ESPE Abstracts

Noonan syndrome is a genetic condition caused by dysregulation of RAS-MAPK pathway (RASopathy) characterized by great clinical variability and genetic heterogeneity. Many genes has been associated with the disease, including recently LZTR1, which is causative of both dominant and recessive forms. Currently less than one hundred cases of Noonan syndrome has been associated with LZTR1 variants then phenotype related to this gene is poorly known. Here we describe phenotypic spectrum of three young subjects carrying three novel heterozygous missense variants in LZTR1. In patient 1 was identified variant c.686G>A p.(Cys229Tyr), in patient 2 variant c.164G>C p.(Arg55Pro), both resulted de novo. In patient 3 variant c.578A>C p.(Tyr193Ser) of maternal inheritance was identified.

Patient 1: 13 yo, boy. In pregnancy increased nuchal translucency had been found, with normal karyotype on CVS. He presented regular psychomotor development, typical facial features, no cardiac abnormalities, right cryptorchidism and a linear growth at the tenth percentile, below the genetic target. At 10 yo aplastic anemia was diagnosed which made necessary bone marrow tansplantation. After the oncohematological treatments he developed growth hormone and gonadotropin deficiency resulting in replacement therapy.

Patient 2: 16 yo, girl. The pregnancy was characterized by cystic hygroma with normal kariotype on CVS. She presented mild psychomotor delay, typical facial features, hypertrophic cardiomyopathy with severe mitralic insufficiency, hearing loss. For important oropharyngeal dysfunction with velopalatin incompetence and vomiting at 6 months a PEG was placed for feeding. At 14 yo she came to our attention with a complete pubertal development with untreated growth deficiency and final height at -2.8 SDS. MRI performed for a worsening of bilateral proptosis detected Chiari malformation with a cervico-dorsal (C4-D11) syringomyelia. Surgical decompression was made with a marked improvement in oral feeding and vomiting.

Patient 3: 6 yo, girl. The pregnancy was characterized by transient cystic hygroma with normal kariotype on CVS and normal fetal array-CGH. She presents typical facial features with mild psychomotor delay, no cardiac abnormalities and a regular linear growth at the tenth percentile, at low limits of the genetic target. The mother, carrying the same mutation, shows slight typical facial features, mild mitral prolapse with minimal mitral tricuspid and pulmonary insufficiency and episodic dizziness; brain and spine MRI were normal. The patients carrying the three novel LTZR1 variants show a broad phenotypic spectrum from a very severe to a very mild picture up to the absence of specific signs of Noonan syndrome.