OA/TOF can sometimes run in families. The role of a clinical geneticist is to give advice to families on the likelihood that a medical condition that has happened once could happen again in the same family. This requires knowledge of the precise diagnosis, and clinical geneticists are often concerned with achieving this important step. Fully understanding the diagnosis is vital before the question of what caused the condition can be addressed.
Sometimes DNA analysis reveals the precise genetic change that has led to the condition, and this can be the basis for a pre-natal genetic test carried out on an unborn child. Alternatively – and just as likely – the genetic basis of a condition may be poorly understood or not known, in which case a geneticist has to rely on other sources of information to provide the family with a recurrence risk.
Although oesophageal atresia and tracheo-oesophageal fistula refer to two different malformations, for the purposes of genetic counselling they can be considered the same. Either separately or together, OA and/or TOF occur with an incidence of approximately 1 in 3,500 births. There is no difference in the incidence in boys and girls.
In around half of cases additional malformations are present, most commonly a congenital heart malformation. Malformations of the vertebral column, kidneys and limbs also occur, and may lead to a diagnosis of VACTERL association.
Where additional features such as these are present, geneticists refer to this as syndromic OA/TOF, whereas OA/TOF occurring in the absence of other anomalies is known as isolated. (215)
It is useful to classify OA/TOF into different groups based on what we currently know about possible causes. The first two in the list below are non-genetic causes, the remainder are genetic causes. These causative factors are summarised in the table below.
OA/TOF may occur because of an exposure to a substance known to be damaging during early development.
This would have to occur during the first few weeks of pregnancy. Alcohol, certain drugs (an example is the anti-thyroid drug methimazole) and exposure to high levels of glucose in a mother with poorly controlled diabetes are all known examples.
The case of maternal diabetes is actually a likely rather than a definitely proven example. Poorly controlled diabetes is known to be associated with a high risk of several congenital malformations, including spina bifida and mal- formations of the heart. Direct evidence for an increased incidence of OA/TOF is lacking, but neither has the possibility been excluded.
This may be an under-appreciated cause of many different congenital malformations, including OA/TOF.
Data from one study showed that a child from a twin pregnancy is nearly three times more likely to have OA/TOF than a child from a singleton pregnancy.
Why this should be the case is not fully understood, perhaps to do with the blood supply to the twins, has been suggested as the cause, but the reason is not really understood at all.
It is possible that some cases of OA/TOF occur in one twin where the co-twin was lost at an early stage of pregnancy, and whose existence may not have been appreciated either by the mother or the doctors looking after her.
The incidence of significant bleeding in the first trimester of pregnancy, followed by the delivery of a child with OA/TOF could signify that a twin had been lost early in pregnancy, although obtaining proof in this situation can be difficult if not impossible. (215)
Syndromic or isolated TOF?
|Proportion of OA/TOF cases|
Maternal diabetes, exposure to medicines in pregnancye.g. methimazole
|Usually syndromic, possibly some isolated cases?||Likely low proportion, but not really known|
|Twinning||Identical twins; apparently singleton pregnancy with possible early pregnancy loss||Not known||Likely low proportion, but not really known|
|Chromosomal diagnosis||Down’s syndrome (trisomy 21) Edwards syndrome (trisomy 18||Always syndromic||Around 5%|
|Single gene disorder||See table below||Syndromic||Likely <1%|
|Unknown cause||The majority of cases of OA/TOF||More likely to be isolated OA/TOF||Majority|
Table showing different categories of causes for OA/TOF
Around 10% of cases of OA/TOF occur in children with a chromosome imbalance. This is usually either Down’s syndrome (three copies of chromosome 21 instead of the usual two, also called trisomy 21) or Edwards syndrome (trisomy 18). A small proportion of cases are due to disorders of other chromosomes; for example, loss of genetic material from chromosome number 17 has been associated with OA/TOF.
Trisomy 21 Down’s Syndrome
Anomalies here include learning difficulties, delayed physical growth, typical facial characteristics, congenital heart diseases, thyroid, gastrointestinal, eye and hearing disorders. Inheritance is autosomal dominant. Only 0.5%-1.0% of individuals with Down’s syndrome have OA/TOF.
