What is Nager syndrome?

Nager Syndrome: Clinical Features, Diagnosis, and Management

Nager syndrome is a rare craniofacial disorder characterized by mandibular hypoplasia, malar hypoplasia, downward slanting palpebral fissures, external ear abnormalities, and upper limb defects including thumb anomalies and radial hypoplasia. 1, 2

Clinical Features

Craniofacial Abnormalities

• Mandibular hypoplasia with retrognathia
• Malar hypoplasia (underdeveloped cheekbones)
• Downward slanting palpebral fissures
• Cleft palate (often with absent soft palate)
• External ear abnormalities including dysplastic ears and external auditory canal atresia
• Microretrognathia
• Small, retroplaced tongue
• High narrow hard palate
• Temporomandibular joint ankylosis

Upper Limb Abnormalities

• Radial hypoplasia
• Thumb hypoplasia or absence
• Preaxial upper limb anomalies
• Extra radial digits in some cases
• Thumb duplication in some cases

Other Clinical Features

• Obstructive sleep apnea (77.8% of patients, with severe OSA in many cases) 3
• Hearing impairment due to ear anomalies
• Speech disorders
• Feeding difficulties, especially in infancy

Genetics and Inheritance

Nager syndrome is primarily caused by:

• Pathogenic variants in the SF3B4 gene, which encodes a component of the spliceosome 2
• The syndrome belongs to the spliceosomopathy group of diseases
• Evidence of both autosomal dominant and autosomal recessive inheritance patterns, suggesting genetic heterogeneity 2

Diagnosis

Diagnosis is based on:

1. Clinical features and physical examination
2. Radiological examination
3. Genetic testing for mutations in the SF3B4 gene 2

Nager syndrome is often mistaken for Treacher Collins syndrome due to similar craniofacial features, but patients with Treacher Collins do not exhibit the hand anomalies characteristic of Nager syndrome 3.

Prenatal diagnosis is possible through ultrasound, which can detect the characteristic facial and limb anomalies as early as 23 weeks of gestation 4.

Management

Management of Nager syndrome requires a multidisciplinary approach:

Respiratory Management

• Assessment and management of obstructive sleep apnea is critical 1
• Polysomnography (sleep study) is recommended prior to any surgical intervention due to high risk of respiratory complications 1

Craniofacial Management

• Mandibular advancement surgery to address retrognathia
• Temporomandibular joint reconstruction when needed
• Genioplasty in selected cases
• Cleft palate repair

Upper Limb Management

• Early pollicization of the index finger in patients with thumb anomalies to improve manual dexterity 3
• Excision of extra radial digits when present
• Correction of thumb duplication when present

Other Interventions

• Hearing assessment and appropriate interventions for hearing loss
• Speech therapy for articulation disorders
• Feeding support in infancy

Treatment Timeline

Treatment typically begins at birth and continues until approximately 20 years of age 2. The surgical procedures are sequenced according to functional needs:

1. Early interventions: Address breathing and feeding difficulties
2. Infancy/early childhood: Repair of oral and facial clefts
3. Childhood: Correction of eyelid deformities and cheekbone reconstruction
4. Later childhood/adolescence: Nasal and external ear surgeries
5. Throughout development: Speech therapy and hearing interventions
6. As appropriate: Upper limb surgeries to maximize function

Prognosis

With appropriate multidisciplinary management, patients with Nager syndrome can achieve good functional outcomes. Early intervention is crucial, particularly for:

• Managing respiratory complications
• Addressing feeding difficulties
• Optimizing upper limb function through timely surgical interventions
• Supporting speech and language development

There is no evidence of intellectual disability in most patients with Nager syndrome 5, which is an important consideration for long-term prognosis and quality of life.

Key Considerations and Pitfalls

1. Misdiagnosis: Nager syndrome is commonly confused with Treacher Collins syndrome; the presence of upper limb anomalies is the key distinguishing feature 3

2. Respiratory risk: The high prevalence of severe obstructive sleep apnea requires careful perioperative planning and monitoring 1

3. Surgical timing: Coordinating the multiple surgical interventions needed requires careful planning to optimize functional outcomes while minimizing anesthetic exposures

4. Genetic counseling: Given the variable inheritance patterns, genetic counseling is important for affected families