Spontaneous Regression of Monosomy 7 Clone in a Premature Infant with
RECQL4
-Associated Syndrome
Authors: Canovas Nunes Sara , Reed Helen D. , Zhou Yu , Harris Chad Everett , Andresen Felicia , Abu-El-Haija Aya , Barbera Christina , Bledsoe Jacob R. , Brundige Karyn , Day-Lewis Megan , Nguyen Alan A , Shimamura Akiko , Williams David A 
Published: December 2024

Acquired monosomy 7 is associated with a high risk of progression to myeloid malignancy but has not been frequently reported at birth. We present a case of a premature newborn with a RECQL4-associated syndrome and acquired monosomy 7 that resolved over the first year of life.
A male infant born at 30-weeks gestation via urgent C-section for non-reassuring fetal heart tracings was found to have multiple congenital anomalies including dysmorphic facies, absent right radius and thumb, hypoplastic left thumb, ectopic left kidney, and a white tuft of hair. He had pancytopenia with persistent macrocytosis, erythroblastosis, and low-level (1-2%) peripheral blood (PB) myeloid blasts after birth. His newborn screening showed abnormal TREC levels. Lymphocyte subset analysis revealed low absolute T, B, and NK cell populations with profound CD8+ lymphopenia, but adequate naïve CD4+ and CD8+ percentages and normal mitogen-induced lymphocyte proliferation.
PB microarray on day 1 of life revealed mosaic monosomy 7, which was not found on buccal microarray, suggestive of a somatic monosomy 7 hematopoietic clone. Suspicion for Fanconi anemia was high, however, MMC/DEB-induced chromosome breakage testing on both PB and skin fibroblasts was negative. His clinical course over the first year of life was notable for chronic diarrhea, poor growth, sparse hair growth, and delayed development of poikiloderma. Bone marrow evaluations at 2 & 10 months of age revealed overt megakaryocyte dysplasia, 7.9% & 6.5% myeloblasts by flow cytometry, and monosomy 7 in 43.5% & 23.5% of cells on fluorescence in situ hybridization (FISH), respectively. Next generation sequencing of the marrow redemonstrated partial loss of monosomy 7 on copy number analysis and no pathogenic single nucleotide variants or small insertions/deletions. Given the concern for progression to leukemia, bone marrow transplantation was considered. Due to his age, prematurity, and poor donor options, a surveillance strategy with regular monitoring of PB counts and FISH was ultimately favored. The % of monosomy 7 in the PB gradually declined and was undetectable by 13 months of age, coinciding with an improvement in cytopenias and resolution of peripheral nucleated red blood cells and panlymphopenia. He demonstrated robust antibody responses to pneumococcal and tetanus vaccines; his infectious history remained unremarkable.
Targeted whole exome sequence sequencing (WES) revealed a likely pathogenic heterozygous RECQL4 variant (RECQL4 c.2414_2419dup, p.Arg807Profs*38). Subsequent clinical whole genome sequencing (WGS) found a second heterozygous intronic variant (RECQL4 g.2746-2756-delTGGGCTGAGGC), an11 base pair (bp) deletion in intron 8. Variants were confirmed to be in trans based on parental WGS. RNAseq analysis confirmed that the RECQL4 c.2414_2419 duplication results in a frameshift leading to a premature stop codon and a predicted 845aa product instead of the full length 1208aa RECQL4 protein. The 11bp deletion in intron 8 results in missplicing and retention of the remaining 66bp of intron 8 as confirmed by RNAseq and guided reverse transcription PCR. This retention leads to a premature stop signal resulting in a 501aa protein. Western blot of patient derived fibroblasts was consistent with RNAseq data and demonstrated 2 smaller sized RECQL4 proteins. An additional band consistent with full-size protein was also observed in these lysates suggesting that intron 8 might be correctly spliced in some instances despite the 11bp deletion.
The biallelic variants in the DNA helicase RECQL4 and clinical findings are consistent with Rothmund-Thomson syndrome (RTS) or associated diseases including Rapidilino or Baller-Gerold syndrome, in which RECQL4 mutations have also been observed. Hematologic abnormalities have been reported in these cancer-predisposition syndromes, including myelodysplastic syndrome. While spontaneous regression of monosomy 7 clones in young children with SAMD9/9L syndromes has been seen rarely, but never previously reported in RTS. This case highlights the complexities of managing acquired monosomy 7 discovered at birth and the utility of WGS clinical data. Decisions regarding management should be made by integrating clinical, pathologic, and molecular trends and with guidance from those with expertise in pediatric monosomy 7 predisposition syndromes.