POEMS syndrome differential diagnosis

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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
  • 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
  • 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
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
  • Flouroscent insitu hybridization (FISH)
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
Hypothyroidism Primary Hypothyroidism
  • Congenital hypothyroidism
  • Autoimmune (Hashimoto's) thyroiditis
  • Resistance to TSH
  • Decreased T3 and T4
  • Increased TSH
  • Serum T3, T4, TSH levels
  • Hormone replacement therapy
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
  • Decreased T3 and T4
  • Decreased TSH
Tertiary Hypothyroidism
  • Hemochromatosis
  • Histiocytosis
  • Developmental abnormalities
  • Internal carotid aneurysms
  • Idiopathic isolated TRH deficiency
  • Decreased T3 and T4
  • Decreased TRH
  • Decreased TSH
Hypopituitarism Congenital
  • Idiopathic
  • Anatomic lesion in sella turcica (Rathke's cyst)
  • CNS malformations:
    • Septo-optic-dysplasia
    • Kallmann syndrome
    • Pituitary stalk interruption syndrome
  • Decreased FSH, LH
  • Decreased TSH
  • Decreased ACTH
  • Decreased GH
  • Decreased ADH
  • Decreased oxytocin
  • Serum hormone levels produced by pituitary
  • Hormone replacement therapy
Acquired
  • Posterior pituitary tumor: astrocytoma, ganglioneuroma
  • Metastatic: breast, lungs, colon, prostate
  • Peripituitary lesions: Craniopharyngioma, meningioma, chordoma, optic nerve glioma
  • Transsphenoidal or transcranial surgery
  • Radiation
  • Traumatic brain injury
  • Sheehan's syndrome
  • Pituitary apoplexy
  • Meningitis
  • Hypophysitis
  • Lymphoma
Organ System Involvement Differential Diagnosis Causes Features Laboratory Findings Gold Standard Test Therapy
M = M-protein ( Hematological Abnormality/Plasma Cell Dyscrasias) Multiple myeloma
  • Anemia
  • Thrombocytopenia
  • Leukopenia
  • Decreased albumin (reversed albumin:globulin ratio)
  • Increased serum creatinine, urea
  • Hypercalcemia
  • Elevated ESR
  • Normal-low alkaline phosphatase
  • RBC rouleaux formation
  • Bence-Jones proteins in urine
  • Clonal plasma cells on bone marrow exam greater than equal to 10%

AND

  • Any one of the following:
    • Evidence of end-organ damage
    • Hypercalcemia (>11 mg/dl)
    • Renal insufficiency
    • Anemia (Hb < 10 mg/dl)
    • Bone lesions
    • Greater than 1 lesions on MRI
Monoclonal gammopathy of undetermined significance (MGUS)
  • Serum M protein (IgG or IgA) <3g/dl

AND

  • Clonal bone marrow plasma cells < 10%

AND

  • No end-organ damage
Observation
Asymptomatic Plasma Cell Myeloma

(Smoldering and Indolent plasma cell myeloma)

  • Serum M protein (IgG or IgA greater than equal to 3 g/dl

OR

  • Urinary M protein greater than equal to500 mg/24 h

AND/OR

  • Clonal bone marrow plasma cells 10-60%

AND

  • No end-organ damage
Observation
Plasmacytoma Surgery
Bone Lesions Osteoporosis
Osteomalacia
Osteogenesis imperfecta
Skin Changes Scurvy
Homocystinuria

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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