Trisomy 18 Edward’s syndrome
Here there is severe neurological, motor and growth retardation, microcephaly, microphthalmia, malformed ears, and severe jaw anomalies. OA/TOF is present in 25% of these patients. (150)
Trisomy 13 Patau syndrome
Anomalies include severe learning difficulties, microcephaly, structural eye defects, meningo-myelocele, polydactyly, cleft palate. OA/TOF is very rarely present in this anomaly.
This is the commonest female congenital anomaly, found in 1/1000 female births, but as it is often very mild, it is only diagnosed in 10% of patients. Physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure can also be associated findings. Learning difficulties and psychological diagnoses are more common. OA/TOF is very rarely associated with this chromosomal anomaly.(149)
In the same way that cystic fibrosis is caused by mutations in a single gene, single gene disorders may can cause OA/TOF. In this situation, there are usually other malformations as well. Considerable progress has been made in understanding single gene disorders causing OA/TOF in the last ten years.
One syndrome, named Feingold syndrome after the doctor who first described it, has been shown to be caused by mutations in a gene called N-MYC, and may be associated with other clinical features such as small head size and subtle changes in the fingers and toes.
Subtle changes in the fingers and toes in Feingold syndrome. In the hand, there is incurving (clinodactyly) of the index and little fingers. There may also be a narrowing of the distance between the finger creases in the index finger compared with the middle and ring fingers. In the foot, some of the toes may also be fused (syndactyly).
The genetic basis of other syndromal forms of OA/TOF has now been worked out. These include CHARGE syndrome, OA/TOF with anophthalmia (congenital absence of the eyes), and a rare condition called Mandibulofacial dysostosis with micro cephaly. Genetic testing is available in the UK for each of these conditions through the Regional Genetics Services. (214,143,216)
Clinical features besides OA/TOF
Small head size, unusual configuration of fingers and toes. Heart and kidney malformations may be associated. May be mild developmental delay/learning difficulties.
Coloboma of the eye, failure to thrive/poor growth, heart and kidney malformations, deafness.
Mandibulo-facial dysostosis with microcephaly
Extremely small head size, unusual facial features, developmental delay/learning difficulties.
Anophthalmia- esophageal- genital syndrome
Absent or very small eyes; hypospadias. Extremely rare.
Here, OA/TOF is very rarely found with these syndromes but these have been included as some anomalies may be diagnosed in adulthood and individuals with these syndromes may be undiagnosed in the community if born prior to the syndromes’ discovery or ability to genetically screen for.
This is due to mutations in MID1/Xp22 gene and is X linked recessive inheritance. Anomalies include hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, and developmental anomalies.
This is due to deletions in UBE3A, NDN,SNRPN genes. Anomalies include mental retardation, movement and behaviour disorders, facial dysmorphisms, and genital anomalies. Mode of inheritance is uncertain.
This is associated with parathyroid hypoplasia, thymic hypoplasia, outflow-tract defects of the heart, cleft palate, facial dysmorphism, hypocalcaemia, hypertelorism, and midline defects.
Genes involved here include 10q24.31, 17q12,1q32, 3p12.3,8q11.23, 16p13.3 These are associated with kidney anomalies (renal dysplasia, duplex kidney, and hydronephrosis) and ureter anomalies (vesicoureteral reflux, megaureter, and ureterovesical junction (UVJ) vesicoureteral reflux obstruction.
This is due to a mutation in the FOXF1 gene, and anomalies include alveolar capillary dysplasia, and VACTERL-associated defects
This is due to mutations in 8q22, 12p13.3, 17q21. These mutations are associated with fused cervical vertebrae, short neck, low posterior hairline, limited neck movement, cardiac defects, craniofacial anomalies, skeletal and ocular anomalies, malformation of the larynx.
This is due to a mutation in 7p13. This mutation is associated with hypothalamic hamartoma, pituitary dysfunction, central polydactyly and organ malformations, anal atresia and occasionally laryngotracheoesophageal cleft.
This is due to a mutation in 17q21. This causes Microcephaly, midface and malarhypoplasia, micrognathia, microtia, dysplastic ears, preauricular skin tags, significant developmental delay, and speech delay.
