50 years of Robinow syndrome

Mazzeu, Juliana Forte; Brunner, Han G.

doi:10.1002/ajmg.a.61756

Cited by 11 publications

(12 citation statements)

References 23 publications

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“…Although omodysplasia 2 (OMOD2) has been related to FZD2 variants in the OMIM database and several individuals, 48 , 49 , 50 , 51 a recent published review 2 as well as our quantitative HPO analysis ( Figure 3 ) indicate that it is unclear whether FZD2 -related phenotypes should be classified as AD-RS, omodysplasia, or both. After the original description of the association of FZD2 with AD OMOD2 by Saal et al., 48 Nagasaki et al.…”

Section: Discussionmentioning

confidence: 97%

“…in 1969. 1 , 2 RS can be arbitrarily subdivided into autosomal recessive (AR) RS and autosomal dominant (AD) RS. There is significant locus heterogeneity, with pathogenic variants having been identified in six genes: DVL1 (MIM: 601365 ), DVL3 (MIM: 601368 ), FZD2 (MIM: 600667 ), NXN (MIM: 612895 ), ROR2 (MIM: 602337 ), and WNT5A (MIM: 164975 ).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, AR-RS is associated with biallelic loss-of-function (LoF) variants in the orphan tyrosine kinase receptor, ROR2 (RRS1 [MIM: 268310 ]) 5 , 6 and in the oxidative stress response protein, NXN (RRS2 [MIM: 618529 ]), 7 , 8 both of which can be caused by single-nucleotide variants (SNVs) combined with large deletions. 2 , 4 In contrast, insertions and deletions (indels) in two out of the three human orthologs of the Drosophila dishevelled ( dvl ) gene, DVL1 and DVL3 , are the most frequent cause of sporadic and AD-RS (DRS2 [MIM: 616331 ], DRS3 [MIM: 616894 ]) 3 , 9 , 10 , 11 and recur independently in an estimated 33% of individuals with a diagnosis of RS. 3 Disease-associated variant alleles found in DVL1 and DVL3 cluster within the penultimate and last exons of each gene, generating a −1 frameshift with a premature termination codon (PTC) in the last exon.…”

Section: Introductionmentioning

confidence: 99%

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Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Zhang¹,

Jolly²,

Shayota

et al. 2022

Human Genetics and Genomics Advances

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Summary Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated ( DVL1 , DVL3 , FZD2 , NXN , ROR2 , and WNT5A ). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2 . We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1 , DVL2 , and DVL3 variants, demonstrating no phenotypic distinction between the NXN -autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A , FZD2 , and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Zhang¹,

Jolly²,

Shayota

et al. 2022

Human Genetics and Genomics Advances

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“…Robinow syndrome was first described in 1969 per Dr. Robinow's assessment as a “familial disorder…different from known disturbances of growth, including achondroplasia…[and with] several characteristic non‐skeletal defects that justify its description as a new dwarfing syndrome” (Mazzeu & Brunner, 2006; Mazzeu & Brunner, 2020; Robinow, Silverman, & Smith, 1969). Characterized as either recessive Robinow syndrome (RRS) or dominant Robinow syndrome (DRS), fewer than 200 affected families have been reported with respect to RRS and fewer than 50 families with respect to DRS (National Organization of Rare Diseases, 2017).…”

Section: Introductionmentioning

confidence: 99%

Craniofacial phenotypes associated with Robinow syndrome

Conlon

Abu‐Ghname

Raghuram

et al. 2020

American J of Med Genetics Pt A

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Robinow syndrome is characterized by mesomelic limb shortening, hemivertebrae, and genital hypoplasia. Due to low prevalence and considerable phenotypic variability, it has been challenging to definitively characterize features of Robinow syndrome. While craniofacial abnormalities associated with Robinow syndrome have been broadly described, there is a lack of detailed descriptions of genotype-specific phenotypic craniofacial features. Patients with Robinow syndrome were invited for a multidisciplinary evaluation conducted by specialist physicians at our institution. A focused assessment of the craniofacial manifestations was performed by a single expert examiner using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnoses consistent with either dominant Robinow syndrome (DRS) or recessive Robinow syndrome (RRS) were evaluated. On craniofacial examination, gingival hyperplasia was nearly ubiquitous in all patients.Orbital hypertelorism, a short nose with anteverted and flared nares, a triangular mouth with a long philtrum, cleft palate, macrocephaly, and frontal bossing were not observed in all individuals but affected individuals with both DRS and RRS. Other anomalies were more selective in their distribution in this patient cohort. We present a comprehensive analysis of the craniofacial findings in patients with Robinow Syndrome, describing associated morphological features and correlating phenotypic manifestations to underlying genotype in a manner relevant for early recognition and focused evaluation of these patients.

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“…Robinow syndrome (RS) is a very rare skeletal disorder characterized by short stature, mesomelic limb shortening, brachydactyly, genital hypoplasia, and distinctive craniofacial features (Mazzeu & Brunner, 2020; Robinow, Silverman, & Smith, 1969). The exact prevalence is unknown, but fewer than 250 cases have been reported in the literature.…”

Section: Introductionmentioning

confidence: 99%

Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome

Schwartz

Fein

Carvalho

et al. 2020

American J of Med Genetics Pt A

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It has been estimated that 10-15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4-51 years were seen for neuropsychological screening. Eight had autosomal-dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal-recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine-motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low-average visuomotor skills. Adaptive functioning was average in autosomal-recessive RS (RRS) but low average in autosomaldominant RS (DRS). Parent-report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self-report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.

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50 years of Robinow syndrome

Cited by 11 publications

References 23 publications

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability

Craniofacial phenotypes associated with Robinow syndrome

Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome

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