Overview

Nager syndrome is a very rare genetic disorder that presents symptoms from birth, with only a few hundred cases ever documented. It is now known that about half of these cases are caused by a dominantly inherited mutation on the splicing factor 3b subunit 4 (SF3B4) gene, although the other half of these cases are still of an unknown origin.^1,6 In the following article, we'll explore its effects on a child's facial features and what can be done to improve their circumstances. 

Symptoms and causes

Individuals with Nager syndrome have small cheekbones (malar hypoplasia), which are underdeveloped, as well as downward-slanting eyes (downslanting palpebral fissures).¹ An absence of eyelashes is also noted, as well as the absence of some tissue in the lower eyelid (eyelid coloboma).^1,2 In addition to this, they have an underdeveloped lower jaw (micrognathia), and the jaw is sometimes displaced into the skull, so it appears to jut into the face (microretrognathia).^1,3 In addition to microretrognathia, the jaw joint can become fused at the fossa (pivot point), so the patients may not be able to move their mouths, or may only be able to do so in a very limited fashion (ankylosis of the temporomandibular joint). Commonly, a gap joining the mouth and the nose together (cleft palate), instead of the roof of the mouth properly forming, can also occur.^1,3 These issues together can cause a variety of problems for the patient, from not being able to feed properly as an infant to an inability to speak or breathe correctly. Hearing issues may also result due to improperly formed ears as well as malformations in the middle ear (conductive hearing loss).^1,3

Lastly, characteristic defective or absent thumbs are present, as well as a missing forearm bone (the radius), which can result in short arms.^1,3 These can cause small motor function issues, such as an inability or trouble fully stretching out their arms.² Due to the developmental process, these issues can also be mirrored in the bones of the lower limbs, to some degree.¹ Cognitive impairment is not reported to be caused in Nager syndrome, though speech delays and impediments may be present due to physical defects in hearing or the jaw.³

To summarise, symptoms include:

• Malar hypoplasia
• Downslanting palpebral fissures
• Eyelid coloboma micrognathia 
• Cleft palate 
• Microretrognathia
• Ankylosis of the temporomandibular joint 
• Conductive hearing loss
• Speech impediments
• Difficulty breathing
•  Short/malformed/ absent forearms
• Short/ malformed/ absent lower legs
• Absent/ malformed thumbs

Causes of nager syndrome

Nager syndrome has been found to be caused by a mutation in the SF3B4 gene, which is dominantly inherited in 50% of cases, meaning that only 1 copy of the faulty gene needs to be inherited from one parent in order for the physical symptoms to be exhibited. However, often this mutation can be de novo, meaning that the parents themselves may be fine and the mutation may spontaneously occur in the infant early on in the course of the pregnancy, or may be caused by damage to the sperm or egg before/ during fertilisation. As a result, depending on when the mutation occurred, different levels of physical characteristics may be present.¹

This SF3B4 gene accounts for only half of the few known Nager cases, whereas the rest are of an unknown origin.¹ It is thought that the rest of the cases are caused by a recessive mutation, meaning a faulty copy of the gene must be inherited from both parents in order for the symptoms to present themselves, although which gene is responsible in these cases has not yet been identified.¹

The face first begins to form at around 6 weeks in pregnancy, mainly from 2 main tissues called the neural crest cells and the pharyngeal arches.⁴ These tissues start to form a frontal nose prominence at 6-8 weeks, and then the face begins to take shape. The left and right sides of the face form separately, and at around 12 weeks, the face fully fuses together with the jaw to form the shape that we take when facing the world.⁴ There are many transcription factors and signalling pathways involved in correctly transforming one type of tissue into many, such as mesoderm into pharyngeal arches, as well as positioning and timing all the different intricate transitions well in order to achieve a fully functioning human being.^4,5 As the face forms in three 

separate parts which fuse together above the upper lip, it is understandable why our faces are often not exactly symmetrical. However, issues with this process, such as in the case of Nager syndrome, can cause microretognathia and malar hypoplasia.¹

Treatments and therapies

Many of the craniofacial defects caused by Nager syndrome, such as malar hypoplasia or ankylosis of the temporomandibular joint, can only be corrected surgically.³ In some cases, surgery may take place purely for aesthetic reasons, to improve the physical appearance of the patient. However, in other cases, such as symptoms of cleft palate or ankylosis of the temporomandibular joint, surgery may be necessary in order to allow the infant to feed or to permit breathing and help prevent speech impediments. Surgeries like tracheostomies, which insert a tube into the patient, can aid in breathing, and gastrostomies are when tubes can be inserted into the stomach to allow food and drink to enter the body without needing to use the mouth.¹ Surgeries to correct cleft palates and improve jaw function at the temporomandibular joint can also provide longer-term solutions when there isn’t an immediate need to provide the body with nutrients or oxygen. 

The earlier the surgery is carried out, the fewer impediments may be seen in the patient as they grow. For example, corrective ear reconstruction surgeries may allow the patient to hear better, so slowly their understanding will develop and they will be able to mimic the language they hear, thus enabling the toddlers to develop their speech properly. However, due to the huge array of different defects seen in Nager syndrome, a multifaceted approach towards treatment is required.³

Physical therapy may be advised to improve a child’s motor function. This can help them deal with both craniofacial defects with their jaw as well as any limb defects they may have. This can help their muscles to develop, and can be done in addition to or without surgery.¹

Speech therapy can assist with any speech impediments or help prevent them from occurring, especially if these have occurred due to hearing loss.¹ This can also be very useful after corrective jaw surgery and can help your child to speak sooner and more clearly.

Geneticists may provide genetic counselling before your child is born. They can use procedures like chorionic villus sampling and amniocentesis to assess the risk of your child having Nager syndrome, and provide aid during pregnancy to support you. Currently, only about 10% of Nager syndrome cases have been diagnosed prenatally (out of only 100 documented cases ever reported), and this was done so using suspected jaw and limb deformities visualised during ultrasounds.³ If you have a child with Nager syndrome and wish to have another child, they can also intervene to help in this case and provide support after the child is born as well.¹ If you 

have Nager syndrome and would like to have a child, they may also be able to help prevent you from passing the gene on to your children in some cases.¹

Psychosocial therapy can help deal with the stress of having Nager syndrome or having a family member with this condition.¹ They can provide useful information on how best to deal with challenging situations and any adaptations that can be made to make your life easier, as well as provide general mental health support for all those affected.  

Summary

Nager syndrome is a genetic condition which often arises sporadically due to a mutation in the SF3B4 gene or can arise from an unknown origin. It can cause many physical craniofacial defects affecting the eyes, cheeks, ears, nose, mouth and jaw, which can lead to hearing, feeding and breathing difficulties in certain cases, depending on the severity of the symptoms. Treatments include surgeries and therapies, with earlier treatment often leading to fewer defects in adulthood. Cognitive disabilities are not caused by Nager syndrome, but speech difficulties may arise due to the other physical defects caused.