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.
We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 ( TRPM3 ) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).
Acute myeloid leukemias (AMLs) frequently harbor activating mutations inFms-like tyrosine kinase 3(FLT3). The use of FLT3 inhibitors (FLT3i) is the standard of care for treatment of newly diagnosed and relapsed patients with AML. Differentiation responses including clinical differentiation syndrome have been previously reported with FLT3i when used as single agents in relapsed disease. We present a case of hypereosinophilia in a patient on FLT3i therapy with persistentFLT3polymerase chain reaction (PCR) positivity in peripheral blood. We sorted mature leukocytes by lineage to determine if the eosinophils were leukemia-derived.FLT3PCR and next-generation sequencing analysis demonstrated monocytic differentiation of theFLT3–ITDleukemic clone with reactive hypereosinophilia that was derived from a preleukemicSF3B1,FLT3wild-type clone. Our case is the first to definitively demonstrate the emergence of clonalFLT3–ITDmonocytes with FLT3i and the first to demonstrate a differentiation response following decitabine, venetoclax, and gilteritinib triplet therapy.
Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.
The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3′ region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.
