Epstein Syndrome - Symptoms, Diagnosis, and Treatment

Introduction

A rare and unknown triad of inherited macrothrombocytopenia, nephritis, and the hearing deficit was first described by Epstein and coworkers in 1972. These symptoms were reported among family members and followed the autosomal dominant pattern of inheritance. The clinical signs and symptoms were found to be closely related to other inherited giant platelet disorders that occur due to mutations in the MYH9 gene. This rare triad was named Epstein syndrome and was classified under MYH9-related disorders.

What Is MYH9-Related Disease?

MYH9 is a gene that codes for a myosin protein. This myosin component is not present in muscles. MYH9 is a nonmuscle myosin-heavy chain IIA that is expressed in various tissues such as kidneys, platelets, leukocytes, and cochlea. Mutations in the MYH9 gene cause a spectrum of syndromes affecting the normal functioning of tissues in which the gene is expressed. These syndromes are grouped as MYH9-related diseases. They are differentiated by variations in clinical signs and laboratory investigations. The four entities of MYH9-related disease are

• May-Hegglin anomaly.

• Sebastian syndrome.

• Fechtner syndrome.

• Epstein syndrome.

These syndromes represent variable expressions of a single genetic disorder and manifest similar clinical signs that vary from mild symptoms to severe complications. The common features of MYH9-related disorders are

• Inherited as autosomal dominant traits.

• Macrothrombocytopenia (platelets are abnormally large but their numbers are low).

• Nephritis (inflammation of the kidneys).

• Sensorineural hearing loss.

• Cataracts.

• Abnormal leukocyte inclusions.

What Is Epstein Syndrome?

Epstein syndrome is an autosomal dominant genetic disease characterized by thrombocytopenia with unusually large platelets, mild hearing dysfunction, and nephritis. It is distinguished from other related syndromes by the absence of inclusion bodies in the neutrophils.

Autosomal Dominant Inheritance

• In autosomal dominant inheritance, only one allele (copy) of a mutated gene is needed for the genetic variant to be expressed.

• It is passed down from parent to child.

• Inheriting one mutated copy from one parent could result in the existence of a genetic condition in the child.

• A child whose parent has a mutated gene gets a 50 % chance of inheriting that genetic condition.

• Since Epstein syndrome genetic defect occurs in autosomal genes, both men and women have an equal chance of passing it on to their children.

• Also, sons and daughters have an equal chance of inheriting them.

What Are the Clinical Manifestations of Fechtner Syndrome?

Epstein syndrome is frequently seen in the young population. Recurrent bleeding episodes occur during childhood. Some individuals usually present with rapidly progressing renal failure at a younger age (in the second decade of life) with no symptoms of hearing difficulty and bleeding tendency. The most commonly reported clinical symptoms are as follows:

• Easy bruising.

• Recurrent episodes of epistaxis from birth.

• Frequent episodes of otitis media during the infancy stage.

• Oral hemorrhage and purpuric lesions in the oral cavity.

• Thrombocytopenia.

• Epigastric pain radiating to the lower back with vomiting.

• Recurrent urinary tract infections.

• Proteinuria.

• Hematuria.

• Nephritis.

• Renal failure (at a younger age with no signs of hypertension).

• End-stage renal failure (in severe cases).

• Hearing impairment.

• Difficulty in hearing(both ears or one ear) is often associated with tinnitus.

• Cataracts.

• Other ocular defects such as retinitis pigmentosa, spherophakia, and lenticonus.

• Acute relapsing pancreatitis (as a coexisting complication).

How Is Epstein Syndrome Diagnosed?

Generally, Epstein syndrome remains asymptomatic and is usually diagnosed in screening tests done for other existing disorders. The clinical symptoms are often misinterpreted in case of the absence of one or two classical signs. A confirmatory diagnosis for Epstein's syndrome includes the presence of triad symptoms such as macrothrombocytopenia, renal impairment, and sensory deafness. Some of the diagnostics to detect Epstein syndrome are as follows:

• Peripheral Blood Film Examination - Using the May-Grunwald-Giemsa-staining method reveals the distribution of giant platelets (diameter of platelets ranging from 4 - 8 micrometers or more than 8 micrometers).

• Absence of cytoplasmic inclusions in leukocytes (a distinctive feature of Epstein syndrome).

• Reduced platelet count (18 x 10^9/L to 129 x10^9/L).

• Mean platelet volume (MPV) is decreased to 8.1 – 12.3 fL.

• Bone marrow aspirate reveals increased numbers of derided megakaryocytes with abnormal morphology and irregular border.

• Bleeding time increases at 13 minutes.

• Prothrombin consumption index increases by 24 %.

• Platelet Aggregation Tests - Show the impaired function of aggregation parameters such as lowered glass adherence, and reduced aggregation in response to collagen and adrenaline.

• Other coagulation tests such as prothrombin time, thrombin clotting time, thromboplastin screening test, and kaolin-cephalin clotting time are normal.

• Normal serum immunoglobulins indicate the absence of immunological reactions.

• Negative antinuclear factor antibody and direct Coombs test (to rule out other platelet disorders).

• Audiometry demonstrates symmetrical or unilateral sensorineural deficit which is often associated with high-frequency sounds.

• Ophthalmoscopy is used to detect cataracts and other ocular defects.

• serum creatinine is increased.

• Urinalysis detects massive proteinuria and microhematuria.

• Renal biopsy indicates abnormal and inflamed nephrons.

• Mutation screening by RT - PCR or real-time PCR identifies the defective genetic mutation.

• Immunocytochemical studies using a monoclonal antibody against NMMHC-IIA (nonmuscle myosin heavy chain IIA) help to confirm the variations in DNA (deoxyribonucleic acid) sequence from other syndromes.

How Is Epstein Syndrome Treated?

The treatment intervention for Epstein syndrome is purely symptomatic management. Also the treatment procedures depend on the severity of the clinical symptoms.

• Blood transfusions are recommended in case of acute blood loss.

• Platelet fraction transfusion improves clotting in recurrent bleeding episodes.

• Prophylactic administration of clotting factors and fibrin precipitate prevents excessive bleeding.

• Corticosteroids are given to reduce the inflammation in the kidneys.

• Hemodialysis or peritoneal dialysis depending on the severity of renal dysfunction.

• Renal transplantation is recommended for end-stage renal failure.

• Deceased-donor kidney (cadaveric kidney) transplantation is also found successful with sufficient graft function.

• Genetic counseling would help in minimizing the inheritance of mutated genes.

Genetic Counseling

• It is a scientific preventive measure where family members and individuals with the existing genetic condition are educated about relevant aspects of inheritance.

• The counselor conveys the nature of the risk involved in genetic diseases and various facilities to predict the risks.

• Carrier detection and screening programs, prenatal analysis, newborn screening, and late-onset disorder screening are some of the genetic testing methods that help in the early detection and prevention of inherited disorders like Epstein syndrome.

Conclusion

Epstein syndrome is a rare genetic disorder that belongs to a class of giant platelet diseases associated with MYH9 mutations. Renal impairment at a young age and the absence of leukocyte abnormalities differentiate Epstein syndrome from other related syndromes. Detailed laboratory investigations help in the early identification of the syndrome. Various treatment interventions are followed to reduce clinical symptoms and prevent organ damage. Awareness and assistance from genetic counseling would help in significant coping lives for people with Epstein syndrome.