Acrofacial Dysostosis 1, Nager Type

A number sign (#) is used with this entry because of evidence that the Nager type of acrofacial dysostosis (AFD1) is caused by heterozygous mutation in the SF3B4 gene (605593) on chromosome 1q21.

Description

Nager syndrome is the prototype for a group of disorders collectively referred to as the acrofacial dysostoses (AFDs), which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of Nager syndrome include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The presence of anterior upper-limb defects and the typical lack of lower-limb involvement distinguishes Nager syndrome from Miller syndrome (263750), another rare AFD; however, distinguishing Nager syndrome from other AFDs, including Miller syndrome, can be challenging (summary by Bernier et al., 2012).

Clinical Features

Nager acrofacial dysostosis was recognized as a specific entity by Nager and de Reynier (1948), but was probably first reported by Slingenberg (1908). The limb deformities in the Nager syndrome 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.

The disorder reported by Walker (1974) in sibs whose parents were normal may have been Nager syndrome.

Weinbaum et al. (1981) described a kindred in which the proband had classic Nager syndrome and 5 other persons covering 4 generations showed lesser expression. 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.

Richieri-Costa et al. (1983) described 2 sisters, offspring of nonconsanguineous parents, who had facial and skeletal anomalies. One had mandibulofacial dysostosis with bilateral radial ray anomalies. The other had cleft lip and palate with hypoplastic thumbs.

Halal et al. (1983) reported 4 patients and reviewed all previous cases. This led to an extended characterization of Nager acrofacial dysostosis, e.g., description of lower limb defects. The differentiation from AFD with postaxial defects (263750), the hemifacial microsomia/Goldenhar radial defect syndrome, and other syndromes was discussed.

Opitz (1987) suggested that Nager acrofacial dysostosis represents an 'anomaly' rather than a syndrome because of its apparent causal heterogeneity.

Aylsworth et al. (1987) described findings in a father and child consistent with the Nager syndrome and supporting autosomal dominant inheritance. In addition to cranial features, the child had a small left thumb and absence of the right thumb. The father had similar facial features, a nonfunctional, proximally placed right thumb, and the history of a rudimentary left thumb that was removed during childhood.

Aylsworth and Lin (1990) described an affected father and 2 sons. One of the sons had Hirschsprung disease.

Goldstein and Mirkin (1988) described an unusually severe form. Palomeque et al. (1990) also reported a severely affected patient.

Bonthron et al. (1993) reported the case of a girl with Nager acrofacial dysostosis who had a maternal aunt and maternal great-grandfather with a short distal phalanx of the thumb (type D brachydactyly) and a maternal grandmother with a bilateral congenital anomaly of the thumbnails referred to as dystrophia unguis mediana canaliformis (Seller, 1974). The thumb in this case was longitudinally divided. The family was presented as supporting dominant inheritance.

Fryns et al. (1996) reported an adult male who, in addition to typical manifestations, had agenesis of the corpus callosum, strabismus, equinovarus position of both feet, cryptorchidism, and blind-ending fistula in the middle of the anoscrotal raphe. The patient died at the age of 50 years from heart failure due to a complete atrioventricular block.

McDonald and Gorski (1993) presented a summary of 76 previously reported cases and added 2 new cases. Proximal radioulnar synostosis was found in 16 of 19 cases in whom appropriate studies were performed.

Of 13 patients with genetically confirmed Nager syndrome and typical features of the disorder, Petit et al. (2014) found that 3 also had cardiac malformations, including patent ductus arteriosus, tetralogy of Fallot, and ventricular septal defect, and 3 also had foot anomalies, including metatarsus varus, talipes with hypoplasia of the metatarsals, and large and short halluces.

See 263750 for the Miller acrofacial syndrome in which postaxial limb changes (rather than preaxial as in Nager syndrome) are associated with facial dysostosis.

See split-hand deformity with mandibulofacial dysostosis (183700).

Inheritance

There is evidence of autosomal dominant and autosomal recessive inheritance of Nager acrofacial dysostosis.

Marden et al. (1964) described an infant with this syndrome whose father and mother were 42 and 41 years of age, respectively, at the time of his birth, thus suggesting dominant mutation.

Lowry (1977) described the anomaly in a patient whose father and mother were 44 and 38 years of age, respectively, at her birth, compatible with new dominant mutation.

Burton and Nadler (1977) described a case in the offspring of first cousins; the father was aged 37 years.

Aylsworth et al. (1987) described a family with affected father and child and Aylsworth and Lin (1990) described a family with affected father and 2 sons, supporting the notion that some cases are caused by autosomal dominant mutations (Aylsworth et al., 1991).

Chemke et al. (1988) reported affected male and female sibs; the parents were unrelated.

Byrd et al. (1988) described 4 patients with Nager acrofacial dysostosis, including a pair of concordantly affected monozygotic twins.

McDonald and Gorski (1993) presented a summary of 76 previously reported cases and added 2 new cases. They favored inheritance as a pleiotropic disorder with markedly variable penetrance and expressivity, but granted that the occurrence of affected sibs with normal parents suggested genetic heterogeneity with the existence of an autosomal recessive form. They found 5 families with normal parents and 2 affected sibs.

