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At a glance

Rare condition characterized by malar hypoplasia, maxillary and mandibular hypoplasia, cleft lip or palate, retroplaced tongue. Radial defects (preaxial limb deficiency), underdevelopment or absence of the thumb, shortened forearms, and poor movement in the elbow. Downward-slanting palpebral fissures. Absent eyelashes (medial third of lower lids). Dysplastic ears and conduction deafness. Trismus and respiratory problem in neonates.

Synonyms

Acrofacial Dysostosis 1; Treacher Collins Mandibulofacial Dysostosis Type with Limb Anomalies; Split-Hand Deformity Mandibulofacial Dysostosis.

History

Nager and de Reynier recognized this condition as a specific entity in 1948. Opitz (1987) suggested that Nager acrofacial dysostosis (AFD) represents an “anomaly” rather than a syndrome because of its apparent causal heterogeneity.

Incidence

Very rare malformation. Less than 100 patients have been reported. Several syndromic associations.

Genetic inheritance

Autosomal dominant. Most cases have been sporadic.

Pathophysiology

Caused by heterozygous mutation in the SF3B4 gene on chromosome 1q21. This gene encodes SAP49 required for the assembly of spliceosomal complexes. Spliceosomes are involved in intron splicing as well as alternative splicing and are important in gene-expression pathways. The severity of the phenotype is highly variable. The lack of clear genotype-phenotype correlations makes genetic counseling particularly difficult for families with this syndrome.

Diagnosis

The diagnosis seems mostly clinical and radiologic. The limb deformities consist of absence of radius, radioulnar synostosis, and hypoplasia or absence of the thumbs. The mandibulofacial dysostosis is characterized mainly by severe micrognathia and malar hypoplasia. They suggested that ptosis of the lower lids, hypoplasia of the lower lid eyelashes, and cartilaginous pegs between the antitragus and lobule are minimal expressions of the syndrome. At birth, the diagnosis is suspected based on the clinical aspect, characterized by varying severities of mandibulofacial dysostosis with preaxial and/or postaxial limb abnormalities.

Clinical aspects

In the predominant facial form, called Nager Acrofacial Dysostosis, the facial changes resemble strikingly those of the Treacher Collins Syndrome: malar hypoplasia, maxillomandibular hypoplasia, cleft lip or palate, conductive hearing loss, and radial limb hypoplasia. Neonates may present respiratory or feeding problems because of severe mandibular hypoplasia. Upper limb malformation is a constant feature of Nager Syndrome and ranges from thumb hypoplasia to the absence of the radial ray. Neurologic: Intelligence is usually normal. Hydrocephalus, agenesis of corpus callosum, polymicrogyria, and spinal cord defects are reported. Airway: Absence of zygomatic arches associated with hypoplastic malar region and frequent hypoplasia of the larynx and epiglottis may contribute to the respiratory distress often observed in these infants. The temporomandibular joint can be affected. Cardiac: Association with congenital heart defect (tetralogy of Fallot) is rare. Musculoskeletal: Short stature, hypoplastic or aplastic radius, radioulnar synostosis. Limited elbow extension. The presence of a hypoplastic or aplastic thumb is almost characteristic ...

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