ESPE Abstracts

Noonan syndrome (NS) is an autosomal dominant, variably expressed, multisystem disorder with an estimated prevalence of 1 in 1000–2500. In 2001, PTPN11 was the first gene associated to Noonan syndrome; now, at least 20 other genes have been discovered especially in the RAS–MAPK signalling pathway. More recently, missense mutations in RIT1 have been reported as causative of NS. A six-years female patient was referred to our Hospital for short stature (<-2 sds) and peculiar phenotype (upper eyelid ptosis). At the age of 3 years old, a clinical diagnosis of Noonan syndrome was suspected. She was submitted to provocative tests for growth hormone (GH) secretion that resulted pathological (arginine with GH peak of 0.75 ng/ml and clonidine with GH peak of 0,78 ng/ml) and she started rhGH therapy at the dosage of 0,18 mg/kg a week until the age of 14, reaching a final height of 148,5 cm (-1.72 SD) and weight of 49 kg (-0,54 SDS). One-year after menarche, she developed secondary amenorrhea, with a normal LHRH test. Endocrine assessment at the age of 17 years showed a GH deficiency at GH retesting (peak of GH after GHRH and arginine: 6,9, ng/ml), low IGF-1 levels (<25 ng/ml) and a secondary hypoadrenalism at ACTH-low-dose test (peak of cortisol: 13,27 mcg/dl). Pituitary MRI revealed an hypoplastic pituitary gland and thin pituitary stalk. Therapies with rhGH (25 mcg/kg/week) and hydrocortisone (8 mg/mq/day) were immediately administered. At the age of 20 years she started levothyroxine therapy (1 mcg/kg/day) for a central hypothyroidism (FT4 0,75 ng/dl and TSH 4,43 mcUI/ml). NGS panel for rasopathies (PTPN11, SOS1, BRAF, RAF1, MEK1, MEK2, KRAS, NRAS, HRAS genes) was performed and resulted normal. Finally, whole exome sequencing (WES) revealed a point mutation (c.284G>C p.Gly95Ala) in heterozygosis in the RIT1 gene, confirming the diagnosis of Noonan syndrome, and a point mutation in the LIM homeobox gene 4 (LHX4) responsible for combined pituitary hormone deficiency. The location of the two genes is in the long arm of chromosome 1(1q22 and 1q25.2, respectively). To our knowledge, this is the first case of association of Noonan syndrome due to RIT1 mutation and panhypopituitarism; further genetic studies will be necessary to evaluate whether the two-point mutations are just a random association or there is another explanation due to their proximity in chromosome 1.