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<p>Known genetic disorders, such as Noonan syndrome and Down syndrome, can present in the neonatal period or early infancy with myeloproliferative disease (MPD) or abnormal myelopoiesis, which often self-resolves. This phenomenon results from an imbalance in differentiation and cell regulation caused by the genetic condition during perinatal hematopoiesis. Recently, <i>SH2B3</i> variants have also been associated with neonatal MPD. However, data on their clinical significance, particularly across the spectrum of extra-hematological manifestations, of <i>SH2B3</i> variants remain limited. Here, we describe the clinical features of ten children with SH2B3-associated disease, arising from germline biallelic <i>SH2B3</i> loss-of-function (LoF) mutations in eight patients and in two patients from monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. Patients displayed a MPD in the first weeks of life, which was mostly self-limiting. Following the normalization of blood counts, thrombocytosis developed during childhood. Moreover, they presented with a multisystemic clinical features consisting in delayed growth, variable neurological impairment, autoimmune disorders. These data contribute to the definition of a clinical phenotype associated with germline biallelic <i>SH2B3</i> LoF variants presenting with neonatal MPD, with important implications for patient management and follow-up.</p>

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Biallelic SH2B3 germline variants are associated with a neonatal myeloproliferative disease and multisystemic involvement

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月6日

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  • Davide Leardini,
  • Elisabetta Flex,
  • Elliot Stieglitz,
  • Sara Cerasi,
  • Salvatore Nicola Bertuccio,
  • Francesco Baccelli,
  • Krisztián Kállay,
  • Paula Kjollerstrom,
  • Sara Batalha,
  • Giovanna Carpentieri,
  • Lucia Pedace,
  • Andrea Ciolfi,
  • Mahmoud Hammad,
  • Maria Miranda,
  • Marta Rojas,
  • Anupama Rao,
  • Andrew J. Innes,
  • Martina Rudelius,
  • Valeria Santini,
  • Marco Raddi,
  • Kok-Hoi Teh,
  • Rita De Vito,
  • Ayami Yoshimi,
  • Marco Tartaglia,
  • Franco Locatelli,
  • Charlotte M. Niemeyer,
  • Riccardo Masetti

摘要

Known genetic disorders, such as Noonan syndrome and Down syndrome, can present in the neonatal period or early infancy with myeloproliferative disease (MPD) or abnormal myelopoiesis, which often self-resolves. This phenomenon results from an imbalance in differentiation and cell regulation caused by the genetic condition during perinatal hematopoiesis. Recently, SH2B3 variants have also been associated with neonatal MPD. However, data on their clinical significance, particularly across the spectrum of extra-hematological manifestations, of SH2B3 variants remain limited. Here, we describe the clinical features of ten children with SH2B3-associated disease, arising from germline biallelic SH2B3 loss-of-function (LoF) mutations in eight patients and in two patients from monoallelic germline LoF variants with loss-of-heterozygosity in hematopoietic cells. Patients displayed a MPD in the first weeks of life, which was mostly self-limiting. Following the normalization of blood counts, thrombocytosis developed during childhood. Moreover, they presented with a multisystemic clinical features consisting in delayed growth, variable neurological impairment, autoimmune disorders. These data contribute to the definition of a clinical phenotype associated with germline biallelic SH2B3 LoF variants presenting with neonatal MPD, with important implications for patient management and follow-up.