A face is unique to each person and is the basis of their own identity. However, the embryological origin is the same for all humans and is similar to other mammals. The development is complex and involves the formation and coordination of various tissues to form the final product. The functions of a face (and head) include hearing, vision, breathing, tasting, feeding, facial expression, and many more. Facial development happens very early during embryogenesis, and facial abnormalities can often be disfiguring and devastating. Treatment is often delayed until after the birth when the patient is stable. Some facial disorders are preventable and caused by teratogens; patients are therefore strongly discouraged from ingesting harmful substances or participating in risky behavior if they are pregnant or believe they may be pregnant. This activity will provide a brief overview of the embryology of facial development and some related pathologies.
The oropharyngeal membrane (where the face will eventually form) can already be seen on the embryo as early as week three, between the enlarging areas of the heart and the brain. Facial embryology begins between weeks four and eight and involves a series of highly coordinated events based on preprogrammed data in cellular DNA. The process includes all the primary embryonic tissues, the ectoderm, endoderm, mesoderm.
The oropharyngeal membrane is surrounded by several prominences (processes) that will eventually give rise to the face.
The nasal placodes are two ectodermal thickenings that appear at the end of the fourth week on the frontonasal processes. These are precursors to the olfactory epithelium. The fifth week, the nasal placodes will be surrounded by the lateral and medial nasal swellings on the frontonasal process. Simultaneously, the maxillary processes from the mandibular branch of the 1st pharyngeal arch will develop and surround the oral cavity. The lower jaw will be formed early as a result of the two mandibular processes. The maxillary processes will also grow and meet the lateral nasal processes and extend midline to meet the medial nasal processes. This fusion with the medial nasal process will form the inter-maxillary process and result in the eventual formation of the philtrum of the upper lip. If this fusion does not occur properly, an orofacial cleft may develop in the newborn. In the fifth week, the oropharyngeal membrane disintegrates, leaving behind a communication between the digestive tract and the external environment.
Additionally, the eyes initially are located on the side of the head but eventually face forward as the rest of the head grows and develops. By the end of developmental week seven, the embryo will have facial features that have a human appearance.
The palate is the tissue between the nasal and oral cavity and is separated in the primary and secondary palates. By the 6th week, the inter-maxillary segment is formed from the fusion of the paired medial nasal prominences and the maxillary prominences. This epithelium will make the core of the primary palate, and posteriorly the nasal epithelium will touch the oral epithelium making the oro-nasal membrane. Importantly, in the posterior region, the membrane will form an opening called the primitive choana that connects the oral cavity to the nasal cavity. The primary palate will also give rise to the anterior triangular one-third from the incisive foramen and include the four upper incisors.
The secondary palate forms the rest of the hard palate and all of the soft palate and develops during the seventh and eighth weeks. It forms from two palatal shelves (medial outgrowths of the maxillary processes) that grow downward and parallel to the tongue. By the eighth week's end, the two secondary palatal processes fuse and with the primary palate to form the definitive palate. During this same time, the nasal septum grows to separate the left and right nasal passages, and its inferior portion will combine with the definitive palate.
It follows that if proper formation and fusion of the palates are necessary for healthy development and disruption may cause a cleft palate. Significant mechanisms that can cause a cleft palate include growth retardation and mechanical obstruction.
Formed during the fourth week of development, consists of a mesenchymal tissue covered externally by ectoderm and internally by endodermal epithelium.
The pharyngeal clefts are produced from the approximation of ectodermal tissue between consecutive arches, while the pharyngeal pouches form from the approximation of endodermal tissue between consecutive arches. Derivatives of the apparatus relevant during facial development are described below:
1st: maxillary (V2) and mandibular (V3) branches of the trigeminal nerve (CNV), mandible, incus, malleus, muscles of mastication, maxillary artery, sphenomandibular ligament, the Meckel cartilage.
2nd: Facial nerve (CNVII), stapes, the body of the hyoid, lesser horn of hyoid, muscles of facial expression.
