Nager syndrome is a rare genetic disorder characterised by abnormalities in the development of the face, arms, and hands due to a genetic mutation. The syndrome does not impact the child's intelligence.

Overview

Nager syndrome, also known as preaxial acrofacial dysostosis, was first described in 1948 by Nager and de Reynier. It is a rare developmental disorder affecting the bones and tissues of the face, forearms, thumbs, and sometimes the legs and feet. During early pregnancy, insufficient development of the cheekbones, eye sockets, and jaw can lead to a distinctive appearance characterised by downward-sloping eyes and a small jaw. Limb abnormalities commonly seen in Nager syndrome include short forearms and missing or malformed thumbs. It occurs in the general population at a frequency of 3 per 1,000,000 live births. In individuals with Nager syndrome, intelligence remains unaffected. Nager syndrome results from a heterozygous mutation in the SF3B4 gene, which is found on chromosome 1 at the q21 position. Most cases of Nager syndrome are sporadaic ( they occor randomly) and are typically de novo (newly occurring mutations within the affected individual's genetic makeup)and are not inherited cases passed down from parents.^1,2

The article provides an overview of Nager syndrome, including its causes and treatment options.

Definition

Nager syndrome is a classic example of acrofacial dysostoses (AFDs), which are characterised by craniofacial malformations and defects of the limbs.

The primary facial characteristics of Nager syndrome include down-slanted eyes, midface retrusion, and a small lower jaw (micrognathia), with the latter often requiring a tracheostomy to be placed in early childhood. Limb defects usually affect the front part (radial side) of the upper limbs, causing conditions like small or missing thumbs, thumbs with three phalanges, underdeveloped or absent radius bones, and fusion of the radius and ulna bones.

A few severely affected individuals have notably shortened upper limbs (phocomelia). Nager syndrome is distinguished from other AFDs due to the absence of lower limb abnormalities; however, accurately making this distinction can be challenging.

Symptoms and characteristics of Nager syndrome

Children with Nager syndrome typically exhibit underdeveloped cheekbones (malar hypoplasia) and a significantly small lower jaw (micrognathia) from birth. Additionally, they often have a cleft palate, which can cause feeding difficulties. The small lower jaw can also partially block the airway, leading to potentially serious breathing problems. Individuals affected by Nager syndrome often have downward-slanted eyes, no eyelashes, and a notch in the lower eyelids known as eyelid coloboma. Approximately 60% of those with Nager syndrome experience hearing loss due to middle ear abnormalities, often resulting in conductive hearing loss.

Nager syndrome does not impact a person's intelligence. However, delayed speech development may occur due to the associated hearing loss.

People with Nager syndrome have bone defects in their hands and arms. The most frequently occurring abnormality is malformed or absent thumbs. Affected people may also have unusually curved (clinodactyly) or fused (syndactyly) fingers. They may have shortened forearms due to partial or complete absence of the radius bone or abnormal fusion of bones in the forearms (radioulnar synostosis).² People with the syndrome may also have difficulty fully extending their elbows. Additionally, this condition can lead to bone abnormalities affecting the legs and feet.

Nager syndrome is distinguished from other syndromes such as Goldenhar, Treacher Collins, Pierre Robin, and Genée–Wiedemann syndromes, by the unique limb abnormalities that set it apart from other syndromes affecting the head and neck (branchial arch syndromes).² 

While most individuals with Nager syndrome are healthy, some are severely affected by serious internal malformations involving the kidneys and/or the heart. Additional rare symptoms reported in medical literature include diaphragmatic hernia (an abnormal opening in the diaphragm), underdevelopment of the larynx which can lead to respiratory problems, and various skeletal abnormalities such as abnormal curvature of the spine (scoliosis), underdevelopment of the first rib, or hip dislocation. Less frequently the syndrome can affect the genitalia and urinary tract.

What causes Nager syndrome?

A study published in 2012 showed that low levels of the SF3B4 gene were found in over half of the patients studied. SF3B4 plays a crucial role in early embryo development and bone formation.

Evidence for the role of SF3B4 gene in embryo development

The SF3B4 gene plays a crucial role in early limb development in mouse embryos, indicating its significance in skeletal formation.² Animal models of Nager syndrome have demonstrated that SF3B4 is essential for the formation of neural crest cells. In Xenopus embryos lacking SF3B4, early development exhibits craniofacial cartilage defects similar to those observed in individuals with Nager syndrome. SF3B4 is also known to encode SAP49, a protein critical for RNA splicing in mammals.³

How is Nager syndrome diagnosed?

Nager syndrome is diagnosed through a combination of the patient’s medical history, clinical signs, genetic testing, and imaging scans such as X-rays, CT scans of the head and limbs. Imaging may also be necessary to assess the internal structures of the ear, alongside hearing tests, for diagnosing hearing loss.²

How is Nager syndrome treated?

Nager syndrome can affect various areas of the head and face, necessitating a multidisciplinary team for effective treatment. This team typically includes craniofacial surgeons, maxillofacial surgeons, throat surgeons, hand surgeons, plastic surgeons, dentists, orthodontists, audiologists, geneticists, and speech and language therapists. Treatment is often provided at a specialist centre where these experts collaborate to address the patient's diverse needs.

For some children, breathing difficulties may be so severe that a tracheostomy is also needed. Feeding problems can be managed with enteral feeding(using a feeding tube or gastrostomy directly into the stomach), bypassing the mouth and throat.

Later in childhood, treatment for the underdeveloped jaw may involve bone grafts and jaw distraction. Ear reconstruction can improve the ear's appearance, although not its function. Children with hearing impairments will need support with hearing aids or cochlear implants, along with speech and language therapy. As bones continue to grow during childhood and adolescence, further surgeries may be required to reconstruct the facial structures.

Summary

Nager syndrome is a congenital condition affecting the face, forearms, thumbs, and occasionally the legs. In early pregnancy, inadequate development of the cheekbones, eye sockets, and jaw can result in a distinctive appearance characterised by downward-sloping eyes and a small jaw. Less frequently, the syndrome can affect the heart, kidneys, and genitalia. In individuals with Nager syndrome, intelligence is typically unaffected. The syndrome arises from a heterozygous mutation in the SF3B4 gene. Nager syndrome treatment requires a multidisciplinary team at a specialist centre. Severe cases may require a tracheostomy and enteral feeding. Later treatments can include jaw surgery, ear reconstruction, and support for hearing impairments with aids or implants. Further surgeries may be needed as the child grows.