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Pharyngeal pouches are endodermal outpockets occurring between the pharyngeal arches in embryological development. Various transcription factors regulate the mechanical bending of the endodermal tube, resulting in pharyngeal pouch formation.[1] The pouches give rise to tissues responsible for the formation of the middle ear cavity and eustachian tube, the palatine tonsils, the thymus, the parathyroid glands, and the parafollicular cells of the thyroid. Malformations in the development of the pharyngeal pouches can cause DiGeorge syndrome, branchio-oto-renal (BOR) syndrome, cyst formation in the neck, and concerns related to the respective structures of individual pouches. Proper pharyngeal pouch formation is essential for the separation of individual pharyngeal arches and for proper organismal development during embryogenesis.[2]

The pathophysiology of pharyngeal pouch malformations covers a broad range of diagnoses due to various derivatives of each pouch. The most recognizable anomalies in pharyngeal pouch development, which cause DiGeorge syndrome, branchio-oto-renal syndrome, and congenital cysts, are discussed below. DiGeorge syndrome results from a 22q11.2 chromosomal microdeletion, leading to malformations in derivatives of the third and fourth pharyngeal pouches. DiGeorge syndrome is the most common microdeletion syndrome in humans, with a prevalence of 1 in every 2000 to 4000 newborns.[16] A myriad of clinical presentations characterize this syndrome as a result of microdeletion heterogeneity on chromosome 22. The more standard disease presentations include cardiac defects, thymic hypoplasia, abnormal faces, cleft palate, and hypocalcemia.[12] The cardiac defects result from neural crest cell migration to the third and fourth pharyngeal pouches during embryonic development, leading to tetralogy of Fallot, ventricular septal defect, truncus arteriosus, or interrupted aortic arch.[15] About 25% of patients with DiGeorge syndrome present with aortic arch abnormalities. Characteristic facial features in individuals with DiGeorge syndrome are micrognathia, low-set ears, a small upper lip, and a smooth philtrum. Less common facial features include a cleft palate and a bifid uvula. Malformation of the third and fourth pharyngeal arches results in thymic and parathyroid hypoplasia. Hypoplasia of the parathyroid gland results in a lack of parathyroid hormone production, thereby disrupting calcium homeostasis. In response to low serum calcium, parathyroid hormone is secreted from the gland, acting on bone, the intestines, and the kidneys to increase serum calcium levels. The loss of parathyroid hormone function in the kidneys results in increased urinary calcium resorption and phosphate retention. Thymic agenesis results in the absence of functional T-cells, leading to recurrent viral and fungal infections in infancy and early childhood.[17][18]

The pathophysiology of pharyngeal pouch malformations covers a broad range of diagnoses due to various derivatives of each pouch. The most recognizable anomalies in pharyngeal pouch development, which cause DiGeorge syndrome, branchio-oto-renal syndrome, and congenital cysts, are discussed below. DiGeorge syndrome results from a 22q11.2 chromosomal microdeletion, leading to malformations in derivatives of the third and fourth pharyngeal pouches. DiGeorge syndrome is the most common microdeletion syndrome in humans, with a prevalence of 1 in every 2000 to 4000 newborns.[16] A myriad of clinical presentations characterize this syndrome as a result of microdeletion heterogeneity on chromosome 22. The more standard disease presentations include cardiac defects, thymic hypoplasia, abnormal faces, cleft palate, and hypocalcemia.[12] The cardiac defects result from neural crest cell migration to the third and fourth pharyngeal pouches during embryonic development, leading to tetralogy of Fallot, ventricular septal defect, truncus arteriosus, or interrupted aortic arch.[15] About 25% of patients with DiGeorge syndrome present with aortic arch abnormalities. Characteristic facial features in individuals with DiGeorge syndrome are micrognathia, low-set ears, a small upper lip, and a smooth philtrum. Less common facial features include a cleft palate and a bifid uvula. Malformation of the third and fourth pharyngeal arches results in thymic and parathyroid hypoplasia. Hypoplasia of the parathyroid gland results in a lack of parathyroid hormone production, thereby disrupting calcium homeostasis. In response to low serum calcium, parathyroid hormone is secreted from the gland, acting on bone, the intestines, and the kidneys to increase serum calcium levels. The loss of parathyroid hormone function in the kidneys results in increased urinary calcium resorption and phosphate retention. Thymic agenesis results in the absence of functional T-cells, leading to recurrent viral and fungal infections in infancy and early childhood.[17][18] Branchio-oto-renal syndrome is an autosomal dominant disease that produces cyst formation in branchial arch remnants, auricular malformations, and renal anomalies.[19] The EYA1 gene on chromosome band 8q13.3 is expressed in pharyngeal pouches and brachial clefts, explaining anomalies outside the pharyngeal pouch derivatives. Branchial cleft malformations are responsible for the presentation of cysts, fistulas, or pits. Expression of EYA1 during pharyngeal pouch formation is responsible for middle ear anomalies, which contribute to cochlear anomalies and hearing loss in BOR syndrome.[20] Additionally, Eya1 is expressed in the kidney mesenchyme, leading to renal abnormalities ranging from hypoplasia to agenesis. Less severe renal malformations can present as end-stage renal disease later on in life.

Branchio-oto-renal syndrome is an autosomal dominant disease that produces cyst formation in branchial arch remnants, auricular malformations, and renal anomalies.[19] The EYA1 gene on chromosome band 8q13.3 is expressed in pharyngeal pouches and brachial clefts, explaining anomalies outside the pharyngeal pouch derivatives. Branchial cleft malformations are responsible for the presentation of cysts, fistulas, or pits. Expression of EYA1 during pharyngeal pouch formation is responsible for middle ear anomalies, which contribute to cochlear anomalies and hearing loss in BOR syndrome.[20] Additionally, Eya1 is expressed in the kidney mesenchyme, leading to renal abnormalities ranging from hypoplasia to agenesis. Less severe renal malformations can present as end-stage renal disease later on in life. Congenital cysts arising from the development of the third and fourth pharyngeal arches can present in newborns. The cysts tend to be large and filled with fluid and air, displacing organs such as the trachea and esophagus anteriorly because of their location in the anterior neck. In some cases, cysts adhere to organs such as the thyroid gland, while in others, abscesses form, compressing the airway and causing respiratory distress.[21]