Tracheal agenesis (also known as tracheal atresia) is a rare

birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities ca ...

with a prevalence of less than 1 in 50,000 in which the

trachea The trachea, also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air- breathing animals with lungs. The trachea extends from the ...

fails to develop, resulting in an impaired communication between the larynx and the alveoli of the lungs. Although the defect is normally fatal, occasional cases have been reported of long-term survival following surgical intervention. The disease was first described in 1900 by Payne. To this date, it is estimated that about 200 cases have been reported and published worldwide. Several types of the disease have been described and the slight anatomical variations have resulted in the establishment of different classification systems. There are three main types of tracheal agenesis, designated Types I, II and III. In 2013, a South Korean child, Hannah Warren, born with tracheal agenesis, was successfully treated at

Children's Hospital of Illinois OSF HealthCare Children's Hospital of Illinois known simply as Children's Hospital of Illinois is a nationally ranked pediatric acute care children's hospital located within OSF Saint Francis Medical Center in Peoria, Illinois. The hospital has 14 ...

, after having been kept alive in an

intensive care unit 220px, Intensive care unit An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensi ...

for the first two and a half years of her life. An artificially created trachea was implanted, that had been created by

tissue engineering Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biolog ...

, by using a nanofiber mesh, coated with her own stem cells. Although the transplant was successful, she died three months later from other health issues. The disease has been more frequently observed in males than in females, at a ratio of 2:1.

Signs and symptoms

Observable signs and symptoms of the disease differ depending on whether the observation in done

in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albin ...

or after

parturition Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...

. Only the signs and symptoms of the embryo are described, due to the lack of research in maternal symptoms.

In utero

Tracheal agenesis - Incidence of congenital malformations

The classic in-utero symptoms of tracheal agenesis are an absence of the trachea leading to congenital high airway obstruction syndrome, lung distention, polyhydramnios, heart malformations, heart displacement and

hydrops fetalis Hydrops foetalis or hydrops fetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion is an accumulation of excessive fluid in ...

. Other congenital malformations such as

genitourinary The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathw ...

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

and

musculoskeletal The human musculoskeletal system (also known as the human locomotor system, and previously the activity system) is an organ system that gives humans the ability to move using their muscular and skeletal systems. The musculoskeletal system prov ...

anomalies are common and occur in 80% of the reported cases. Tracheal agenesis may lead to a distention of the foetus’ lung due to a build-up of pulmonary fluid within them. In this case,

ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

scans show bilaterally enlarged and homogeneously echogenic lungs as well as the inversion of both hemidiaphragms. Although lung distention has been described as a classic symptom, hypoplasia or complete aplasia of the lungs can also occur, in an estimated 26% of cases. In some cases, normal lung development was also reported in neonates with tracheal agenesis. The abnormal development of the foetus’ lungs leads to cardiovascular abnormalities. Distention of the lungs results in a compressed and displaced

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, hindering the normal growth and development of the organ. Depending on the severity of the compression of the heart, normal venous return to the organ would correspondingly be hindered, resulting in a condition known as

(also known as fetalis ascites), in which

oedema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...

form in the developing foetus.

Hydrops fetalis Hydrops foetalis or hydrops fetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion is an accumulation of excessive fluid in ...

can be observed in utero via

scan. Polyhydramnios occurs in embryos presenting with a

tracheoesophageal fistula A tracheoesophageal fistula (TEF, or TOF; see spelling differences) is an abnormal connection (fistula) between the esophagus and the trachea. TEF is a common congenital abnormality, but when occurring late in life is usually the sequela of surgic ...

as the liquid produced by the lungs supposedly pass to the stomach, in the amniotic fluid.

At birth

More than half of the recorded cases of tracheal agenesis have led to

premature Premature may refer to: * ''Premature'' (2014 film), an American comedy film * ''Premature'' (2019 film), an American romantic drama film * '' PREMature'', a 2015 British television drama miniseries See also * Premature aging, of an organism * ...

deliveries and in almost all reported cases, infants die shortly after birth due to lack of oxygenation. Neonates with tracheal agenesis present with symptoms characteristic to congenital high airway obstruction syndrome with no audible cry after birth, respiratory insufficiency,

respiratory distress Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...

and cyanosis. No trachea is palpable below the cricoid cartilage.

