Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive and relapsing immune-mediated inflammation characterized by peripheral muscle weakness and sensory impairment (17). CIDP has multiple subtypes, one of which is associated with MGUS, in which monoclonal IgM antibodies are directed against myelin-associated glycoprotein (MAG) in around half of the patients leading to demyelination of distal large sensorimotor fibers (17). In a population-based study of 17,398 Minnesota residents (603 with MGUS and 16,793 controls), individuals with MGUS were shown to have a six-fold increased risk of CIDP compared to the general population (18). The typical picture of nerve biopsy includes the widening of the myelin lamellae as well as IgM and C3d deposits on myelin sheaths (18, 19). The primary treatment options for MG-associated CIPD involve plasmapheresis (19, 20), IVIG (21, 22), and steroids alone (23–25) or in combination with cyclophosphamide (19, 20, 25) ( Table 2 ). Patients with slow progression and minimal symptoms may not require any intervention (19, 27). Interestingly, CIDP-MGUS is more responsive to plasma exchange (reaching on average 74%) compared to other types of CIDP, such as sensory, multifocal, or diabetes-associated (26). The cumulative efficacy of IVIG across studies is around 60% but ranges from 33% to 76%, likely attributable to other patient characteristics, such as disease severity or the origin of neuropathy (e.g., diabetes) (21–23, 27). Similarly, the success of plasma exchange (average response rate of 74%) and steroids (average response rate of 60%) in clinical improvements may also vary substantially from case to case (20, 38–40). Plasmapheresis can be effective in combination with chemotherapy or immunosuppression (20). The combination of cyclophosphamide with steroids gives a 55% response rate on average (19, 25). Adjunction of immunosuppressant (azathioprine, mycophenolate-mofetil, cyclosporin A) or immunomodulatory (lenalidomide) drugs may be warranted in treatment-resistant situations, but the data in this area is very limited (20, 24, 38–41). A case report on severe CIDP-MGUS showed a sustainable improvement with rituximab (42).

A slightly distinct peripheral nervous system disorder associated with MGUS is distal, acquired, demyelinating, symmetric neuropathy with M protein (DADS-M), which occurs in older males affecting large sensory nerve fibers, resulting in sensory ataxia and diminished sensory response, and motor neurons with decreased motor conduction velocity and prolonged distal latencies (43). Muscles of the face, proximal limbs and trunk are usually intact (44). This syndrome is distinct from the classical DADS by the clinical picture and pathogenesis, which is recognized as a subtype of CIDP. Nonetheless, the treatment, which is largely similar to the one described for CIDP with comparably worse outcomes overall, is based primarily on the severity of neurological symptoms, rather than on the levels of IgM. Moreover, the detection of anti-MAG, which is present in about 50-70% of patients (44, 45), takes a decisive role in the choice of therapy as it is mostly resistant to standard treatment options (28, 41), such as IVIG, plasmapheresis, or systemic glucocorticoids (44, 45). Second-line treatment includes rituximab, lenalidomide, carfilzomib, or cyclophosphamide, the data on which is however limited (40).

Another complex syndrome observed in patients with MGUS is chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD). The proposed pathophysiology of CANOMAD involves IgM-mediated autoantibodies against gangliosides with disialosyl groups affecting sensory, ocular, and bulbar nerves leading to gait problems, muscle weakness, and paresthesia (28, 29). The disease is progressive in its nature with possible chronic relapses (28). Several effective treatment options exist based on data from case reports and series, with the most supported being IVIG (46–48) and rituximab-based strategies (46, 47, 49, 50). A French multicenter retrospective study of 45 patients with CANOMAD found 53% and 52% clinical response with IVIG and rituximab, respectively, while immunosuppressants were not shown to be particularly beneficial (28). These findings were supported by an earlier series of 11 cases (29), although some case reports claimed the efficacy of steroids (51, 52).

