Epstein Syndrome
Epstein syndrome is a rare genetic disease characterized by a mutation in the MYH9 gene in nonmuscle myosin. This disease affects the patient’s renal system and can result in renal failure. Epstein Syndrome was first discovered in 1972 when two families had similar symptoms to Alport syndrome.[1] Epstein syndrome and other Alport-like disorders were seen to be caused by mutations in the MYH9 gene, however, Epstein syndrome differs as it was more specifically linked to a mutation on the R702 codon on the MYH9 gene. Diseases with mutations on the MYH9 gene also include May–Hegglin anomaly, Sebastian syndrome and Fechtner syndrome.[2]
Signs/Symptoms
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Initial symptoms are often described as bleeding tendency and thrombocytopenia. Other symptoms may include macrothrombocytopenia, proteinuria, nephropathy, sensorineural hearing loss, low platelet count, oral lesions and cataracts. The most common symptoms include macrothrombocytopenia, mild sensorineural hearing loss and nephritis.[2] The symptoms and the severity of these symptoms vary between patients where most patients experience nephritis in childhood and then progress to renal failure in adolescence.[3] In macrothrombocytopenia platelet sizes can reach to approximately 6.6um compared to a normal platelet size of 2.5um. This large platelet size can be compared with MYH9 disorders where platelet size can vary between 4.5 um and the 6.6um that is found in Epstein Syndrome with mutations on the R207 codon.[4]
Causes
Epstein Syndrome is caused by a mutation in MYH9 gene. [4]This mutation is autosomal dominant and is thereby inherited if one or both parents carry the mutated gene. However, there have been cases where Epstein Syndrome has been sporadic or non-congenital.[5]Mutations are found in the nonmuscle myosin heavy chain IIA and is associated with chromosome 22.
Pathophysiology
The main symptom in Epstein Syndrome is thrombocytopaenia. Thrombocytopaenia is generally inherited as an autosomal dominant gene and platelets are found to aggregate with either epinephrine or collagen. Platelets assist in blood clotting and coagulate when there are damages blood vessels. This coagulation attempts to cease bleeding. Thrombocytopaenia means there is low platelet volume in the blood. This means there are less platelets to coagulate in presence of a damaged blood vessel, which can result in bleeding problems.[6] The platelets are large (macrothrombocytopenia) and often consist of neutrophil inclusions[7]The large size of platelets may be due to excess microtubule coils and tublin. This large size of the platelets also affects their ability to bind to each other to seal damaged blood vessels and stop bleeding.[8]
Nephritis involves the inflammation of the kidney and this inflammation results in a reduced ability to filter blood and remove nitrogenous wastes. This excessive accumulation of wastes will result in a continued build-up of wastes including urea which interferes with metabolism.
One of the kidney’s functions include osmoregulation which involves the regulation of osmotic pressure in the blood by regulating the water content in blood pressure. Through osmosis (water movement from a low solute concentration to an area of high solute concentration) water is reabsorbed back into the blood from nephron tubules in the kidney. This maintenance of water concentration in the blood is essential for maintaining blood pressure and is affected in nephritis.[9]
Diagnosis
The cardinal symptom in Epstein syndrome is thrombocytopaenia with giant platelets (macrothrombocytopenia). A peripheral blood smear is taken from the patient and an electron microscope is used to these identify giant platelets. Leukocyte inclusions are also examined for, because approximately 41.1% of R207 mutations have leukocyte inclusions. These are often abnormal neutrophils with a small size of approximately less than 0.7um and have an abnormal
location on the non-muscle myosin heavy chain IIA (NMMHC-II).[10] These inclusion bodies have RNA and no DNA.[11]
Hematology analysers or a hemocytometer can be used to determine the amount of platelets.[12] A sample of blood is drawn from a patient’s arm. A small amount of platelets in blood smears compared to the normal range of 150,000 to 450,000 platelets in microliter of blood suggest thrombocytopaenia, which is a common symptom in Epstein syndrome.[6]
A urine sample is often collected where a urinalysis can be used to determine the volume of proteins excreted in urine. Abnormal amounts of protein detected means the patient has proteinuria. Patients with Epstein syndrome often have large proteinuria where they excrete above 3.5g of protein in their urine in a day. [13] This is one of the initial signs of renal disease. [3]
Easy bruising and abnormal bleeding tendencies are also described in initial diagnosis.
Treatment
Epstein syndrome is regarded as a refractory disease. Treatments include renal transplantation, however, this may become problematic as patient’s low platelet account and thrombocytopaenia increase the risks of complications in surgery.[14] Successful Renal transplants can arise from cadavers or from live donors.[8] To minimize the risk of patient’s losing too much blood during the perioperative period, HLA-matched platelet infusions can be used to maintain satisfactory platelet levels.[15] Nephritis involves the inflammation of the kidney and this inflammation results in a reduced ability to filter blood. [9]. In order to ensure the transplanted kidney is recognised as ‘self’ by Major Histocompatibility cells, immunosuppression drugs are used post operation. Immunosuppression medication may include calcineurin inhibitor, antimetabolite and methylprednisolone and assist in suppressing the immune system's response to the transplanted kidney[15].
Maintenance
As a result of nephritis, a healthy blood pressure becomes difficult to maintain and hence medication including vasopressin may be prescribed to maintain blood pressure. Severe nephritis may mean kidney dialysis is required to ensure
the blood is being filtered. This may include either peritoneal dialysis or haemodialysis, however, haemodialysis is most common as Epstein syndrome patients will often eventually have renal transplants.[8] Peritoneal dialysis involves blood being filtered through a membrane in the abdomen (peritoneum). Whereas haemodialysis involves blood being filtered through a dialyser, which consists of a semi-permeable membrane where toxins including urea are removed from the blood. Haemodialysis also filters blood quicker than peritoneal dialysis. [16]
Intravenous immunoglobin treatments can be used to support the patient’s immune system as well as medication with Prednisolone to reduce inflammation.[17].
Sensorineural hearing loss is a common symptom in Epstein syndrome and can be treated with cochlea implants. Cochlea implants have four main parts including the electrode array, the transmitter, the receiver/stimulator and the microphone. The microphone is positioned behind the ear and receives sound waves, the processor then converts the sound into electrical signals. These electrical signals are further converted into electrical impulses in the cochlea where the transmitter is located, which in turn sends the signal to the auditory nerve. This results in a nervous impulse sent to the brain where the ‘sound’ is deciphered.[18]
Prognosis
In most case Epstein syndrome patients will endure early-onset end-stage renal disease (ESRD) at the end of adolescence. Expected renal failure means patients will need renal transplants in the near future.[14]
See Also
Hematologic Diseases Information Service
Reference List
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