POEMS syndrome
Encyclopedia
POEMS syndrome is a rare
medical syndrome
. It is defined as the combination of a plasma-cell proliferative disorder (typically myeloma), polyneuropathy
, and effects on many other organ systems. It begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women. If untreated it is progressive and often fatal, with only 60% of sufferers remaining alive five years after onset. However, the symptoms can improve if the blood disorder is successfully treated.
The name 'POEMS syndrome', now the most prevalent, was coined in 1980 by Bardwick et al. The name is an acronym deriving from some of the main features: Polyneuropathy
(peripheral nerve damage), Organomegaly
(abnormal enlargement of organs), Endocrinopathy
(damage to hormone-producing glands) or Edema
, M-protein
(an abnormal antibody) and Skin abnormalities (including hyperpigmentation
and hypertrichosis
). However, these features are neither an exhaustive list nor seen in all individuals with the condition.
, motor
and autonomic
neurones are all affected. The typical symptoms are therefore of numbness, tingling and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction
; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.
Myeloma is the most common plasma-cell proliferative disorder associated with POEMS syndrome, present in more than half of all cases. Most myelomas associated with POEMS syndrome are osteosclerotic, in contrast to the osteolytic bone lesions in most other myelomas. Other blood disorders occur in a significant minority of cases, including Castleman's disease
, plasmacytoma
and MGUS.
and preretinal haemorrhage.
Pulmonary disease: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension
is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.
Organomegaly: The liver
may be enlarged, and less often the spleen
or lymph nodes
, though these organs usually function normally.
Oedema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral oedema, pulmonary oedema, effusions such as pleural effusion
or ascites
, or generalised capillary leakage (anasarca
).
Endocrinopathy: In women, amenorrhoea
, and in men, gynaecomastia, erectile dysfunction
and testicular atrophy
, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism
and adrenal insufficiency
.
Monoclonal paraprotein: In most cases a serum paraprotein
can be detected, although this is not universal (75–80%). This may represent IgG or IgA
, but the light chain type is almost always lambda. This is in contrast to most paraproteinaemic neuropathies, in which the paraprotein is usually an IgM
antibody.
Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation
. The fingernails may be clubbed or white, There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis
), skin angioma
s or haemangiomas, or there may be changes reminiscent of scleroderma
.
, arthralgia
, cardiomyopathy
(systolic dysfunction), fever
, low vitamin B12
levels and diarrhea
.
for neuropathy or CT scan and bone marrow biopsy
for myeloma), two other tests give abnormal results. These are: a raised level of VEGF in blood; and a raised CSF
protein level, as in some other neuropathies. Even when myeloma is present, anaemia and thrombocytopaenia are rare; on the contrary, polycythaemia and thrombocytosis
are often found.
s produced by plasmacytoma cells have therefore been linked with the features of POEMS syndrome, specifically interleukin 1β
, interleukin 6
and TNFα. There also seems to be a role of vascular endothelial growth factor
(VEGF), given the angiogenetic
changes in many tissues.
Dispenzieri et al. list numerous treatments, the effect of many of which is almost anecdotal. Prednisolone
and alkylating agent
s are the most commonly used. The Mayo Clinic group attempted hematopoietic stem cell transplantation in sixteen patients; one patient died during the treatment, and in several others respiratory problems were unmasked in the course of the procedure. The outcome of the treatment, though, was good.
Given that VEGF plays a central role in the symptoms of POEMS syndrome, some have tried bevacizumab
(Avastin), a monoclonal antibody directed against VEGF. While some reports were positive, others have reported capillary leak syndrome
suspected to be the result of overly rapid lowering of VEGF levels. It therefore remains doubtful as to whether this will become part of standard treatment for POEMS syndrome.
, first described the combination of osteosclerotic myeloma, polyneuropathy and various unusual features (such as pigmentation and clubbing) in two patients aged 54 and 67.
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
medical syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
. It is defined as the combination of a plasma-cell proliferative disorder (typically myeloma), polyneuropathy
Polyneuropathy
Polyneuropathy is a neurological disorder that occurs when many peripheral nerves throughout the body malfunction simultaneously. It may be acute and appear without warning, or chronic and develop gradually over a longer period of time. Many polyneuropathies have both motor and sensory...
, and effects on many other organ systems. It begins in middle age – the average age at onset is 50 – and affects up to twice as many men as women. If untreated it is progressive and often fatal, with only 60% of sufferers remaining alive five years after onset. However, the symptoms can improve if the blood disorder is successfully treated.
The name 'POEMS syndrome', now the most prevalent, was coined in 1980 by Bardwick et al. The name is an acronym deriving from some of the main features: Polyneuropathy
Polyneuropathy
Polyneuropathy is a neurological disorder that occurs when many peripheral nerves throughout the body malfunction simultaneously. It may be acute and appear without warning, or chronic and develop gradually over a longer period of time. Many polyneuropathies have both motor and sensory...