Sporadic late-onset nemaline myopathy (SLOMN) is characterized by subacute and progressive muscular weakness, pain, and atrophy involving myofibers of the proximal limbs, neck, and face (36). Clinical presentation typically includes head drop, dysphagia, dysarthria, nemaline bodies in the cytoplasm, heart failure, and severe respiratory insufficiency leading to death within a few years of onset (32, 35, 36). It occurs in middle-aged men and women with more than half of patients having MGUS (34, 35). The exact mechanism and etiology of SLOMN are unclear. For the first-line treatment of SLOMN autologous hematopoietic cell therapy (AHCT) following high-dose melphalan should be considered, which demonstrated high rates of favorable response with hematologic and muscular improvements with over half of patients having positive long-term outcomes (33, 35, 37, 53). Chemotherapy directed against MM (lenalidomide with dexamethasone, rituximab with cyclophosphamide, or bortezomib with cyclophosphamide and dexamethasone) for patients not suitable for AHCT was shown to lead to some positive outcomes, such as disease stabilization and improved muscular performance (33, 53). IVIG is another alternative with comparably modest efficacy (35, 36, 53). Plasmapheresis is only partially effective, whereas steroids and other immunosuppressive therapies showed not promising outcomes for patients with SLOMN (30, 32, 36, 37, 54).

Schnitzler syndrome is a rare systemic late onset autoinflammatory disease characterized by periodic fever, urticarial rash (neutrophilic urticarial dermatosis), bone pain with osteosclerotic changes, myalgia, lymphadenopathy, and arthralgia, as well as immunoproliferative disorders, such as B-cell lymphoma or MGUS (primarily IgM with kappa component). The disease mainly affects middle-aged adults of all ethnic groups and both sexes (76). Complications include lymphoproliferative disorder and AA amyloidosis, if left treated (76, 77). Schnitzler syndrome is thought to be a result of abnormal activation of the innate immune system with aberrant functioning of cytokines (77). Data from individual cases and clinical trials indicate that the most effective treatment option to date is anakinra (100 mg), the IL-1 receptor antagonist, which targets the key pathogenic mechanism of this disease and leads to complete remission in over 80% of patients (72, 74, 75, 78–82). Other therapies blocking IL-1 include rilonacept (IL-1 inhibitor) and canakinumab (IL-1 beta inhibitor), both of which demonstrated substantial clinical efficacy (83, 84). Second-line therapies, used previously before the introduction of anti-IL-1 treatment, include systemic glucocorticoids, NSAIDs, antihistamines, immunosuppressants, biologics, antimetabolites, showing limited efficacy and unfavorable safety profile overall (72, 73, 80, 81, 85–87). Emerging data also suggests promising use of Bruton tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) as a mode of anti-clonal therapy (88).

Scleromyxedema is a rare cutaneous mucinosis with some systemic manifestations in association with MG. It usually occurs in middle-aged adults and is characterized by a generalized papular rash with sclerosis, which is the result of fibrosis and mucin deposition (70, 71). Multiorgan involvement (e.g., cardiac, digestive, lung, kidney, musculoskeletal and nervous systems) is the main cause of high morbidity and mortality (71). The etiology and pathogenesis of scleromyxedema are not fully clear but include fibroblast proliferation which might be stimulated by cytokine dysregulation and paraproteins (89). MGUS mostly involves IgG with lambda light chain (90). Based on case series and observational studies, the preferred treatment usually includes IVIG with systemic glucocorticoids, and immunomodulatory drugs (thalidomide or lenalidomide) being a second-line choice. High-dose IVIG (2g per kg given over 5 consecutive days every 4-6 weeks) has been shown to result in clinical remission of the disease for non-severe forms of scleromyxedema (i.e., without cardiac or CNS involvement) (71). The majority of the patients reach at least partial response after 4-6 cycles of this treatment, although improvements might be already visible after just the first two cycles as well (70). Remission may last from a few months to several years; therefore, maintenance therapy (every six to twelve weeks) is often warranted. For severe cases (i.e., refractory to high-dose IVIg or with cardiac and CNS involvement), anti-plasma cell therapies should be advocated.

Alternative therapies include thalidomide or lenalidomide, which are combined with IVIG or used in patients that cannot receive the latter one. Thalidomide. given at a dose of 50-100mg/day and further increased to 200-400mg/day, was shown to lead to improvements in skin lesions and paraprotein concentrations, as well as amelioration of some clinical symptoms within several months to a few years (91–93). Thalidomide adjunction to IVIG may also potentiate the therapeutic effects in complex cases (94). The limitations of the treatment include side effects (peripheral neuropathy) and the length of therapy required until clinical results are seen. Lenalidomide (10-25mg/day for days 1–21 of a 28-day cycle) has a better safety profile but has been tested only in combination with dexamethasone and IVIG (70, 95).

