Transcription factors set the pace and pattern of nuclear DNA conversion to mRNA. From amidst more than 1500 such factors, RUNX2, SALL1, and SAMD9 are especially prominent. The genes coding for these products thus control cell division, migration, body plan architecture, and apoptosis. While any disruption of these factors typically is poorly tolerated, often catastrophic, and usually apparent in childhood, this patient experienced an active, healthy childhood while carrying previously unreported variants in all three. Remarkably, the most dramatic highlight against a rather ordinary pediatric background was hospitalization for Covid-19. Attribution of findings discussed here to genetic etiologies vs. Covid-19 is challenging, given the unclassified status of these specified variants and the expansive, evolving nature of ‘Long Covid’. Curiously, the high MPV seen with Covid-19 infection documented by others  was absent here. Perhaps the three variants dampened MPV by altering individual platelet responsiveness, even though overall platelet output was unaffected. Likewise, the observed low serum IgA and IgG levels alongside normal total immunoglobulin may reflect a synthesis of coordinated action by these variants.
To date, some 150 mutations in SAMD9 have been associated with outcomes ranging from spontaneous remission to malignant progression . Most SAMD9 variants presage early death from myeloid dysplasia, immune system imbalance, adrenal insufficiency, or chronic undernourishment from feeding difficulty . SAMD9 mutations via germline transmission predispose to low platelets, acquired monosomy 7, constitutional abnormalities (e.g., ambiguous genitalia) and immune dysfunction . Less is known about SAMD9 variants which appear as de novo events. Computer modeling has envisioned a protein-protein interaction network of differentially expressed genes, and human SAMD9 was among the ‘hub genes’ having special relevance after SARS-CoV-2 infection . Thomas et al  assessed the functional impact of wild-type and mutant SAMD9 in primary mouse or human hematopoietic stem and progenitor cells. Using protein interactome analyses, transcriptional profiling, and functional validation, it was concluded that SAMD9 mutations tend to favor interference with DNA damage repair, and ultimately apoptosis, in hematopoietic cells . The hypocellular terrain noted here on bone marrow biopsy may be a partial expression of this SAMD9 influence.
RUNX2 is considered to be a centrally regulating transcription factor for osteoblast and chondrocyte differentiation and overall skeletal architecture [22, 23]. Some 80 variants in RUNX2 have been identified [1, 24] and while heterozygous loss of function mutations can lead to cleidocranial dysplasia, this is inconsistent . Triplication  or quadruplication  of RUNX2 accompanies more serious syndromic phenotypes, including coronal/sagittal synostosis or pan-craniosynostosis [26, 27] suggesting a dosage effect . For our patient, sequence analysis did identify a 3’ duplication involving at least exons 6 through 9 of RUNX2 , so connecting osseous and dental changes observed here as related to this gene variant seems plausible.
In late adolescence or early adulthood third molar impaction is not unusual, and others have investigated differential expression of RUNX2 regarding tooth location before surgical removal . While RUNX2 was not implicated, another transcription factor (MSX1) was differentially expressed depending on depth of molar impaction  and RUNX2 is itself partially controlled by MSX1 . As alveolar bone remodeling is central to orthodontic tooth movement, a novel regulatory mechanism whereby FOXO3 induces osteocalcin transcription by promoter activation in concert with RUNX2  could help explain dental features in this case.
The T > C mutation in codon 453 of the TSH receptor gene found here was previously reported in the setting of nonautoimmune hyperthyroidism  but without any RUNX2, SALL1, or SAMD9 involvement. Wide tissue expression of TSHRs is well established, and includes brain, bone marrow, lymphocytes, pituitary, thymus, testes, kidney, adipose tissue, and fibroblasts . While oocyte growth is influenced via TSHR/cAMP signaling , there has been no reason to obtain ovarian tissue sampling in this patient. Pelvic ultrasound will be useful to identify any changes in gross ovarian anatomy. Similarly, tracking thyroid size, nodularity, and tenderness, as well as the thyroid laboratory panel will be important.
Concerning SALL1, some 50 different mutations are currently known . SALL1 and RUNX2 may have special relevance in human reproduction. Mammalian estrogen receptor β (ERβ) is required for ovarian follicles to advance past the antral stage, and work in rat granulosa cells has placed RUNX2 within the ERβ-regulated genes directing folliculogenesis, oocyte maturation, and ovulation . While SALL1 is essential for stem cell maintenance in kidney, heart, and spermatogonial progenitors [4, 37], its role in human ovarian tissue awaits better characterization. Should undetectable serum AMH persist and ovarian histology be normal, this patient may consider fertility treatment including platelet-rich plasma for ‘ovarian rejuvenation’  as an alternative to donor egg IVF.
The Venn diagram for worldwide clinical experience with RUNX2, SALL1, and SAMD9 returned a null union set, prior to this patient. The detrimental consequences of mutation of these genes in isolation may have been mitigated by the chance occurrence of all three variants in concert—an offset possibly enabled by cross-gene effects or epigenetic silencing . Monitoring for patients with a SAMD9 variant includes CBC with differential every six months, and repeat bone marrow aspirate/biopsy (and karyotype) should anemia, thrombocytopenia, or neutropenia develop . Red blood cell dysplasia, agglutination, or fragmentation are unlikely given the low/normal red-cell distribution width measured here. Serum BUN and creatinine levels evidenced no discernable pattern whenever these were abnormal, but as cystatin-C may be superior to BUN/Cr to detect early-stage disease [39, 40] a screening panel including all three will guide the need for repeat renal biopsy. Since this case incorporates a de novo variant, the risk to siblings is considered somewhat greater than the general population  and cytogenetic testing for an older half-brother is pending. Clinical guidelines for RUNX2 or SALL1 have not been developed, probably due to the exceptionally low frequency of these variants. Because not all instances of marrow hypocellularity will render immediate effects  periodic reassessment of this patient is planned.