Monosomy 7 and deletion 7q are among the most common chromosomal aberrations in pediatric myeloid malignancies and generally associated with an increased risk of rapid progression to advanced neoplasia, warranting allogeneic hematopoietic stem cell transplantation (HSCT). However, several cases of transient monosomy 7 and spontaneous hematologic recovery upon loss of monosomy 7 in young children have been described in the literature. In several cases, germline mutations in sterile alpha-motif domain-containing protein 9 (SAMD9) and SAMD9-like (SAMD9L), both located on chromosome 7q, have been identified. Gain of function (GOF) mutations in SAMD9 and SAMD9L cause phenotypically overlapping syndromes that predispose to pediatric myelodysplastic syndrome (MDS) and are associated with non-hematological anomalies and variable immunodeficiency. GOF SAMD9/9L mutations inhibit cell proliferation and reduce cell survival of hematopoietic stem and progenitor cells (HSPCs). This may exert strong selection pressure on HSPCs to acquire somatic aberrations that improve their competitive fitness. To no surprise, a distinctive feature of SAMD9/9L syndromes is their propensity for somatic genetic reversion, including somatic loss of function mutations in SAMD9/9L in cis, uniparental isodisomy 7q, and non-random loss of chromosome 7 or 7q of the mutant allele. Multiple hematopoietic subclones with clone-defining somatic mutations can exist in the bone marrow and their composition may change over time due to the exceptionally high plasticity of hematopoiesis in young children. Consequently, monosomy 7 may spontaneously disappear in young patients with SAMD9/9L syndromes. Earlier observations had suggested that somatic compensatory mutations may be more frequent in SAMD9L than in SAMD9 mutated patients. Here, we investigate the natural history of young children with SAMD9L syndrome and monosomy 7.

We report on seven patients with SAMD9L syndrome and monosomy 7 presenting before the age of 5 years in whom an initial surveillance strategy was electively chosen rather than timely allogeneic HSCT. All patients presented with refractory cytopenia of childhood with monosomy 7 at a median age of 1.0 years (range: 0.4-3.1 years). Six patients had an additional non-hematologic phenotype, including prematurity (P2, P5), small for gestational age (P1, P2, P7), cerebellar atrophy and developmental delay (P1), bilateral cleft lip and palate (P2), macrocephaly (P3, P6), shorter thumbs (P6), and big eye bulbs and dystrophy (P7). Immunodeficiency was present in five patients ranging from hypogammaglobulinemia (P1, P2, P5, P6, P7) to B and NK cell deficiency patients (P2, P5, P6, P7). At a median follow-up of 35 months (range: 10-51 months), allogeneic HSCT had been employed in four patients for severe neutropenia and/or bacterial infection (P1, P7), persistence of monosomy 7 beyond the age of 5 years (P5) or disease progression to MDS with excess blasts (P2). One patient (P2) suffered transplant-related mortality, while the remaining patients were alive at last follow-up. Three patients did not require definitive treatment. Two of the three patients had complete loss of the monosomy 7 clone with concomitant recovery of blood counts (P4, P6), a third patient had normalized blood counts, but cytogenetic and molecular studies at follow-up were missing (P3). Secondary somatic mutations were detected in six patients. Five patients carried somatic SAMD9L mutations in cis (P2, P3, P4, P6, P7). Two patients with spontaneous loss of monosomy 7 carried large somatic SAMD9L subclones that were stable over time and presumably maintained hematopoiesis (P4, P6). In addition, two patients carried somatic mutations in oncogenic driver genes (P2, P5). P2, who developed MDS-EB 14 months after diagnosis, had two RUNX1 mutations at the time of progression. P5 had one RUNX1 and one EZH2 mutation, but without evidence of disease progression.

Our results suggest that loss of monosomy 7 can occur in young patients with SAMD9L syndrome but is a rare event. If a watch and wait strategy is chosen, close monitoring with frequent bone marrow examinations including SAMD9L sequencing, cytogenetics and search for somatic oncogenic events is advised. Importantly, presence of severe infections, severe neutropenia, increase in blast percentage, and persistence of monosomy 7 beyond the age of 5 years should prompt timely allogeneic HSCT.

Niemeyer:BMS: Honoraria; Novartis: Honoraria; Apriligen LLC: Honoraria. Erlacher:Gilead Sciences: Research Funding.

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