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 distinctive 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

• Most cases are caused by pathogenic variants in the SF3B4 gene, which encodes a component of the spliceosome 2
• Nager syndrome belongs to the spliceosomopathy group of diseases 2
• Both autosomal dominant and autosomal recessive inheritance patterns have been documented, suggesting genetic heterogeneity 2
• The syndrome is extremely rare with only about 100 cases described in the literature 2, 5

Diagnosis

Diagnosis 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, which shares similar craniofacial features but lacks the characteristic upper limb abnormalities 3.

Management

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

Critical Early Interventions:

• Assessment and management of obstructive sleep apnea is critical as there is a high prevalence of severe OSA in these patients 1, 3
• Polysomnography (sleep study) is recommended prior to any surgical intervention 1
• Addressing breathing and feeding difficulties takes priority in early management 2

Surgical Management:

• Mandibular advancement surgery
• Temporomandibular joint reconstruction
• Genioplasty
• Cleft palate repair
• Correction of thumb anomalies (pollicization of the index finger is recommended early to prevent impairment in manual dexterity)
• Excision of extra radial digits when present 1, 3

Additional Interventions:

• Speech and hearing disorder management
• Rehabilitation and physiotherapy to maximize function and reduce insufficiency 2
• Staged surgical approach based on age and developmental needs:
  1. First: Address breathing and feeding issues
  2. Second: Repair oral and facial clefts
  3. Third: Correct eyelid deformities and cheekbone reconstruction
  4. Later: Nose and external ear surgeries 2

Clinical Considerations

• Careful perioperative planning and monitoring are essential due to the high risk of respiratory complications 1
• Early pollicization in patients with thumb anomalies is recommended to prevent manual dexterity impairment 3
• Prenatal diagnosis is possible through ultrasound, with at least one case reported as early as 23 weeks of gestation 5
• Mental development is typically normal in patients with Nager syndrome 4

Recent research using animal models suggests that SF3B4 mutations cause major splicing defects and gene dysregulation that specifically disrupt cranial neural crest development, explaining the craniofacial manifestations of the syndrome 6.