Maxillonasal Dysplasia, Binder Type

Clinical Features

Binder (1962) described a syndrome of maxillonasal dysplasia characterized by a short nose with a flat bridge, a short columella, an acute nasolabial angle, perialar flatness, a convex upper lip, and a tendency to an angle class III malocclusion. Critical features of the syndrome appear to be midfacial hypoplasia, lack of anterior nasal spine, and malocclusion.

Sheffield et al. (1989) reviewed 103 cases of chondrodysplasia punctata (CDP; see 215100) seen in Melbourne over a 20-year period. They concluded that Binder syndrome should be classified as a mild form of CDP. Sheffield et al. (1991) pointed out that most patients with Binder syndrome seek medical attention in adolescence; by this age, the diagnostic radiologic features of chondrodysplasia punctata have disappeared and so the diagnosis of CDP is often not considered. Older patients may show terminal phalangeal hypoplasia of the hand, sometimes only in some digits, and patchy distortion of vertebrae, a residuum of vertebral clefting. Some of the patients labeled as Binder phenotype in a craniofacial unit had a maternal history of warfarin ingestion during pregnancy (see 118650).

Quarrell et al. (1990) reported a case and reviewed the clinical features, concluding that the disorder does not represent a single nosologic entity and that the use of the word syndrome or the word dysplasia is inappropriate. They suggested that the phenotype be considered an 'association.'

Gross-Kieselstein et al. (1986) reported an affected mother and daughter. Olow-Nordenram and Radberg (1984) reported the syndrome in mother and daughter also. Roy-Doray et al. (1997) described Binder syndrome in a mother and her son. The mother was the last-born of 7 children; her mother was 40 and her father 49 at the time of her birth. The parents were unaffected and unrelated; the other children were normal. The son was strikingly affected. Photographs of both patients as infants and of the mother at age 19 were provided.

The Keutel syndrome (245150) shares some features with Binder syndrome, such as midfacial hypoplasia. Munroe et al. (1999) suggested that Binder syndrome might be an allelic variant of Keutel syndrome, which has been shown to be due to mutations in the gene encoding matrix Gla protein (MGP; 154870).

Inheritance

In a formal genetic analysis, Olow-Nordenram and Valentin (1988) found low segregation ratios and suggested that recurrence in their pedigrees could be explained by either autosomal recessive inheritance with reduced penetrance or by multifactorial inheritance.

Animal Model

Noguchi et al. (2002) noted that retinoic acid, a metabolic product of retinol, is essential for craniofacial morphogenesis, and that transthyretin (TTR; 176300) is a plasma protein delivering retinol to tissues. They produced several transgenic mouse lines using the TTR val30-to-met mutation (176300.0001), and found that one of the lines showed an autosomal dominant inheritance of maxillonasal deformity which the authors termed Nax. The Nax malformation was characterized by a hypoplastic developmental defect of the frontonasal region. Homozygous mice with higher transgene expressions showed more severe phenotypes, but a subline, in which the copy number and expression of the transgene was reduced, showed a normal phenotype. Nax mice began to express the mutant TTR gene in the nasal placode from embryonic day 10.5 (E10.5), which was 2 days earlier than in the other transgenic lines with a normal phenotype. Excessive cell death was observed in the nasal placode of the E10.5 Nax embryos. In addition, the forced expression of mutant TTR in the nasal placode of transgenic mice resulted in similar phenotypes.