Introduction

Nager syndrome is a rare genetic disorder that disrupts the development of the face and the upper limbs. It results in a characteristic set of physical features and functional challenges for affected individuals.¹ 

Signs and symptoms of nager syndrome

The most commonly seen abnormality is the presence of malformed upper limbs, small or missing thumbs, unusual fingers which may be curved or fused together (a condition known as syndactyly). The thumb anomaly may significantly impact general day-to-day functioning. Another feature of Nager syndrome is that the forearm is usually very small and underdeveloped due to the absence of a bone called the radius, which not only affects appearance but also functionality. People with Nager syndrome may have difficulty in extending their elbows and experience limited motion in their arms.¹

Craniofacial abnormalities are another defining aspect of Nager syndrome. Children with Nager syndrome have underdeveloped cheekbones, which gives them their characteristic appearance. Additionally, the presence of a very small lower jaw (a condition medically termed micrognathia) can often cause feeding problems, which can be critical. Beyond feeding difficulties, often the small lower jaw causes the tongue to be placed posterior, which can cause airways to be blocked and lead to breathing problems that can be life-threatening (especially in infants). Many children with Nager syndrome require medical intervention, including surgery, to manage these airway issues and ensure they get enough oxygen.¹

The characteristic facial features extend beyond the jawline. These individuals have downward-slanting eyes, giving them a distinctive gaze. They lack eyelashes, which can affect the eye’s natural protective mechanism. The ears of individuals with Nager syndrome are often small and may be malformed, contributing to the syndrome's impact on hearing. About 60% of these individuals suffer from hearing defects and speech delays. These speech delays are a result of the physical hearing impairment and do not reflect the individual's cognitive abilities or intelligence. With appropriate interventions, such as hearing aids or cochlear implants, many individuals with Nager syndrome can develop normal speech and language skills.¹,⁶

Genetic basis of nager syndrome

Nager syndrome is a genetic condition (i.e., can be passed down in families). It is caused by mutations (changes) in a gene called SF3B4. These changes could be inherited from a parent who has the condition, or it could be a ‘sporadic’ case of the mutation. If one of the parents has Nager syndrome, there is a 50% chance that they could pass it on to their child (i.e., the child would only need to inherit the mutated gene from one parent to develop the condition).²

Nager syndrome is very rare. As of 2023, medical literature had described approximately 100 reported cases worldwide. The estimated frequency of Nager syndrome is about 3 per 1,000,000 live births. Despite its overall rarity, there appears to be a slight gender disparity in its occurrence, with those assigned female at birth (AFAB) being affected somewhat more frequently than those assigned male at birth (AMAB). Given its rarity and complex presentation, Nager syndrome poses significant challenges for affected individuals, their families, and the medical professionals involved in their care.³

The severity of this disorder can vary among affected individuals. Some people have severe symptoms, while others might have milder symptoms with fewer complications. This variability in expression makes each case of Nager syndrome unique, requiring individualised medical care and support.¹ There is also a more severe form called Rodriguez syndrome, which is considered an extreme version of Nager syndrome.³

Management of nager syndrome

Nager syndrome presents a range of complex challenges that require long-term, multidisciplinary care. Treatment is highly individualised and can begin in the neonatal stage, often continuing until the patient reaches adulthood (~20 years of age). Below is an overview of the treatment approach:³

1. Initial focus: Survival and basic functions
   • Breathing support: Some individuals may need assistance with breathing due to blocked airways. This is prominent especially during the night. These interventions are necessary to help children breathe independently and may even prevent the need for immediate surgery (in severe cases, the windpipe may need to be artificially opened through surgical means)
   • Feeding solutions: Enteral feeding or tube feeding might be necessary. In these cases, a feeding tube is inserted directly into the stomach to bypass the mouth and throat
2. Surgical procedures are usually performed in the following order:
   • Addressing breathing and feeding issues
   • Correcting oral and facial defects
   • Repairing eyelid deformities and reconstructing cheekbones, and 
   • Improving the nose and external ear appearance to enhance the overall quality of life

The age at which these procedures are performed depends on the severity and the impact of the deformity on the child’s health. Notably, the efficacy of the surgery also depends on the intensity of the symptoms and the severity of the defect.

