A familial SAMD9 variant present in pediatric myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and a SAMD9 germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.

Two mutations in the SBDS gene reveal a diagnosis of Shwachman-Diamond syndrome in a patient with atypical symptoms.

We present the case of a 53-yr-old woman with an inherited bone marrow failure coexisting with uncommon extrahematological symptoms, such as cirrhosis and skin abnormalities. Whole-exome sequencing revealed a diagnosis of Shwachman-Diamond syndrome (SDS) with an atypical presentation. Unexpected was the age of disease expression, normally around the pediatric age, with a predominantly median survival age of 36 yr. To our knowledge, she was the first adult patient with a molecular diagnosis of Shwachman-Diamond in Uruguay. The patient was referred to our service when she was 43-yr-old with a history of bone marrow failure with anemia and thrombocytopenia. All secondary causes of pancytopenia were excluded. Bone marrow aspirate and biopsy specimens were hypocellular for the patient's age. Numerous dysplastic features were observed in the three lineages. She had a normal karyotype and normal chromosomal fragility. A diagnosis of low-risk hypoplastic MDS was made. Dermatological examination revealed reticulate skin pigmentation with hypopigmented macules involving the face, neck, and extremities; nail dystrophy; premature graying; and thin hair. Extrahematological manifestations were present (e.g., learning difficulties, short stature). Last, she was diagnosed with cryptogenic liver cirrhosis CHILD C. This rules out all other possible causes of chronic liver disease. This clinical presentation initially oriented the diagnosis toward telomeropathy, so we did a telomeropathy NGS panel that came up negative. Finally, we did an exome sequencing that confirmed the diagnosis of SDS. Using whole-exome sequencing, we were able to find two compound heterozygous mutations in the SBDS gene that were responsible for the phenotype of a patient that was undiagnosed for 10 years. An earlier genetic diagnosis could have influenced our patient's outcome.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.

Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.(Asp207Thrfs*22), or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.

Aplastic anemia in a patient with CVID due to NFKB1 haploinsufficiency.

Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation. Here we report a patient with familial common variable immunodeficiency (CVID) caused by a pathogenic variant in NFKB1, who developed AA as an adult. The patient had a difficult clinical course and was unable to tolerate standard AA therapy with cyclosporine A and eltrombopag, with complications attributed in part to the effect of cyclosporine A on NF-κB signaling. Our case suggests a novel link between genetic disorders of immune regulation and AA and highlights the importance of recognizing inherited autoimmunity syndromes in AA patients for the selection of optimal therapy and prognostic counseling.

Distinct mutation profile and prognostic relevance in patients with hypoplastic myelodysplastic syndromes (h-MDS).

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased BM cellularity (NH-MDS), some have hypocellular BM (h-MDS). The reports concerning the differences in genetic alterations between h-MDS and NH-MDS patients are limited. In this study, 369 MDS patients diagnosed according to the WHO 2008 criteria were recruited. h-MDS patients had lower PB white blood cell and blast counts, and lower BM blast percentages, than those with NH-MDS. h-MDS was closely associated with lower-risk MDS, defined by the International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R). IPSS-R could properly predict the prognosis in h-MDS (P<0.001) as in NH-MDS patients. The h-MDS patients had lower incidences of RUNX1, ASXL1, DNMT3A, EZH2 and TP53 mutations than NH-MDS patients. The cumulated incidence of acute leukemic transformation at 5 years was 19.3% for h-MDS and 40.4% for NH-MDS patients (P= 0.001). Further, the patients with h-MDS had longer overall survival (OS) than those with NH-MDS (P= 0.001), and BM hypocellularity remains an independent favorable prognostic factor for OS irrespective of age, IPSS-R, and gene mutations. Our findings provide evidence that h-MDS indeed represent a distinct clinico-biological subgroup of MDS and can predict better leukemia-free survival and OS.