Epstein syndrome

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Epstein syndrome
Giant Platelet, Peripheral Blood Smear (6032662354).jpg
Giant platelet in a peripheral blood smear
Specialty Nephrology, medical genetics, haemotology
Symptoms Macrothrombocytopenia, nephritis, proteinuria, nephropathy, sensorineural hearing loss, low platelet count, oral lesions and cataracts
CausesMutations in the MYH9 nonmuscle myosin heavy chain IIA on the R702 codon
Diagnostic method Analysis of peripheral blood smear
TreatmentRenal transplant

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 kidney 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 (myosin heavy chain 9) [2] 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. [3]

Contents

Signs and symptoms

Initial symptoms are often described as bleeding tendency and thrombocytopenia. Bleeding tendency may be observed in epistaxis and purpura. [4] 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. [3] The symptoms and the severity of these symptoms vary between patients where most patients experience nephritis in childhood and then progress to kidney failure in adolescence. [5] In macrothrombocytopenia platelet sizes can reach to approximately 6.6 um compared to a normal platelet size of 2.5 um where 30% platelets can reach the size of an erythrocytes. This large platelet size can be compared with MYH9 disorders where platelet size can vary between 4.5 um and the 6.6 um that is found in Epstein syndrome with mutations on the R207 codon. [6] [7]

Causes

DNA strand Bdna cropped.gif
DNA strand

Epstein syndrome is caused by a mutation in MYH9 gene. [6] 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. [8] Mutations are found in the nonmuscle myosin heavy chain IIA and is associated with chromosome 22. The MYH9 gene encodes for tissues including platelets, cochlea, renal cells, neutrophils and eyes. [4]

Pathophysiology

Kidney tubules Kidney tubules.png
Kidney tubules

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. [9] The platelets are large (macrothrombocytopenia) and often consist of neutrophil inclusions. [10] 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. [11]

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. [12]

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. [12]

Diagnosis

The cardinal symptom in Epstein syndrome is thrombocytopaenia with giant platelets (macrothrombocytopenia). A peripheral blood smear is taken from the patient and a light 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 0.7 um and have an abnormal[ citation needed ]

location on the non-muscle myosin heavy chain IIA (NMMHC-II). These inclusion bodies have RNA and no DNA. [13] RNA in these inclusion bodies can be located in immunofluorescence analysis with the anti nonmuscle heavy chain IIA antibody. [7]

Hematology analysers or a hemocytometer can be used to determine the amount of platelets. 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. [9]

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. This is one of the initial signs of renal disease. [14]

Easy bruising and abnormal bleeding tendencies are also described in initial diagnosis. [5] This supports the common misdiagnosis for chronic idiopathic thrombocytopaenia purpura in patients with Epstein syndrome. These symptoms are often noticed in early childhood due to the congenital cause of the disease. [15]

Treatment

Epstein syndrome is regarded as a refractory disease. Treatments include renal transplantation, however, this may become problematic as patient's low platelet count (thrombocytopaenia) increase the risks of complications in surgery. [16] Successful Renal transplants can arise from cadavers or from live donors. [11] 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. [14] Nephritis involves the inflammation of the kidney and this inflammation results in a reduced ability to filter blood. [12] 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 [14]

Maintenance

Peritoneal dialysis. Peritoneal dialysis.gif
Peritoneal dialysis.

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. [11] 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. [17]

Intravenous immunoglobin treatments can be used to support the patient's immune system as well as medication with Prednisolone to reduce inflammation. [18]

Sensorineural hearing loss is a common symptom in Epstein syndrome and can be treated with cochlea implants. [4] 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. [19]

Prognosis

In most case Epstein syndrome patients will endure early-onset end-stage renal disease (ESRD) at the end of adolescence. Expected kidney failure means patients will need renal transplants in the near future. [16]

Notable cases

In a study which investigated suitable management for severe Epstein syndrome, four patients were observed. Patient 1 demonstrated a common background and symptoms for Epstein syndrome. Patient 1 was a male who was initially diagnosed with chronic idiopathic thrombocytopaenia purpura in early childhood and then macrothrobocytopaenia. He progressed to kidney failure and began haemodialysis at seventeen years old. Patient 1 was only diagnosed with Epstein syndrome at the age of thirty-three where the mutation in the nonmuscle myosin was noticed. His eldest son also carried the same mutation. [15]

An Epstein syndrome patient with oral lesions was recorded to be the first with this symptom. The patient was a twenty-six-year-old female who was diagnosed with thrombocytopaenia with purpura at age four. She was then finally diagnosed with Epstein syndrome at twenty-two years old when she developed symptoms for hearing loss as well as proteinuria and hematuria revealing poor kidney function. After an oral examination, palatal purpua in her mouth was observed. [20]

