The clinical features include craniofacial, limb (mainly upper), and musculoskeletal anomalies.
Nager Acrofacial Dysostosis; Acrofacial Dysostosis Type 1; Preaxial Acrofacial Dysostosis; Preaxial Mandibulofacial Dysostosis.
First described in 1948 by two otorhinolaryngologists, the Swiss Felix Robert Nager (1877–1959) and the French Jean-Pierre de Reynier (1914–2001).
To date, approximately 100 cases have been described.
Most cases are sporadic. However, there have been reports with either autosomal dominant or autosomal recessive inheritance and variable penetrance and expressivity. The mutations affect the Splicing Factor 3b, Subunit 4 (SF3B4) gene, which has been mapped to chromosome 1q21.2. Slight female preponderance (approximately 2/3:1/3) has been reported.
Based on the characteristic facial features in combination with the typical limb anomalies.
The cardinal features include lateral downslanting of the palpebral fissures, malar hypoplasia, a high and broad nasal bridge, micrognathia, micro- or macrostomia, and external ear defects (low set and posteriorly rotated auricles, stenotic or atretic ear canals, abnormal pinnae). Ossicular chain anomalies may be present even in the absence of external ear anomalies, and bilateral conductive hearing loss is a common feature. Ankylosis and fibrosis of the temporomandibular joints and hypoplasia of the larynx and the epiglottis have been described, but are considered rare. Cleft lip-palate or absent soft palate with velopharyngeal insufficiency occur occasionally. Obstructive sleep apnea should be expected in these patients. Reduced number of eyelashes and lower eyelid coloboma are other infrequent findings. Thoracolumbar scoliosis, anomalies of the cervical spine, and the ribs have been reported infrequently. The limb anomalies mainly affect the upper extremity with phocomelia, hypoplastic or absent radius, proximal radioulnar synostosis with severely limited range of motion in the elbow, and usually asymmetrically hypoplastic or absent thumbs. Triphalangeal or duplicated thumbs and other hand anomalies, such as syn-, clino-, and camptodactyly are less frequent. Sporadically, also lower limb anomalies are present, such as dislocation of the hips, phocomelia, absent tibia and/or fibula, talipes equinovarus, and metatarsus varus. Toe abnormalities include overlapping toes, syndactyly, and rare cases of hypoplastic or absent toes, posteriorly placed hypoplastic halluces, broad halluces, halluces valgi, dorsal angulation of the second toe, or medial deviation of the toes. The majority of these patients are mentally normal, although severe mental delay has also been described. Speech and language problems are frequent, which are often considered secondary to impaired hearing. In the largest case series, 20% of the patients were either stillborn or died in the neonatal period. In more than half of these patients, death resulted from respiratory distress secondary to the craniofacial anomalies. Cardiovascular (ventricular septal defect, tetralogy of Fallot, and infundibular obstruction of the right ventricular outflow tract), central nervous system (microcephaly, polymicrogyria, aqueductal stenosis with hydrocephalus), ...