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

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.

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Publication Details

Journal
European Journal of Human Genetics
Published
2025-06-06
DOI
https://doi.org/10.1038/s41431-025-01877-y
Citations
8
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
6.45

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article

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

Lucia Pedace, Francesco Baccelli, Krisztián Kállay, Giovanna Carpentieri et al.
8 citations
European Journal of Human Genetics
Protein Tyrosine Phosphatases
6.45
article

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

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

Abstract

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.

European Journal of Human GeneticsVol. 33(9)
Università Cattolica del Sacro Cuore (IT), Cairo University (EG), Imperial College Healthcare NHS Trust (GB), University of Freiburg (DE), University of California, San Francisco (US), Istituto Superiore di Sanità (IT), Hospital Kuala Lumpur (MY), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), University Medical Center Freiburg (DE), Hammersmith Hospital (GB), Hospital de Dona Estefânia (PT), Azienda USL di Bologna (IT), Liga Nacional Contra el Cáncer (GT), Bambino Gesù Children's Hospital (IT), UCSF Benioff Children's Hospital (US), National Center for Epidemiology (HU), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Stollery Children's Hospital (CA), University of Florence (IT), Ludwig-Maximilians-Universität München (DE)
Bundesministerium für Bildung und Forschung, Ministero della Salute, Associazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 3%
Protein Tyrosine Phosphatases
6.45
DOIOpen Access PDFOpenAlex
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