The Evaluation of Molecular Genetics and Clinical Manifestations in Patients With LZTR1-Associated Noonan Syndrome: A Retrospective Chart Review and Review of Literature

LZTR1

Pathogenic LZTR1 variants, uniquely causing Noonan syndrome through both autosomal dominant and autosomal recessive inheritance

This multicentre retrospective chart review assembled 21 previously unreported patients aged 6 months to 49 years, followed at three tertiary centres for LZTR1-associated Noonan syndrome: 15 with autosomal dominant and 6 with autosomal recessive disease. A literature review covering 2015-2025 added 100 individuals for comparative analysis by inheritance mode. The picture confirms the frequency of craniofacial dysmorphism and neurodevelopmental and multisystem involvement, with pulmonary valve stenosis the most common cardiac lesion and hypertrophic cardiomyopathy more prominent in recessive cases. Lymphatic abnormalities were observed more frequently than previously reported. Two observations fall outside the expected picture: co-occurrence of dominant disease with a 22q11.2 deletion, and two recessive patients with features suggestive of schwannomatosis.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

LZTR1 remains one of the few genes where inheritance mode determines both phenotype and genetic counselling, and this series strengthens the notion that hypertrophic cardiomyopathy marks recessive disease — and should therefore be actively sought before discussing recurrence risk. The signal on lymphatic abnormalities, under-reported until now, deserves a place in the initial workup. The two recessive patients with schwannomatosis features raise a genuine surveillance question, but with only two patients it is too early to derive management guidance.

Analysis by Dr Thibaut Benquey