(peripheral nerve damage), Organomegaly
Organomegaly
Organomegaly is the abnormal enlargement of organs. For example, clitoromegaly is the enlargement of the clitoris, hepatomegaly is enlargement of the liver, cardiomegaly is enlargement of the heart, and splenomegaly is enlargement of the spleen....
(abnormal enlargement of organs), Endocrinopathy
Endocrinology
Endocrinology is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions called hormones, the integration of developmental events such as proliferation, growth, and differentiation and the coordination of...
(damage to hormone-producing glands) or Edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, M-protein
Paraprotein
A paraprotein is an immunoglobulin or immunoglobulin light-chain that is produced in excess by the clonal proliferation of plasma cells. Detection of paraproteins in the urine or blood is most often associated with benign MGUS , where they remain "silent", and multiple myeloma. An excess in the...
(an abnormal antibody) and Skin abnormalities (including hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...
and hypertrichosis
Hypertrichosis
Hypertrichosis is an abnormal amount of hair growth on the body; extensive cases of hypertrichosis have informally been called werewolf syndrome. There are two distinct types of hypertrichosis: generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is...
). However, these features are neither an exhaustive list nor seen in all individuals with the condition.
Signs and symptoms
The following are the most common clinical features of POEMS syndrome, either symptoms or signs. The first two are present by definition; the remainder are frequent but not universal, and different individuals experience different combinations of them.Defining features
The polyneuropathy is usually symmetrical and distal. There is a combination of demyelination and axonal damage, and sensorySensory neuron
Sensory neurons are typically classified as the neurons responsible for converting external stimuli from the environment into internal stimuli. They are activated by sensory input , and send projections into the central nervous system that convey sensory information to the brain or spinal cord...
, motor
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
and autonomic
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
neurones are all affected. The typical symptoms are therefore of numbness, tingling and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.
Myeloma is the most common plasma-cell proliferative disorder associated with POEMS syndrome, present in more than half of all cases. Most myelomas associated with POEMS syndrome are osteosclerotic, in contrast to the osteolytic bone lesions in most other myelomas. Other blood disorders occur in a significant minority of cases, including Castleman's disease
Castleman's disease
Castleman's disease is an uncommon lymphoproliferative disorder that can involve single lymph node stations or...
, plasmacytoma
Plasmacytoma
Plasmacytoma refers to a malignant plasma cell tumor growing within soft tissue or within the skeleton. The skeletal forms usually have other occult tumors and frequently disseminate to multiple myeloma over the course of 5–10 years. The soft tissue forms most often occur in the upper respiratory...
and MGUS.
Common features
Papilloedema is a common sign of POEMS syndrome, occurring in a significant proportion of cases. Less frequent ocular features include uveitisUveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
and preretinal haemorrhage.
Pulmonary disease: The lungs are often affected at more severe stages of the illness, although since by then physical exertion is usually limited by neuropathy, shortness of breath is unusual. Pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
is the most serious effect on the lungs, and there may also be restriction of chest expansion or impaired gas exchange.
Organomegaly: The liver
Hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
may be enlarged, and less often the spleen
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
or lymph nodes
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
, though these organs usually function normally.
Oedema: Leakage of fluid into the tissues is a common and often severe problem. This may take several forms, including dependent peripheral oedema, pulmonary oedema, effusions such as pleural effusion
Pleural effusion
Pleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...
or ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
, or generalised capillary leakage (anasarca
Anasarca
Anasarca, also known as "extreme generalized edema" is a medical condition characterised by widespread swelling of the skin due to effusion of fluid into the extracellular space....
).
Endocrinopathy: In women, amenorrhoea
Amenorrhoea
Amenorrhoea , amenorrhea , or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation , the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method...
, and in men, gynaecomastia, erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and testicular atrophy
Testicular atrophy
Testicular atrophy is a medical condition in which the male reproductive organs diminish in size and may be accompanied by loss of function. This does not refer to temporary changes, such as those brought on by cold.Some medications can cause testicular atrophy...
, are common early symptoms due to dysfunction of the gonadal axis. Other hormonal problems occurring in at least a quarter of patients include type 2 diabetes, hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
and adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
.
Monoclonal paraprotein: In most cases a serum paraprotein
Paraprotein
A paraprotein is an immunoglobulin or immunoglobulin light-chain that is produced in excess by the clonal proliferation of plasma cells. Detection of paraproteins in the urine or blood is most often associated with benign MGUS , where they remain "silent", and multiple myeloma. An excess in the...
can be detected, although this is not universal (75–80%). This may represent IgG or IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
, but the light chain type is almost always lambda. This is in contrast to most paraproteinaemic neuropathies, in which the paraprotein is usually an IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
antibody.
