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Revision as of 19:19, 10 February 2019

Overview

POEMS syndrome must be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.

Differentiating POEMS Syndrome From Other Diseases

The table below summarizes how to differentiate POEMS syndrome from other conditions that have a similar presentation:^[1]^[2]^[3]^[4]^[5]^[6]^[7]

Organ System Involvement		Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
P = Polyneuropathy		POEMS syndrome (Demyelinating)	Monoclonal plasma cell proliferation Cytokine storm (IL-1, IL-6, IL-12, TNF alpha, VEGF)	Symmetrical, ascending chronic progressive polyneuropathy with both sensory (pin-prick and vibration) and motor disability (motor > sensory) Generalized/extermity pain Areflexia	Increased number of thrombocytes^[8]^[9]^[10] Increased number of erythrocytes^[8]^[9]^[10] Elevated cerebrospinal fluid (CSF) protein content^[9] Increased number of leukocytes^[10] High levels of IgG lambda or IgA lambda M-protein in the serum^[10] Increased number of plasma cells in the bone marrow^[10] Increased serum VEGF level^[11] Elevated levels of antitiroglobulin antibody and antithyroid peroxydase antibody^[12]	International Myeloma Working Group (IMWG) clinical and laboratory diagnostic criteria
		Metabolic Syndrome (Axonal pathology)	Diabetes mellitus	Symmetric sensorimotor polyneuropathy Autonomic neuropathy "Glove and stocking" type pain Muscle wasting Hammer toes Polyuria Polydipsia	Uncontrolled hyperglycemia Slowed nerve conduction Small fiber dysfunction	Fasting blood sugar level greater than equal to 126 mg/dl on 2 separate ocassions	Anti-diabetic therapy Gabapentin Carbamazepine Foot care
		Vitamin Deficiencies (Axonal Pathology)	Vitamin B12 deficiency (Decreased S-adenosyl methionine) Vitamin B1 deficiency	Primarily sensory deficiets Vibration and proprioception affected Gait abnormalities Cognitive impairment Irritability Glossitis	Anemia (megalosblastic in case of B12 deficiency) Decreased serum Vitamin B12 levels (< 200 pg/ml) Elevated methymalonic acid	Serum Vitamin B12 levels	Vitamin B12 supplement
		Guillain-Barre Syndrome (Demyelinating)^[13]	Anti-ganglioside and anti-myelin antibodies^[14] Viral infections:^[15] Epstein Barr virus HIV Cytomegalovirus Varicella Zoster virus Bacterial infections:^[16] Campylobacter infection Mycoplasma pneumoniae	Rapid onset and quick progression Progression stops after 2-3 weeks Bilateral ascending paraesthesias and paralysis (generalized) Weakness Ataxia Areflexia No fever 4 sub-types: Acute inflammatory demyelinating polyneuropathy Acute motor axonal neuropathy Acute motor and sensory axonal neuropathy Miller Fisher syndrome	Delayed F waves^[17]	Clinical diagnostic criteria (progressive weakness of more than two limbs, areflexia, and progression for no more than four weeks)^[18]	Intravenous immunoglobulins^[19] Plasma exchange^[20] Respiratory support DVT/PE prevention
		Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (Mixed axonal and demyelinatiing)^[21]^[22]	Abnormal immune (both IgG based humoral and T-Cell mediated) response to unknown antigen (possible culprits include myelin proteins P0, P2 and PMP22)^[23]^[24]^[25]	Slow onset and gradual progression Relapsing and remitting course Symmetrical proximal and distal motor and sensory weakness (legs>arms) Foot drop Numbness, tingling and pain Areflexia	Elevated CSF protein (oligoclonal bands with normal WBCs)^[26] Slowed motor nerve conduction velocities^[27] Prolonged distal motor latencies (period between F wave and initial stimulation) Delayed F wave latencies (recorded from the feet, hence called "F" waves)^[28] MRI contrast enhancement and enlargement of T2 spinal segments^[29]	EFNS/PNS criteria^[30] Koski criteria^[31]	Corticosteroids Intravenous immunoglobulin (IVIG) Imuunosupressants (Alemtuzemab Azathioprine Cyclophosphamide Cyclosporin Etanercept Interferon-alpha)
		Multifocal Motor Neuropathy^[32]	Abnormal immune response (Anti ganglioside GM-1 IgM antibodies)	Progressive, asymmetric, distal and upper limb predominant weakness No significant sensory abnormalities Areflexia	Elevated CSF protein	Clinical criteria (EFNS/PNS):^[33] Slowly progressive or stepwise progressive, focal, asymmetric limb weakness; i.e., motor involvement in the motor nerve distribution of at least two nerves for > 1 month. No objective sensory abnormalities except for minor vibration sense abnormalities in the lower limbs	Intravenous immunoglobilins Cyclophosphamide Rituximab
