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Lipoid proteinosis caused specific changes in the brain, larynx, and cervical esophagus of a young adult man. Laryngography clearly depicts the distribution and degree of pharyngeal and laryngeal pathology. Florid calcification, conforming to the classical temporal lobe distribution, is documented by plain films and tomography. The clinical picture and the pertinent literature are reviewed.
The aim of this study has been to assess the clinical presentation and biochemical profile of lipoid proteinosis within a defined pedigree. Glycoprotein analysis was compared to normal values in an attempt to define a biochemical phenotype. Six affected family members were identified with variable degrees of disease expression. The most likely mode of inheritance is autosomal recessive due to consanguinity. Routine laboratory investigations were normal in all family members tested. The total content of mucopolysaccharides, sialic acid and hexosamine in biopsed tissue was significantly lower than normal. Our findings demonstrate that a defect in glycoprotein synthesis, possibly enzymatic, may be the cause of lipid proteinosis and its protean clinical manifestations.
The vascular permeability factor (VPF) is a lymphokine that has been shown to play a role in lipoid nephrosis (LN). Prior studies have shown that interleukin (IL) 12 promotes T helper type 1 differentiation and enhances production of T helper type 1 cytokines such as gamma interferon and IL-2. We, therefore, investigated the effects of recombinant human IL-12 on the release of VPF by peripheral blood mononuclear cells (PBMC) from LN patients. The VPF activity was measured according to the method of Ovary, with minor modifications. The goal of the present study was to examine the importance of IL-12 in concanavalin A induced VPF release in vitro. The levels of VPF were measured in a group of healthy subjects, LN patients with or without the nephrotic syndrome, and patients suffering from IgA nephropathy. There was a significantly increased concanavalin A induced release of VPF in LN and IgA nephropathy patients with nephrotic syndrome as compared with normal controls. Recombinant human IL-12 was found to enhance VPF release in a dose-dependent manner. Neutralization of endogenously produced IL-12 by anti-IL-12 antibody resulted in a decreased release of VPF by LN PBMC. These data indicate that endogenously produced IL-12 functions as a costimulatory molecule in vitro. Our data show that IL-12 can upregulate the release of VPF derived from LN PBMC. Thus IL-12 might be a potent adjuvant for inducing VPF. Therefore, IL-12 antagonists may interfere with newly initiated and ongoing VPF release associated with nephrotic syndrome.
The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the in vitro proliferation of peripheral blood lymphocytes (PBL) was evaluated in patients with lipoid nephrosis (LN). The cytokine increased the proliferation of LN PBL in response to phytohemagglutinin (PHA), measured by the [3H]thymidine uptake. The effects were abrogated by antibody against human GM-CSF. We then investigated the effect of GM-CSF on the release of interleukin-1 (IL-1) from peripheral blood monocytes (PBM) in LN patients and normals. In vitro IL-1 production by LN PBM treated with lipopolysaccharide (LPS) was enhanced by coculture with GM-CSF. Potentiation was approximately 2-fold. The immunological identity of the thymocyte comitogenic activity as IL-1 was confirmed by neutralization with a specific rabbit antihuman IL-1 antiserum. Taken together, these observations suggest that one mechanism by which GM-CSF acts to restore immune responses in LN patients may be enhancing the signals which enable activated monocytes/macrophages to secrete IL-1.
Cell-mediated immunity (CMI) was evaluated in 26 patients with lipoid nephrosis (LN), 50 patients suffering from chronic diffuse proliferative glomerulonephritis (CGN) without renal sufficiency and 24 healthy controls. The following parameters were measured: delayed hypersensitivity skin test responses to purified protein derivative (PPD) and candida, circulating lymphocytes. T lymphocytes and T lymphocytes with receptors for the Fc portion of IgG (T gamma cells) or IgM (Tmu cells). Patients with LN in relapse had less mean induration of skin reactivity and a smaller proportion reacting to both antigens as compared with the control subjects. In contrast, the intensity of skin reactivity and the frequency of negative reactions in patients with LN in remission and CGN were similar to those of the control subjects. It was also found that the LN patients in relapse had a significant T lymphocytopenia as well as a significant decrease in absolute numbers of Tmu and T gamma cells, whereas the patients with LN in remission and CGN did not differ significantly from the control population. Thus, the majority of patients with LN in relapse demonstrated an impaired response in a CMI assay system. The disturbed CMI may be secondary to hypoproteinemia and other nutritional factors induced by the nephrotic syndrome.
