Noonan syndrome (NS, OMIM 163950) is a common autosomal dominant RASopathy caused mainly by gain‐of‐function germline pathogenic variants in genes involved in the RAS/MAPK signaling pathway. LZTR1 gene has been associated with both dominant and recessive NS. Here, we present seven patients with NS and variants in the LZTR1 gene from seven unrelated families, 14 individuals in total. The detection rAte of LZTR1 variants in our NS cohort was 4% similar to RAF1 and KRAS genes, indicating that variants in this gene might be frequent among our population. Three different variants were detected, c.742G>A (p.Gly248Arg), c.360C>A (p.His120Gln), and c.2245T>C (p.Tyr749His). The pathogenic variant c.742G>A (p.Gly248Arg) was found in five/seven patients. In our cohort 50% of patients presented heart defects and neurodevelopment delay or learning disabilities, short stature was present in 21% of them and one patient had acute lymphoblastic leukemia. This study broadens the spectrum of variants in the LZTR1 gene and provides increased knowledge of the clinical phenotypes observed in Argentinean NS patients.

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Rasopathies are a group of phenotypically overlapping conditions that include Noonan, Noonan with multiple lentigines, Noonan with loose anagen hair, Costello, Cardio‐facio‐cutaneous, and Neurofibromatosis‐Noonan syndromes. Noonan syndrome with loose anagen hair (NS‐LAH) is clinically characterized by prominent forehead, macrocephaly, growth hormone deficiency, sparse, loose and slow‐growing anagen hair, hyperpigmented skin with eczema or ichthyosis, mild psychomotor delays, hypernasal voices, and attention deficit hyperactivity disorder. Variants in SHOC2 are responsible for the majority of the cases. Gripp et al. identified four unrelated individuals with similar phenotype to NS‐LAH with pathogenic variants in PPP1CB. In this study, we present one family and one patient with NS‐LAH and variants in PPP1CB. The first patient belongs to a family with a likely pathogenic variant, c.545T>A (p.Met182Lys), the first family published so far with a variant in this gene. The second patient harbors a de novo pathogenic variant, c.146C>G (p.Pro49Arg). This study presents two additional patients with this rare syndrome in order to increase the clinical characterization of the syndrome and provide more evidence of the pathogenicity of the c.545T>A (p.Met182Lys) variant in PPP1CB, a gene recently associated with NS‐LAH.

Noonan syndrome (NS) is caused by pathogenic variants in genes involved in the RAS/MAPK pathway. On the other hand, 22q11.2 Deletion Syndrome (22q11.2DS) is caused by heterozygous microdeletion on chromosome 22q11.2. The clinical characteristics of both syndromes are expected to be relatively distinct, and, in fact, there is only one report of these syndromes occurring together, but on daily clinical practice and especially in early childhood phenotypes may overlap. In this study, we describe a patient with NS and 22q11.2DS features harboring a heterozygous 2.54 Mb deletion of chromosome 22q11.2 and a variant in LZTR1, c.1531G > A p.(Val511Met). In 1993, Wilson et al reported a patient with both 22q11.2DS and NS, proposing that probably more than one gene is deleted in the proband and that one of the deleted genes is responsible for Noonan's phenotype. In our patient, one of the deleted genes within the 22q11.2 region was the LZTR1 gene which was associated with NS in 2015. This case also highlights the importance of the long‐term patients' follow‐up to detect evolutionary changes that may appear in the phenotype and alerts clinicians of the co‐occurrence of two syndromes that may manifest over time.