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ATYPICAL HAEMOLYTIC URAEMIC SYNDROME ASSOCIATED WITH A CD46
MUTATION UNMASKED BY A SHIGELLA DIARRHOEAL ILLNESS
Vicky Brocklebank1, Edwin Wong2, Roy Ward3, Rick Fielding1, Tim Goodship1,2 , David
Kavanagh1,2
1
Renal Services Centre, Freeman Hospital, Newcastle upon Tyne, 2The Institute of Genetic
Medicine, Newcastle University, Newcastle upon Tyne, 3Department of Immunology,
Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne
BACKGROUND: Haemolytic uraemic syndrome (HUS) is characterised by the triad of
microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. The typical
form is caused by infection with Shiga-toxin (Stx)-producing bacteria, most commonly
Escherichia coli 0157:H7 and Shigella dysentariae. The atypical form (aHUS) results from
complement dysregulation; a number of causative complement gene mutations have been
identified.
CLINICAL DESCRIPTION: A 38 year old British woman presented with diarrhoea to A&E
in Holland and was found to have acute kidney injury (creatinine 663μmol/L),
thrombocytopenia and microangiopathic haemolytic anaemia. Blood and stool cultures were
positive for Shigella flexneri and antibiotics were administered. A diagnosis of Stx-associated
HUS was made and she was treated with steroids and plasmapheresis. She did not require
dialysis and her creatinine normalized. She returned to the UK and was referred to our renal
clinic.
S. flexneri does not usually produce Stx and Stx-PCR at the time of this patient’s
presentation was negative. This led us to investigate for aHUS.
GENETIC AND FUNCTIONAL ANALYSIS: Genetic analysis revealed a mutation in the
complement regulatory protein CD46 (c.286+2T>G). Functional analysis demonstrated a nonsecreted protein.
In individuals with mutations in complement genes, incomplete penetrance is seen and
disease may not manifest until middle age, suggesting that a triggering stimulus (e.g. infection)
is required. In this case, non-Stx diarrhoea unmasked the latent complement defect resulting in
aHUS.
DISCUSSION: This case raises important management issues as the patient is at risk of
recurrent aHUS at times of infection. She has been advised to present for assessment
immediately whenever she is unwell. Her relatives are also at risk and could be counselled. This
patient would be a candidate for the complement inhibitor Eculizumab during a future
recurrence.
In conclusion, HUS presenting in the context of diarrhoea is not necessarily typical (Shigatoxin) HUS, because atypical HUS is not uncommonly triggered by a diarrhoeal illness in
patients with complement gene mutations. We would recommend that investigating for aHUS is
considered when there are unusual features in the case history, because it has important
implications for management.