Introduction

Nager syndrome is a condition that presents itself at birth, which can affect the development of facial bones and tissues, as well as the normal development of upper and lower limbs (such as arms, hands, legs and feet).¹

Nager syndrome symptoms can vary in severity, however, it does require long-term monitoring, which is especially important from childhood to adolescence, which is why it is vital to have early intervention in children who suffer from this condition.¹

This article will describe how Nager syndrome is diagnosed during pregnancy.

What is nager syndrome, and what causes it?

Nager syndrome is a condition found at birth caused by a mutation (an erroneous modification) in a gene called SF3B4. 

This disease can follow a pattern of inheritance called autosomal dominant, in which a single copy of these genes is sufficient to cause this disorder. In most cases, however, Nager syndrome is not inherited but is caused by a new mutation occurring mostly in families with no previous medical history of this condition. ²

In certain cases, Nager syndrome can be inherited in an autosomal recessive pattern, in which the unaffected parents of the affected individual both carry a copy of the gene leading to the disease; in this case, parents show no symptoms but can have more than one affected child. ²

What are the symptoms of nager syndrome?

The symptomatology of Nager syndrome can vary between individuals, even between family members.

People affected by this condition show facial and limb abnormalities already at birth, including:

• Abnormalities in cheekbones (malar hypoplasia)
• Small lower jaw (micrognathia)
• Incomplete development of the mouth roof (cleft palate)
• Malformation of the soft palate of the mouth (velopharyngeal insufficiency)
• Narrowing of the back nasal cavity (choanal atresia)
• Malformation of internal and/or external ears; this symptom can vary widely
• Downward slanting of the upper and lower eyelids
• Missing tissue from lower eyelids (colobomas)
• Partial or total absence of eyelashes of the lower eyelid
• Droopy or sagging upper eyelids

Some symptoms, such as cleft palate and choanal atresia, might lead to feeding and breathing difficulties. If not treated and monitored properly, these can lead to life-threatening complications.

Other complications, such as ear malformation, might cause hearing loss, while the severity of hearing loss can vary widely between individuals. This symptom might cause a delay in speech development.³

The abnormalities affecting the limbs might affect the development of thumbs (which are in some cases missing), can cause the presence of an extra bone or lead to abnormalities of the forearm. In other, less frequent cases, fingers might be stuck in a bent position or webbed.

While in Nager syndrome, abnormalities of forearms and hands are common, affected individuals might show abnormalities of lower limbs (feet and legs), with conditions equal to those of the upper limbs (webbed toes, clubfeet, abnormally shaped big toe).³

How is nager syndrome diagnosed before birth?

Nager syndrome can be diagnosed through a clinical exam, medical history and identification of physical characteristics, or it can be identified before birth when some of the abnormalities are identified after ultrasounds, or through other forms of prenatal testing.

Prenatal testing options include:

Ultrasound imaging

Nager syndrome is usually diagnosed during the second or third trimester with a detailed ultrasound assessment., This assessment can be carried out when suspecting facial anomalies, mandible hypoplasia, absence of external ears, or additional abnormal limbs.⁴

Molecular testing

Molecular testing is an alternate form of testing which can help gain accurate information on specific conditions your child might have. Molecular testing includes:

Non-invasive Prenatal testing, or NIPT, is a type of molecular testing which involves blood testing. It is usually carried out after a previous screening identifies an anomaly or when a certain condition is suspected.

NIPT is a non-invasive procedure and does not cause any harm to the pregnancy.⁵

NITP aims to identify the DNA released in the mother’s bloodstream from the placenta. If the test finds a certain level of gene alteration, it could indicate the fetus is affected by this condition.

It is important to note that while NITP is a valid non-invasive procedure, it is not suitable for everyone, and if the expectant mother has had recent transfusions, cancer or other identified genetic conditions, contacting a healthcare provider and making an informed decision is the best course of action.

This test can have 3 different outcomes:

• A low chance result, this result means the fetus has a low chance of carrying the mutation.
• A high chance result doesn’t mean the fetus has the condition but can mean your child has a high likelihood of carrying the mutation, in this case, other tests are going to be carried out to have a definite answer, it is important to note that in rare instances false positives can also happen even when the fetus does not have the condition⁵
• No result, in some cases, the test might not give a result. This can be caused by a lack of DNA in the retrieved sample or by technical issues during testing; in this case, the test can be repeated or passed to diagnostic testing⁵
• Chronic villus testing and amniocentesis

Chorionic villus sampling is not a routine test; when offered, it is because of a suspected genetic or chromosomal condition.

This test is carried out after previous tests identified some type of condition or when the mother has had previous pregnancies affected by a genetic condition.

This test is performed between the 11^th and 14^th week of pregnancy, but can be carried out later. The test consists of taking a sample of cells from the placenta. This procedure can happen in 2 ways:

• Transabdominal CVS, with this method, the needle is inserted through the tummy
• Transcervical CVS, with this method, a tube or small forceps are inserted into the cervix (at the neck of the womb)

This procedure can take up to 30 minutes, including the consultation, and can be uncomfortable for expectant mothers, as you can also experience cramps afterwards.

If the test suggests the fetus suffers from this condition, the midwife and doctor will explain the results and discuss further options.

Conditions identified with CVS are not curable, so any option is to be carefully considered.

There can be downsides to CVS, and any possible complications will be discussed with the expectant mother. This type of testing can lead to miscarriages in the first 23 weeks, with a chance of 1 in 200 for single pregnancies and 1 in 100 for multiple pregnancies (twins).

In some cases, mothers can decide to terminate the pregnancy after considering different options.

Amniocentesis can be an alternative form of the CVS test; in this test, a sample of the amniotic fluid is removed and tested. This test is carried out between the 15^th and 18^th week or later. This test can also lead to miscarriage, but is carried out at a later stage of the pregnancy.⁶

Because of the advanced stage of pregnancy, however, mothers might have less time to consider their options.

Fetal MRI

Fetal MRI is a non-invasive procedure, detailing the anatomic structure (brain, spinal cord and body) of the fetus with clear and high-resolution images. This test is used to gain additional information regarding a diagnosis. This test can be performed between the 2^nd and 3^rd trimesters, adding precious information.⁷

Conclusion

In conclusion, Nager syndrome is a rare genetic condition present at birth. Due to the debilitating symptoms that can come with the disease, early diagnosis with prenatal testing is an important start for the long-term monitoring of each individual.

Understanding how the disease works and its genetic basis can help provide the appropriate tests and interventions.

Prenatal diagnostic techniques such as ultrasounds, molecular testing, and more invasive testing such as CVS and amniocentesis play a very important role in the identification of Nager syndrome before birth, allowing each family to plan and prepare for the right postnatal care, and to improve the quality of life of these children and their families.

Summary of key points

• Nager syndrome is caused by a mutation SF3B4
• Nager syndrome can cause the malformation of facial bones and upper and lower limbs
• Nager syndrome can be inherited, but it is most frequently caused by a new mutation independent of the parents 
• Nager syndrome can be diagnosed through ultrasounds and molecular testing before birth
• More invasive tests, such as CVS and amniocentesis, can provide a more accurate prenatal diagnosis