Causes

The exact causes of tracheal agenesis remain unknown. Different embryological theories have arisen to explain the congenital development of the disease.

Embryological causes

The relative similarities between the different subtypes of the disease suggest that there is a common stage at which the development is hindered. In normal embryogenesis, the trachea differentiates from the foregut during the fourth week of gestation. The

respiratory diverticulum The lung bud sometimes referred to as the respiratory bud forms from the respiratory diverticulum, an embryological endodermal structure that develops into the respiratory tract organs such as the larynx, trachea, bronchi and lungs. It arises ...

, a ventral projection formed from the foregut, appears. Eventually, the

tracheoesophageal ridges The tracheoesophageal septum is an embryological structure. It is formed from the tracheoesophageal folds or ridges which fuse in the midline. It divides the oesophagus from the trachea during prenatal development. Developmental abnormalities ca ...

will fuse to form a septum. The laryngotracheal tube will then fully separate from the foregut. Two primary bronchial buds form at the end of the tube, which then elongates to form the trachea. The buds then branch to form the bronchi, lungs and alveolar tissue. The development of the respiratory tract is closely associated to that of the

oesophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to th ...

. Both organs regulate each other’s growth via molecular interactions. In tracheal agenesis, a delay in the development of the primary bronchial buds causes a transient arrest in the growth of the laryngotracheal tube, hindering the normal development of the trachea. The failure of the lung buds to develop from the primitive foregut leads to tracheoesophageal malformations. The development of the buds occurs after the elongation of the oesophagus, causing a dissociation in the growth of the two organs. Due to this dissociation, the buds directly develop to form the lungs, without forming the trachea, resulting in tracheal agenesis. Different degrees of this malformation result in different types of tracheal agenesis.

Genetic determinants

No clear genetic pattern or karyotype has been established to support the development of tracheal agenesis. The genes that have been postulated to influence the development of the disease are all associated to the congenital development of the lungs, trachea and oesophagus. These are

BMP-4 Bone morphogenetic protein 4 is a protein that in humans is encoded by ''BMP4'' gene. BMP4 is found on chromosome 14q22-q23. BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfam ...

BMPR1A The bone morphogenetic protein receptor, type IA also known as BMPR1A is a protein which in humans is encoded by the ''BMPR1A'' gene. BMPR1A has also been designated as CD292 (cluster of differentiation 292). Function The bone morphogenetic pr ...

and

BMPR1B Bone morphogenetic protein receptor type-1B also known as CDw293 (cluster of differentiation w293) is a protein that in humans is encoded by the ''BMPR1B'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gen ...

, Gli2 and

Gli3 Zinc finger protein GLI3 is a protein that in humans is encoded by the ''GLI3'' gene. This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription ...

, sonic hedgehog and

NK2 homeobox 1 NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the ''NKX2-1'' gene. Function Thyroid transcription factor-1 (TTF-1) is a protein that regulates transcription of genes ...

. It is highly likely that tracheal agenesis results from the mutation of several of these genes.

is an important signalling molecule in the early development of the embryo.

null mutations in the foregut endoderm and in its surrounding mesoderm results in atresia of the trachea and under developed lungs. The Bmp family restricts the site of formation of lung buds as well as to induce cell proliferation via the suppression of Sox2. Gli2 and

null mutations were also found to result in delayed lung, tracheal and oesophageal development. The two signalling molecules are implicated in the mediation of Sonic hedgehog signalling, which regulates the proliferation and differentiation of the

and lungs. In mice,

null mutation results in a significantly shorter

, connected to the

via a

. In embryos with a homozygous mutated

locus, the tracheoesophageal ridges fail to fuse and form a septum.

Diagnosis

The diagnosis of the disease is dependent on observable signs and symptoms and on the stage of gestation. There are two ways to diagnose tracheal agenesis: early

, or later at

birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...

