Characterization of the Robinow syndrome skeletal phenotype, bone micro-architecture, and genotype-phenotype correlations with the osteosclerotic form

Am J Med Genet A. 2020 Nov;182(11):2632-2640. doi: 10.1002/ajmg.a.61843. Epub 2020 Sep 5.


Robinow syndrome (RS) is a genetically heterogeneous skeletal dysplasia with recent reports suggesting an osteosclerotic form of the disease. We endeavored to investigate the full spectrum of skeletal anomalies in a genetically diverse cohort of RS patients with a focus on the bone micro-architecture. Seven individuals with molecularly confirmed RS, including four with DVL1 variants and single individuals with variants in WNT5A, ROR2, and GPC4 underwent a musculoskeletal focused physical examination, dual-energy X-ray absorptiometry (DEXA) scan, and high-resolution peripheral quantitative computed tomography (HR-pQCT). Skeletal examination revealed variability in limb shortening anomalies consistent with recent reports. DEXA scan measures revealed increased total body bone mineral density (BMD) (3/7), cranial BMD (5/7), and non-cranial BMD (1/7). Cranial osteosclerosis was only observed in DVL1-RS (4/4) and GPC4-RS (1/1) subjects and in one case was complicated by choanal atresia, bilateral conductive hearing loss, and cranial nerve III, VI, and VII palsy. HR-pQCT revealed a unique pattern of low cortical BMD, increased trabecular BMD, decreased number of trabeculations, and increased thickness of the trabeculations for the DVL1-RS subjects. The spectrum of skeletal anomalies including the micro-architecture of the bones observed in RS has considerable variability with some osteosclerosis genotype-phenotype correlations more frequent with DVL1 variants.

Keywords: DEXA; DVL1; HR-pQCT; Robinow syndrome; WNT5A; bone density.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Absorptiometry, Photon
  • Adolescent
  • Adult
  • Bone Density
  • Bone and Bones / pathology
  • Bone and Bones / ultrastructure*
  • Child
  • Cohort Studies
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology
  • Dishevelled Proteins / genetics
  • Dwarfism / genetics*
  • Dwarfism / pathology
  • Female
  • Femur
  • Genetic Association Studies*
  • Genetic Variation
  • Glypicans / genetics
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / pathology
  • Male
  • Middle Aged
  • Osteosclerosis / genetics*
  • Osteosclerosis / pathology
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics
  • Tomography, X-Ray Computed
  • Urogenital Abnormalities / genetics*
  • Urogenital Abnormalities / pathology
  • Wnt-5a Protein / genetics
  • Young Adult


  • DVL1 protein, human
  • Dishevelled Proteins
  • GPC4 protein, human
  • Glypicans
  • WNT5A protein, human
  • Wnt-5a Protein
  • ROR2 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors

Supplementary concepts

  • Robinow Syndrome