Leardini Davide, Flex Elisabetta, Stieglitz Elliot, Cerasi Sara, Bertuccio Salvatore Nicola, Baccelli Francesco, Kállay Krisztián, Kjollerstrom Paula, Batalha Sara, Carpentieri Giovanna, Pedace Lucia, Ciolfi Andrea, Hammad Mahmoud, Miranda Maria, Rojas Marta, Rao Anupama, Innes Andrew J, Rudelius Martina, Santini Valeria, Raddi Marco, Teh Kok-Hoi, De Vito Rita, Yoshimi Ayami, Tartaglia Marco, Locatelli Franco, Niemeyer Charlotte M, Masetti Riccardo
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Istituto Superiore di Sanità, Department Oncology and Molecular Medicine, Rome, Italy.
Eur J Hum Genet. 2025 Jun 6. doi: 10.1038/s41431-025-01877-y.
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.
已知的遗传疾病，如努南综合征和唐氏综合征，可在新生儿期或婴儿早期出现骨髓增殖性疾病（MPD）或异常骨髓生成，且通常可自行缓解。这种现象是由围产期造血过程中遗传状况导致的分化和细胞调节失衡引起的。最近，SH2B3变异也与新生儿MPD有关。然而，关于SH2B3变异的临床意义的数据仍然有限，尤其是在血液学以外的表现方面。在此，我们描述了10例与SH2B3相关疾病患儿的临床特征，其中8例患者因种系双等位基因SH2B3功能丧失（LoF）突变发病，2例患者因单等位基因种系LoF变异且造血细胞杂合性丧失发病。患者在出生后的头几周出现MPD，大多为自限性。血细胞计数恢复正常后，儿童期出现血小板增多症。此外，他们还表现出多系统临床特征，包括生长发育迟缓、不同程度的神经功能损害、自身免疫性疾病。这些数据有助于明确与新生儿MPD相关的种系双等位基因SH2B3 LoF变异的临床表型，对患者的管理和随访具有重要意义。