Systemic glucocorticoids (prednisone at 0.5-1 mg/kg per day, prednisolone at 0.3-0.5 mg/kg per day, or oral dexamethasone at 40 mg/day) are another option when the initial therapy has failed. They can be applied either alone or in combination with IVG or thalidomide. The mixed efficacy is based on the data from the case series showing regression of skin manifestations (69), although treatment failure has also been reported (70, 71).

Bortezomib (1.3 mg/m², on days 1, 4, 8, and 11 every 21 days) in combination with 40 mg dexamethasone has been reported in severe and refractory cases with some success (96, 97) as well as in dermato-neuro syndrome, which is an acute and potentially fatal neurological complication (98). Successful addition of thalidomide to this regimen was also described (99).

Melphalan, a chemotherapeutic agent, has been previously widely used for scleromyxedema but was later abandoned due to severe adverse events, such as sepsis or secondary hematological malignancy (100). Currently, it may be combined with other therapies, such as IVIG, AHCT, or glucocorticoids (68, 100, 101).

Several case reports described high dose melphalan followed by AHCT in selective patients to result in partial remission of systemic manifestations of scleromyxedema (68, 102, 103). Similarly, plasmapheresis has been described to be used in severe and acute cases of scleromyxedema with some efficacy (70).

A myriad of other therapeutic options tried for the treatment of scleromyxedema included retinoids (acitretin and oral isotretinoin) (71, 104), immunosuppressants (mycophenolate mofetil, cyclosporine) (105, 106), and biologics (TNF-alpha inhibitors, interferon-alfa) (107, 108), and chemotherapeutics (methotrexate, cyclophosphamide) (109, 110). The efficacy of these options needs to be further investigated.

Necrobiotic xanthogranuloma (NXG) is another idiopathic cutaneous pathology associated with paraproteinemia observed in older adults with a mean age of 62 years (111). Classically, it is described as a non–Langerhans cell histiocytosis manifested with papules, plaques, or nodules of various colors most commonly on the periorbital skin, although other regions of the body can also be affected (66). Systemic lesions with ocular, gastrointestinal, cardiac, and respiratory involvement may also occur (65). It has been estimated that 82% of the patients with NXG present with MG, with IgG-kappa being the most common subtype followed by IgG-lambda, IgG-kappa, IgA, and IgM (111).

The optimal treatment of NXG is still unclear providing undefined pathogenesis of the disease. Chemotherapy is reasonable for patients with underlying malignancy (e.g., multiple myeloma or chronic lymphocytic leukemia). Alkylating agents, such as chlorambucil (2-4mg/day) or melphalan (10mg), alone or in combination with other systemic therapies, were shown to result in cutaneous lesion improvements and lesser normalization in paraproteinemia in retrospective observational studies and case reports (65, 67, 112–114). Severe adverse events however limit the applicability of both drugs. Alternatively, oral cyclophosphamide (1 mg/kg per day for six months) can be used alone or in combination with steroids (112, 115, 116). Similarly, bortezomib alone or combined with steroids and/or lenalidomide/thalidomide is another choice for patients for whom chemotherapy is an option as it may lead to improved skin disease (66, 67). Successful application of IVIG inducing a complete or partial clinical response was described in several reports (66, 111, 117). Systemic glucocorticoids (pulsed dexamethasone or prednisone) were associated with symptomatic regression of NXG in a series of cases (65, 118). Some limited data also exist on benefits from the treatment with thalidomide and lenalidomide, including remission of skin lesions and decrease in gammopathy (65, 119, 120). Plasmapheresis or AHCT should be reserved for refractory cases (65, 121). Patients with more localized scenarios may benefit from topical or intralesional preparations, such as immunomodulators or steroids, as well as ultraviolet or radiotherapy (122–125). Surgery is an important component of the management of these patients both from cosmetic and functional point of view (126, 127). Other potential therapy options may include dapsone (128), antimalarials (111), and biologics (125, 129, 130).