A Japanese male was diagnosed with sporadic Epstein syndrome where both his parents did not have the R702H mutation. He was initially diagnosed with chronic macrothrombocytopaenia at three years old and throughout childhood symptoms for hearing loss and proteinuria were observed. At 24 years old his kidney failure had severely progressed as well as his hearing loss and thrombocytopenia. A genetic test confirmed he had the R702H mutation despite having no familial record of Epstein syndrome. [8]

Related Research Articles

<span class="mw-page-title-main">Nephritis</span> Inflammation of the kidneys

Nephritis is inflammation of the kidneys and may involve the glomeruli, tubules, or interstitial tissue surrounding the glomeruli and tubules. It is one of several different types of nephropathy.

<span class="mw-page-title-main">Thrombotic thrombocytopenic purpura</span> Medical condition

Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Repeated episodes may occur.

<span class="mw-page-title-main">Thrombocytopenia</span> Abnormally low levels of platelets in the blood

In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients and a third of surgical patients.

<span class="mw-page-title-main">Hemolytic–uremic syndrome</span> Group of blood disorders related to bacterial infection

Hemolytic–uremic syndrome (HUS) is a group of blood disorders characterized by low red blood cells, acute kidney injury, and low platelets. Initial symptoms typically include bloody diarrhea, fever, vomiting, and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, especially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure.

<span class="mw-page-title-main">Kidney disease</span> Damage to or disease of a kidney

Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.

<span class="mw-page-title-main">IgA nephropathy</span> Disease of the kidney

IgA nephropathy (IgAN), also known as Berger's disease, or synpharyngitic glomerulonephritis, is a disease of the kidney and the immune system; specifically it is a form of glomerulonephritis or an inflammation of the glomeruli of the kidney. Aggressive Berger's disease can attack other major organs, such as the liver, skin and heart.

<span class="mw-page-title-main">Alport syndrome</span> Medical condition

Alport syndrome is a genetic disorder affecting around 1 in 5,000-10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses.

<span class="mw-page-title-main">Wiskott–Aldrich syndrome</span> Medical condition

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea. It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. The WAS-related disorders of X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN) may present with similar but less severe symptoms and are caused by mutations of the same gene.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

<span class="mw-page-title-main">Bernard–Soulier syndrome</span> Medical condition

Bernard–Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder that is caused by a deficiency of the glycoprotein Ib-IX-V complex (GPIb-IX-V), the receptor for von Willebrand factor. The incidence of BSS is estimated to be less than 1 case per million persons, based on cases reported from Europe, North America, and Japan. BSS is a giant platelet disorder, meaning that it is characterized by abnormally large platelets.

<span class="mw-page-title-main">Nail–patella syndrome</span> Medical condition

Nail–patella syndrome is a genetic disorder that results in small, poorly developed nails and kneecaps, but can also affect many other areas of the body, such as the elbows, chest, and hips. The name "nail–patella" can be very misleading because the syndrome often affects many other areas of the body, including even the production of certain proteins. The severity of these effects varies depending on the individual. It is also referred to as iliac horn syndrome, hereditary onychoosteodysplasia, Fong disease or Turner–Kieser syndrome.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">May–Hegglin anomaly</span> Medical condition

May–Hegglin anomaly (MHA), is a rare genetic disorder of the blood platelets that causes them to be abnormally large.

The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with normal blood clotting and/or lysis of blood clots. The condition therefore may cause pathological bleeding and/or thrombosis. Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. It is associated primarily with pathological bleeding. Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.

<span class="mw-page-title-main">MYH9</span> Mammalian protein found in Homo sapiens

Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene.

Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.

EAST syndrome is a syndrome consisting of epilepsy, ataxia, sensorineural deafness and salt-wasting renal tubulopathy. The tubulopathy in this condition predispose to hypokalemic metabolic alkalosis with normal blood pressure. Hypomagnesemia may also be present.

Harris platelet syndrome, previously known as asymptomatic constitutional macrothrombocytopenia, is the most common inherited giant platelet disorder in the Indian subcontinent. It is characterized by a functional thrombocytopenia due to the presence of giant platelet cells.

<span class="mw-page-title-main">Giant platelet disorder</span> Medical condition

Giant platelet disorders, also known as macrothrombocytopenia, are rare disorders featuring abnormally large platelets, thrombocytopenia and a tendency to bleeding. Giant platelets cannot stick adequately to injured blood vessel walls, resulting in abnormal bleeding when injured. Giant platelet disorder occurs for inherited diseases like Bernard–Soulier syndrome, gray platelet syndrome and May–Hegglin anomaly.