Organ System Involvement		Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
O = Organomegaly (Hepatosplenomegaly and Lymphadenopathy)		Malaria	Plasmodium falciparum P. ovale P. malariae P. knowlesi	Tertian (vivax, ovale, falciparum), quartan (malariae), quotidian fever (knowlesi) Vector is female Anopheles mosquito Hepatosplenomegaly Lymphadenopathy Jaundice Icterus Tachycardia Tachypnea Productive cough Hemeturia Altered mental status	Microcytic anemia Thick and thin blood films (Giemsa staining) Rapid diagnostic test (antigen detection Polymerase chain reaction (PCR) Enzyme linked immunosorbent assay (ELISA)	Thick and thin films	Non-falciparum species: Choloroquine (in susceptible) Artemisinin plus mefloquin or lumefantrine (in chloroquine resistant) Falciparum species: Chloroquine (in susceptible) Artemether plus lumefantrine (in chloroquin resistant) OR Artesunate plus mefloquin OR Artesunate plus sulfadoxine-pyrimethamine Atovaquone plus proguanil
		Kala-azar	Leshmania donovani L. infantum L. chagasi	Fever Vector is sandfly Hepatosplenomegaly Lymphadenopathy Hyperpigmentation	Anemia Direct Agglutination Test (DAT) rk39 dipstick ELISA	Splenic aspiration	Liposomal amphotericin B Sodium stibogluconate Pentamidine
		Infective Hepatitis	Hepatitis A virus (HAV) HBV HCV HDV (co-infection with HBV) HEV	Fever Transmitted via fecal-oral route (HAV, HBV, HDV, HEV), infected sera (HCV), sexual contact with infected individuals Hepatosplenomegaly (may become shrunken in cases of cirrhosis due to chronic infection) Lymphadenopathy Jaundice Palmar erythema Spider angiomata Gynecomastia Arthritis-dermatitis syndrome	Antigen and antibody detection Total and direct bilirubin (increased) Severe disease is often associated with persistent bilirubin levels >340 mol/L ALT and AST (increased) Alkaline phosphatase (normal or mildly elevated) Prothrombin time (prolonged from synthetic defect, caused by hepatocellular necrosis) Total protein (decreased) Globulin (mildly elevated) Initial lymphopenia and neutropenia, followed by relative lymphocytosis Low hemoglobin	Antigen and antibody detection	Interferon (IFN) Nucleoside analogs Nucleotide analogs
		Chronic Myelogenous Leukemia (CML)^[34]^[35]^[36]^[37]^[38]^[39]^[40]^[41]^[42]^[41]	BCR/ABL gene fusion product due to translocation mutation t(9;22)(q34;q11)^[43]	Fever Weight loss Hepatosplenomegaly Lymphadenopathy Bruises Petechiae Ulcers Vesicles Malaise Early satiety	Anemia Leukocytosis (median of 100,000/µL) with a left shift Thrombocytosis Blasts usually <2% Absolute basophilia Absolute eosinophilia Monocytosis Thrombocytosis Thrombocytopenia suggests an alternative diagnosis or the presence of advanced stage Elevated uric acid Elevated histamine levels	Flouroscent insitu hybridization (FISH)	Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Cytarabine HDAC (high-dose cytarabine) Hydroxyurea Busulfan Busulfex Stem cell transplantation
		Lymphoma	Various causes based on type: Hodgkin's Non-Hodgkin's	Fever Weight loss Lymphadenopathy Hepatosplenomegaly Night sweats, constant fatigue Purplish scaly rash in cases of cutaneous lymphoma	Elevated ESR Increased CRP Increased LDH Anemia of chronic disease	Lymph node biopsy
		Primary (AL) Amyloidosis^[44]^[45]	Aggregation and deposition of immunoglobulin light chains that usually produced by plasma cell clones^[46]^[47]	Nephrotic syndrome (peripheral edema Restrictive cardiomyopathy (fatigue, dyspnea, syncope) Peripheral neuropathy (numbness, tingling) Hepatomegaly with elevated liver enzymes Macroglossia Purpura Bleeding diathesis	Typical green birefringence under polarized light after Congo red staining (appears in red under normal light)	Congo red staining	Melphalan-prednisone/dexamethasone^[48] Dexamethasone plus Cyclophosphamide-thalidomide ^[49] Stem cell transplantation^[50]
		Gaucher's Disease	GBA gene mutation Aberrant metabolism of glucocerebroside (lipid)	Hydrops fetalis Dry, scaly skin (ichthyosis) or other skin abnormalities Hepatosplenomegaly Distinctive facial features Neurological problems Gall stones Growth retardation	Hypocholesterolemia Splenic nodules Cytopenias (especially thrombocytopenia) Increased ferritin levels Increased tartarate resistant acid phosphatase (TRAP) levels	Enzyme assay for glucocerebrosidase DNA analysis for GBA mutation	Enzyme replacement Splenectomy Blood transfusion
Organ System Involvement		Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