Diagnosis

Prenatal Diagnosis

Hecht et al. (1987) identified the Nager syndrome in a newborn infant and in a subsequent sib by prenatal ultrasonography. They presented this as evidence of autosomal recessive inheritance.

Cytogenetics

Waggoner et al. (1999) reported a case of Nager syndrome with deletion of the heterochromatic block and adjacent euchromatin of chromosome 1q ([46,XY,del(1)(q12q21.1)] or [46,XY,del(1)q12q21.3]). The affected child also had severe aortic stenosis and right pulmonary bronchial stenosis. The authors suggested that the deleted 1q region may contain genes crucial for normal limb, craniofacial, and/or cardiopulmonary development.

Genetic Heterogeneity of Nager Syndrome

Zori et al. (1993) suggested that the gene for this disorder may reside on chromosome 9; they observed the Nager syndrome in an infant with an apparently balanced X;9 translocation 46,X,t(X;9)(p22.1;q32).

Dreyer et al. (1998) identified a novel zinc finger gene, termed ZFP37 (602951), that maps to chromosome 9q32 and encodes a putative transcription factor expressed in several tissues including human fetal cartilage. On the basis of its map location and expression pattern, Dreyer et al. (1998) suggested ZFP37 as a candidate gene for Nager acrofacial dysostosis.

Scapoli et al. (2003) described an infant with Nager syndrome and a chromatid gap within band 3p14. The parents were unavailable for karyotype analysis. The chromatid gap was interpreted as the expression of the chromosomal fragile site FRA3B (601153), which is located at 3p14. Scapoli et al. (2003) noted that although FRA3B is the most highly expressed common fragile site, its molecular basis and phenotypic effect were unknown (Wang et al., 1999). No repeat motifs, such as trinucleotide repeats, had been identified within FRA3B. The authors pointed out, however, that FRA3B lies within the FHIT locus in both mouse and human. The FHIT gene is frequently deleted in a variety of human cancers.

Molecular Genetics

After exome sequencing in patients with the Nager type of acrofacial dysostosis pointed to SF3B4 (605593) as a strong candidate gene, Bernier et al. (2012) identified 18 different heterozygous SF3B4 mutations in 20 (57%) of 35 families affected by Nager syndrome (see, e.g., 605593.0001-605593.0004). Because of overlap in features between Nager syndrome and mandibulofacial dysostosis with microcephaly (MFDM; 610536), which is caused by mutation in the EFTUD2 gene (603892), Bernier et al. (2012) analyzed EFTUD2 in AFD patients who were negative for mutation in SF3B4 and identified a nonsense mutation in the EFTUD2 gene in 1 patient (603892.0006). In retrospect, the patient also had microcephaly, suggesting that MFDM rather than Nager syndrome was the appropriate diagnosis.

Czeschik et al. (2013) analyzed the SF3B4 gene in 12 patients with Nager syndrome and identified heterozygous mutations in 7 (63.6%) (see, e.g., 605593.0003 and 605593.0005). In the 4 cases in which parental DNA was available, the mutation was confirmed to have arisen de novo. The only significant difference between the mutation-positive and -negative patients was the more frequent presence of midface hypoplasia/retrusion in patients with SF3B43 mutations (p = 0.045). Czeschik et al. (2013) also observed that more than half of both mutation-positive and -negative patients exhibited anomalies of the feet and toes, a clinical sign that had previously been considered a rare manifestation of Nager syndrome.

Petit et al. (2014) identified heterozygous loss-of-function mutations in the SF3B4 gene in affected individuals from 9 (64%) of 14 families with a clinical diagnosis of Nager syndrome. The mutations included loss of the initiator methionine as well as nonsense, frameshift, and splice site mutations. The severity of the phenotype was highly variable, even within families, and several mildly affected parents were identified only after the diagnosis of a severely affected child or fetus. The findings confirmed that haploinsufficiency of SF3B4 is the major cause of Nager syndrome, and suggested that genetic counseling may be difficult for this disorder.

History

Gobbel et al. (2005) examined a fetus, dating from the early 19th century, in the Meckel anatomic collection at the University of Halle, Germany, and observed mandibulofacial defects and preaxially malformed limbs. Radiologic and CT examination showed complex facial malformations with mandibular hypoplasia and dysgenesis of the ear capsule. The ossified thorax was slender with ribs pointing downward, hypoplastic claviculae, and ankylosis of the shoulder joint on both sides. Although the upper limbs were of normal length, there was bilateral radial agenesis with laterally convex diaphyses of the ulnae, left-sided aplasia and right-sided hypoplasia of the thumbs, and bilateral club hands. The right foot showed varus, adduction, and supination, while the face of the left tibia rotated outward. Comparative genomic hybridization analysis did not reveal any chromosomal imbalance. Gobbel et al. (2005) stated that the Meckel specimen is likely the earliest known fetus with Nager AFD.