Introduction

The branchial arches are embryologic structures that develop into anatomic structures in the adult human. The term “branchial” derives from the Latin “branchia,” meaning gills, and is used to describe the development of many species of fish and amphibia. Therefore, the term “branchial arches” is alternatively named “pharyngeal arches” to more accurately describe human anatomy. The branchial arches give rise to the lower face, neck, and part of the upper thorax, while the frontonasal prominence gives rise to the forehead and nose. The adult structures formed by the branchial arches are the result of contributions from the primary germ layers, including endoderm, mesoderm, ectoderm, and neural crest cell derivatives. Failure of the branchial arches to correctly develop results in anatomical, developmental defects manifesting in many ways that will be detailed further below.[1]

Development

The branchial arches that develop in humans include arches 1 through 6. Branchial arch 5 involutes during development and does not contribute to the formation of adult structures. Branchial arches 1 and 2 are referred to as the mandibular and hyoid arches, respectively. Each of the arches is lined internally by endoderm and externally by ectoderm tissue. Between the endoderm and ectoderm lies the mesenchyme, composed of both mesoderm and neural crest tissue. The adult structures that derive from the individual germ cell layers will be covered in the following section.

The approximation of ectoderm and endoderm between consecutive arches results in the formation of pharyngeal clefts and pharyngeal pouches. 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 each are described below and in further detail in the following sections.

Pharyngeal Clefts

The anatomic space formed by the first pharyngeal cleft between the first and second branchial arches gives rise to the adult external auditory meatus. The space created by the second, third, and fourth pharyngeal clefts gives rise to the adult cervical sinus.

Pharyngeal Pouches

The first pharyngeal pouch between the first and second branchial arches gives rise to the primitive tympanic cavity and auditory tube. The second pharyngeal pouch gives rise to the adult palatine tonsil. The third pharyngeal pouch paradoxically forms the inferior parathyroid glands and thymus, while the fourth pharyngeal pouch forms the superior parathyroid glands and the ultimobranchial body.[1][2][3]

Cellular

The development of the branchial arches relies on contributions from endoderm, mesoderm, ectoderm, and neural crest cells (NCC), which facilitate the development of individual structures. This section will describe the individual contributions from each germ cell layer.

Endoderm

The endoderm of the branchial arches develops into endocrine viscera of the neck, including the thymus, thyroid, and parathyroid glands.

Mesoderm

The mesoderm germ cell layer forms adult vasculature and musculature structures from endothelial cells and myoblasts, respectively, in the head, neck, and upper thorax. The importance of the vascular system to overall bodily function necessitates its early development in embryogenesis. The first major vessels to develop embryologically include the left and right dorsal aortae that connect the heart and umbilical arteries. While it is true that the scaffold of arterial tubes consisting of endothelial cells derives from mesoderm tissue, mural cells, including pericytes and smooth muscle cells of the arterial wall, arise from NCC derivatives. The vascular system initially forms symmetrically and eventually remodels through a series of apoptotic regressions to depict the mature vasculature seen in adult anatomy.

Ectoderm

Ectoderm derivatives can subdivide into the medial and lateral domains. The medial domain of neural ectoderm gives rise to nervous system derivatives, while the lateral domain of surface ectoderm gives rise to the skin. The neural ectoderm generates NCC that migrate to either the frontonasal prominence or branchial arches to give rise to the bones of the skull, jaw, ear, as well as cartilage found in the head and neck. The peripheral nervous system itself derives from a dual origin of surface ectoderm and NCC.[1][2][4]

Molecular Level

The molecular basis underlying the formation of the branchial arch derivatives is dependent on a vast array of genes that facilitate proper growth. This section will highlight many of the important genes identified in this process.

Homeobox (Hox) genes are a group of genes that serve to facilitate proper growth and segmentation along an anterior-posterior axis. These genes express in branchial arches 2 through 6, and each arch associates with an individual group of Hox genes. Transcription regulation of Hox genes throughout development is influenced heavily by retinoic acid (RA) and its interaction with retinoic acid response elements (RARE) found in the promoter region of Hox genes.

Dlx genes help to establish the pattern and polarity of both neural crest cell-derived facial bones and the first branchial arch. Similar to the relationship of RA to Hox genes, endothelin signaling serves to regulate Dlx gene expression as an upstream regulator. Studies involving various Dlx gene deletions in mice suggest that regulation of the formation of the lower jaw is by Dlx transcription factor activity.

