RASopathy

Background: RASopathies are a group of conditions caused by a genetic change. People with a RASopathy may have developmental issues, cognitive disability, poor growth, and birth defects. They may also have an increased risk for developing cancer. Researchers want to learn more. Objective: To learn more about RASopathies, how genes and environmental factors contribute to cancer development in people with RASopathies, and the best way to find these cancers and other conditions early or prevent them. Eligibility: People of any age who have or may have a RASopathy, and their family members. Design: Participants will complete questionnaires about their personal and family medical history. Their medical records will be reviewed. Participants will give blood and urine samples. They will give a saliva or cheek cell sample. Some samples will be used for genetic testing. Participants may have a skin biopsy. Participants may have a physical exam by the RASopathies study team. They may also have exams by additional specialists, such as dentists; urologists; ear, nose, and throat doctors; and neurologists. Participants may have computed tomography of the face and mouth. They may have an ultrasound of the abdomen. They may have a bone density scan. They may have skeletal and/or spine x-rays. They may have magnetic resonance imaging of the brain, low back, chest, and/or heart. They may be photographed. Participants may have other tests, such as sleep, brain and heart electrical activity, speech and swallow, metabolism, hearing, eye, and colon function tests. Participants may sign separate consent forms for some tests. Participation will last indefinitely. Participants may be contacted once in a while by phone or mail. They may have follow-up visits.

RASopathy-associated hypertrophic cardiomyopathy (RAS-CM) is a disease with high morbidity and high mortality if presenting during infancy. Targeted therapies have shown significant activity in preclinical models and case reports. Drugs that target the underlying cause of this disease are now developed in cancer patients. Conducting randomized trials is not possible in severely ill infants with RAS-CM. Existing historical controls from older eras are not sufficient as external controls to support drug development as they lack critical clinical and genetic information to allow comparison with the cohort planned for future clinical trials. The purpose of this investigator-initiated retrospective natural history study is to collect clinical information and genetic information in patients with RAS-CM. The first goal is to establish a data set that meets regulatory requirements for the use as external control data in a future clinical trial, composing non-randomized, single-arm, open-label study cohorts. The second goal is to obtain natural history information that supports the selection of secondary exploratory endpoints chosen in a clinical trial.

Retrospective, single-centre, non-profit, observational study on pubertal development in patients with RASopathies. Literature data shows that puberty can be delayed by about 2 years in patients with RASopathies and this has been associated with a reduced peak growth rate. To date, only a few numerically limited case series without molecular characterisation have been published. This descriptive study should improve knowledge of pubertal development and its influence on growth and final stature. The primary aims are to describe the age of onset and progression of pubertal development in the cohort of patients with RASopathies, both male and female, and to describe the influence of pubertal development on statural growth and final stature in the same cohort.

The study aims to evaluate the prevalence of thyroid disease, particularly with autoimmune pathogenesis (isolated hyperthyrotropinemia, hyperthyroidism, hypothyroidism, thyroid nodules) and/or morphostructural abnormalities of the thyroid gland in patients with RASopathy genetically confirmed by NGS technique (analysis of the genes: BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NRAS, PPP1CB, PTPN11, RAF1, RIT1, RRAS2, SHOC2, SOS1, SOS2) and to compare the data obtained in our sample with those of the general population. The secondary aim of the study is to evaluate the association between vitamin D deficiency and/or other abnormalities of bone metabolism and thyroid disease and/or morphostructural anomalies of the thyroid gland in patients with RASopathy.

RASopathies are a group of syndromes, caused by variants of genes involved in the regulation of the Ras/MAP/ERK pathway. This intracellular transduction pathway profoundly affects embryogenic development, organogenesis, synaptic plasticity and neuronal growth. RASopathies are characterized by multi-organ involvement, growth delay, premature aging and haemato-oncological manifestations. Based on evidences provided by literature, cancer screening protocols are applied in some individuals affected by RASopathies, even though detailed information about prevalence and molecular pathogenesis of such tumors is still not clearly elucidate.