Robinow syndrome

Robinow syndrome is caused by germline pathogenic variants in WNT5A-ROR2 pathway components and downstream effectors. This non-canonical WNT signalling pathway regulates planar cell polarity, embryonic patterning, limb elongation, and craniofacial morphogenesis. The implicated genes include ROR2 (the most frequently reported), DVL1, WNT5A, DVL3, and NXN. Biallelic loss-of-function variants in ROR2 or NXN, and heterozygous gain-of-function or dominant-negative variants in DVL1, DVL3, or WNT5A, disrupt this pathway and produce the characteristic skeletal and craniofacial dysplasia.

Inheritance of Robinow syndrome is genetically heterogeneous, comprising autosomal recessive and autosomal dominant forms. In autosomal recessive forms, the recurrence risk for siblings of a proband is 25%. In autosomal dominant forms, each child of an affected parent has a 50% risk of inheriting the pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

There are no established consensus clinical or biochemical diagnostic criteria for Robinow syndrome. Clinical suspicion is supported by the distinctive fetal-face appearance and by skeletal radiographs documenting mesomelic or acromesomelic limb shortening, brachydactyly, and, in the recessive form, hemivertebrae and rib fusions. The diagnosis is established by molecular genetic testing identifying pathogenic variants in the implicated genes.

Main differential diagnoses include:

• Aarskog syndrome: facial and genital hypoplasia overlap, but with shawl scrotum and widow’s peak; FGD1 (X-linked).
• Omodysplasia type 2: facial dysmorphism and genital hypoplasia, but with normal stature and rhizomelic limb shortening; FZD2.
• : macrocephaly and depressed nasal bridge overlap, but with trident hand and rhizomelic shortening of all long bones; FGFR3.

• Establishing a molecular diagnosis confirms the clinical suspicion and provides a precise basis for genetic counselling.
• Identification of the underlying genetic cause enables specific and individualised surveillance and forms the prerequisite for targeted medical care, with monitoring and management decisions made by the treating physicians in consultation with the affected individual.
• Once a pathogenic variant is identified in an affected individual, predictive testing of at-risk relatives becomes possible, allowing them to clarify their own variant status.

• Bacino CA. ROR2-related Robinow syndrome. 2005 Jul 28 [updated 2019 Sep 12]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301418.
• Roifman M, Brunner H, Lohr J, Mazzeu J, Chitayat D. Autosomal dominant Robinow syndrome. 2015 Jan 8 [updated 2019 Oct 3]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. . GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:25577943.
• Lima AR, Ferreira BM, Zhang C, Jolly A, Du H, White JJ, et al. Phenotypic and mutational spectrum of ROR2-related Robinow syndrome. Hum Mutat. 2022;43(7):900-18. doi:10.1002/humu.24375. PMID:; PMCID: PMC9177636.
• Zhang C, Jolly A, Shayota BJ, Mazzeu JF, Du H, Dawood M, et al. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability. HGG Adv. 2022;3(1):100074. doi:10.1016/j.xhgg.2021.100074. PMID:; PMCID: PMC8756549.