This is due to a mutation in 1q21 and causes low platelets, limb malformations, cardiac and renal anomalies.(217)
A study was carried out in the 1970s to determine whether or not OA/TOF can run in families. The study was designed to determine what the chance was for a male or female adult who was born with OA/TOF of having an affected child. This study only became possible in the 1970s because this was the first time that children born with OA/TOF were able to survive long enough to have their own children.(217)
The results were reassuring: the chance of having a child affected with OA/TOF was about 1% – or, put another way, the chance of their child not being affected was 99%.
This study seems to suggest that OA/TOF is not a genetic condition, and this is mainly true. However, there are rare cases where OA/TOF does occur for genetic reasons, as explored above.
Where OA/TOF occurs in isolation (non-syndromic the recurrence risk is low, of the order of 1%, and specialist genetic advice need not be sought.
In order to show that someone born with OA/TOF does indeed have isolated OA/TOF, a careful clinical examination must be performed by the clinician to rule out other malformations. The patient will have the following investigations:
This is usually performed in childhood. However, in older individuals born with OA/TOF, these were not routine and thus some anomalies may be missed until a later age.
Within the UK, anyone interested in the possibly genetic nature and likely recurrence risk of a medical condition may seek genetic counselling simply by asking their GP or primary care physician to refer them to a Genetic Counselling Service.
The whole of the UK is covered by a network of twenty or so Regional Genetics Centres, located in hospitals of major towns and cities.
Advice is usually sought for one of these reasons:
In the event that additional malformations besides OA/TOF are identified, it is reasonable to seek the advice of a clinical geneticist to determine whether the pattern of malformations conforms to a known syndrome or association.
During a consultation with a clinical geneticist, a detailed family history will be taken; the child’s case history will be taken and a careful examination performed. Further imaging investigations may be needed, depending upon which the child has had already. Genetic tests may also be requested. If investigations are required, a second consultation is used to feed back the results of the tests, and information about recurrence risk, to the family. (215,143, 216)
What causes VACTERL association? Clinical geneticists use the word association when they appreciate that one or more malformations can appear together, but they don’t know the underlying cause. When they do understand the cause, then the condition is re-designated as a syndrome. For example, another acronym, CHARGE, was considered to be an association until 2004, when it was shown that this condition, which sometimes features oesophageal atresia, was due to mutations in a gene called CHD7. Now it is called CHARGE syndrome. Before this information was known, clinicians sometimes had difficulty in distinguishing between CHARGE and VACTERL, because certain malformations (cardiac, renal) are common to both.
Now that doctors can test for gene faults or mutations in CHD7, it is possible to make a clear separation between these cases and VACTERL association. The same is true of a condition called Feingold syndrome, another condition resembling the VACTERL association.
The discovery of mutations in a gene called N-MYC in patients with Feingold syndrome in 2005 cemented the status of this condition as a syndrome of known cause, although clinicians had before that time clearly delineated it as a syndrome based on its characteristic features and tendency to run in families. As time goes on, other causes of VACTERL association will be identified – and once this has happened, the new condition can be given a name that reflects the cause and clinical features.
As with oesophageal atresia, non-genetic causes of VACTERL association are recognised, including
It is fair to say that any child diagnosed with VACTERL association should be referred to a clinical geneticist, where the question of the underlying cause of the malformations can be addressed in detail. In the scenario where the child is growing and developing normally, with no suggestion of delayed milestones, a syndromic cause is less likely, and the recurrence risk is similar to or lower than that for isolated oesophageal atresia, that is, around a 1% chance of recurrence in the family. If the child’s growth or development are not normal, then a syndromic cause should be carefully sought by the clinical geneticist.
One UK-based study has suggested that there is an increased incidence of VACTERL-type malformations in first degree relatives of individuals with OA/TOF, and similar findings were reported in an American study. Adults born with VACTERL may also ask to be referred for genetic counselling pre or during pregnancy to explore the risk of VACTERL being diagnosed in future children.
If the person with VACTERL also has ano-rectal malformations, pre-conception appointments with gynaecology or urology should also be considered to explore whether there are any physical barriers to conception.(218)