Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome
ABSTRACT Autosomal recessive Robinow syndrome is caused by mutations in ROR2 and is characterized by short stature, mesomelic limb shortening, brachydactyly, vertebral abnormalities, and a characteristic "fetal face" dysmorphology. We report the clinical and molecular studies on two adults with this condition. Besides typical skeletal and facial features, one patient developed hydronephrosis, nephrocalcinosis, and renal failure. The second patient had characteristic skeletal manifestations including severe spinal involvement and showed endocrinological abnormalities including elevated gonadotropic hormones. The facial phenotype in both patients remained distinctive into adulthood. Analysis of the ROR2 gene revealed a homozygous c.1937_1943delACAAGCT mutation in Patient 1, and compound heterozygosity for c.355C > T (p.R119X). and c.550C > T (p.R184C) in Patient 2.
- SourceAvailable from: Parag M Tamhankar
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- "Previously, another mutation R119X in the Ig like domain has been reported by Tufan et al (19) in a patient with RRS. However the phenotype in the Turkish case reported by Tufan et al (19) is severe, whereas our cases (family 2) are mild because they lack the rib and vertebral findings of RRS. "
ABSTRACT: Objective: Robinow syndrome (RS) is an extremely rare genetic disorder characterized by short-limbed dwarfism, defects in vertebral segmentation and abnormalities in the head, face and external genitalia. Mutations in the ROR2 gene cause autosomal recessive RS (RRS) whereas mutations in WNT5A are responsible for the autosomal dominant (AD) form of RS. In AD Robinow patients, oral manifestations are more prominent, while hemivertebrae and scoliosis rarely occur and facial abnormalities tend to be milder. Methods: Three unrelated patients from different parts of India were studied. These patients were diagnosed as RRS due to presence of characteristic fetal facies, mesomelia, short stature, micropenis, hemivertebrae and rib abnormalities. One of the patients had fetal facies and micropenis but unusually mild skeletal features. This patient’s mother had mild affection in the form of short stature and prominent eyes. Testosterone response to human chorionic gonadotropin was investigated in two patients and were normal. The exons and exon-intron boundaries of the ROR2 gene were sequenced for all probands. Bioinformatics analysis was done for putative variants using SIFT, PolyPhen2 and Mutation Taster. Results: Patients 1, 2 and 3 were homozygous for c.G545A or p.C182Y in exon 5, c.227G>A or p.G76D in exon 3 and c.668G>A or p.C223Y in exon 6 respectively. Prenatal diagnosis could be performed in an ongoing pregnancy in one family and the fetus was confirmed to be unaffected. Conclusion: ROR2 mutations were documented for the first time in the Indian population. Knowledge of the molecular basis of the disorder served to provide accurate counseling and prenatal diagnosis to the families.Journal of Clinical Research in Pediatric Endocrinology 06/2014; 6(2):79-83. DOI:10.4274/Jcrpe.1233
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- "However, apart from the hypertelorism, the facial gestalt of Robinow syndrome seems to differ from our patients, since it includes broad prominent forehead, midface hypoplasia that results in the appearance of ''pseudoexophthalmus,'' short upturned nose, tented upper lip with an inverted ''V'' appearance and gum hypertrophy [Patton and Afzal, 2002]. The most consistent skeletal abnormality in Robinow syndrome is mesomelic or acromesomelic limb shortening [Tufan et al., 2005], which does not present in neither of our patients. Moreover, in contrast with our patients who displayed a variable degree of mental retardation, Robinow syndrome usually is characterized by normal intelligence and in most cases normal development [Patton and Afzal, 2002]. "
ABSTRACT: We report on three individuals of Muslim Arab origin from a village located in Northern Israel affected by an apparent autosomal recessive syndrome characterized by distinctive facial phenotype of which the most prominent feature is ocular hypertelorism. The other clinical features of the syndrome include variable degree of mental retardation, genital abnormalities dominated by short penis, and skeletal abnormalities including chest deformity (combination of upper pectus carinatum with lower pectus excavatum), and short palms with broad short fingers. Affected individuals displayed distinctive facial features including upslanting palpebral fissures, thick eyebrows, long philtrum, wide mouth with thin upper lip and upturned corners of the mouth, widow's peak, broad nasal bridge, and simple ears with fleshy overfolded helices. This phenotype does not fully meet typical diagnostic features of any known condition.American Journal of Medical Genetics Part A 12/2009; 149A(12):2655-60. DOI:10.1002/ajmg.a.33127 · 2.05 Impact Factor
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- "In comparison with BDB, the range of severity in RRS is broad. Clinical and molecular examinations of two adults with RRS identify nephrological abnormalities (hydronephrosis , nephrocalcinosis, and renal failure) and endocrinological abnormalities (elevated gonadotropic hormones), respectively (Tufan et al., 2005 "
ABSTRACT: The Ror-family receptor tyrosine kinases (RTKs) play crucial roles in the development of various organs and tissues. In mammals, Ror2, a member of the Ror-family RTKs, has been shown to act as a receptor or coreceptor for Wnt5a to mediate noncanonical Wnt signaling. Ror2- and Wnt5a-deficient mice exhibit similar abnormalities during developmental morphogenesis, reflecting their defects in convergent extension movements and planar cell polarity, characteristic features mediated by noncanonical Wnt signaling. Furthermore, mutations within the human Ror2 gene are responsible for the genetic skeletal disorders dominant brachydactyly type B and recessive Robinow syndrome. Accumulating evidence demonstrate that Ror2 mediates noncanonical Wnt5a signaling by inhibiting the beta-catenin-TCF pathway and activating the Wnt/JNK pathway that results in polarized cell migration. In this article, we review recent progress in understanding the roles of noncanonical Wnt5a/Ror2 signaling in developmental morphogenesis and in human diseases, including heritable skeletal disorders and tumor invasion.Developmental Dynamics 11/2009; 239(1):1-15. DOI:10.1002/dvdy.21991 · 2.67 Impact Factor