Nager acrofacial dysostosis

Overview

Nager acrofacial dysostosis, also known simply as Nager syndrome, is a rare congenital condition that affects the development of the face and limbs. It is classified under the group of acrofacial dysostoses disorders characterized by malformations of the craniofacial region (particularly the jaw and cheekbones) along with abnormalities in the limbs, particularly the arms and hands. First described in 1948 by Nager and de Reynier, the syndrome presents with variable severity but often includes underdeveloped facial bones, cleft palate, and limb defects, especially affecting the thumbs and forearms.

Nager syndrome can affect both males and females and is typically apparent at birth. Although it shares some features with Treacher Collins syndrome, it is distinguished by the additional presence of limb anomalies. Individuals with Nager syndrome may face feeding difficulties, breathing problems, and hearing loss due to the anatomical abnormalities associated with the condition.

Causes

Nager syndrome is primarily caused by mutations in the SF3B4 gene, which provides instructions for making a protein that is part of the spliceosome, a complex involved in processing RNA. The mutation disrupts normal gene expression during early embryonic development, particularly affecting the development of the first and second pharyngeal arches, which contribute to facial structures and limb formation.

The condition is most often inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene is sufficient to cause the disorder. However, many cases result from de novo mutations, occurring spontaneously in individuals with no family history. Rare autosomal recessive forms have also been reported but are far less common.

Symptoms

Nager syndrome presents with a combination of craniofacial and limb anomalies. The severity and range of symptoms can vary widely between individuals. Common features include:

Facial Features

• Malar hypoplasia (underdeveloped cheekbones)

• Micrognathia (small lower jaw)

• Down-slanting palpebral fissures (outer corners of eyes point downward)

• Coloboma or notching of the lower eyelid

• High-arched or cleft palate

• External ear malformations or low-set ears

• Conductive hearing loss due to malformation of middle ear structures

• Choanal atresia or nasal airway obstruction

Limb Anomalies

• Underdeveloped or absent thumbs

• Shortened or fused radius and ulna (bones of the forearm)

• Limited elbow extension or joint contractures

• Occasional lower limb anomalies, though these are less common

Other Associated Features

• Feeding difficulties due to jaw and palate abnormalities

• Breathing problems, especially in infancy

• Speech delays related to oral anomalies and hearing impairment

• Normal intelligence in most cases, though some may have mild learning challenges

Diagnosis

Diagnosis of Nager acrofacial dysostosis is based on clinical evaluation and confirmed with genetic testing. The following approaches are used:

• Clinical assessment: Identification of characteristic facial and limb abnormalities at birth or during prenatal imaging (e.g., ultrasound).

• Radiographic imaging: X-rays or CT scans to assess bone malformations in the skull and limbs.

• Audiological tests: Hearing evaluation to detect and manage conductive hearing loss early.

• Genetic testing: Identification of mutations in the SF3B4 gene confirms the diagnosis.

• Prenatal testing: May be offered to at-risk families using amniocentesis or chorionic villus sampling (CVS) if a causative mutation is known.

Treatment

There is no cure for Nager syndrome, and treatment focuses on managing the symptoms and supporting development. A multidisciplinary team is essential, often involving pediatricians, geneticists, craniofacial surgeons, ENT specialists, orthopedic surgeons, and speech therapists. Common interventions include:

• Surgical correction: Procedures to repair cleft palate, reconstruct jaws or ears, and address limb malformations.

• Airway management: In severe cases, a tracheostomy may be needed to address breathing difficulties in infancy.

• Feeding support: Special feeding techniques or gastrostomy tubes may be used until oral feeding is safe.

• Hearing aids: To manage conductive hearing loss and support speech development.

• Physical and occupational therapy: To improve mobility and function of affected limbs.

• Speech therapy: To address articulation difficulties due to oral structural anomalies.

• Psychosocial support: Counseling and educational support to help with social and developmental challenges.

Prognosis

The prognosis for individuals with Nager syndrome varies based on the severity of physical anomalies and associated complications. With early intervention and appropriate medical care, many individuals can lead functional and fulfilling lives. Most have normal cognitive development and can attend school and work with proper accommodations.

Lifelong monitoring may be required for hearing, dental health, and musculoskeletal development. Early surgical interventions, particularly for airway and feeding issues, are critical to improving survival and long-term outcomes in more severe cases. Genetic counseling is recommended for affected individuals and their families to understand inheritance patterns and reproductive options.