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Título

Hickam’s dictum on a case of progressive weakness and hypermobility: a double genetic hit disorder

RESUMO

Case presentation: Son of consanguineous parents, a 14-year-old male patient presented with slowly progressive, symmetrical, distal predominant neurogenic weakness since he was 1-year-old. He also experienced striking joint hypermobility and spinal deformities. His whole exome sequencing (WES) first revealed a homozygous class 4 variant at the IGHMBP2 gene (c.2796delC, p.Cys932TrpfsTer46), related to distal hereditary motor neuropathy (dHMN) type VI and CMT2S. This variant, however, failed to explain the hypermobility. Therefore, a thorough search at the WES was conducted, revealing a second class 4 homozygous variant at the ALDH18A1 gene (c.121 C>T, p.Arg41Cys) associated with cutis laxa, and thus elucidating the clinical picture.

Discussion: Occam’s razor is a heuristic tool much applied in medicine. It values simplicity, asserting that multiple symptoms should have a common explanation. Hickam’s dictum, on the other hand, states that concomitant symptoms can be due to different reasons. In this case, we demonstrate the antitheses. When in face of a pathogenic variant that only partially explained the clinical scenario, we decided to further investigate by expanding molecular analysis. This led to the discovery of a second pathogenic variant, in a double-hit genetic disorder. The clinical evaluation remains sovereign to the point of directing the reasoning and defining whether the eventual finding is sufficient for the diagnosis or if we need to look for a second explanation, invoking Hickam’s dictum.

Final considerations: The implementation of the next-generation sequencing (NGS) technics in clinical practice changed the molecular assessment and improved patient and family care. However, the massive information obtained with these tests is still not fully manageable. We emphasize the importance of interpreting genetic findings in light of clinical manifestations. We also stress that Occam's razor is not always superior to Hickam's dictum. In genetic conditions, when a strong pathogenic variant does not explain the full clinical picture, the possibility of a double-hit genetic disorder should be considered. In such cases, a judicious clinical analysis is essential to shape the genetic data search.

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Área

Neurogenética