E = Endocrinopathy (Hypogonadism, Hypothyroidism, Hypopituitarism)	Hypogonadism	Primary Hypogonadism (Hypergonadotrophic)	Klinefelter's syndrome Myotonic dystrophy Sertoli-cell tumor Enzymatic defects Viral orchitis (mumps) Cryptorchidism Polyglandular autoimmune syndrome Testicular trauma and tumors Polycystic ovarian syndrome	Fatigue Decreased libido Delayed secondary sexual characteristics: Absent/scant pubic hair Impotence Erectile dysfunction Amenorrhea Delayed breast development Small testicular size Decreased muscle mass Osteoporosis Depression Infertility Irritability Mood swings Pot belly Weight gain	Decreased sex hormone levels: Decreased testosterone Decreased dihydrotestosterone Decreased estrogen Increased gonadrotrpins: Increased LH Increased FSH	Serum sex hormone levels	Hormone replacement therapy
		Secondary Hypogonadism (Hypogonadotrophic)	Panhypopituitarism Hyperprolactinemia Isolated gonadotropin deficiency Kallman's syndrome Congenital Prader-Willi syndrome Hemochromatosis Massive obesity Malnutrition		Decreased sex hormone levels: Decreased testosterone Decreased dihydrotestosterone Decreased estrogen Decreased gonadrotrpins: Decreased LH Decreased FSH
		Combined Primary and Secondary	Late-onset hypogonadism Hepatic cirrhosis Sickle cell disease
	Hypothyroidism	Primary Hypothyroidism	Congenital hypothyroidism Autoimmune (Hashimoto's) thyroiditis Resistance to TSH
		Secondary Hypothyroidism	Pituitary mass lesions, especially pituitary adenomas Brain cysts and abscesses Meningiomas Dysgerminomas Metastatic tumors Craniopharyngiomas Pituitary apoplexy Sheehan syndrome (postpartum pituitary necrosis) Idiopathic isolated TSH deficiency Lymphocytic or granulomatous hypophysitis
		Tertiary Hypothyroidism	Hemochromatosis Histiocytosis Developmental abnormalities Internal carotid aneurysms Idiopathic isolated TRH deficiency
	Hypopituitarism
Organ System Involvement		Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
M = M-protein ( Hematological Abnormality/Plasma Cell Dyscrasias)		Multiple myeloma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Diffuse bone pain and tenderness with osteolytic lesions Renal failure Hypercalcemia Anemia			Induction chemotherapy with bortezomib, lenalidomide, and dexamethasone Bisphosphonates RANK ligand inhibitors (denosumab) Autologous stem cell transplantation
		Monoclonal gammopathy of undetermined significance (MGUS)	Chromosomal aberrations or other genetic insults Clonal plasma cell proliferation	Asymptomatic Serum M protein of <30 g/L Fewer than 10% plasma cells in the bone marrow No evidence of bone or organ damage			Observation
		Asymptomatic Plasma Cell Myeloma (Smoldering and Indolent plasma cell myeloma)	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Asymptomatic Serum M protein of >30 g/L Greater than 10% plasma cells in the bone marrow No evidence of bone or organ damage			Observation
		Plasma Cell Leukemia	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells	Renal failure Hypercalcemia Cytopenias No bone lesions			Chemotherapy
		Plasmacytoma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells	Solitary bone plasmacytoma (bone) Extramedullary plasmacytoma (soft tissues) Clinical manifestations related to tumor mass and compression symptoms			Surgery
Bone Lesions		Osteoporosis	Imbalance between bone resorption and bone formation Preceded by osteopenia Decreased bone mineral density	Acute musculoskletal pain if fractures develop Severe decrease in BMD on dual-energy X-ray absorptiometry (DEXA) test T score less than -2.5 on DEXA scan			Calcium and vitamin D supplementation Bisphosphonates Weight-bearing exercise Teriparatide RANK ligand inhibitors (denosumab)
		Osteomalacia	Inadequate mineralization of bone Deficiency of vitamin D calcium, or phosphorus Renal tubular acidosis Malabsorption	Diffuse bone pain, fatigue, and fractures Low bone mineral density (BMD) Hypocalcemia			Vitamin D3 supplementation
		Osteogenesis imperfecta	Mutations in COL1A1 or COL1A2 Impaired type I collagen synthesis	Short stature, scoliosis, and propensity for fractures Blue discoloration of sclera			Bisphosphonates Physical therapy Surgical fixation of brittle bones Genetic counseling for offspring
Skin Changes		Scurvy	Vitamin C deficiency Malabsorption Hemodialysis	Gum disease such as gum bleeding Loose teeth Easy bruising Impaired immune response Impaired wound healing			Vitamin C supplementation Citrus fruits
		Homocystinuria	Deficiency of cystathionine beta synthase Deficiency of folate, vitamin B12, or vitamin B6	Diffuse bone pain and musculoskeletal symptoms			High-dose vitamin B6 supplementation Betaine supplementation