Xanthomatosis is a skin manifestation (cholesterol depositions) of a disturbance in lipid metabolism with or without hyperlipidemia. The condition is often associated with MGUS of IgG lambda or IgG kappa chains (131–134). Data on the treatment of xanthomatosis is lacking, but one report showed regression of xanthomas with probucol combined with topical steroid and oral antihistamines (132). However, others failed to demonstrate any benefits with cholestyramine, gemfibrozil (131), or steroids (67, 124). Chemotherapy for underlying hematological malignancy led to positive outcomes in some patients but did not show results in others (131, 133).

TEMPI syndrome (Telangiectasias, Erythrocytosis and Erythropoetininemia, Monoclonal Gammopathy, Periphiric fluid accumulation, Intrapulmonary shunting) is a very rare, acquired disease manifested in middle-aged men and women across all ethnicities around the world (135, 136). The disorder has no definitive identified genetic component and is not fully clear in its pathogenesis (although the role of macrophage migration inhibitory factor (MIF) was suggested in the development of disease) (137), and MGUS, seen in all reported patients, is not restricted to any specific type, unlike in other conditions described here (135, 136). As of 2022, there have been a little more than 30 cases reported worldwide (135–147). Therefore, the treatment options are based on individual data only. To date, bortezomib is the most frequently tested treatment revealing mostly positive outcomes in several reports (135, 138–142). Treatment with daratumumab (anti-CD38 monoclonal antibody) was shown to elicit a complete symptomatic remission in two patients (143), but did not help in the management of another individual (144). AHCT was also described and resulted in complete hematological remission in one patient but was unsuccessful in two other cases (138, 145, 146). Similarly, lenalidomide was also attempted with ambiguous clinical results (143, 147).

Acquired cutis laxa is a rare form of connective tissue disorder manifested by loose and inelastic skin due to the degradation of cutaneous elastic fibers. Patients of different ages usually present with “premature aging skin”, which has multiple wrinkled lesions (148). It has been often associated with systemic and cutaneous inflammatory conditions, drug exposure, as well as hematological malignancies and MG, which primarily contains IgG lambda or kappa light chains (58, 148–152). Treatment of acquired cutis laxa is targeted at associated hematological or systemic diseases as no specific options (aside from reconstructive surgery or laser tightening) exist for that condition (148, 149). It is also believed that the management of related disorders will lead to dermatological improvement (58, 150–152); however, this hypothesis has not been proven yet.

Neutrophilic dermatosis is a diverse group of skin disorders characterized by severe infiltrations involving different cutaneous layers and manifests as ulcerations, pustules, ulcers, or nodules (153–155). Although neutrophilic dermatosis is often associated with inflammatory conditions and extracutaneous involvement, the disease itself is not mediated by infections or vasculitis (154). The exact mechanisms of pathologies are not well understood, and histopathology varies from type to type (154, 155). Despite evolving evidence suggesting the role of myeloid dysfunction in neutrophilic dermatosis, some forms of the disease have been associated with MGUS, including pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, Sweet’s syndrome, and neutrophilic urticarial dermatosis (153–156). Treatment varies depending on the type of neutrophilic dermatosis. MGUS mostly relates to IgA and rare IgG with kappa or lambda bounds (153–168).

For pyoderma gangrenosum, which is characterized by bullous or pustular painful ulcers, wound management is the key treatment component with application of topical corticosteroids and local calcineurin inhibitors for localized disease (162). Systemic glucocorticoids or cyclosporine are usually considered for more advanced cases (163, 164). In patients with concomitant MG, systemic glucocorticoids and dapsone (with or without minocycline) have been the most commonly used options with mixed results (153, 158). Bortezomib–dexamethasone regimen led to resolution of lesions in one report (161). Other potential options described in the literature include colchicine, splenectomy, thalidomide, cyclophosphamide, clofazimine, methotrexate, IVIG, and azathioprine, the efficacy of which is yet to be determined (153).

Subcorneal pustular dermatosis (also known as Sneddon-Wilkinson disease) is defined by annular flaccid pustules localized to the axial and inguinal regions (165). Standard therapy involves dapsone, systemic glucocorticoids, or phototherapy (166). Acitretin (25 mg/day or higher) was described in several patients with concurrent gammopathy to lead to the resolution of lesions (153, 157, 159, 163). The potential use of biologic agents (infliximab, etanercept, and adalimumab) was also described in another case report (160).