3rd: Hypoglossal nerve (CNIX), the body of the hyoid, greater horn of hyoid, stylopharyngeus muscle.
4th: superior laryngeal branch of the vagus nerve (CNX), thyroid, cricoid, arytenoid, cuneiform cartilage, levator veli platini, cricothyroid muscle.
6th: recurrent branch of the vagus nerve (CNX), thyroid, cricoid, arytenoid, cuneiform cartilage, larynx intrinsic muscles.
Cranial neural crest cells or multipotent cells are fundamental for the development of facial tissues: bones, teeth, cartilage, connective tissue, and more. The cranial neural crest cells derive from the ectoderm leaflet from the dorsal midline portion. The cranial neural crest cells migrate towards pharyngeal arches and the frontonasal process; in this way, the tissues of the skull and the upper cervical tract form. In this event play critical role signaling pathways such as BMPs (bone morphogenic proteins); FGF (fibroblast growth factor); SHH (sonic hedgehog); WNT (wingless-related integration site). The ectodermal leaflet at week four covers the stomodeum, which ectoderm comes into contact with the endoderm leaflet, due to the development of the oropharyngeal membrane. During the fifth week, the ectoderm meets the mesoderm to start forming the nasal processes. Between the fourth and fifth week, the cells of the three main sheets meet to develop the different structures of the face.
The mechanism of chemical waves plays a vital role in the development process, that is, of mechanical-chemical information that transports information from one cell to another quickly. These waves or signals are patterns that help tissue morphogenesis. Probably, the management and initiation of these waves occur via chemical reactions at the centrosome level (MTOC - microtubule organizing center).
The ectodermal placodes, from which future sense organs and cranial ganglia will form, develop different molecular responses; in anterior areas, coding molecules will express as Pax (paired box protein), Six3 (homeobox protein SIX3), and Otx2 (homeobox protein OTX2). In the posterior portion of the placodes, we will find other molecules such as Irx1 / 2/3 (Iroquois-class homeodomain protein IRX-1) and Gbx2 (homeobox protein GBX-2). These proteins will help develop specific genes for specific functions.
For example, Pax6 will be more concentrated in the developmental areas of the sense of smell and the lens, while Pax3 and Pax2/8 will help to develop the trigeminal ganglia and the hearing area.
The face musculature arises from prechordal mesenchyme and the unsegmented paraxial mesoderm. The prechordal mesenchyme derives from the prechordal plate, which is in front of and on the tip of the anterior notochord. The musculature will have multiple functions, including feeding, relaxing, breathing, and more.
The pathophysiology of facial development malformations can have many external and internal causes that span a complex range that can be due to genetic and environmental causes. Maternal factors include fetal alcohol syndrome, uterine growth restriction, oligohydramnios, maternal infections. Disordered facial development may be a part of more extensive syndromes such as Pierre Robin syndrome, Treacher Collins syndrome, Fragile-X syndrome, Down syndrome, DiGeorge syndrome, and many others. This article will focus on the most common cause of facial abnormalities and appropriate management.
An orofacial cleft can carry links to genetic and environmental factors. It has been known to run in families, and several genes are involved, including the CLPTM1, PVRL1, GABRB3 genes. Cleft palates have also been known to occur as part of other syndromes, including Treacher Collins syndrome, Stickler syndrome, and Loeys-Dietz syndrome. Environmental factors have been found to result in clefts, such as fetal hypoxia from maternal smoking, alcohol abuse, maternal anticonvulsant therapy, and retinoid (vitamin A) intake.
Holoprosencephaly (HPE) occurs with forebrain midline defects due to the lack of separation of the two cerebral hemispheres; this pathology leads to facial midline defects. The defect results from the alteration of the class of bone morphogenic proteins (BMPs).
There are many abnormalities associated with head and facial development that can be due to genetic, environmental, and other causes. Any facial abnormality should prompt clinicians to search for other defects as they often occur as a part of syndromes. Therefore, a full exam, including the heart, lungs, rectal, ophthalmologic, and skin exam, should be done.