Other Differentials

POEMS syndrome must also be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.^[51]^[52]^[53]^[54]^[55]

Disease	Addison's disease	Type 1 diabetes mellitus	Hypothyroidism	Other disorders present
POEMS syndrome	+	Less common	Less common	Hypoparathyroidism Candidiasis Hypogonadism
APS type 2	+	+	+	Hypogonadism Malabsorption
APS type 3	-	+	+	Malabsorption
Thymoma	+	-	+	Myasthenia gravis Cushing syndrome
Chromosomal abnormalities (Turner syndrome, Down's syndrome)	-	+	+	Cardiac dysfunction
Kearns–Sayre syndrome	-	+	-	Myopathy Hypoparathyroidism Hypogonadism
Wolfram syndrome	-	+	-	Diabetes insipidus Optic atrophy Deafness
POEMS syndrome	-	+	-	Polyneuropathy Hypogonadism Plasma cell dyscrasias

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@@ Line 413: / Line 413: @@
 * Polycystic ovarian syndrome
 | rowspan="3" style="padding: 5px 5px; background: #F5F5F5;" |
+* Fatigue
+* Decreased libido
+* Delayed secondary sexual characteristics:
+** Absent/scant pubic hair
+** Impotence
+** Erectile dysfunction
+** Amenorrhea
+** Delayed breast development
+** Small testicular size
+* Decreased muscle mass
+* Osteoporosis
+* Depression
+* Infertility
+* Irritability
+* Mood swings
+* Pot belly
+* Weight gain
 | style="padding: 5px 5px; background: #F5F5F5;" |
-| style="padding: 5px 5px; background: #F5F5F5;" |
+* Decreased sex hormone levels:
-| style="padding: 5px 5px; background: #F5F5F5;" |
+** Decreased testosterone
+** Decreased dihydrotestosterone
+** Decreased estrogen
+* Increased gonadrotrpins:
+** Increased LH
+** Increased FSH
+| rowspan="3" style="padding: 5px 5px; background: #F5F5F5;" |
+* Serum sex hormone levels
+| rowspan="3" style="padding: 5px 5px; background: #F5F5F5;" |
+* Hormone replacement therapy
 |-
 | style="padding: 5px 5px; background: #F5F5F5;" |'''Secondary Hypogonadism (Hypogonadotrophic)'''
@@ Line 430: / Line 456: @@
 *
 | style="padding: 5px 5px; background: #F5F5F5;" |
-| style="padding: 5px 5px; background: #F5F5F5;" |
+* Decreased sex hormone levels:
-| style="padding: 5px 5px; background: #F5F5F5;" |
+** Decreased testosterone
+** Decreased dihydrotestosterone
+** Decreased estrogen
+* Decreased gonadrotrpins:
+** Decreased LH
+** Decreased FSH
 |-
 |'''Combined Primary and Secondary'''
@@ Line 438: / Line 469: @@
 * Hepatic cirrhosis
 * Sickle cell disease
-|
-|
 |
 |-