Familial Takayasu arteritis - a pediatric case and a review of the literature
© Morishita et al; licensee BioMed Central Ltd. 2011
Received: 21 September 2010
Accepted: 2 February 2011
Published: 2 February 2011
Takayasu arteritis (TA) is a rare chronic inflammatory disease of the aorta and its major branches. It is seen predominantly in females during the second and third decades of life, although it can occur in childhood. The aetiology of TA remains unknown. To date, familial cases of TA have been considered rare; however, a review of the literature suggests that cases are accumulating. We report a case of two sisters affected by severe TA, and review other reported familial cases.
Takayasu arteritis (TA) is a chronic, idiopathic large vessel vasculitis. It primarily involves the aorta and its main branches. Although the aetiology of TA has been extensively investigated, it remains unknown. The disease is more common in females and is seen predominantly in Asian countries although it has a worldwide distribution. Despite several reported associations with HLA alleles, results are heterogeneous and differ across populations. A review of the literature suggests that familial TA may not be as rare as once thought and this finding may have both aetiological and clinical implications for family screening. The following case describes a 4-year old girl with severe TA whose older sister died of the same disease.
Our female patient was born to non-consanguineous Italian parents in 1990 after an uneventful pregnancy. Both parents were healthy and the family history was unremarkable except for the following history in her sibling. Her older sister had been diagnosed with TA in Belgium at the age of 10 years. Only limited information was available to us regarding this sibling: she had a history of severe hypertension and persistently elevated acute phase markers (high erythrocyte sedimentation rate, ESR; and high C-reactive protein, CRP) as well as involvement of her cerebral, abdominal, and renal arteries. At the age of 15 years this sibling died of a massive cerebral haemorrhage. No autopsy was performed; therefore, the cause of the haemorrhage was never identified. Our patient was transferred to Great Ormond Street Hospital (GOSH), London in 2006 after a severe and resistant course. She had been diagnosed with TA at the age of 4 years after presenting with hypertension and persistently raised inflammatory markers (ESR 50-105 mm/hour; CRP 40-95 mg/L). Catheter arteriography at the time of diagnosis revealed stenotic abnormalities of the superior mesenteric, renal and internal carotid arteries. Her initial management included prednisone, nifedipine, and labetolol. Over the next several years she developed impaired renal function with glomerular filtration rates between 50-60 ml/min/1.73 m2 and had ongoing hypertension despite addition of enalapril and commencement on azathioprine. In 2002, at the age of 12 years she underwent bilateral balloon dilatation of her renal arteries. In 2004 she had three intracranial haemorrhages from a basilar artery aneurysm, which was subsequently coiled. Between 2003 and 2006 she developed recurrent gastrointestinal complaints of abdominal pain, diarrhoea and weight loss due to superior mesenteric artery (SMA) stenosis and secondary intestinal ischemia. She required balloon dilatation of the SMA on four separate occasions. During the same time period she was diagnosed with episodic atrial fibrillation requiring treatment with flecainide. Her echocardiogram showed bilateral ventricular hypertrophy, mild aortic regurgitation, and mild stenosis of the distal main pulmonary artery. The atrial fibrillation and cardiac changes were felt to be secondary to longstanding hypertension in the context of large vessel vasculitis. Acetylsalicylic acid (ASA) or other antiplatelet agent was not initiated due to the patient's previous history of intracranial bleeds, precarious vasculature, and persisting hypertension.
Summary of familial cases of Takayasu arteritis
Affected family members
Possible genetic associations
HLA A11, Bw40, Bw52
HLA A9, A10
HLA A9, DRw4
HLA DR2, DR4
Brother and sister
Mother and daughter
Aunt and niece
Our literature search revealed that a large proportion of familial cases were reported over 15 years ago. The reason for this is unclear. The availability and quality of imaging modalities used in the past may have affected diagnostic accuracy; however, for those cases in which clinical details were provided, many cases had angiographic findings typical of TA suggesting that the diagnoses were reliable (3, 8, 9, 12, 15). Most of the older studies originated in Japan, and it is possible that even if new cases are occurring, they are simply not being reported unless they are unique in some way.
Our review of familial cases also revealed that many affected siblings were only diagnosed after they presented with late signs and symptoms of disease, without having previously been evaluated for absent pulses, four-limb blood pressure inequality, or hypertension [8, 9, 15]. This was especially true for non-twin cases. Tsai and colleagues report a case of two teenage sisters in which there was a significant delay in diagnosis of the second sister in part due to failure to palpate pulses and obtain 4-limb blood pressures at the time of initial evaluation . An asymmetric radial pulse was noted incidentally on follow-up examination after a two month history of fever of unknown origin and vague left arm pain, even though the patient's older sister had previously been diagnosed with TA. Makino and colleagues report a case of two brothers aged 17 and 14 years, where the younger brother was diagnosed 4 years after the older brother when he presented with neck pain and general malaise. Physical examination revealed blood pressures of 144/60 and 160/54 mmHg in the right and left arms, respectively. Arteriography showed a grossly dilated aortic arch and bilateral carotid artery narrowing . Other cases are similarly described with delayed diagnosis of familial TA with considerable late disease related damage and large vessel injury .
Differential diagnosis for Takayasu arteritis
Septicemia or endocarditis (mycotic aneurysms)
Human immunodeficiency virus
Giant cell arteritis (adults)
Systemic lupus erythematosus
Congenital coarctation of the aorta
Congenital mid-aortic syndrome
Ehlers-Danlos type IV
Neurofibromatosis type I
Post radiation therapy
Familial TA is an important clinical entity, which may not be as rare as we once thought. This case and review provides further support for the role of as yet undefined genetic factors in the development of TA, and emphasizes the need for studying such informative familial cases to look for candidate genes. In addition, physicians should maintain a high index of suspicion for the possibility of TA in the siblings or other family members of affected patients. Screening using four-limb blood pressure measurements and pulse checks should be considered in these cases, progressing to non-invasive imaging such as ultrasound followed by MRA if abnormalities are detected. Such relatively non-invasive screening may prevent delays in diagnosis and minimize morbidity of other familial cases.
Written consent was obtained from the patient's mother for this publication.
We thank Lil-Sofie Muller, MD, Great Ormond Street Hospital, London, UK for further review of the radiological data.
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