Unidad Regiomontana de Diagnostico, Monterrey, N.L., Mexico.

Synonyms: Acrofacial dysostosis, Nager type. Preaxial acrofacial dysostosis, Mandibulofacial dysostosis, Treacher Collins type, with limb anomalies. Nager acrofacial dysostosis. A variant of acrofacial dysostosis is the Rodriguez type associated to internal organ anomalies, and the postaxial form (Genée-Widemann or Miller syndrome).

Definition: Nager syndrome or acrofacial dysostosis is a malformation characterized by limb and facial deformities. The limb anomalies consist of hypoplasia or absence of radius, radioulnar synostosis, and hypoplasia or absence of the thumbs. The mandibulofacial dysostosis is characterized mainly by severe micrognathia and malar hypoplasia.

Case report: A 29-year-old woman with no family history of malformations or genetic disorders attended the ultrasound unit at 22 weeks and had a routine examination. The scan showed a normally developed male fetus, with severe micrognathia associated to shortening of both forearms, in the left side with fixed elbow, curved ulna, and absence of the radius and the thumb. Lower limbs were of normal length. The rest of the exploration was also normal.

Figures 1-3: Fetal profile with severe micrognathia.

Figures 4-6: Left forearm, curved ulna and absence of radius

Figure 7-8: Short right forearm, hypoplastic ulna and radius

Figures 9: Coronal view of the fetal nose and upper lip

Figure 10-12: Short left forearm

Figure 13-15: Short left forearm, normal size of the hand. Transverse view of the left hand with absence of the thumb. Left forearm  transverse view with absence of the radius.

Figure 16-17: Fixed left elbow. Left forearm 

Figures 18-19: Normal lower limbs.

Figure 20: Fetal gender.

Figures 21-23: Normal four-chamber, interventricular septum and left ventricle outflow tract

Figure 24: Fetal heart rate

Incidence: More than 80 cases of Nager syndrome have been reported in neonates and infants, although there are only two reports on the prenatal diagnosis of the condition.

History: Nager acrofacial dysostosis was recognized as a specific entity by Nager and De Reynier in 1948.

Etiology: The gene for this disorder may reside on chromosome 9. The gene is termed ZFP37, and maps to chromosome 9q32, encoding a putative transcription factor expressed in several tissues including human fetal cartilage. More recently chromosome 1 and 3 have also been suggested as having the gene responsible of Nager acrofacial dysostosis.

Sonographic findings: Nager syndrome can be suspected prenatally at ultrasound if severe micrognathia, forearm shortening and absence of one or more digits are detected.

Differential Diagnosis: The most common condition to consider in the differential diagnosis is trisomy 18, since all features (micrognathia, radial hypo/aplasia) can be present in this syndrome. However, trisomy 18 is usually associated with clinodactyly, not with absence of digits. Treacher Collins syndrome may share some of the features of Nager syndrome (mandibular hypoplasia), but limb and digit abnormalities are not part of the syndrome. Other conditions to rule out are those characterized by upper limb mesomelic hypoplasia, such as Roberts syndrome or thrombocytopenia absent radius syndrome, but facial anomalies have not been reported as part of them.

Associated anomalies: There is a type of acrofacial dysostosis associated to absent fibulae, microtia, cleft palate, internal organ anomalies including arrhinencephaly and abnormal lung lobulation. This acrofacial dysostosis is termed type Rodriguez.

Prognosis:  Neonates with Nager syndrome may present with acute upper airway obstruction due to severe micrognathia.

Management: Early prenatal recognition of the syndrome is important to provide parents with the option of pregnancy termination, and in case of pregnancy continuation, appropriate management by an experienced team of neonatologists is mandatory to ensure neonatal survival. 

References

 1) Nager FR, de Reynier JP. Das Gehorogan bei den angeborenen Kopfmisbildungen. Pract Otorhinolaryngol 1948; 10: 1-7

 2) Paladini D, Tartaglione A, Lamberti A, Lapadula C, and Martinelli P. Prenatal ultrasound diagnosis of Nager syndrome. Ultrasound Obstet Gynecol 2003; 21: 195-197

 3) Benson CB, Pober BR, Hirsh MP, Doubilet PM. Sonography of Nager acrofacial dysostosis syndrome in utero. J Ultrasound Med 1988; 7: 163-167

 4) Wesssels MW, Hollander NS, Cohen Overbeek TE. Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez. 2002 American Journal of Medical Genetics 113: 97-100

 5) Waggoner DJ, Ciske DJ, Bruce S, Watson MS. Deletion of 1q in a patient with acrofacial dysostosis. 1999 American Journal of Medical Genetics 82: 301-304.