Easy Bruising, Cataracts, and Hearing Loss in a 27-Year-Old Female

Alexandra Harrington, MD, MT(ASCP); Patrick C. J. Ward, MB, BCh; Steven H. Kroft, MD


Lab Med. 2008;39(1):20-22. 

In This Article

Principle Laboratory Results

Table 1


  1. What are the patient's most striking clinical and laboratory findings?

  2. How do you explain this patient's most striking clinical and laboratory findings?

  3. What is this patient's most likely diagnosis?

  4. How do you best explain the discrepancy between the automated and manual platelet counts?

  5. What is the genetic basis of this patient's condition?

  6. What additional tests are available to confirm this diagnosis?

  7. With which disease is this patient's condition most often misdiagnosed?

  8. What is the treatment for individuals with this patient's disease?

Possible Answers

  1. The most striking clinical findings are a history of medically- and surgically-refractory thrombocytopenia, presenting as easy bruising during childhood, a history of renal failure secondary to Alport's syndrome requiring a renal transplant, obese and cushingoid body habitus, and multiple bruises which could be explained by recent trauma. The most striking laboratory findings include severe thrombocytopenia with an elevated mean platelet volume, giant platelets, small DF6hle-like bodies in many neutrophils, target cells, and Howell-Jolly bodies in the red blood cells ( Table 1 and Image 1).

  2. The patient's clinical and laboratory findings suggest a congenital macrothrombocytopenia syndrome. This rare inherited group of disorders, including May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, Epstein syndrome, Bernard-Soulier syndrome, DiGeorge syndrome, Gray platelet syndrome, and X-linked macrothrombocytopenia with dyserythropoiesis is characterized, as the name implies, by low platelet counts and giant platelets (defined as platelets equal to or greater than the size of a red cell). Congenital macrothrombocytopenias are variable in their clinical presentations, ranging from asymptomatic, incidentally-discovered conditions to severe bleeding disorders.[1,2] A subset of these disorders—May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome—are characterized by mutations in the myosin heavy chain 9 (MYH9) gene, and are therefore classified as MYH9-related diseases.[1,2,3] Despite the genetic commonality and shared macrothrombocytopenia, the individual disorders are distinguished by variable manifestations of Alport's syndrome, (including nephritis, cataracts, and hearing loss) and variable presence of leukocyte inclusions. For example, patients with May-Hegglin anomaly and Sebastian syndrome do not have clinical signs of Alport's syndrome but do have different types of DF6hle-like leukocyte inclusions, which can be discriminated from each other ultrastructurally. Fechtner syndrome patients have the triad of nephritis, cataracts, and hearing impairment, along with DF6hle-like bodies within the leukocytes. Finally, patients with Epstein syndrome have hearing impairment and nephritis but do not have identifiable leukocyte inclusions. These 4 macrothrombocytopenia syndromes may represent a single disorder (MYH9-related disease) with variable expression of the discussed clinical and laboratory findings[3] ( Table 2 ).

    The red blood cell changes in this case, including Howell-Jolly bodies and increased target cells, can be explained by the prior splenectomy. A normally-functioning spleen will remove red cell inclusions from circulating erythrocytes. The patient's cushingoid body habitus is the result of her chronic corticosteroid use.

  3. Most likely diagnosis: Fechtner syndrome. This syndrome was first described in 1985 by Peterson and colleagues in a study of a family with nephritis, cataracts, deafness, macrothrombo cytopenia, and small, pale blue, irregularly-shaped cytoplasmic inclusions resembling DF6hle bodies within their leukocytes.[4] In this original report, it was demonstrated that these inclusions are ultrastructurally distinct from the light microscopically-similar inclusions seen in May-Hegglin anomaly and the DF6hle bodies seen in toxic neutrophils. On Wright-Giemsa-stained smears, Fechtner inclusions were smaller and paler than May-Hegglin inclusions, and compared with the irregularly-distributed DF6hle bodies of sepsis, Fechtner inclusions were present in nearly every cell examined and were present without other toxic changes.[4]

  4. A manual platelet count was performed in this case because of the inaccuracy of automated counts in the presence of significant numbers of giant platelets. Most automated analyzers enumerate platelets based on cell size thresholds. When platelets are enlarged, analyzers may count them as red cells or even leukocytes, thus reporting a falsely-low platelet count.

  5. In addition to their clinical heterogeneity, the MYH9-related disorders are genetically heterogeneous. The group shares mutations in the MYH9 gene, located on chromosome 22q12-13, which encodes for the heavy chain of the non-muscle myosin IIA (NMMHC-IIA) protein, a cytoskeleton protein in hematopoietic cells.[2] In the literature, 22 different MYH9 gene mutations have been described in 77 unrelated families with disease associated with this genetic locus.[3] The majority of these mutations are transmitted in an autosomal dominant fashion, with a minority (20%) representing sporadic, acquired mutations.[1]

  6. Immunofluorescence and immunocytochemical assays for neutrophil NMMHC-IIA protein are available.[1,3,5,6] In MYH9-related disease, this protein abnormally localizes in the cytoplasm of leukocytes. The localization of NMMHC-IIA corresponds to the DF6hle-like inclusions seen on Giemsa-stained preparations.[3] These localization assays are performed on peripheral blood and are highly sensitive and specific.[6] Additionally, MYH9 gene mutation analysis can be performed, but these assays are not widely available.[5]

  7. Congenital macrothrombocytopenias are often misdiagnosed as immune thrombocytopenic purpura (ITP),[2,7] an acquired autoimmune disorder characterized by peripheral destruction of platelets. Peripheral blood smear examination may provide diagnostic clues in differentiating these 2 entities. Though present in varying proportions, giant platelets may be seen in both conditions, the result of multiple mechanisms in congenital macrothrombocytopenias and accelerated platelet production in ITP.[2] In general, a greater proportion of platelets will be enlarged in the congenital macrothrombocytopenias as compared with ITP.[1] The presence of leukocyte inclusions limits the differential to MYH9-related disorders, as previously discussed. If available, previous platelet counts may also be helpful. Patients with congenital syndromes will have persistently-low platelet counts since birth, while normal platelet counts may have been documented at a previous time in patients with ITP. Finally, obtaining a detailed history and physical examination is important. Of note, because some of the disease manifestations of the congenital syndromes do not present until later in life, such as cataracts, nephritis, and deafness, a detailed family history is essential, especially in the pediatric population.[7]

  8. Despite the thrombocytopenia, the majority of patients with MYH9-related disease do not have clinically-significant bleeding problems[1,2] and in general do not require treatment. When serious bleeding does occur, platelet transfusions, recombinant factor VII, and antifibrinolytics may be effective.[1] Patients may require prophylactic platelet transfusions prior to procedures or surgery.[1] As illustrated in this case study, patients are usually unresponsive to the standard ITP therapies of corticosteroids, IVIG, and splenectomy.

Figure 1.

The patient´s peripheral blood smear revealed (A) giant, well-granulated platelets, occasional target cells (black arrows) and (B) small, basophilic Döhle-like inclusion bodies within many of the neutrophils (blue arrow). Also seen were rare large Döhle-like inclusion bodies (C, arrowhead) and occasional Howell-Jolly bodies within the red blood cells (red arrow). The leukocyte inclusions are, in general, smaller than those seen in May-Hegglin anomaly and are not accompanied by the toxic changes that are typically present in sepsis.


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