Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy

Abstract

Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk.

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

“…FGFR alterations are known to activate the MAPK-ERK pathway [24,17,16]. Thus we investigated the possible consequences of p.R661P and p.N546K on MAPK-ERK signaling.…”

Treatment with Growth Hormone in Noonan Syndrome Observed during 25 Years of KIGS: Near Adult Height and Outcome Prediction

“…In the KIGS cohort, 4 patients developed a cardiovascular SAE and 2 a benign or malignant tumor, however, Noonan syndrome patients have an inherent risk for cardiac and hematological co-morbidities as well as for the development of malignancies [11, 42-44]. The data entry in KIGS is usually limited to the rhGH treatment period.…”

Occurrence of high‐grade glioma in Noonan syndrome: Report of two cases

“…The most common brain tumors observed with NS were low‐grade glial and glioneuronal tumors. DNETs are rare WHO grade I glioneuronal tumors that comprise <1% of childhood brain tumors, but their incidence appears significantly higher in NS . In our search, nine out of 24 identified cases were DNETs, a fact that might suggest a noncoincidental relation between NS and the development of DNETs.…”

“…DNETs are rare WHO grade I glioneuronal tumors that comprise <1% of childhood brain tumors, 13 but their incidence appears significantly higher in NS. 5,6,15…”