Cell-mediated immunity (CMI) was evaluated in 76 patients with renal disease by summation of delayed cutaneous hypersensitivity (DHS) responses to 4 test antigens, purified protein derivative (PPD), candida, mumps and keyhole limpet hemocyanin (KLH). Patients with lipoid nephrosis (LN) in the nephrotic stage had less mean induration of skin reactivity and a smaller proportion reacting to the former 3 antigens as compared with normal controls or LN patients without the nephrotic syndrome (NS). In contrast, the intensity of skin reactivity and the frequency of negative reactions in LN patients in remission and chronic mesangial proliferative glomerulonephritis (CGN) were similar to those of the control subjects. Immune response to KLH was also impaired in LN patients with the NS as measured by skin testing. The data indicate an impaired DHS in LN and suggest that the impairment relates to the clinical stage of disease.
In order to predict the steroid response in lipoid nephrosis (LN), we studied age, sex, proteinuria level, histological features and proteinuria selectivity index (SI; ratio between IgG and transferrin clearances) in 52 LN cases (minimal-change disease: n = 39; focal glomerulosclerosis+IgM nephropathy: n = 13). The multivariate analysis showed that age, sex and proteinuria level were not contributive, whereas histology and SI were. The predictive value of SI was much higher than that of histological type (McFadden's r2: 47% vs. 22%, p < 0.001). Thus, SI should be systemically assessed in idiopathic nephrotic syndrome for reviewing the pathologic classification obtained by histology. However, if its prognostic value is lower than that of selectivity, initial renal biopsy remains necessary for diagnosis in adults.
The effect of recombinant human interleukin 10 (IL-10) on the in vitro secretion of vascular permeability factor (VPF) of peripheral blood mononuclear cells (PBMC) was evaluated in patients with lipoid nephrosis (LN). Significantly increased spontaneous and concanavalin A (ConA) stimulated secretion of VPF was detected in PBMC cultures of LN patients with the nephrotic syndrome as compared with those of normal controls. In the present study, IL-10 inhibited the ConA-stimulated VPF secretion of PBMC in LN. A significant inhibitory effect of IL-10 was observed in cultures of PBMC from LN and IgA nephropathy patients as well as from normal persons. When both ConA and anti-IL-10 antibody were added together to the PBMC, a further increase in ConA-stimulated secretion of VPF occurred. These data suggest that IL-10 is a powerful inhibitor of the secretion of VPF in LN patients.
It has been proposed that a vascular permeability factor (VPF) is involved in the pathogenesis of lipoid nephrosis (LN). There is now increasing evidence that interleukin 10 (IL-10) and interleukin 13 (IL-13) have regulatory effects on cytokine production by activated macrophages. These results prompted us to study the effects of recombinant human IL-10 and IL-13 on VPF secretion in LN. In the present study, we demonstrate that the regulatory cytokines IL-10 and IL-13 are potent inhibitors of the VPF activity of activated peripheral blood mononuclear cells. Each cytokine was found to suppress VPF secretion in a dose-dependent fashion. More importantly, the combination of the cytokines was found to give a potent synergistic suppression of VPF by concanavalin A activated peripheral blood mononuclear cells from patients with LN. When both anti-IL-10 and anti-IL-13 antibodies were added together to the peripheral blood mononuclear cells, a further increase of concanavalin A enhanced secretion of VPF occurred. These data establish IL-10 and IL-13 as potent inhibitors of VPF activity and suggest their utility in controlling deleterious VPF-mediated responses such as occur in LN patients with nephrotic syndrome.
Cell-mediated immunity (CMI) was studied in 28 patients with biopsy-proven lipoid nephrosis (LN). The LN patients with nephrotic syndrome (NS) had a significant depression in CMI, characterized by impaired delayed hypersensitivity skin reactivity to purified protein derivative (PPD), depressed local graft-versus-host reaction (GVHR), decreased proportion of T lymphocytes and diminished lymphocyte transformation to phytohemagglutinin (PHA). Concanavalin A (Con A)-induced suppressor cell activity (SCA) was found to be significantly increased in LN patients with NS compared to that in normal individuals. In contrast, the mean levels of CMI and SCA studied in LN patients in remission and in patients with chronic mesangial proliferative glomerulonephritis (CGN) did not differ from normal subjects. Our findings support the notion that at least in some LN patients with the NS, activated suppressor cells are present and possibly account for their decreased CMI.
Children with lipoid nephrosis were studies during clinical relapse and after complete remission. As expected, the calculated serum oncotic pressure was reduced severely from the remission value of 28.6 +/- 0.9 mm Hg to 15.4 +/- 1.1 (P less than 0.005) during relapse. Although no apparent change in plasma volume was noted using the volume of distribution of labeled human albumin, calculated plasma volume was reduced 13 +/- 8% during relapse when estimated from changes in hematocrit. After a water load, the ability to excrete water was markedly blunted during relapse. The clearance of solute-free water (CH2O) was 0.9 +/- 0.8 ml/min during relapse, compared with 3.6 +/- 0.6 ml/min during remission (P less than 0.005). In addition, there was a reduced maximal urinary concentrating ability during relapse in four of the six patients examined. Mean urine osmolality for the group during relapse was 778 +/- 82 mOsm/kgH2O and 991 +/- 71 during remission (P less than 0.05). The demonstrated alteration in nephron function during relapse of nephrotic syndrome could result from either (1) a decrease in the amount of sodium delivered to the ascending limb of the loop of Henle because of increased proximal reabsorption or (2) a change in the intrinsic characteristics for sodium reabsorption in that segment. Although this observation does not prove that proximal reabsorption is increased, it suggests a common underlying mechanism for altered nephron function in all of the major edema-forming conditions.
