Introduction

What is Nager syndrome?

Nager Syndrome (NS) belongs to a family of rare disorders called Acrofacial Dysostosis (AFD).¹ Although NS is often unheard of, it is the most common form of AFD.² NS causes visual craniofacial malformations (an abnormal formation of the bones within the skull and face).²

NS is so rare that publications only describe around one hundred cases as of 2024.³ You can distinguish NS from other forms of AFD by its unique abnormalities of limbs. Limb abnormalities in NS patients are most commonly found in the forearm and the thumb.²

A rare syndrome may feel very overwhelming, however, there is positive news. Although there is no cure, appropriate intervention will help better the quality of life of patients, whilst having no impact on their intellectual abilities.⁴

There are several different names that are used to refer to NS which you may notice pop up as you explore the answers to your questions. These are all defining the same syndrome:

• Acrofacial dysostosis 1, Nager type
• AFD1
• NAFD
• Nager acrofacial dysostosis
• Nager acrofacial dysostosis syndrome
• Preaxial acrofacial dysostosis
• Preaxial mandibulofacial dysostosis

Why is it important to understand?

It is important to understand this rare disorder in order to be able to diagnose it accurately. If you were to be diagnosed with NS, we would want you to have the utmost potential in life with the disorder, which only highlights how important early intervention will be. Occupational, speech and physical therapy are all involved in aiding your development and function with NS.² Now although this will not cure the challenges you would face with NS, it will certainly relieve them which gives hope to an improved quality of life.

Physical characteristics of Nager syndrome

Although not all physical characteristics of NS are related to our bones (skeletal system), it is a key distinction to note that most of the visible symptoms are.

Facial features

Unique facial features NS patients develop include the following:^3,4

• Cleft palate
• Downward slanting eyes with no bottom-row eyelashes
• Small lower jaw
• Small ears
• Underdeveloped cheekbones

Hand and arm differences

NS patients also experience changes within their hands and arms, such as:^3,4

• Curved fingers
• Missing or malformed thumbs
• Short forearms
• Little range of motion in the elbows

How these physical differences happen (Pathophysiology)

What causes Nager syndrome?

Half of NS cases are caused by a change (otherwise described as a genetic mutation) in a gene called SF3B4. It is not understood how the other half of the cases are caused, but it is known that NS can be inherited in both an autosomal recessive and dominant manner. Children get two copies of the same gene, one from each parent. When a gene is autosomal recessive, both parents must pass down a mutated version of the gene for the child to be affected with NS. If you have inherited NS in an autosomal dominant manner, only one parent passed down the mutated gene and the other parent passed down an unchanged gene.

How do genetic changes lead to Nager syndrome?

As mentioned, the only known cause of NS is a mutation in the SF3B4 gene, so let’s be scientists for the minute and explore what this gene does.

For our body systems to function like the well-oiled machine it is, then we require components called proteins. The SF3B4 gene codes for a protein responsible for assembling spliceosomes.⁵ Spliceosomes are important as they ensure other important proteins can form properly to allow their correct functioning.⁶ A specific spliceosome the SF3B4 gene codes for is SAP49 which is associated with a bone-developing protein. This suggests why skeletal development is compromised in NS.⁷

Associated health issues

Since bone development is crucial in the correct functioning of our body, it can have quite significant impacts on certain structures and functions. This includes:^3,4

• Hearing loss – specifically conductive hearing loss
• Breathing and feeding difficulties
• Speech and language delays

Although not as common, it is important to note that there are risks of developing abnormalities in the heart, kidneys, genitalia and urinary tract.

How is Nager syndrome diagnosed?

There is no specific diagnostic tool used to diagnose NS. Since NS presents visible symptoms, medical professionals can simply observe these.⁸ You may find that scans such as MRI, X-ray and CT scans might be used to help monitor bone development during and after treatment.⁸

There is an option for a small sample of blood to be taken from the heel of a child which will be assessed in a lab to detect the changes in DNA. The genetic tests will confirm the NS observations taken by the healthcare provider.⁴

Management of symptoms

Management varies because NS can affect people differently, some more severe than others.³

Surgical procedures

Breathing and feeding help

• Tracheostomy: A procedure to help newborns breathe better by creating an opening in the windpipe
• Gastrostomy: A small tube placed in the stomach to make feeding easier for those who have trouble swallowing

These surgeries are commonly the first surgeries performed on NS patients since feeding and breathing are essential functions needed to survive.