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is a systemic inflammatory condition characterized by widespread erythematous papules or plaques with neutrophilic infiltrates as well as arthritis, fever, and neutrophilia. It is classified as idiopathic, drug-induced or malignancy-associated (167). Traditionally, systemic, topical, or intralesional glucocorticoids are the first-line treatment choice (168). Alternative options include colchicine, dapsone (168). The presence of monoclonal gammopathy seems to not alter the treatment approach in these patients (153).

Neutrophilic urticarial dermatosis is a chronic and recurrent condition with erythematous macules and plaques on extremities and trunk usually resolving in 24-48 hours after eruptions without any residual lesions (169). Aside from being a pathologic hallmark of Schnitzler syndrome, it is commonly associated with adult-onset Still’s disease, lupus erythematosus, and cryopyrin-associated periodic syndromes (169). Dapsone, colchicine, topical steroids, and anakinra are linked to clinical improvements (153, 155, 170).

Clarkson disease or systemic capillary leak syndrome, first described in 1960, is characterized by sporadic and recurrent episodes of hypovolemic shock and anasarca, which are caused by widespread leakage of plasma and proteins into the extravascular compartment of various tissues and subsequent hypoalbuminemia and hemoconcentration (171, 172). Complications include pulmonary edema, compartment syndrome, and ischemic damage of organs (64, 173). MGUS seen in a majority of patients is IgG kappa or lambda light chains (63, 64). Despite the potential pathologic role of elevated levels of vascular permeability factors (174), the exact etiology is unknown, and the severity of the clinical manifestations varies from case to case (63). Judicious fluid resuscitation and hemodynamic support with the aim to restore the perfusion but at the same time avoid potential complications (e.g., pulmonary edema and compartment syndrome) are key for the management of acute episodes of hypovolemic shock (175, 176). A number of reports described successful application of high-dose IVIG (2g/kg) as a prophylactic measure and long-term treatment leading to a decrease in severity and frequency of attacks (63, 175). Terbutaline with aminophylline or theophylline was reported in several patients with variable efficacy for the prevention of subsequent episodes (173, 175–178). In a study of 69 patients with Clarkson disease, treatment with IVIG was associated with lower mortality and fewer recurrence rate compared to terbutaline in a median follow-up of 5 years (63). Limited data also exist regarding treatment with bevacizumab, infliximab, verapamil, thalidomide, leukotriene inhibitors, and glucocorticoids (64, 176, 179–181).

Paraproteinemic keratopathy (also known as keratopathy of monoclonal gammopathy or immunotactoid keratopathy) is caused by bilateral corneal depositions of immunoglobulins mostly of IgG-kappa origin causing distinct opacities and potentially leading to tissue dystrophy with gradual visual acuity loss (183, 193–196). The depositions can be in the form of crystals (called crystalline keratopathy) or non-crystalline (peripheral bands/patches/granules, or lattice) (183, 195, 197). In some cases, immunoglobulin-bound copper depositions (reminding Kayser-Fleischer rings of Wilson disease) can also be seen (198, 199). Therapy consisting of MG-specific treatment and reconstructive surgery depends on the severity of ocular involvement. In some cases, the disease might be asymptomatic requiring no intervention but continuous monitoring of MGUS and visual function (197). In more severe cases of ocular involvement and MGUS progression, chemotherapy and/or AHCT aiming at hematological correction can resolve symptoms and stop the disease progression (186, 200). Keratoplasty or corneal transplantation usually carries a short-term benefit for visual repair as high rates of recurrences have been reported (201–204), while topical agents (steroids and tacrolimus) were not shown to be effective (205).

A much rarer manifestation of ophthalmologic injury in MGUS is maculopathy with the possibility of unilateral or bilateral retinal detachment and subsequent visual loss (206). Clinical presentation may include inflammation of the iris and vitreous body as well as macular detachment (207). Besides immunoglobulin depositions, paraproteins acting as autoantibodies against macula were proposed as potential pathogenesis, however, the exact mechanism of maculopathy in MGUS is unknown (207). Due to a low number of reports, optimal treatment is yet to be discovered. Hematologic targeting (chemotherapy, rituximab, plasmapheresis) may lead to clinical resolution (206, 207), whereas ocular surgery, acetazolamide or eplerenone, and topical agents (glucocorticoids, triamcinolone, dorzolamide, anti-vascular endothelial growth factors) are not always effective with only short-term symptomatic correction of visual function (208, 209).