Skin changes: A very wide variety of skin problems have been reported in association with POEMS syndrome. The most common is non-specific hyperpigmentation
Hyperpigmentation
In dermatology, hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin.-Causes:Hyperpigmentation may be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris...
. The fingernails may be clubbed or white, There may be thickening of the skin, excess hair or hair in unusual places (hypertrichosis
Hypertrichosis
Hypertrichosis is an abnormal amount of hair growth on the body; extensive cases of hypertrichosis have informally been called werewolf syndrome. There are two distinct types of hypertrichosis: generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is...
), skin angioma
Angioma
Angiomas are benign tumors derived from cells of the vascular or lymphatic vessel walls or derived from cells of the tissues surrounding these vessels....
s or haemangiomas, or there may be changes reminiscent of scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
.
Possible features
Some features have been observed in patients with POEMS syndrome but are not yet certain to form part of the syndrome itself. These include thrombophiliaThrombophilia
Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis . Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes...
, arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, cardiomyopathy
Cardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
(systolic dysfunction), fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, low vitamin B12
Vitamin B12
Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
levels and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
.
Laboratory findings
In addition to tests corresponding to the above findings (such as EMGElectromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
for neuropathy or CT scan and bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
for myeloma), two other tests give abnormal results. These are: a raised level of VEGF in blood; and a raised CSF
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
protein level, as in some other neuropathies. Even when myeloma is present, anaemia and thrombocytopaenia are rare; on the contrary, polycythaemia and thrombocytosis
Thrombocytosis
Thrombocytosis is the presence of high platelet counts in the blood, and can be either primary or reactive...
are often found.
Criteria
The most recent criteria for the diagnosis of POEMS syndrome require that all of the following be present:- polyneuropathy
- a monoclonal plasma-cell proliferative disorder
- one or more of the following major criteria:
- sclerotic bone lesions
- Castleman's diseaseCastleman's diseaseCastleman's disease is an uncommon lymphoproliferative disorder that can involve single lymph node stations or...
- elevated VEGF levels
- one or more of the following minor criteria:
- organomegaly (enlarged spleen, liver or lymph nodes)
- extravascular volume overload (oedema, pleural effusion or ascites)
- endocrinopathy (adrenal, pituitary, gonadal, parathyroid); diabetes or hypothyroidism alone are insufficient
- skin changes
- papilloedema
- thrombocytosisThrombocytosisThrombocytosis is the presence of high platelet counts in the blood, and can be either primary or reactive...
or polycythaemia
Pathogenesis
While the main features of the disease have been described, the exact mechanism of the disease has remained elusive. The paraprotein alone is insufficient to explain the multi-organ features, and various cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s produced by plasmacytoma cells have therefore been linked with the features of POEMS syndrome, specifically interleukin 1β
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...
, interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
and TNFα. There also seems to be a role of vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF), given the angiogenetic
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
changes in many tissues.
Treatment
There are no randomised controlled trials of treatment in POEMS syndrome, owing to its rarity. Conventional treatments for demyelinating neuropathy, such as steroids, intravenous immunoglobulin and plasma exchange, are ineffective; treatment must be aimed at the haematological disorder.Dispenzieri et al. list numerous treatments, the effect of many of which is almost anecdotal. Prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
and alkylating agent
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
s are the most commonly used. The Mayo Clinic group attempted hematopoietic stem cell transplantation in sixteen patients; one patient died during the treatment, and in several others respiratory problems were unmasked in the course of the procedure. The outcome of the treatment, though, was good.
Given that VEGF plays a central role in the symptoms of POEMS syndrome, some have tried bevacizumab
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
(Avastin), a monoclonal antibody directed against VEGF. While some reports were positive, others have reported capillary leak syndrome
Capillary leak syndrome
Capillary leak syndrome is a rare medical conditioncharacterized by self-reversing episodes during which the endothelial cells which line the capillaries are thought to separate for a few days, allowing for a leakage of fluid from the circulatory system to the interstitial space, resulting in a...
suspected to be the result of overly rapid lowering of VEGF levels. It therefore remains doubtful as to whether this will become part of standard treatment for POEMS syndrome.
History
Crow, working in BristolBristol
Bristol is a city, unitary authority area and ceremonial county in South West England, with an estimated population of 433,100 for the unitary authority in 2009, and a surrounding Larger Urban Zone with an estimated 1,070,000 residents in 2007...
, first described the combination of osteosclerotic myeloma, polyneuropathy and various unusual features (such as pigmentation and clubbing) in two patients aged 54 and 67.