Citation: De La Flor, J.C.; Monroy- Condori, M.; Apaza-Chavez, J.; Arenas-Moncaleano, I.; Díaz, F.; Guerra-Torres, X.E.; Morales-Montoya, J.L.; Lerma-Verdejo, A.; Sandoval, E.; Villa, D.; et al. Monoclonal Gammopathy of Renal Significance with Deposits of Infrequent Morphology: Two Case Reports of Light and Heavy Chain Deposition Disease with Atypical Presentation and Literature Review. Medicines 2023, 10, 55. https:// doi.org/10.3390/medicines10100055 Academic Editor: Guy Rostoker Received: 21 July 2023 Revised: 2 September 2023 Accepted: 26 September 2023 Published: 4 October 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). medicines Case Report Monoclonal Gammopathy of Renal Significance with Deposits of Infrequent Morphology: Two Case Reports of Light and Heavy Chain Deposition Disease with Atypical Presentation and Literature Review José C. De La Flor 1, * , Maribel Monroy-Condori 2 , Jacqueline Apaza-Chavez 3 , Iván Arenas-Moncaleano 2 , Francisco Díaz 4 , Xavier E. Guerra-Torres 2 , Jorge L. Morales-Montoya 2 , Ana Lerma-Verdejo 5 , Edna Sandoval 6 , Daniel Villa 7 and Coca-Mihaela Vieru 4 1 Department of Nephrology, Hospital Central de la Defensa, 28046 Madrid, Spain 2 Section of Nephrology and Hypertension, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; mmonroy@sescam.jccm.es (M.M.-C.); igarenas@sescam.jccm.es (I.A.-M.); xguerra@sescam.jccm.es (X.E.G.-T.); jmmontoya@sescam.jccm.es (J.L.M.-M.) 3 Department of Nephrology, Hospital Fuensanta, 28027 Madrid, Spain; japaza77@gmail.com 4 Department of Anatomic Pathology, Hospital Gregorio Marañón, 28007 Madrid, Spain; fdiazc@salud.madrid.org (F.D.); vieru.mihaela26@gmail.com (C.-M.V.) 5 Department of Hematology, Hospital General Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; analermaverdejo@gmail.com 6 Department of Hematology, Hospital Central de la Defensa, 28046 Madrid, Spain; esanba5@mde.es 7 Department of Nephrology, Hospital Clínica Universiad Navarra, 31009 Pamplona, Spain; daniel.villa.hurtado@gmail.com * Correspondence: jflomer@mde.es or josedelaflor81@yahoo.com Abstract: Background: Monoclonal immunoglobulin deposition disease (MIDD) includes three entities: light chain deposition disease (LCDD), heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD). The renal presentation can manifest with varying degrees of proteinuria and/or nephrotic syndrome, microhematuria, and often leads to end-stage renal disease. Given the rarity of LHCDD, therapeutic approaches for this condition remain inconclusive, as clinical trials are limited. Case presentation: We report two male patients with underlying monoclonal gammopathy of renal significance (MGRS) associated with LHCDD lesions. Both cases had non- nephrotic proteinuria, moderately impaired renal function, and normal levels of C3 and C4. Light microscopy of the renal biopsies in both patients did not show lesions of nodular glomerulosclerosis. Immunofluorescence showed a staining pattern with interrupted linear IgA-κ in patient #1 and IgA-λ in patient #2 only along the glomerular basement membrane (GBM). Electron microscopy of patient #1 revealed electrodense deposits in the subendothelial and mesangial areas only along the GBM. Discussion: In this case series, we discuss the clinical, analytical, and histopathological findings of two rare cases of LHCDD. Both patients exhibited IgA monoclonality and were diagnosed with monoclonal gammopathy of undetermined significance (MGUS) by the hematology department at the time of renal biopsy. Treatment with steroids and cytotoxic agents targeting the clone cells responsible for the deposition disease resulted in a favorable renal and hematologic response. Keywords: monoclonal gammopathy of renal significance; monoclonal immunoglobulin deposits disease; light and heavy chain deposition disease 1. Introduction Monoclonal gammopathy of renal significance (MGRS) is a hematologic disorder characterized by the proliferation of B lymphocyte or small plasma cell clones that produce and release a monoclonal immunoglobulin (MIg) or its components (light or heavy chains) in patients who do not meet the diagnostic criteria for multiple myeloma (MM) or other Medicines 2023, 10, 55. https://doi.org/10.3390/medicines10100055 https://www.mdpi.com/journal/medicines