3. Ongoing support
   • Hearing aids or cochlear implants help manage hearing impairment
   • Speech and language therapy, including specialised logopedic treatment
   • Ear reconstruction can be performed in late childhood to improve appearance 

4. Multidisciplinary care should be carried out in specialised centres with a team that typically includes:
   • Maxillofacial surgeon
   • Laryngologist
   • Hand surgeon
   • Plastic surgeon
   • Physiotherapist - To ensure the functioning of organs is enhanced during surgery (i.e., the patient must be able to function after the structure has been changed). This could include activating the chest and diaphragm to support normal breathing.
   • Audiologist
   • Dentist
   • Orthodontist
   • Geneticist
   • Speech and language therapist
   • Paediatric specialists

Apart from this, the caretakers of the child need to be trained in basic techniques and to help with exercises at home. This approach ensures that all aspects of Nager syndrome are addressed, from critical survival needs to improvements in the quality of life.³

FAQs

Does nager syndrome also affect the lower limbs?

While Nager syndrome predominantly affects the face and the hands, there are occasional cases of it affecting the legs and feet too.⁴

How is Nager syndrome diagnosed?

Children with Nager syndrome have a characteristic appearance and hence there are no specific diagnostic tests. A physical examination by a healthcare provider is usually reliable as part of the diagnosis. However, genetic tests may help confirm the diagnosis. An X-ray, CT scan or MRI scan may be recommended to examine bone formation, growth and health during the treatment. Hearing tests may be used to diagnose the extent of hearing loss.⁴

What is the life expectancy of people with nager syndrome?

Although individuals born with Nager syndrome require a lot of surgeries, they usually have a normal life span.⁵

Can people with nager syndrome have biological children?

An individual with Nager syndrome can have biological children, but there would be a 50% chance of transmitting the syndrome to their children.²

How can one reduce the risk of having a child with nager syndrome?

As Nager syndrome is often caused by sporadic genetic mutations in the SF3B4 gene, there is no way to prevent the condition. If one of the parents has Nager syndrome, genetic tests and other assessments by healthcare providers may be necessary to reduce the chances of transmission.⁶

What is the difference between miller syndrome and nager syndrome?

Both Miller syndrome and Nager syndrome are inherited conditions that affect the development of the eyelids, cheeks, ears, and jaws. Patients with either syndrome have abnormalities of the upper limbs (i.e., their hands and fingers, in addition to their distinct facial features). People with Nager syndrome have small or absent thumbs, while people with Miller syndrome develop abnormalities of the small finger of the hand (or the fingers are fused together).⁷

Summary

Nager syndrome is a rare genetic disorder that affects the development of facial tissues and upper limbs. It is characterised by malformed or missing thumbs, curved or fused fingers, and underdeveloped forearms due to the absence of the radius bone. This results in limited elbow extension and arm motion. Craniofacial abnormalities include underdeveloped cheekbones and a very small lower jaw, causing life-threatening feeding and breathing problems. Other facial features include downward-slanting eyes, no eyelashes, and small, malformed ears. Many individuals with Nager syndrome experience hearing impairment, leading to speech delays. However, this does not affect the intelligence of the individual. The severity of the syndrome varies among individuals, with some cases being milder than others.

The condition is caused by changes in the SF3B4 gene, which can be inherited or occur spontaneously. Management of Nager syndrome requires long-term, multidisciplinary care, focusing initially on survival and basic functions like breathing and feeding. Treatment often involves multiple surgeries to address the different issues, including airway obstruction, facial deformities, and limb abnormalities. Ongoing support includes hearing aids, speech therapy, and intervention from medical specialists. Despite the challenges, individuals with Nager syndrome usually have a normal life expectancy. Though there is no way to prevent Nager syndrome, genetic counselling can help understand transmission risks for affected parents.