ESPE Abstracts

Mutations in genes of the RAS/MAPK signalling pathway have been shown to cause several syndromes characterized by dysmorphic features, growth retardation, cognitive impairment, heart disease and cutaneous abnormalities. The GHrh treatment has been used to improve growth in children with Noonan syndrome.

Material and methods: 201 cases of patients referred with clinical suspicion of S. Noonan and other RASopathies was studied. Analysis of the genes A2ML1, BRAF, CBl, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, NRAS, PPP1CB, PTPN11, RAF1, RALA, RASA1, RASA2, RIT1, RRAS, RRAS2, SHOC2, SOS1, SOS2, SPRED1, NF1, NF2, SPRED1 was performed. Growth and therapeutic response to GH in patients diagnosed with Noonan Syndrome who have continued to be followed up in our center have been analyzed.

Results: 1) 32.8% shown molecular alterations: 51 pathogenic. 8 probably pathogenic and 7 variants of uncertain significance. 28 patients had mutations in the PTPN11 gene: in this group the most frequent mutation (25%) was NM_0028343 (PTPN11): c922A>G (PAsn308Asp). 8 patients have mutations in SOS1, 5 in NF1, 4 in BRAF, 3 in RAF1, 3 in RASA1, 2 in RIT1, 2 in LZTR1, 2 in MAP2K2, 2 in AZML1 and 1 in GRIN2A, A2ML1, SHOC2, KRAS, CBL and SOS2 respectively. 2) Growth hormone treatment: Seven of these patients followed up in our center for short stature have received GH treatment. 1 male and 2 females had started treatment with GH in other indications (SGA and GH deficiency) previously a Noonan GH indication. They have reached adult height with a good response to treatment: the boy (PTPN11 mutation) with a height SDS gain of +1.89 and the two girls: one with a PTPN11 mutation and the other with SOS1 showed a gain of height of +1.15 and +1.19 respectively. The other four cases are girls and started treatment in the last year. The SDS for height at the start of treatment are less than -2.5 SDS and they have positive changes in height SDS.

Conclusion: -The clinical suspicion of Noonan syndrome and other RASopathies were confirmed genetically in 32.8% of the cases referred for study.

-Patients diagnosed with Noonan syndrome and treated with GH have a good therapeutic response.

-Molecular genetic analyzes are a useful tool for diagnostic confirmation and clinical and therapeutic orientation of patients with suspected alterations in the RAS/MAPK pathway.