A Novel Frameshift Mutation in a Case of Familial May-Hegglin Anomaly.

The May-Hegglin anomaly is a rare, autosomal dominant condition that is characterised by thrombocytopaenia, anisocytosis, and Dohlë-like inclusion bodies in leukocytes. The disorder generally results in a mild bleeding tendency. May-Hegglin anomaly results from defects in the MYH9 gene, which encodes the heavy chain of nonmuscle myosin IIA. The gene maps to chromosome 22q12.3-q13.2, comprises 40 exons, and produces a 5.8kb mRNA transcript.

We present a case of familial May-Hegglin anomaly. This kindred was first identified, and published, in 1964; but no further analyses were carried out until recently.

The proband, now aged 80 years, has a life long history of easy bruising and epistaxis, although the symptoms have improved with increasing age. Her sister (deceased) and daughter reported similar symptoms: the daughter requiring splenectomy for thrombocytopaenia at age 9 years. The proband has also suffered from deafness for in excess of 60 years.

Recent investigations of the proband revealed a mild thrombocytopaenia, and the characteristic blood film of May -Hegglin anomaly. Platelet and neutrophil morphology were also consistent with the disorder. Karyotype analysis revealed good quality G banding throughout chromosome 22, and no gross alteration in the region 22q11.2., 22q13. Direct sequencing of the MYH9 gene identified a heterozygous deletion of a single base in a run of Gs at nucleotide positions 5818–5821 (codons 1940–1941). This frame shift mutation leads to the creation of a premature termination sequence at codon 1947, and the loss of the last fourteen amino acids. The deletion introduces a restriction site, and endonuclease digestion of a panel of normals failed to detect this change. Together with the fact that this is a conserved region across species (human, rat, rabbit, chicken), it is probable that this deletion is the causative mutation in this kindred.

This novel mutation represents the second reported defect affecting the tail-piece domain in May-Hegglin anomaly. The protein’s two heavy chains homodimerise in this region to form a tail, and multiple polypeptides associate through this tail domain to form bipolar filaments. Therefore, a mutation in this domain may exert its effect by the inhibition of myosin filament assembly.

To date, approximately 20 different mutations have been described in the MYH9 gene giving rise to not only May-Hegglin anomaly, but also the similar disorders of Fechtner syndrome, Sebastian syndrome and Epstein syndrome. In fact some mutations have been identified in patients with different diagnoses. The proband presented here has a long standing diagnosis of May-Hegglin anomaly, but does exhibit one symptom (deafness) more usually associated with Fechtner syndrome. The genetic, phenotypic and clinical overlap in these disorders suggest that these actually represent allelic variations of a single genetic disorder, which should more correctly be termed ‘MYHIIA syndrome’.