What is Nager syndrome?

Nager syndrome, also known as Nager Craniofacial Dysostosis, is a rare genetic condition leading to facial, hand, and arm malformations. Examples include cleft palate, a small jaw, underdeveloped cheekbones, small ears, absent thumbs and short forearms.¹ Nager syndrome is uncommon, with less than 100 cases in the medical literature.¹ This syndrome has a genetic basis, with more than half of cases caused by changes in the SF3B4 gene.¹ The remainder of cases are considered to have another genetic cause, though the exact cause is yet unknown.

Clinical features of Nager syndrome

Nager syndrome can cause several craniofacial abnormalities, including a small jaw, underdeveloped cheekbones, a malformed nose, and a cleft palate. Nager syndrome often causes abnormalities like small ears, eyes with a downward slant, and an indenture in the lower eyelid.¹ Limb anomalies include an absent or underdeveloped radius bone in the arm, an absent or underdeveloped thumb, short limbs, and stiff joints.² Other body systems can be affected as well, including cardiovascular malformations, respiratory issues, and sparse or absent eyebrows and eyelashes. Less commonly, Nager syndrome can cause problems in other organs, such as the kidneys, heart, or diaphragm (NORD).

Growth delay in Nager syndrome

The effects of Nager syndrome can contribute to growth issues in those with Nager syndrome. For instance, the missing or malformed bones in the limbs can cause small stature. Common musculoskeletal effects include malformed thumbs, a shortened radius bone in the arm, and the inability to straighten the arm fully at the elbow.³ Less commonly, individuals may have abnormalities of the legs and feet, such as clubfeet, inward turning of the big toes, and absent or underdeveloped toes.³ 

The underdeveloped structures of the face and throat can cause feeding difficulties in infants, affecting their growth. Individuals with Nager syndrome have underdeveloped cheekbones, along with a small jaw, and many also have a cleft palate.¹ These malformations can cause breathing problems in the infant that can even necessitate a tracheostomy, a surgery to create an opening in the throat, to facilitate breathing. These issues can also cause feeding problems in infants that can cause growth delays and failure to thrive.

Developmental delays

Nager syndrome does not affect an individual’s intelligence level, though it can cause speech and language delays due to hearing problems. Nager syndrome can cause malformed ears affecting the internal and external ear structures that vary in severity. These issues can cause conductive hearing loss, which happens when sound cannot be conducted from the outer to the inner ear, potentially impacting speech development.² The underdevelopment or malformation of the facial bones, including cleft palate, small jaw, and possible need for tracheostomy can also lead to a speech delay by affecting the movement of the tongue and oral cavity.⁴

The musculoskeletal malformations associated with Nager syndrome can lead to motor skill delays. The shortened limbs and missing or deformed digits can cause functional disabilities that necessitate work with a physical or occupational therapist. For instance, deformities of the thumbs can lead to difficulty using the hands. The severity of the associated delays depends on the individual’s clinical presentation and individual needs. 

Medical management and interventions

A diagnosis of Nager syndrome can be made after birth through clinical evaluation and identification of classic physical features associated with the condition. Imaging of the affected area, such as x-rays, and genetic testing can confirm the diagnosis. Medical management requires a multidisciplinary approach and may include paediatricians, surgeons, ear, nose and throat doctors, eye doctors, and physical and occupational therapists, among others. 

In the infant, treatment is often focused on managing breathing and feeding problems, which may include a tracheostomy and placement of a feeding tube to ensure the child is getting the necessary nutrition. Craniofacial surgery is often performed at a young age to enlarge the jawbone and correct a cleft palate, if present.⁵ In the teenage years, corrective surgery of the cheekbones or nasal cavity may be undertaken.⁵ Other cosmetic or functional surgeries, such as ear reconstruction, may be indicated depending on the individual’s symptoms. 

Hearing impairment is typically treated with hearing aids or cochlear implants along with speech therapy. Physical and/or occupational therapy helps the individual to maximise their physical and developmental outcomes and may include exercises to help open the jaw, help with chewing, exercise the tongue, improve any joint problems and help with walking.⁵

Support for individuals with Nager syndrome

Nager syndrome does not affect cognitive ability, or academic aptitude, or lead to a shortened life span compared to the unaffected population, but it is important to consider the social and emotional impacts of the condition. Families affected by Nager syndrome can seek out support groups and community resources for extra assistance and education. Organisations such as Contact a Family and FACES: The National Craniofacial Association provide resources, education, and peer support for those affected by Nager syndrome and other conditions.

FAQs

What is Nager Syndrome? 

Nager Syndrome is a rare genetic condition characterised by craniofacial and limb abnormalities. It often involves malformations such as a small jaw, underdeveloped cheekbones, cleft palate, absent or underdeveloped thumbs, and short forearms.

How common is Nager Syndrome?

Nager Syndrome is very rare, with fewer than 100 documented cases in medical literature. It has a genetic basis, with a majority of cases caused by mutations in the SF3B4 gene.

What are the clinical features of Nager Syndrome? 

Individuals with Nager Syndrome typically have craniofacial abnormalities including small ears, downward-slanting eyes, and underdeveloped facial bones. Limb anomalies may include missing or shortened radius bones, absent thumbs, and stiff joints. Other potential issues include cardiovascular malformations and respiratory difficulties.

How does Nager Syndrome affect growth and development? 

Nager Syndrome can lead to growth delays due to musculoskeletal issues such as malformed thumbs and short limbs. Feeding difficulties, often due to cleft palate and jaw abnormalities, can also impact growth in infants. Developmental delays in motor skills and speech may occur but do not affect intelligence.

What medical interventions are used for Nager Syndrome?

 Diagnosis involves clinical evaluation, imaging (like X-rays), and genetic testing. Treatment typically involves a multidisciplinary approach including surgery (craniofacial, limb correction), management of breathing and feeding issues (possibly requiring a tracheostomy or feeding tube), and therapies such as physical, occupational, and speech therapy.

What is the outlook for individuals with Nager Syndrome? 

Nager Syndrome does not typically affect life expectancy. With appropriate medical management and support, individuals can lead fulfilling lives, though they may require ongoing medical care and therapeutic interventions to manage symptoms and optimise development.

Summary

Nager syndrome leads to a complex array of craniofacial and limb abnormalities, stemming from genetic mutations like those in the SF3B4 gene. Individuals with Nager syndrome benefit from a multidisciplinary approach to medical management, including specialities like surgical interventions, physical therapy, and ongoing psychosocial support. While challenges such as feeding difficulties and speech and motor delays are common, the condition does not impact cognitive function or life expectancy.