Acquired C1 inhibitor deficiency, also known as acquired angioedema, is a rare disease manifested with recurrent episodes of angioedema of the skin and mucosa of gastrointestinal and upper respiratory tracts (210). Pathogenesis involves autoantibodies against C1 inhibitor, involvement of bradykinin and cytokines, as well as abnormal activity of the classical complement pathway by neoplastic tissue (211). Clinical presentation is identical to hereditary angioedema with the difference that patients with acquired C1 inhibitor deficiency are older (≥40 years of age) with no family history and usually have associated diseases (in 70-85%), including lymphoproliferative disorders, MGUS, and non-Hodgkin lymphoma (NHL), and autoimmune diseases (188, 212). MGUS (without a specific predominant type) has been reported in 30-40% of patients occurring before, at or after the diagnosis of acquired C1 inhibitor deficiency with a low likelihood of progressing into multiple myeloma (188–191). The disease management focuses on acute treatment for angioedema episodes (i.e., C1 inhibitor replacement, fresh frozen plasma, icatibant, or ecallantide), which may prompt intubation in severe cases (188–191, 213). Prophylactic measures for the prevention of episodes include antifibrinolytics (tranexamic acid), corticosteroids, androgens (danazol), or regular use of C1 concentrate (188, 212, 214). Management of associated diseases can also be of significant clinical benefit (191, 212). Rituximab was reported to be effective in two reports, leading to symptomatic relief in eight out of eleven patients in total (187, 206) ( Table 4 ).

Acquired von Willebrand disease (aVWD) is the less common type of VWD due to an underlying medical disorder affecting von Willebrand Factor (VWF) (215). It corresponds to only 1-5% of all cases with a similar clinical and laboratory presentation also seen in the inherited type of VWD (i.e., spontaneous major and minor bleeding) (215). This disease has been associated with a number of conditions, including cardiovascular disease (216), Wilms tumor in children (217), hypothyroidism (218), autoimmune disorders (219), drug use (220), and hematological malignancies, such as myeloproliferative neoplasms and lymphoproliferative disorders (221), the latter nearly always having an underlying MGUS (192). The prevailing majority have IgG with only a small proportion carrying IgM paraprotein (192, 222). Clinical management of aVWD is similar to the inherited form and the presence of monoclonal gammopathy does not substantially affect the treatment strategy. Correction of bleeding is the main approach, for which desmopressin (DDAVP), factor-replacing therapy with concentrates of VWF/recombinant activated factor VII, as well as antifibrinolytic therapy have been used with varying degrees of success (222–225). IVIG (1g/kg/day for two days with 3-week interval repeats) can also lead to positive outcomes and is most reasonable in cases of related autoimmune diseases (222, 225–227), and a recent systematic literature review found an 85% response rate in patients with MGUS (228) Successful combination of concentrates with IVIG were also reported (229). Limited data also exist regarding the applications of lenalidomide (230), rituximab (231), daratumumab (232) and plasmapheresis (233) ( Table 4 ). Clinicians should aim at revealing the underlying condition as its management can alleviate the symptom severity and disease progress.

Crystal-storing histiocytosis (CSH) is a rare condition, in which abnormal immunoglobulins are accumulated in the form of crystals in lysosomes of histiocytes resulting in single-organ or multiorgan damage, involving the kidney, eye, lungs, bone marrow, gastrointestinal tract, or spleen (234). The disease is thus categorized as an Ig deposition disease along with other pathologies caused by MGUS (primarily IgG with kappa light chain) (234–239). Treatment is based on the underlying condition as well as the severity and progression of the clinical picture. Careful monitoring is optimal for limited pathological lesions (234). In more severe circumstances, different chemotherapeutic regimens (bortezomib-based, daratumumab-based, or R-CHOP) led to considerable clinical improvements in case reports (236–239). AHCT was successful in a complex of ocular and periorbital crystal-storing histiocytosis with Fanconi syndrome (200) ( Table 4 ).