Nager Syndrome

Rare condition characterized by malar hypoplasia, maxillary and mandibular hypoplasia, cleft lip or palate, retroplaced tongue, radial defects (preaxial limb deficiency), downward-slanting palpebral fissures, absent eyelashes (medial third of lower lids), dysplastic ears and conduction deafness, trismus, and respiratory problem in neonates. There may be underdevelopment or absence of the thumb, shortened forearms, and poor movement in the elbow.

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

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.

Rare malformation, of which several syndromic associations have been reported.

No clear genetic background and no molecular data. Most cases have been sporadic. However, it has also been suggested that a dominant mutation was possible. In 1987, the presentation of a father and child consistent with Nager syndrome supported an autosomal dominant inheritance, but no further investigations were able to sustain this observation. It has been reported that a deletion of the heterochromatic block and adjacent euchromatin of chromosome 1q was possible. In this situation, the affected child also presented with severe aortic stenosis and right pulmonary bronchial stenosis. This association with a deletion of chromosome 1q may suggest that this gene region contains crucial information for normal limb, craniofacial, and/or cardiopulmonary development. The association with chromosome 9 has been reported. An infant with Nager syndrome and a chromatid gap within band 3p14 was reported, but there remains no indication that this disease is genetic rather than sporadic. Opitz (1987) suggested that Nager AFD represents an “anomaly” rather than a syndrome because of its apparent causal heterogeneity.

No known pathophysiologic explanation for this medical condition.

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.

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. Intelligence is usually normal. Neurologic: 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. Cardiac: Association with congenital heart defect 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 of this condition. Other features include syndactyly, clinodactyly, or camptodactyly. The humeri are often shortened. Cervical vertebral deformities are frequent. Visceral: Association with Hirschsprung disease has been suggested.

In neonates, the presence of severe respiratory depression might require placement of a preventive tracheostomy, which requires proper airway evaluation. Complete evaluation of the upper airway must include opening of the mouth, severity of micrognathia, and presence of laryngeal hypoplasia and/or absence of epiglottis. The potential for associated abnormalities of the heart, brain, kidney, or urogenital tract must be evaluated carefully prior to anesthesia. Vertebral body malformations, especially cervical, must be assessed carefully. Evaluate and anticipate the airway obstruction and difficult intubation.

The need for urgent tracheostomy, most often immediately after birth, can be performed under local anesthetics and controlled sedation. Maintaining spontaneous lung ventilation and oxygenation is highly recommended. Tracheal intubation via a laryngeal mask airway or retrograde technique has been reported. If the patient's trachea is intubated, the child must be carefully assessed postoperatively and extubated while fully awake. Venous access may be difficult in view of the limb deformities. The indication for invasive monitoring, such as radial artery access, can be difficult because of radial aplasia or hypoplasia.

Muscle relaxants and opioids should be avoided before tracheal intubation is achieved and lung ventilation confirmed. Sedative agents should be used with great caution in the preoperative period, especially in the younger patient.

Six forms of AFD have been described: AFD syndrome of Kelly, Rodriguez or Madrid form, Reynolds or Idaho form, Arens or Tel Aviv type, presumed AFD syndrome of Richieri-Costa, and AFD Patterson-Stevenson-Fontaine syndrome. These disorders have been distinguished based on limb anomalies into preaxial, postaxial, lethal, and atypical forms.

Weyers Syndrome II: Syndrome in which hexadactyly is associated with fusion of the fifth and sixth metacarpal bones and of the proximal phalanges of the fifth and sixth toes. The tooth anomaly involves particularly the lower incisors, which are peg-shaped, small or missing, and widely spaced. A bony cleft of the mandibular symphysis may occur because of delayed ossification.

Rodriguez Lethal Acrofacial Dysostosis (Acrofacial Dysostosis Syndrome of Rodriguez; Madrid AFD Form): Characterized by severe mandibular hypoplasia, phocomelia and oligodactyly of the upper limbs, absence of fibulas, microtia, cleft palate, internal organ anomalies including arrhinencephaly and abnormal lung lobulation, and early lethality. All patients die of respiratory complications resulting from severe mandibular hypoplasia in the neonatal period. The limb deficiencies are predominantly preaxial (include severe hypoplasia of the shoulder and pelvic girdles), and the postaxial limb anomalies are rare types. Most patients present with cardiac and central nervous system malformations. An autosomal recessive mode of inheritance has been suggested. It has been suggested that the principal disorders that must be differentiated are Genee-Wiedemann syndrome and Nager syndrome.

Miller Syndrome (Postaxial Acrofacial Dysostosis; Genee-Widemann Syndrome): Characterized by the presence of postaxial limb deficiency, cup-shaped ears, and malar hypoplasia. Coloboma of the eyelids and accessory nipples are not present in this medical condition. Micrognathia is the rule and tends to improve with age. Cleft palate has been reported in all patients, whereas a cleft lip is present in only 20% of cases. Other features include bilateral absence of the fifth digit, including the fifth metacarpal, or unilateral aplasia or hypoplasia of the fifth digit. Shortened forearms and radiologic evidence of ulnar hypoplasia. Intelligence appears to be normal. Autosomal recessive inheritance has been suggested. Possible.

Treacher Collins Syndrome: Characterized by malar and mandibular hypoplasia, slanted eyes, notching of lower eyelids, and micrognathism. Severe respiratory problems can be seen in the neonatal period because of hypoplastic mandible. The pinna and the external auditory meatus bilaterally may be malformed. The tympanic membrane may be absent. Other facial features include a beak-like nose and acute deafness.

Goldenhar Syndrome: Rare congenital disorder that involves unusual facial characteristics, such as partial absence of the upper eyelid or an unusual slant of the eyelid, skull asymmetry, prominent forehead, absence of nostrils, cleft palate, and micrognathism. Unilateral paralysis of the eye muscles may occur. Unusual cysts and fatty tissue can be observed at the edge of the eye, and skin tags are often present around the ears. Congenital heart defects are usually present.

Oral-Facial-Digital Syndrome (OFD): Rare genetic disorder characterized by episodes of neuromuscular disturbances. It is associated with a split tongue, splits in the jaw, midline cleft lip, overgrowth of the frenulum, a broad-based nose, and epicanthic folds. Polysyndactyly and clinosyndactyly are frequent.

Juberg-Hayward Syndrome: Rare hereditary disorder characterized by cleft lip and palate, microcephaly, deformities of the thumbs and toes, and growth hormone deficiency resulting in short stature.

Hemifacial Microsomia (HFM): Syndrome that affects 1:5000 births. Although it is often mistaken for Treacher Collins syndrome, this condition is not genetic. Furthermore, some patients present with abnormalities on both sides of the face, whereas both sides of the face appear equally affected in Treacher Collins syndrome. The facial nerve is frequently paralyzed in hemifacial microsomia. Other features include micrognathism, unilateral facial tilting, microtia, facial nerve weakness (40%), macrostomia, and underdevelopment of the cheek and eye on the affected side of the face. Other abnormalities may include fatty tumors over the eye, vertebral body anomalies, ribs deformities, and cleft lip/palate. The association with congenital heart defects and kidney abnormalities has been reported and should be considered.