Phenotypic Expansion of Autosomal Dominant LZTR1-Related Disorders with Special Emphasis on Adult-Onset Features

Abstract

Leucine zipper-like transcription regulator 1 (LZTR1) acts as a negative factor that suppresses RAS function and MAPK signaling; mutations in this protein may dysregulate RAS ubiquitination and lead to impaired degradation of RAS superfamily proteins. Germline LZTR1 variants are reported in Noonan syndrome, either autosomal dominant or autosomal recessive, and in susceptibility to schwannomatosis. This article explores the genetic and phenotypic diversity of the autosomal dominant LZTR1-related disorders, compiling a cohort of previously published patients (51 with the Noonan phenotype and 123 with schwannomatosis) and presenting two additional adult-onset cases: a male with schwannomatosis and Parkinson's disease and a female with Noonan syndrome, generalized joint hypermobility, and breast cancer. This review confirms that autosomal dominant LZTR1-related disorders exhibit an extreme phenotypic variability, ranging from relatively mild manifestations to severe and multi-systemic involvement, and offers updated frequences of each clinical feature. The aim is to precisely define the clinical spectrum of LZTR1-related diseases, using also two new emblematic clinical cases. Gaining insight into the mechanisms underneath this variability is crucial to achieve precision diagnostics and the development of therapeutic interventions.

Keywords: LZTR1; Noonan syndrome; generalized joint hypermobility; schwannomatosis.

Figure 1

Pie chart exhibiting LZTR1 variants indexed on ClinVar database as Noonan syndrome 10, schwannomatosis, and LZTR1-related disorders, majority of which are not indexed as associated with disease phenotypes.

Figure 2

LZTR1 protein representation displaying variants described in literature-based cases affected by Noonan syndromes (A) and by schwannomatosis (B). Numbers within circles correspond to variants mentioned in Table 1 and Table 2. Red boxes indicate our cases. Yellow boxes specify common variants in two patients’ cohorts. Circle colors are indicative of variant type (missense, frameshift, nonsense, and splicing), while protein-domain regions are depicted using distinct colors.

Figure 3

The families and facial features of the patients. On the left, family pedigrees of case 1 (A) and case 2 (B). On the right, front and lateral views of the probands described as case 1 (A) and case 2 (B). Arrows indicate the probands.