Lipoid proteinosis (LP) is an autosomal recessive disease that typically presents with papular, verrucous, poxlike, or acneiform scars and lesions and hoarseness. LP was recently mapped to the 1q21 locus and shown to result from mutations in the extracellular matrix protein 1 gene (ECM1). Epilepsy, mental retardation, and hippocampal calcifications can occur. The authors describe a patient with generalized dystonia caused by striatal calcifications.
Lipoid proteinosis is a rare disease that presents with hyaline deposits in many tissues. It involves predominantly the skin and upper aerodigestive tract, presenting with small yellowish papules and hoarseness. It may involve the central nervous system and cause intracerebral calcifications. Laryngeal lesions may resemble singer's nodule or chronic laryngitis. The pathogenesis of the disease is not clear although several studies suggest a defective collagen production and/or lysosomal storage disease. In this article two cases with skin and larynx involvement are reported.
Two cases of lipoid proteinosis, in which biopsies of the vocal cords were done, are presented. The condition is briefly discussed.
Two sisters, aged 16 and 11, presented with skin lesions and hoarseness since early childhood. Skin lesions consisted of infiltrated warty nodules, and papules over elbows, axillae, and hands. The oral mucosa, tongue, lips, larynx, and vocal cords also showed infiltration. The characteristic beaded papules on eyelid margin and hoarseness pointed to the rare diagnosis of lipoid proteinosis.
Lipoid nephrosis or idiopathic nephrotic syndrome, the most frequent glomerular disease in childhood, is defined by the association of a nephrotic syndrome and minimal changes on renal biopsy or unspecific lesions such as focal and segmental glomerular sclerosis or diffuse mesangial proliferation. Several complications related to the nephrotic syndrome may occur: infections particularly bacterial infections, thrombo-embolic accidents, hypovolemia with shock. Other complications are secondary to the treatment: steroid therapy, immunosuppressants. The outcome is related to the response to steroid therapy. In case of steroid responsiveness, the risk is the relapse when the steroid dosage is tapered or stopped and the complications related to the treatment which is given to maintain remission. In case of steroid resistance, the risk is that of progression to renal failure which occurs in approximately 50% of patients after 5 years. Moreover, the nephrotic syndrome may recur after renal transplantation.
A 12-year-old male child born of non-consanguineous parents presented with multiple skin lesions, hoarseness of voice, and episodes of epilepsy since early childhood. The findings of characteristic beaded eyelid margins, patchy alopecia of the scalp, hoarseness of voice, and epilepsy were consistent with a rare clinical diagnosis, lipoid proteinosis. Skin biopsies obtained from representative skin lesions were subjected to histology and electron microscopy. Light microscopy demonstrated PAS-positive diastase-resistant material in the papillary dermis of skin. Ultrastructure revealed granulo-filamentary aspect of the accumulated material. Although this rare autosomal recessive disorder has been described in the literature, its occurrence is rare in India.
Lipoid nephrosis was identified by light, immunofluorescence and electron microscopy in 34 children aged 1 month to 10 years (23 males). These patients were followed up for a mean of 6.8 years (range 2.2 to 14 years). Treatment included oral prednisone (2 mg.kg.day for 4 weeks and then four days a week for 2 months). In steroid dependent or resistant patients oral cyclophosphamide 2.5 mg.kg.day was given for 2 months. Satisfactory responses to steroid therapy were recorded in 73.5% steroid dependence in 23.5% and steroid resistance in 3% of cases respectively. As a whole, 97% of patients responded before 8 week to steroids, cyclophosphamide or both. No morphologic differences were recorded from kidney biopsies among corticoid responders, dependents or resistants, neither between first and second biopsies which were done in four steroid dependent and one steroid resistant children. Slight morphologic differences were observed depending on the time elapsed from initial symptoms to renal biopsy: 39 days (means) when total disappearance of foot processes was seen (5 cases); 11 month (means) in 14 cases with partial pedicular absence and 20 months (means) in 15 children with segmental pedicular absence alternating with zones of normal foot process morphology. The total number of nephrotic episodes was 149, with a mean of 4.3 recurrences per patient, including three children (all girls) whose disease never recurred. Serious infections were detected in 4.7% of recurring episodes. At 5 years follow up 94% of patients were in remission. No deaths occurred among these patients.