ROBINOW SYNDROME

Overview

Robinow syndrome is a rare genetic disorder characterized by specific craniofacial features, short stature, brachyclinodactyly V, and hypoplastic genitals. There are both autosomal dominant and autosomal recessive forms of inheritance. Pathogenic variants in the ROR2 or NXN gene cause the recessive form, while mutations in the WNT5A, DVL1, and DVL3 genes are associated with the dominant form.

Also called

Fetal face syndrome

Symptoms

The main symptoms of Robinow syndrome are

• Characteristic craniofacial features (prominent forehead and flat midface, short nose with everted nasal floor, wide-set eyes)
• Short stature with mesomelic shortening, especially of the upper extremities
• Brachydactyly-clinodactyly V
• Hypoplastic genitals, especially in males.

Cognitive abilities are normal in 80 to 90% of cases. In 10 to 20% a developmental disorder is described.

Cause

The first report by Meinhard Robinow et al. (1969) of a family with affected persons in six generations suggested an autosomal dominant pattern of inheritance. Affected siblings of healthy parents, especially in cases of consanguinity, showed that there is also an autosomal recessive form. Pathogenic variants in the ROR2 gene (Afzal et al., Bokhoven et al.), which codes for a tyrosine kinase, were found to be the cause of this form; its pathogenic variants also cause an autosomal dominant form of brachydactyly type B. Person et al. (2010) found pathogenic variants in the WNT5A gene to be the genetic cause of the autosomal dominant form in the family that was originally described, and in 2015, pathogenic changes in the DVL1 and DVL3 genes were found as further causes (White et al.). This means that three forms are currently distinguished genetically; clinically, the dominant forms are similar, while the recessive form seems to be associated with more pronounced short stature and additional skeletal malformations in the ribs and vertebrae.

Inheritance

Robinow syndrome is inherited in an autosomal dominant or autosomal recessive pattern, depending on the causative variants.

References

White et al. 2018, Am J Hum Genet 102:27 / White et al. 2016, AJHG, 98:553 / White et al. 2015, AJHG 96:645 / Person et al. 2010, Dev Dyn 239:327 / van Bokhoven et al. 2000, Nat Genet 25:423 / Afzal et al. 2000, Nat Genet 25:419 / Robinow et al. 1969, Am J Dis Child 117:645