Clinically, one of the most common abnormalities seen is an oral cleft, in the form of a cleft lip, cleft palate, or a combination of both. According to the world health organization, an oral cleft abnormality occurs in about one in every 700 live births worldwide. It is the second most common congenital disability in the United States, affecting one in 940 births and 4437 cases every year (cleft lip with or with cleft palate). The diagnosis is made clinically upon birth, but can also be done via ultrasonography in utero at an OB/GYN office. Complications of orofacial clefts can include feeding difficulties, speech, and cognition depending on the severity. Although the kind of treatment depends on the type and severity of the condition, the definitive treatment is surgery.
During fetal development, the oro-nasal membrane (choana) normally recanalizes. Failure of this process can result in blockage of the nasal passage by abnormal tissue. This anomaly may be seen associated with other defects remembered by the mnemonic CHARGE (coloboma, heart disease, atresia choanae, retarded growth and retarded development and/or CNS anomalies, genital hypoplasia, and ear anomalies). The presentation of choanal atresia can differ based on the severity and the involvement of either one or both nasal passages. Unilateral choanal atresia many go undetected because the newborn manages to breathe with the normal nostril. However, the bilateral blockage can be life-threatening, and the baby may present with cyanosis during feeds as the baby will be unable to use their mouth to compensate for breathing. The cyanosis improves when the baby cries. A diagnostic tool is the inability to pass a nasogastric tube due to blockage of the nasal passageway and confirmed with a CT scan. The only definitive treatment is the correct the defect surgically.
|||Som PM,Naidich TP, Illustrated review of the embryology and development of the facial region, part 1: Early face and lateral nasal cavities. AJNR. American journal of neuroradiology. 2013 Dec; [PubMed PMID: 23493891]|
|||Grindley JC,Davidson DR,Hill RE, The role of Pax-6 in eye and nasal development. Development (Cambridge, England). 1995 May; [PubMed PMID: 7789273]|
|||Johnson JM,Moonis G,Green GE,Carmody R,Burbank HN, Syndromes of the first and second branchial arches, part 1: embryology and characteristic defects. AJNR. American journal of neuroradiology. 2011 Jan; [PubMed PMID: 20299437]|
|||Stampalija T,Quadrifoglio M,Casati D,Zullino S,Maggi V,Di Martino D,Rosti E,Mastroianni C,Signorelli V,Ferrazzi E, First trimester placental volume is reduced in hypertensive disorders of pregnancy associated with small for gestational age fetus. The journal of maternal-fetal [PubMed PMID: 31232131]|
|||Jones NC,Lynn ML,Gaudenz K,Sakai D,Aoto K,Rey JP,Glynn EF,Ellington L,Du C,Dixon J,Dixon MJ,Trainor PA, Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nature medicine. 2008 Feb; [PubMed PMID: 18246078]|
|||Wilson DI,Burn J,Scambler P,Goodship J, DiGeorge syndrome: part of CATCH 22. Journal of medical genetics. 1993 Oct; [PubMed PMID: 8230162]|
|||Turhani D,Item CB,Watzinger E,Sinko K,Watzinger F,Lauer G,Ewers R, Mutation analysis of CLPTM 1 and PVRL 1 genes in patients with non-syndromic clefts of lip, alveolus and palate. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2005 Oct; [PubMed PMID: 16122939]|
|||Scapoli L,Martinelli M,Pezzetti F,Carinci F,Bodo M,Tognon M,Carinci P, Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Human genetics. 2002 Jan; [PubMed PMID: 11810291]|
|||Rodrigues VJ,Elsayed S,Loeys BL,Dietz HC,Yousem DM, Neuroradiologic manifestations of Loeys-Dietz syndrome type 1. AJNR. American journal of neuroradiology. 2009 Sep; [PubMed PMID: 19556353]|
|||Stanier P,Moore GE, Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Human molecular genetics. 2004 Apr 1; [PubMed PMID: 14722155]|
|||Pagon RA,Graham JM Jr,Zonana J,Yong SL, Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. The Journal of pediatrics. 1981 Aug; [PubMed PMID: 6166737]|