Wiedemann–Rautenstrauch syndrome: A phenotype analysis

Abstract

Wiedemann-Rautenstrauch syndrome (WRS) is a neonatal progeroid disorder characterized by growth retardation, lipodystrophy, a distinctive face, and dental anomalies. Patients reported to date demonstrate a remarkable variability in phenotype, which hampers diagnostics. We performed a literature search, and analyzed 51 reported patients, using the originally reported patients as "gold standard." In 15 patients sufficient information and photographic evidence was available to confirm the clinical diagnosis. In 12 patients the diagnosis was suggestive but lack of data prevented a definite diagnosis, and in 24 patients an alternative diagnosis was likely. Core manifestations of the syndrome are marked pre-natal and severe post-natal growth retardation, an unusual face (triangular shape, sparse hair, small mouth, pointed chin), dental anomalies (natal teeth; hypodontia), generalized lipodystrophy with localized fat masses, and-in some cases-progressive ataxia and tremor. It has been suggested that the syndrome might be caused by biallelic variants in POLR3A, identified by exome sequencing in a single patient only. Therefore, we compared the WRS phenotype with characteristics of conditions known to be caused by autosomal recessively inherited POLR3A mutations. There are major differences but there are also similarities in phenotype, which sustain the suggestion that the syndrome can be caused by disturbed POLR3A functioning.

POLR3A variants with striatal involvement and extrapyramidal movement disorder

“…One variant seen in our cohort, c.1048 + 5G > T, has also been found in spastic ataxia [12] and Wiedemann-Rautenstrauch syndrome [16]. However, our patient did not have the intrauterine and marked postnatal growth retardation, lipodystrophy, or distinctive facies characteristic of the progeroid syndrome of Wiedemann-Rautenstrauch [17].…”

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts

“…Recently, increased function of POLR3A had gain interest due to its potential oncogenic function by increasing the levels of tRNA Met The cellular and molecular characteristics of WRS fibroblasts suggest that they undergo an early entrance into cell senescence, associated to a slightly larger nuclei and an increase in the number and area of nucleoli. WRS syndrome, which is considered a developmental disorder with aging characteristics, POLR3 function seems to be a key determinant of proper cellular development and its decrease/absence causes severe development alterations, including a premature senescence/aging phenotype with early lethality (Paolacci et al, 2017;Paolacci et al, 2018). In the present study, we demonstrate that fibroblast from a WRS patient have a sharp increase in the expression of a mutated version of POLR3A (~142 KDa).…”

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome

“…6 Variants in POLR1C can cause hypomyelinating leukodystrophy type 11 (MIM 614494) and variants in POLR3B have been found in individuals with cerebellar hypoplasia-endosteal sclerosis (CHES; MIM 213002) 38. This entity shows overlap with both 4H and WRS as well, but individuals with CHES lack the facial phenotype and lipodystrophy as present in WRS and show osteosclerosis, which is absent in both WRS and 4H 6. The three entities, WRS, 4H and CHES, share the unusual dentition and disturbed growth,6 8 38 but growth has not been stated to be abnormal in the individuals with progressive ataxia.…”

“…We collected a cohort of carefully phenotyped individuals with clinical manifestations fitting the disorder 6. Most of the presently reported families and patients have been published (patients have the full number; parents are indicated by this number followed by b for father and c for mother): WRS001, 6 WRS005, 6 WRS0012, 6 WRS002 (patient number 2 in the report of Rautenstrauch and Snigula in 1977),17 WRS003 (German origin, unpublished), WRS004,18 WRS006b and WRS006c (father and mother, respectively, of patients number 1 and 2 in the Arboleda’s report of 1997),19 WRS007, WRS008, WRS009 (patients number 1, 2 and 3 in the report of Morales et al ),20 WRS010b and WRS10c (father and mother, respectively, of three affected sibs)21 and WRS011 (Colombian origin, unpublished).…”