Background
RUNX2, SALL1 and SAMD9 are independently assorted genes responsible for multisystem actions where disruption often results in severe developmental or functional impairment. Alteration in any of these ‘master regulators’ is usually diagnosed in early childhood when missed milestones, anatomical dysmorphia, or chronic infection/immune impairment initiate cross-disciplinary evaluation.
Methods
New variants were recently discovered in all three genes during SARS-CoV-19 hospitalization in an otherwise healthy 46,XX adolescent. Our research expands the clinical characterization for this unusual convergence based on medical records covering the 5 year interval before admission.
Results
Diffuse bone marrow hypocellularity without cytogenetic derangement was present, with no anemia or reduction in total immunoglobulin production. However, bone age was below mean by 1.5yrs and multiple dental anomalies were documented. Macrocytosis and elevated serum creatinine were consistent findings. Ovaries and uterus appeared undersized with collapse of endogenous estradiol output leading to secondary amenorrhea by age 13yrs. Besides oral contraceptives, no other daily hormone treatment was required. A TSH receptor gene mutation of uncertain significance was also identified.
Conclusions
This is the first work to correlate immunoglobulin patterns, bone marrow and dental morphology, hematology/renal screening, pelvic anatomy, ovarian reserve data and thyroid features with coincident variants in RUNX2, SALL1 and SAMD9. While the expected impact from each mutation alone would normally be adverse, this study suggests a milder phenotype can prevail when these three variants occur together. Nevertheless, focused monitoring is appropriate given the uncertain status of this unique combination of mutations.