The pathogenesis of HCDD is related to the deficiency of the HC constant region 1 (CH1 domain), which prevents HC binding to its chaperone protein in the endoplasmic reticulum, resulting in the secretion of a truncated HC by the B-cell or plasma-cell clone [9]. The deposition of pathogenic HCs in systemic tissues and organs causes dysfunction, most commonly involving the kidneys. According to our data, 80.8% of patients with HCDD showed CH1 fragment deletion of the HC, a few patients had CH2 fragment deletion, CH1 and CH2 fragments were deleted simultaneously, or VH and VH3 fragments were deleted (Table 1).

The authors searched PubMed and China National Knowledge Infrastructure using the following keywords: heavy-chain deposition disease, monoclonal immunoglobulin deposition disease, HCDD, MIDD. A total of 142 cases or series of reports had been published since the first report in 1993, of which six cases could not be counted, and one case involving only the eyes was excluded. A total of 136 reports were included in the statistics, including this patient. HCDD mainly occurred in the middle-aged and older population (> 50 years old), without significant sex differences. 55.2% of the patients had onset of nephrotic syndrome, 85.8% had hematuria, mainly microscopic hematuria, and > 90% had renal failure. Approximately 80% of patients had hypertension at onset, 90% had anemia and edema, 56.5% had myeloplasmacytosis, and approximately 8.7% had multiple myeloma. Five of these patients presented with AL or AH amyloidosis [10,11,12,13,14]. Patients with HCDD may present with amyloidotic changes after many years of follow-up and may present with cardiac, hepatic, and splenic symptoms [14]. In some patients, extrarenal manifestations were mainly presented as skin laxity (8.1%), manifested as excessive wrinkling and laxness of the skin on the face, neck, abdomen, and thighs, with reduced elasticity. Skin recoiled slowly on being released after stretching [15,16,17,18,19,20,21]. Skin biopsies showed decreased elastic fibers in the dermis, with heavy chain deposition confirmed by immunofluorescence in four of them [16, 17, 20, 21]. The development of cutis laxa may be a cutaneous manifestation of the secretory activity of HCDD [17]. Chavarot et al. [15] pointed out that in γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious factors for an early diagnosis, which is crucial to avoid the progression of irreversible renal and elastic tissue damage. Extrarenal manifestations also involve the liver, heart, digestive tract, minor salivary gland, thyroid, and skeletal muscles [7], as well as lymphocytic vasculitis, emphysema, chronic obstructive pulmonary disease, hiatal hernia, and osteoarthropathy [15,16,17,18]. Most patients presented hypocomplementemia, and C3 mainly decreased, as well as C4 and/or CH50. In some patients, monoclonal bands of IgG κ or IgG λ were observed in the serum immune-solid phase electrophoresis, and monoclonal bands of κ or λ were observed in the urine immune-solid phase electrophoresis.

Pathologically, > 90% of the renal biopsy showed nodular glomerulosclerosis by light microscopy, which may be accompanied by crescent formation, membrane proliferation-like changes, and capillary proliferation, and Congo red staining was negative. Some patients had associated interstitial fibrosis and arteriolosclerosis. Most were positively stained with IgG (86.9%) by immunofluorescence, and IgG1-4 subtypes were all present, of which the IgG1 subtype was the most common (46.9%). Followed by IgA deposition (10.8%), IgM and IgD deposition were rare. Some patients may have C3 and C1q deposition. Royal et al. found the only case of IgD HCDD by laser microdissection (LMD) and mass spectrometry (MS), which results in extensive focal glomerulosclerosis, tubular atrophy, and interstitial fibrosis, with poor renal recovery [22]. Immunofluorescence and electron microscopy showed that immune complexes were mainly deposited in the glomerular basement membrane, mesangial, tubular basement membrane, and small vessels in linear, powdered, or fine granular deposits. A few could be deposited in the Bowman’s capsule and/or glomerular capillary walls. Electron microscopy showed extensive fusion and disappearance of foot processes in some patients (Table 1) [3,4,5,6,7,8, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44, 46].

Regarding treatment, the prognosis of patients treated with bortezomib combined with dexamethasone was better than that of melphalan combined with methylprednisolone (MP) and other regimens, and the former had a higher renal survival rate than the latter. However, complications of peripheral neuropathy developed in some patients, and they had to reduce or stop bortezomib. A small number of patients with neuropathy could be controlled by gabapentin. In addition, Turner et al. [23] reported a case of HCDD with high anti-GBM antibodies, and the clinical and pathological findings were dominated by HCDD without crescentic nephritis. The patient achieved complete remission with daratumumab, was treated with stem cell transplantation, and recovered well. Zhang et al. [24] reported a case of HCV-positive HCDD with κ plasma-cell tumor in a patient with poor renal outcome and dependence on hemodialysis (Table 2) [3,4,5,6,7,8, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. After treatment, urinary protein and renal functions improved or remained stable in 46.8% of the patients, and more than half of the patients experienced continuous progression of renal function to end-stage renal disease several months to years later and required dialysis or even died.

This patient had clinical and pathological findings consistent with the diagnosis of HCDD. This patient was a young man who presented with nephritic syndrome with acute kidney injury, anemia, skin laxity, and a significant increase in serum and urine κ:λ free light chain ratio. Bone puncture showed a high proportion of plasma cells (1.2%); however, not meet the diagnostic criteria of multiple myeloma diagnosis. In this case, bortezomib combined with dexamethasone was used, which achieved good efficacy.

The limits of this case were that the patient’s skin biopsy showed no abnormality, and an immunofluorescence examination was not performed; the former may be related to the insufficient depth of skin sampling. Based on the literature, his skin laxity might be associated with HCDD, although we could not reliably identify it by pathological section. After treatment, the patient showed improvement of abdominal skin laxity, but the skin manifestations in the face and neck were further aggravated, which was difficult to explain. Only one of the 10 cases of HCDD with skin laxity reported in the literature showed no improvement in skin symptoms four years after treatment, and 9 others were not described. It has been suggested that there is no effective medical treatment for the cutaneous manifestations of cutis laxa, and excess skin can be removed surgically [20].

In conclusion, we report a rare case of HCDD with an excellent renal recovery during a follow-up period of four years. We also summarized and reviewed previously reported cases. HCDD mainly occurs in the patients aged > 50 years, with no significant sex difference. Most patients showed proteinuria, hematuria, edema, hypertension, anemia, renal function, and hypocomplementemia at onset. More than half of the patients with HCDD experience continuous progression of renal function. A small number of patients may present with multiple myeloma or amyloidosis, and extrarenal involvement is dominated by skin laxity. Light microscopy showed characteristic nodular glomerulosclerosis, and immunofluorescence revealed HC deposition but negativity for LC. Sensitive techniques such as immunoelectron LMD/MS can be used to evaluate renal biopsies when routine assessment fails to reach an accurate diagnosis [47, 48]. In conclusion, this is the first large-scale review summarizing the characteristics of HCDD.