7 patients have bilateral bony atresia. It also showed other congenital anomalies in the head region. One patient is with an ear abnormality. One patient had congenital nasal pyriform aperture stenosis. One of these patients had several congenital abnormalities, including cardiac and renal deformities and a hypoplastic lateral semicircular canal. Of the 6 patients diagnosed to have choanal atresia, 1 patient had esophageal atresia and a tracheoesophageal fistula. The remaining patients had no other CHARGE syndrome lesions. Conclusions. Local Contrast medium with the application of the low-dose technique helps to delineate the cause of the nasal obstruction avoiding a high radiation dose to the child.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PMID 21772853


Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia

Jugessur A, Shi M, Gjessing HK, Lie RT, Wilcox AJ, Weinberg CR, Christensen K, Boyles AL, Daack-Hirsch S, Nguyen TT, Christiansen L, Lidral AC, Murray JC. PLoS One. 2010 Jul 9;5(7):e11493. PMID: 20634891

Abstract BACKGROUND: Fetal conditions can in principle be affected by the mother's genotype working through the prenatal environment. METHODOLOGY/PRINCIPAL FINDINGS: Genotypes for 1536 SNPs in 357 cleft candidate genes were available from a previous analysis in which we focused on fetal gene effects. After data-cleaning, genotypes for 1315 SNPs in 334 autosomal genes were available for the current analysis of maternal gene effects. Two complementary statistical methods, TRIMM and HAPLIN, were used to detect multi-marker effects in population-based samples from Norway (562 case-parent and 592 control-parent triads) and Denmark (235 case-parent triads). We analyzed isolated cleft lip with or without cleft palate (iCL/P) and isolated cleft palate only (iCP) separately and assessed replication by looking for genes detected in both populations by both methods. In iCL/P, neither TRIMM nor HAPLIN detected more genes than expected by chance alone; furthermore, the selected genes were not replicated across the two methods. In iCP, however, FLNB was identified by both methods in both populations. Although HIC1 and ZNF189 did not fully satisfy our stringency criterion for replication, they were strongly associated with iCP in TRIMM analyses of the Norwegian triads. CONCLUSION/SIGNIFICANCE: Except for FLNB, HIC1 and ZNF189, maternal genes did not appear to influence the risk of clefting in our data. This is consistent with recent epidemiological findings showing no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefts in these two populations. It is likely that fetal genes make the major genetic contribution to clefting risk in these populations, but we cannot rule out the possibility that maternal genes can affect risk through interactions with specific teratogens or fetal genes.

PMID 20634891


Treacher Collins syndrome: etiology, pathogenesis and prevention

Eur J Hum Genet. 2009 Mar;17(3):275-83. Epub 2008 Dec 24.

Trainor PA, Dixon J, Dixon MJ. Source Stowers Institute for Medical Research, Kansas City, MO 64110, USA.


Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development that arises as the result of mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein known as Treacle. Individuals diagnosed with TCS frequently undergo multiple reconstructive surgeries, which are rarely fully corrective. Identifying potential avenues for rescue and/or repair of TCS depends on a profound appreciation of the etiology and pathogenesis of the syndrome. Recent research using animal models has not only determined the cellular basis of TCS but also, more importantly, unveiled a successful avenue for therapeutic intervention and prevention of the craniofacial anomalies observed in TCS.

PMID 19107148

Treacher Collins syndrome: unmasking the role of Tcof1/treacle

Int J Biochem Cell Biol. 2009 Jun;41(6):1229-32. Epub 2008 Nov 5.

Sakai D, Trainor PA. Source Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.


Treacher Collins syndrome (TCS) is a rare congenital birth disorder characterized by severe craniofacial defects. The syndrome is associated with mutations in the TCOF1 gene which encodes a putative nucleolar phosphoprotein known as treacle. An animal model of the severe form of TCS, generated through mutation of the mouse homologue Tcof1 has recently revealed significant insights into the etiology and pathogenesis of TCS (Dixon and Dixon, 2004; Dixon et al., 2006; Jones et al 2008). During early embryogenesis in a TCS individual, an excessive degree of neuroepithelial apoptosis diminishes the generation of neural crest cells. Neural crest cells are a migratory stem and progenitor cell population that generates most of the tissues of the head including much of the bone, cartilage and connective tissue. It has been hypothesized that mutations in Tcof1 disrupt ribosome biogenesis to a degree that is insufficient to meet the proliferative needs of the neuroepithelium and neural crest cells. This causes nucleolar stress activation of the p53-dependent apoptotic pathway which induces neuroepithelial cell death. Interestingly however, chemical and genetic inhibition of p53 activity can block the wave of apoptosis and prevent craniofacial anomalies in Tcof1 mutant mice [Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med 2008;14:125-33]. These findings shed new light on potential therapeutic avenues for the prevention of not only TCS but also other congenital craniofacial disorders which share a similar etiology and pathogenesis.

PMID 19027870


Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function

Nat Med. 2008 Feb;14(2):125-33. Epub 2008 Feb 3.

Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, Glynn EF, Ellington L, Du C, Dixon J, Dixon MJ, Trainor PA. Source Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, Missouri 64110, USA.


Treacher Collins syndrome (TCS) is a congenital disorder of craniofacial development arising from mutations in TCOF1, which encodes the nucleolar phosphoprotein Treacle. Haploinsufficiency of Tcof1 perturbs mature ribosome biogenesis, resulting in stabilization of p53 and the cyclin G1-mediated cell-cycle arrest that underpins the specificity of neuroepithelial apoptosis and neural crest cell hypoplasia characteristic of TCS. Here we show that inhibition of p53 prevents cyclin G1-driven apoptotic elimination of neural crest cells while rescuing the craniofacial abnormalities associated with mutations in Tcof1 and extending life span. These improvements, however, occur independently of the effects on ribosome biogenesis; thus suggesting that it is p53-dependent neuroepithelial apoptosis that is the primary mechanism underlying the pathogenesis of TCS. Our work further implies that neuroepithelial and neural crest cells are particularly sensitive to cellular stress during embryogenesis and that suppression of p53 function provides an attractive avenue for possible clinical prevention of TCS craniofacial birth defects and possibly those of other neurocristopathies. Comment in Nat Med. 2008 Feb;14(2):115-6.

PMID 18246078