Case Presentation:  A 65 yo female with chronic fatigue syndrome was referred for workup of low platelets, presumed to be from Idiopathic Thrombocytopenic Purpura. Family history was significant for clinical bleeding diathesis with thrombocytopenia in patient’s child, twin sister, nieces from sister, and two of the niece’s children. Family pedigree suggested a non-X-linked Autosomal Dominant inheritance. Initial bone marrow biopsy in 2012 was normal. Work-up showed negative ANA, hepatitis panel, Helicobacter pylori and for autoimmune diseases and no paraproteinemia. Wiskott Aldrich syndrome gene analysis was negative and abdominal ultrasound showed no hepatosplenomegaly. Peripheral smear showed normal sized platelets, no clumping and no blasts. Repeat bone marrow biopsy showed normocellular bone marrow with trilineage hematopoiesis; normal female karyotype; FISH negative for myelodysplastic syndrome mutations. Patient was unresponsive to a trial of prednisone. Eventually, genetic testing revealed heterozygosity in ANKRD26c.-126T>C, consistent with Nonsyndromic Thrombocytopenia (THC2).

Impact/Discussion: Thrombocytopenia, defined as having a platelet count of less than 150 × 103 per μL, is a commonly encountered problem in medical practice.5 Differential causes for thrombocytopenia include; decreased production, increased consumption, or sequestration.6 ANKRD26 is a gene mutation that causes Autosomal Dominant Nonsyndromic Thrombocytopenia (THC2), and is associated with mild bleeding tendencies along with mild to severe thrombocytopenia.1 The point mutation in ANKRD26 is thought to alter the binding of key transcription factors, resulting in abnormal signal transduction which adversely affects platelet formation, and also indirectly affects other signal transduction pathways which may increase the risk of myeloid precursor transformation.4 There are 21 known families affected with this syndrome worldwide.1

Conclusion: ANKRD26/ TH2 is identified by mild to severe thrombocytopenia with normal platelet size and no phenotypic complications.4

The predominating theory regarding thrombocytopenia in ANKRD26 mutations is dysregulation of pathways which affect platelet formation.2

The ability to recognize this disorder is important for proper management and surveillance of the affected population. Incorrect diagnosis and anchoring bias during evaluation can lead to unnecessary and potentially harmful treatments suchas chronic steroids and/or splenectomy.4

Patients with this syndrome may need surveillance by annual blood counts for early detection of myeloid neoplasms as they are at increased risk for developing acute leukemias.4

References and Resources

1. 1. Noris, P., Favier, R., Alessi, M.-C., Geddis, A. E., Kunishima, S., Heller, P. G., … Balduini, C. L. (2013). ANKRD26-related thrombocytopenia and myeloid malignancies. Blood, 122(11), 1987–1989. doi: 10.1182/blood-2013-04-499319
2. Pippucci, T., Savoia, A., Perrotta, S., Pujol-Moix, N., Noris, P., Castegnaro, G., … Balduini, C. L. (2011). Mutations in the 5′ UTR of ANKRD26, the Ankirin Repeat Domain 26 Gene, Cause an Autosomal-Dominant Form of Inherited Thrombocytopenia, THC2. The American Journal of Human Genetics, 88(1), 115–120. doi: 10.1016/j.ajhg.2010.12.006
3. Noris, P., Perrotta, S., Seri, M., Pecci, A., Gnan, C., Loffredo, G., … Savoia, A. (2011). Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood, 117(24), 6673–6680. doi: 10.1182/blood-2011-02-336537
4. Botero, J. P., Dugan, S., & Anderson, M. (2018). ANKRD26-Related Thrombocytopenia. ANKRD26-Related Thrombocytopenia. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK507664/
5. Lee, E. J., & Lee, A. I. (2016). Thrombocytopenia. Primary Care, 43(4). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27866576
6. Gauer, R., & Braun, M. M. (2012, March 15). Thrombocytopenia. Retrieved December 22, 2019, from https://www.aafp.org/afp/2012/0315/p612.html.