Zimmermann-Laband syndrome is a rare, heterogeneous disorder characterized by gingival hypertrophy or fibromatosis, aplastic/hypoplastic nails, hypoplasia of the distal phalanges, hypertrichosis, various degrees of intellectual disability, and distinctive facial features. Three genes are considered causative for ZLS: KCNH1, KCNN3, and ATP6V1B2. We report on a pair of female concordant monozygotic twins, both carrying a novel pathogenic variant in the KCNN3 gene, identified using exome sequencing. Only six ZLS patients with the KCNN3 pathogenic variant have been reported so far. The twins show facial dysmorphism, hypoplastic distal phalanges, aplasia or hypoplasia of nails, and hypertrichosis. During infancy, they showed mild developmental delays, mainly speech. They successfully completed secondary school education and are socio-economically independent. Gingival overgrowth is absent in both individuals. Our patients exhibited an unusually mild phenotype compared to published cases, which is an important diagnostic finding for proper genetic counseling for Zimmermann-Laband syndrome patients and their families.

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Intelligent Systems Faculty of Information Technology Brno University of Technology Brno Czech Republic

Department of Stomatology Motol University Hospital Prague Czech Republic

See more in PubMed

Adelman, J. P., Maylie, J., & Sah, P. (2012). Small-conductance Ca2+-activated K+ channels: Form and function. Annual Review of Physiology, 74, 245-269. https://doi.org/10.1146/annurev-physiol-020911-153336

Bauer, C. K., Calligari, P., Radio, F. C., Caputo, V., Dentici, M. L., Falah, N., High, F., Pantaleoni, F., Barresi, S., Ciolfi, A., Pizzi, S., Bruselles, A., Person, R., Richards, S., Cho, M. T., Sepulveda, D. J., Pro, S., Battini, R., Zampino, G., … Tartaglia, M. (2018). Mutations in KCNK4 that affect gating cause a recognizable neurodevelopmental syndrome. American Journal of Human Genetics, 103(4), 621-630. https://doi.org/10.1016/j.ajhg.2018.09.001

Bauer, C. K., Schneeberger, P. E., Kortüm, F., Altmüller, J., Santos-Simarro, F., Baker, L., Keller-Ramey, J., White, S. M., Campeau, P. M., Gripp, K. W., & Kutsche, K. (2019). Gain-of-function mutations in KCNN3 encoding the small-conductance Ca2+-activated K+ channel SK3 cause Zimmermann-Laband syndrome. American Journal of Human Genetics, 104(6), 1139-1157. https://doi.org/10.1016/j.ajhg.2019.04.012

Castori, M., Valiante, M., Pascolini, G., Leuzzi, V., Pizzuti, A., & Grammatico, P. (2013). Clinical and genetic study of two patients with Zimmermann-Laband syndrome and literature review. European Journal of Medical Genetics, 56(10), 570-576. https://doi.org/10.1016/j.ejmg.2013.08.004

Garneau, L., Klein, H., Banderali, U., Longpré-Lauzon, A., Parent, L., & Sauvé, R. (2009). Hydrophobic interactions as key determinants to the KCa3.1 channel closed configuration. An analysis of KCa3.1 mutants constitutively active in zero Ca2+. Journal of Biological Chemistry, 284(1), 389-403. https://doi.org/10.1074/jbc.M805700200

Gripp, K. W., Smithson, S. F., Scurr, I. J., Baptista, J., Majumdar, A., Pierre, G., … Kutsche, K. (2021). Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-A subgroup of K+ channelopathies. European Journal of Human Genetics, 29, 1384-1395. https://doi.org/10.1038/s41431-021-00818-9

Hamilton, M. J., & Suri, M. (2020). “Electrifying dysmorphology”: Potassium channelopathies causing dysmorphic syndromes. Advances in Genetics, 105, 137-174. https://doi.org/10.1016/bs.adgen.2020.03.002

Kortüm, F., Caputo, V., Bauer, C. K., Stella, L., Ciolfi, A., Alawi, M., Bocchinfuso, G., Flex, E., Paolacci, S., Dentici, M. L., Grammatico, P., Korenke, G. C., Leuzzi, V., Mowat, D., Nair, L. D. V., Nguyen, T. T. M., Thierry, P., White, S. M., Dallapiccola, B., … Kutsche, K. (2015). Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nature Genetics, 47(6), 661-667. https://doi.org/10.1038/ng.3282

Laband, P. F., Habib, G., & Humphreys, G. S. (1964). Hereditary gingival fibromatosis: Report of an affected family with associated splenomegaly and skeletal and soft-tissue abnormalities. Oral Surgery, Oral Medicine, and Oral Pathology, 17, 339-351. https://doi.org/10.1016/0030-4220(64)90506-7

Reddy, M., Mehetre, V., Gir, P. J., & Ranmare, V. (2018). An extremely rare presentation of Zimmermann-Laband syndrome in a twin. Annals of Maxillofacial Surgery, 8(2), 352-354. https://doi.org/10.4103/ams.ams_203_17

Zimmermann, K. W. (1928). Ueber anomalien des ektoderms. VierteljahrsschriftfürZahnheilkunde, 1928(44), 419-434.