What is Nager syndrome?

Nager Syndrome

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

Clinical Features

Nager syndrome presents with distinct craniofacial and limb abnormalities:

Craniofacial Features:

• Mandibular hypoplasia with retrognathia
• Malar (cheekbone) hypoplasia
• Downward slanting palpebral fissures
• External ear abnormalities
• Cleft palate
• Microretrognathia
• Ankylosis of the temporomandibular joint
• High narrow hard palate
• Small retroplaced tongue 1, 2, 3

Limb Abnormalities:

• Thumb anomalies (hypoplasia or absence)
• Radial hypoplasia
• Upper limb shortening
• Preaxial limb defects 2, 3, 4

Genetics and Etiology

• Nager syndrome is primarily caused by pathogenic variants in the SF3B4 gene, which encodes a component of the spliceosome 2
• It belongs to the spliceosomopathy group of diseases 2
• Both autosomal dominant and autosomal recessive inheritance patterns have been documented, suggesting genetic heterogeneity 2
• When unaffected parents have more than one affected child, an autosomal recessive inheritance pattern is suspected 4

Diagnosis

Diagnosis of Nager syndrome is based on:

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

It's important to differentiate Nager syndrome from Treacher Collins syndrome, as they share similar craniofacial features. However, Treacher Collins syndrome does not present with the hand anomalies characteristic of Nager syndrome 3.

Management

Management of Nager syndrome requires a multidisciplinary approach that typically begins at birth and continues until approximately 20 years of age 1, 2:

Critical Early Interventions:

1. Assessment and management of obstructive sleep apnea - 77.8% of patients have obstructive sleep apnea, with many cases classified as severe 1, 3
2. Polysomnography (sleep study) is essential prior to any surgical intervention due to high risk of respiratory complications 1
3. Initial focus on facilitating breathing and feeding 2

Surgical Interventions (age-dependent):

• Mandibular advancement surgery
• Temporomandibular joint reconstruction
• Genioplasty
• Cleft palate repair
• Oral and facial cleft correction
• Eyelid deformity correction
• Cheekbone reconstruction
• Nose and external ear surgery in later years 1, 2, 3

Upper Limb Management:

• Early pollicization of the index finger for patients with thumb anomalies to prevent impairment in manual dexterity
• Excision of extra radial digits
• Thumb duplication correction 3

Additional Therapies:

• Speech and hearing disorder treatment with specialized logopedic intervention
• Rehabilitation and physiotherapy to maximize functional outcomes 2

Prognosis and Considerations

• Nager syndrome is extremely rare, with only about a hundred cases described in literature 2
• Prenatal diagnosis is possible through ultrasound, with cases detected as early as 23 weeks of gestation 5
• Careful perioperative planning and monitoring are essential due to the high prevalence of severe obstructive sleep apnea 1
• Recent research indicates that SF3B4 mutations cause major splicing defects and gene dysregulation affecting cranial neural crest development 6

Clinical Pitfalls to Avoid

1. Misdiagnosis: Nager syndrome is commonly mistaken for Treacher Collins syndrome; always assess for upper limb abnormalities to differentiate 3
2. Respiratory complications: Failure to assess for obstructive sleep apnea before surgical interventions can lead to serious complications 1
3. Delayed upper limb intervention: Early pollicization is recommended to prevent developmental delays in manual dexterity 3
4. Fragmented care: The complexity of this syndrome requires coordinated care by a craniofacial team rather than isolated specialist interventions 4