. Recognisable clinical patterns are associated with tracheal agenesis. Most commonly, the in-utero diagnosis of the disease requires using

radiography Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeu ...

and

scans. At birth, the diagnosis is suspected clinically through the observations of characteristic signs and symptoms of the disease. Tracheal agenesis should be suspected when tracheal intubation is impossible. The confirmation of the diagnosis relies on results of endoscopic laryngoscopies and oesophagoscopies at birth.

X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

studies are necessary to determine the class and the severity of the disease. CT scans remain an option to provide more information if required.

Classification

Tracheal agenesis is classified according to anatomical subtypes. Different classifications exist but the universally accepted one, by Floyd and colleagues in 1962, distinguishes three anatomical subtypes: type I, II and III.

Type I

Type I is described as tracheal atresia, rather than tracheal agenesis. The trachea is absent proximally but there remains a short normal segment of the distal trachea. A

links the distal segment of the proto

to the

. It is estimated that 13% of cases of the disease are of type I.

Type II

Type II tracheal agenesis is the most common form of the disease, estimated to appear in 60% of cases. Type II is characterised by a complete absence of the

. The

bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...

are normal and fuse at the

carina Carina may refer to: Places Australia * Carina, Queensland, a suburb in Brisbane * Carina Heights, Queensland, a suburb in Brisbane * Carina, Victoria, a locality in Mildura Serbia * Carina, Osečina, a village in the Kolubara District ...

. In most cases, the

and the carina are joined by a

fistula A fistula (plural: fistulas or fistulae ; from Latin ''fistula'', "tube, pipe") in anatomy is an abnormal connection between two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other hollow or ...

Type III

In type III tracheal agenesis, the trachea is completely absent and the bronchi develop individually, originating from the oesophagus directly and without joining at the carina. No tracheoesophageal fistula is present in this case as the trachea is completely absent. It is estimated that 27% of all cases are type III.

Other classifications

In 1979, Faro described seven types of tracheal agenesis (A-G). This classification system differs from Floyd’s early propositions as it encompasses a more detailed description of the disease, including the surrounding organs such as the larynx and the lungs. The importance of this more detailed classification system is that the presence of surrounding organs, such as the larynx, might alter the observed symptoms of the traditionally defined tracheal agenesis. For example, neonates with a larynx might emit a faint cry at birth, while those with complete agenesis of the trachea and of the larynx will not. Acknowledging these different anatomical subtypes allows for a more comprehensive diagnosis and better management of the disease. Faro type A describes a total pulmonary agenesis, in which none of the

respiratory organs The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gre ...

are present. Type B is comparable to Floyd’s type III and describes complete agenesis of the

, with no joining of the

. Faro type C describes total agenesis of the trachea with normal bronchi fusing at the

. A

is present and links the carina to the oesophagus. In Faro type D, the larynx is joined to the distal trachea and a

links the carina to the

. Faro type E is comparable to Floyd’s type I, as the distal trachea is present and joined to the oesophagus via a fistula. Faro type F describes the proximal absence of the trachea but the normal presence of the distal trachea. In this case, the trachea is not attached to the oesophagus. In Faro type G, a segment of the trachea is absent, defining it as partial tracheal agenesis.

Management

In patients with tracheal agenesis, surgical correction is required to allow for a relatively temporary survival of the neonate.

Tracheal intubation Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs. It is frequentl ...

is proven to be impossible in almost all cases. In most cases, if surgery is unsuccessful, severe

asphyxia Asphyxia or asphyxiation is a condition of deficient supply of oxygen to the body which arises from abnormal breathing. Asphyxia causes generalized hypoxia, which affects primarily the tissues and organs. There are many circumstances that ca ...

results in the death of the neonate, on average two days after birth. The longest survival ever reported was six years.

References

External links

{{Medical resources , ICD10 = Q32.1 , ICD9 = , ICDO = , OMIM = , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = C536975 , GeneReviewsNBK = , GeneReviewsName = , Orphanet = 3346 Congenital disorders of respiratory system