Fibroblast growth factor (Fgf) is another signaling regulator that plays a role in pharyngeal segmentation and lateral migration of endodermal cells. This process helps to facilitate the formation of pharyngeal pouches through the evagination of the endoderm tissue towards the ectoderm. This process of endodermal tissue migration is referred to as 'outpocketing' and is crucial for branchial arch segmentation through the approximation of endoderm and ectoderm.[1][5][6]

Function

This section will describe the derivatives of the clefts, arches, and pouches of the various branchial arches, including cranial nerves that contribute to proper anatomical function in adults.

First branchial arch:

• Cleft: external auditory canal
• Arch: mandible, incus, malleus, muscles of mastication, cranial nerves (CN) V2 and V3
• Pouch: eustachian tube, mastoid air cells
• Nerve: maxillary nerve and mandibular branches of the trigeminal nerve (CN V2 & V3)

Second branchial arch:

• Cleft: cervical sinus
• Arch: stapes, the body of the hyoid, lesser horn of hyoid, muscles of facial expression, and CNVII
• Pouch: palatine tonsil
• Nerve: facial nerve (CN VII)

Third branchial arch:

• Cleft: cervical sinus
• Arch: the body of the hyoid, greater horn of hyoid, superior constrictor muscles, internal carotid arteries, CNIX
• Pouch: thymus, piriform recess, inferior parathyroid glands
• Nerve: glossopharyngeal nerve (CN IX)

Fourth branchial arch:

• Cleft: cervical sinus
• Arch: thyroid/cuneiform cartilages, CN X, aortic arch, right subclavian artery, various laryngeal muscles
• Pouch: apex of piriform sinus, superior parathyroid glands
• Nerve: vagus nerve (CN X), superior laryngeal nerve

Fifth and Sixth branchial arches[2]:

• Cleft: None
• Arch: Inferior pharyngeal constrictors, CN XI, various laryngeal muscles
• Pouch: parafollicular C cells of the thyroid
• Nerve: vagus nerve (CN X), recurrent laryngeal nerve

Pathophysiology

The pathophysiology of branchial arch malformations spans a broad and complex range. Anomalies are detectable in isolation from other issues, or part of a more extensive developmental syndrome, including DiGeorge syndrome, auriculocondylar syndrome, Pierre Robin syndrome, Treacher Collins syndrome, or velocardiofacial syndrome, among many others. This article will focus on the most common isolated defects associated with branchial arch derivatives in the following section rather than the complex syndromes of craniofacial developmental.[2]

Clinical Significance

Failure of the branchial arches to properly develop results in a myriad of physical manifestations. This section will describe many of the most common congenital craniofacial malformations resulting from branchial arch dysfunction. The majority of branchial cleft malformations involve the first and second arch complexes.  

Facial clefting, most commonly seen as cleft lip or palate, is the most common congenital craniofacial malformation and second only to clubfoot in the overall incidence of birth anomalies. The pathophysiology of facial clefting appears to be multifactorial, containing both a genetic and environmental component. The malformation itself results from a failure of fusion between adjacent structures in the developing face and can present in varying degrees of severity, in combination, or isolation. The defect itself is often corrected surgically when available — the failure of surgical correction of facial clefting results in an increased incidence of serious infection leading to death.

Auricular atresia is another disorder that shows varying degrees of phenotypic presentation based on the severity of the malformation. Anomalies of auricular atresia can affect any part of the auditory transduction system, including the auricle, external auditory canal, middle ear, and inner ear. The varying severity of this disorder can result in a wide range of both audiological and cosmetic manifestations.

Micrognathia refers to the improper development of the mandible leading to a hypoplastic mandible. This defect most often associates with an identified syndrome of developmental defects, including Pierre Robin syndrome consisting of the classic triad, including micrognathia, glossoptosis (posterior displacement of the tongue base), and upper airway obstruction from both anomalies as mentioned above. The degree of micrognathia causing dysfunction of normal physiological processes, including breathing and swallowing, determines the necessity of surgical intervention and correction.

Branchial cleft cysts result from incomplete or persistent development of embryonic tissue in the head and neck. This condition can manifest in many ways, including the formation of an isolated cyst, fistulous tract, or sinus tract. Second branchial cleft cysts are seen most commonly and manifest as a fluctuant lateral cervical mass most often anterior to the sternocleidomastoid muscle. These masses are often surgically excised in the first few decades of life, as their growth can lead to breathing or swallowing difficulties as well as creating a nidus for infection. Branchial cleft cyst diagnosis is usually by CT or MRI and only surgically excised in the absence of infection. Incomplete excision of a branchial cleft cyst can lead to further growth and recurrence, necessitating subsequent surgical resection.[2][7][4][8]