Rothmund–Thomson syndrome type 1 caused by biallelic ANAPC1 gene mutations

Abstract

Background Rare syndromic skin disorders may represent a diagnostic challenge. Aims We report a unique case associating cutaneous manifestations and developmental delay. Materials & Methods The affected 14 months old boy had poikiloderma, facial dysmorphism with deep‐set eyes, atrichia, as well as nail dysplasia and non‐descended testes. In addition, his psychomotor development was delayed. Exome sequencing and molecular karyotyping via array‐CGH (oligo‐array, 180k Agilent, design 22060) were performed. Results Mutations in RECQL4 (found in patients with RTS2) were first excluded. In the ANAPC1 gene, a novel combination of a recurrent intronic mutation (c.2705‐198C>T) and a deletion of the second ANAPC1 allele was detected, thus confirming the clinical diagnosis of RTS1. The deletion on chromosome 2q13 comprised further genes and spanned 1,7 megabases. Heterozygous deletions in this region are known as 2q13 microdeletion syndrome and are associated with developmental delay, autism and facial dysmorphism. Discussion The genetic findings most probably explain both, the RTS1 features and the developmental delay. Genetic diagnosis in RTS is indispensable to confirm the specific subtype and its associated risks: juvenile cataracts are features of RTS1 (ANAPC1 gene), whereas a high risk of osteosarcoma is part of RTS2 (RECQL4 gene). Thus, the patient described here is at high risk for the development of juvenile cataracts and requires regular ophthalmologic examination. Conclusion This case report underlines the necessity of thorough clinical diagnosis prior to genetic diagnosis of RTS1, since the recurrent intronic ANAPC1 mutation is otherwise missed.

Germline NUP98 Variants in Two Siblings with a Rothmund–Thomson-Like Spectrum: Protein Functional Changes Predicted by Molecular Modeling

“…Filtering about 38.800 variants in each of the five loaded genomic DNA samples and prioritizing (under the hypothesis of a rare autosomal recessive condition) homozygous “identical by descent” variants transmitted by consanguineous parents to the affected siblings, allowed us to rule out the pathogenic alterations of ANAPC1 gene (OMIM*608473), which were identified as causative of RTS1 [ 20 ]. ANAPC1 encodes a component of the anaphase-promoting complex/cyclosome (APC/C) and its mutations account for 10% of clinically suspected RTS cases [ 20 , 22 ]. No alterations were disclosed in other candidate genes such as WRN and BLM : these genes encode RECQL3 and RECQL2 helicases, and their alterations are responsible for Werner (OMIM#277700) and Bloom (OMIM#210900) syndromes, which display clinical overlap with RTS [ 18 , 19 ].…”

Paciente pediátrico con poiquilodermia de inicio temprano

“…El 68% de los pacientes han presentado anomalías óseas, en ellos existe alteración del gen RECQL4, el mismo que se ha relacionado con mayor probabilidad de presentar osteosarcoma. Suelen ser pacientes con talla baja, en su nacimiento presentan bajo peso y talla; alteraciones en las piezas dentales como hipoplasia, erupción tardía, predisposición a padecer de caries, entre otros (10,11). Los criterios de diagnóstico clínico para establecer un diagnóstico definitivo de SRT no están disponibles, debido a que la naturaleza de la enfermedad es inespecífica.…”

Rothmund-Thomson syndrome, a disorder far from solved

“…While the clinical presentation of RTS patients can be heterogeneous and hamper a precise diagnosis (Haytaç et al, 2002;Stinco et al, 2008;Polese et al, 2011;Barisonek et al, 2016;Miranda et al, 2016;Pasagadugula et al, 2016;Chinmayee et al, 2017;Ahn et al, 2019;Zirn et al, 2021), current guidelines indicate that the individual must have, in addition to poikiloderma, at least two of the following clinical findings (Wang et al, 2001;Wang and Plon, 2020).…”