# Molecular characterization of pediatric mastocytosis revealed different somatic mutations with uncertain prognostic value

## TL;DR

This study analyzed genetic mutations in 36 children with mastocytosis, finding various c-KIT and other mutations, but their impact on prognosis remains unclear.

## Contribution

The study reports novel and known mutations in pediatric mastocytosis, highlighting the need for further research on their prognostic significance.

## Key findings

- c-KIT D816V mutations were found in 4 out of 36 patients using RT-PCR and in 3 using NGS.
- Five novel mutations (ETV6 A215P, c-KIT Y553C, NFE2 I291T, SH2B3 G382D, SH2B3 L438V) were identified.
- Nine patients experienced spontaneous regression of cutaneous lesions after a median of 25 months.

## Abstract

Mastocytosis is a rare clonal hematological neoplasm, characterized by cutaneous manifestations in children and categorized as: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM) and mastocytoma. Systemic mastocytosis (SM) typically occurs in adults with c-KIT D816V mutation. Additional genetic mutations (TET2, NRAS, SF3B1, ASXL1, etc.) have been detected using Next-Generation Sequencing (NGS) in the adult population while limited information is available in the pediatric setting.

36 patients (pts) with pediatric mastocytosis diagnosed between 1997 and 2021 were included. Peripheral blood samples were collected to detect c-KIT D816V mutation, using both RT-PCR and ddPCR techniques, and to investigate other molecular mutations using NGS panel for rare and myeloid genes.

Median age of lesion onset was 4.7 months (range birth-17.8 years). 58% of the cohort underwent cutaneous biopsy after a median 3.77 months from lesion onset (range 2.49 months–11.6 years). 20 (55%) were classified as MPCM, 10 (28%) as DCM and 6 (17%) as mastocytoma. Median tryptase value at the onset was 5 ng/mL: MPCM (range 1.2–141 ng/mL) vs. DCM (range 2.71–19.4 ng/mL) vs. mastocytoma (range 3.8–7.3 ng/mL). Two MPCM pts developed indolent SM (ISM) after 10 and 20 years from the onset of disease. RT-PCR identified c-KIT D816V mutation in 4 pts (2 MPCM, 1 DCM, 1 ISM). NGS revealed the precedent mutation in 3 pts, c-KIT D816Y and c-KIT Y553C in 2 pts. An additional 10 myeloid gene mutations were detected by NGS: 5 already known (ASXL1 G1397S; JAK2 L393V; c-KIT D816Y; LNK E208Q; TET2 Y867H) and 5 not previously described (ETV6 A215P; c-KIT Y553C; NFE2 I291T; SH2B3 G382D; SH2B3 L438V). A single mutation was found in 7 pts (3 MPCM, 3 DCM, 1 ISM), while two or more mutations in 3 DCM pts. Overall, 9/36 pts (5 DCM, 3 MPCM, 1 mastocytoma) presented spontaneous complete regression of cutaneous lesions after a median time of 25 months (range 17 months–25 years).

c-KIT mutations resulted in 35% of the children tested. The RT-PCR technique resulted more sensitive in finding c-KIT D816V, while NGS in detecting other mutations whose prognostic roles require further investigation.