Jaw surgery

• Jaw Lengthening (Osteodistraction): Surgery to extend a small or underdeveloped lower jaw
• Further Jaw Corrections: Other surgeries to fix jaw alignment such as Orthognathic surgery

Cleft lip and palate repair

Cleft lip or palate (mouth) surgeries are done to fix gaps in the lip and roof of the mouth.

Cheekbone and face surgery

Bone grafts or cheek implants are done to rebuild or improve cheekbones.

Nose surgery

Rhinoplasty or septoplasty are procedures performed to fix the shape of the nose and to help with breathing.

Ear reconstruction

Surgery can be done to create or reshape ears for appearance, however, it doesn’t restore hearing. This can involve taking a mould from the second ear, or either parents’ ears, if the child has little to no ear structure. 

Eyelid surgery

Surgery to fix droopy or misshapen lower eyelids (Blepharoplasty) can be done.

Thumb surgery

• Strengthening Procedures: To make weak thumbs work better
• Thumb Replacement (Pollicisation): Moving the index finger to where the thumb should be if the thumb is missing or doesn’t work well

It is quite overwhelming visualising all these surgery options available. If it helps, these surgeries are done over time to help with both appearance and function as the child grows. Some of these are completely optional and also may only be required if the symptoms are severe enough.

Therapies

Due to the range of symptoms and the difference in their severity, therapy is often specific to each case and can be as long-lasting as 20 years. The following therapies aim to support development and improve the quality of life for individuals with Nager Syndrome:^3,4

• Speech therapy: To help with speech development, particularly due to difficulties from cleft palate or hearing issues
• Occupational therapy: To improve hand function, especially if there are issues with the fingers or thumbs
• Physical therapy: To enhance overall motor skills and mobility if there are physical impairments
• Hearing aids and auditory therapy:  If hearing loss is present, hearing aids or special auditory therapies can be used to improve hearing and communication
• Psychological therapy: NS can have a range of impacts on not only the child with NS but also the surrounding family and friends. Psychological therapy can provide guidance and support for the mental health of everyone involved

What does the future look like?

Since not all cases of NS are caused by a mutation in the SF3B4 gene, further research into different gene mutations would be a sensible route to take. Each mutation found could potentially improve the diagnosis of NS through genetic screening. Genetic screening is a process of looking into possible mutations that may affect how we function and these research methods are on the rise.⁹ A genome is a scientific term that simply means “complete set of genetic information in an organism”. Methods like Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) are now used to detect changes in our genes, exactly like the SF3B4 mutation that causes NS.

The development of research is excellent news for those with NS. Since NS already has a promising outlook regarding the management that can improve symptoms and the resulting quality of life impacts, research can only improve this further.

Summary

Nager Syndrome (NS) is a rare genetic disorder affecting facial and limb development. It’s caused by changes in the SF3B4 gene, which impacts bone growth, though in some cases, the cause is unknown. Fewer than 100 cases have been documented, making it extremely rare.

People with NS often have distinct facial features, such as smaller jaws, underdeveloped cheekbones, and missing lower eyelashes. They may also experience abnormalities in their arms and hands, like shortened forearms or small/missing thumbs, which can limit movement.

Health challenges include hearing loss due to underdeveloped ear bones, as well as difficulties with breathing and feeding caused by a smaller jaw. Despite these challenges, intelligence is not affected, and many individuals can lead fulfilling lives with the right support.

Diagnosis is usually based on visible symptoms and confirmed with genetic tests. Treatment focuses on managing symptoms and may involve surgeries to improve breathing and eating, with cosmetic surgeries often being an option later down the line. Surgeries are supported with a range of therapies, to give the utmost improvement in symptoms of NS. Though there is no cure, early intervention and supportive care significantly improve quality of life, enabling people with NS to thrive despite their challenges.