Fechtner Syndrome - Diagnosis and Treatment

Introduction

Fechtner syndrome is a genetic disorder characterized by collective inherited clinical abnormalities such as platelet dysfunction, renal failure, hearing, and visual defects. These symptoms, with no previous documented evidence, were first reported in individuals belonging to four different generations from a single family. The syndrome was named after the family name of propositus (the person in whom the disease was first identified and studied) who showed these clusters of unusual findings. The National Institutes of Health (NIH) - Genetic and Rare Diseases Information Center (GARD) has included Fechtner syndrome under the class of MYH9-related thrombocytopenia.

What Is MYH9-Related Thrombocytopenia?

MYH9-related thrombocytopenia is a group of genetic disorders caused by genetic defects in the MYH9 (myosin heavy chain 9) gene. The mutation in this gene causes untimely release of immature platelets from the bone marrow characterized by macrothrombocytopenia and leukocytes with cytoplasmic inclusions. This condition is inherited as an autosomal dominant trait. It is characterized by:

• Unusually large platelets (macrothrombocytes).

• Thrombocytopenia (low number of platelets).

• Mild to severe bleeding episodes.

• Varying frequency of onset from newborn to adult.

• Hearing loss due to sensorineural defects.

• Early onset of cataract formation.

• Kidney disease.

The subtypes of MYH9-related thrombocytopenia (MHY9RD) include:

• Sebastian syndrome.

• May-Hegglin anomaly.

• Fechtner syndrome.

• Epstein syndrome.

What Is Fechtner Syndrome?

Fechtner syndrome is a rare autosomal dominant inherited disorder characterized by macrothrombocytopenia and neutrophil (leukocyte) inclusions with associated hereditary nephropathy, hearing loss (sensorineural defects), and cataract (ocular) anomalies. The majority of the affected individuals are asymptomatic and show minor bleeding manifestations. In many people it is identified only by chance detection; diagnosed during other routine blood screening tests.

In autosomal dominance, inheriting only one copy of the defective gene is sufficient for the expression of the disease-causing change and the particular person exhibits the disease. Each offspring of the affected individual with an autosomal dominant trait has a 50 percent chance of inheriting the defective gene variant.

What Are the Clinical Features of Fechtner Syndrome?

The symptoms could begin at any time in a person’s life. Age of onset varies widely from 14 weeks old newborn to adults of 19 to 65 years of age. The manifestation of symptoms differs from one individual to another. The severity also ranges from mild to severe. The most common signs and symptoms are as follows:

• History of epistaxis (nasal bleeding) and frequent bruising in childhood.

• Macrothrombocytopenia.

• Leukocyte inclusions.

• Hereditary nephritis (inflammation of the renal tubules in the kidney).

• Nephropathy and renal insufficiency.

• Hematuria (blood in urine).

• Albuminuria (presence of proteins in the urine).

• Sensorineural deafness (hearing impairment due to the development of lesions and abnormal functioning of the cochlear nerve).

• Cataracts (presenile - early onset at a younger age).

• Ecchymosis (bruising and skin discoloration).

• Increased susceptibility to bruising.

• In females, increased and excessive menstrual flow (excess of 80 mL and lasting for more than seven days) recurrent urinary tract infections.

• Heart attack (very rare in severe cases).

• End-stage renal failure.

What Are the Diagnosis Available for Fechtner Syndrome?

The diagnosis of Fechtner syndrome is challenging because of its rare occurrence, mild phenotypic bleeding, and heterogeneous clinical manifestations. Detailed family history and molecular diagnosis approach help to analyze the outcome of the disease. The following diagnostic approach is beneficial to detect Fechtner syndrome.

• Detailed family history and past history of bleeding episodes are to be recorded.

• Standardized diagnostic criteria include assessment of platelet count, mean platelet volume, and platelet function tests.

• Complete hemogram screening - mean platelet volume (MPV) is markedly higher than normal (7 to 10 fl).

• Increased platelet count.

• Platelet histogram and platelet scatter plot helps to identify immature platelet fractions.

• Peripheral blood smear indicates giant platelets (diameter larger than four to seven micrometers) and neutrophils with cytoplasmic inclusions.

• Prolonged bleeding time.

• Elevated liver enzymes such as SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic oxaloacetic transaminase) in the serum, are suggestive of liver damage.

• Increased platelet volume higher than the upper limit of the normal standard interval.

• Hearing examination shows conductive deafness and perforations in the tympanic membrane in both or single ears.

• Audiometric evaluation detects moderate high-tone sensorineural hearing loss bilaterally (maximum loss of 80 dB).

• The neutrophils of affected individuals show small (1- to 2-μm), irregularly shaped, several cytoplasmic inclusions that appear pale blue in Wright's-Giemsa stain under light microscopy.

• Chemiluminescence immunoassay on neutrophils helps in detecting ultrastructural details.

• The striking feature of neutrophils that is unique for Fechtner syndrome is that they are distinctively smaller in size and comparatively less well stained than other inclusion bodies.

• Fechtner inclusions show clusters of ribosomes and rough endoplasmic reticulum fragments at the ultrastructural level.

• Platelet functioning tests such as platelet aggregation is normal.

• Flow cytometry also shows normal platelet functions.

• The bleeding time (BT), prothrombin (PT), thrombin time (TT), activated partial thrombin time (aPTT), and fibrinogen levels are normal.

• A slit lamp examination of the eyes shows bilateral cerulean (deep blue discoloration) cataracts.

• DNA analysis including NGS (next generation sequencing) helps in identifying genetic mutations in the MYH9 gene.

What Are the Management Protocols for Fechtner Syndrome?

No specific guidelines are available for the management of Fechtner syndrome. However, in case of severe clinical symptoms, appropriate interventions are followed to prevent severe blood loss and organ damage.

• Platelet transfusion is required in severe bleeding.

• Non-leukocyte transfusions are recommended to prevent reactive overload on the kidneys.

• Antifibrinolytic therapy like Aminocaproic acid and Tranexamic acid are used to stop mucocutaneous bleeding, menorrhagia (menstrual bleeding more than seven days), and gastrointestinal bleeding.

• The use of recombinant activated factor VII is found to be effective.

• Dialysis and renal transplantation.

• The use of corticosteroid therapy is effective in controlling inflammatory reactions.

• Renal allograft also proves functionally effective.

• Thrombopoietin-receptor agonists are effective in elevating platelet count.

• Genetic counseling and prenatal analysis would help to prevent the transfer of defective genes to the offspring.

Conclusion

Fechtner syndrome is an inherited disorder of defective platelets associated with multiple abnormalities- renal dysfunction, hearing loss, and early cataract formation. Though the majority of the affected individuals are asymptomatic, few exhibit mild forms of bleeding tendency. The prime challenge in its diagnosis is its heterogeneous clinical presentation. Detailed past and family history, advanced diagnostics, and early therapeutic interventions would result in a better prognosis for the syndrome.