Atypical hemolytic uremic syndrome (aHUS), also known as complement-mediated hemolytic uremic syndrome, is an extremely rare, life-threatening, progressive disease that frequently has a genetic component. In most cases it can be effectively controlled by interruption of the complement cascade. Particular monoclonal antibodies, discussed later in the article, have proven efficacy in many cases.

References

  1. ↑ Balwani, Manish (2016). "An unusual cause of renal failure; Epstein syndrome". Journal of Nephropharmacology. 5 (1): 63–65. PMC   5297510 . PMID   28197502.
  2. ↑ Higashi, Midoriko; Kaku, Keizo; Okabe, Yasuhiro; Yamaura, Ken (2020). "Anesthetic Management of Living-Donor Renal Transplantation in a Patient with Epstein Syndrome Using Rotational Thromboelastometry: A Case Report". A&A Practice. 14 (13): e01350. doi:10.1213/XAA.0000000000001350. PMC   7688077 . PMID   33236872.
  3. 1 2 Seri, Marco (2003). "MYH9-Related Disease: May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness". Medicine. 82 (3): 203–215. doi: 10.1097/01.md.0000076006.64510.5c . PMID   12792306. S2CID   25549125.
  4. 1 2 3 Nabekura, Takashi (2015). "A case of cochlear implantation in a patient with Epstein syndrome". Auris Nasus Larynx. 42 (2): 160–162. doi:10.1016/j.anl.2014.09.004. PMID   25293679.
  5. 1 2 "MYH9-related disorder: MedlinePlus Genetics". medlineplus.gov.
  6. 1 2 Murayama, Shizuko (2013). "Familial cases with MYH9 disorders caused by MYH9 S96L mutation". Pediatrics International. 55 (1): 102–104. doi: 10.1111/j.1442-200X.2012.03619.x . PMID   23409987. S2CID   27074143.
  7. 1 2 Kunishima, Shinji (2006). "Haematological characteristics of MYH9 disorders due to MYH9 R702 mutations". European Journal of Haematology. 78 (3): 220–226. doi:10.1111/j.1600-0609.2006.00806.x. PMID   17241369. S2CID   22638636.
  8. 1 2 Makino, Shigeru (2015). "Sporadic Epstein syndrome with macrothrombocytopenia, sensorineural hearing loss and renal failure". Pediatrics International. 57 (5): 977–981. doi:10.1111/ped.12736. PMID   26387855. S2CID   206262497.
  9. 1 2 "What are Platelets and Why are They Important?". 10 January 2022.
  10. ↑ Smith, Owen P. (2006). "Inherited and Congenital Thrombocytopenia". Pediatric Hematology. pp. 505–525. doi:10.1002/9780470987001.ch22. ISBN   9780470987001.
  11. 1 2 3 Alving, Barbara (1986). "Successful Renal Transplantation for Epstein Syndrome". American Journal of Hematology. 21 (1): 111–113. doi:10.1002/ajh.2830210113. PMID   3518415. S2CID   22706545.
  12. 1 2 3 "Nephritis" (PDF). Archived from the original (PDF) on 2019-08-12. Retrieved 2019-05-19.
  13. ↑ Hao, Jihong; Kada, Akiko; Kunishima, Shinji (2018). "Further classification of neutrophil non-muscle myosin heavy chain-IIA localization for efficient genetic diagnosis of MYH9 disorders". Annals of Hematology. 97 (4): 709–711. doi:10.1007/s00277-017-3195-3. PMID   29199357. S2CID   3647689.
  14. 1 2 3 Hashimoto, Junya (2015). "Successful Kidney Transplantation in Epstein Syndrome With Antiplatelet Antibodies and Donor-specific Antibodies: A Case Report". Transplantation Proceedings. 47 (8): 2541–2543. doi:10.1016/j.transproceed.2015.09.010. PMID   26518967.
  15. 1 2 Hashimoto, Junya (2018). "Management of patients with severe Epstein syndrome: Review of four patients who received living‐donor renal transplantation". Nephrology. 24 (4): 450–455. doi:10.1111/nep.13253. PMID   29532554. S2CID   3873853.
  16. 1 2 Hamasaki, Yuko (2018). "Management of patients with severe Epstein syndrome: Review of four patients who received living‐donor renal transplantation'". Nephrology. 24 (4): 450–455. doi:10.1111/nep.13253. PMID   29532554. S2CID   3873853.
  17. ↑ "Health Library | Michigan Medicine". www.uofmhealth.org.
  18. ↑ "Prednisolone & Prednisone".
  19. ↑ "Cochlear Implants". 2015-08-18.
  20. ↑ Richards (1991). "Epstein syndrome: oral lesions ina patient with nephropathy,deafness and thrombocytopenia". Journal of Oral Pathology and Medicine. 20 (10): 512–513. doi:10.1111/j.1600-0714.1991.tb00415.x. PMID   1753355.
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