Brain & Development xxx (2012) xxxxxx www.elsevier.

com/locate/braindev

Case report

Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome

Ryo Narazaki a,b, Mika Makimura b, Masafumi Sanefuji b, Shigeru Fukamachi a, Hidetaka Akiyoshi a, Hidenori So a, Kenichiro Yamamura b, Sayoko Doisaki c, Seiji Kojima c, Kenji Ihara b, Toshiro Hara b, Shouichi Ohga a,b,d,
a Division of Pediatrics, Tagawa Municipal Hospital, Fukuoka, Japan Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan c Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan d Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan b

Received 14 May 2012; accepted 14 October 2012

Abstract Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease, caused by a de novo mutation of lamin-A gene, LMNA G608G. Accumulation of abnormal lamin-A (progerin) compromises nuclear membrane integrity and results in the accelerated senescence. Aected patients show a typical feature of birdlike face, alopecia, sclerotic skin, loss of subcutaneous fat, and short stature with advancing years. Neonatal scleroderma is the rst presentation, although early diagnosis is challenging. The leading cause of death is cardio-/cerebro-vascular accidents associated with atherosclerosis. However, not all ndings may recapitulate the aging process. We herein report a 9-year-old Japanese male with HGPS who developed cerebral infarction. The genetic study of peripheral blood-derived DNA determined a heterozygous c.1824C>T mutation, p.G608G. Telomere length of lymphocytes was normal. Bilateral stenosis of carotid siphons was prominent, while systemic arteriosclerosis was unremarkable assessed by the ankle-brachial index, carotid ultrasound imaging and funduscopic study. HGPS patients have marked loss and functional defects in vascular smooth muscle cells, leading to the vulnerability to circulatory stress. Symmetrical stenosis of siphons might occur as a distinctive cerebral vasculopathy of HGPS, rather than simple vascular senescence. Peripheral blood study on LMNA G608G and telomere length could screen progerias in infancy for early therapeutic intervention. 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Cerebral infarction; Laminopathy; Progerin

1. Introduction Hutchinson-Gilford progeria syndrome (HGPS; OMIM 176670) is a rare premature aging disorder [1]. According to the progression, it is called childhood progeria, in contrast to adult progeria of Werners syndrome (WS). HGPS patients show baldness, salient scalp veins, frontal bossing, goggle eyes, a glyphic nose, micrognathia, short clavicles and joint contractures.

Abbreviations: CT, computed tomography; HGPS, Hutchinson-Gilford progeria syndrome; MR, magnetic resonance; WS, Werner syndrome Corresponding author at: Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel.: +81 92 642 5421. E-mail address: ohgas@pediatr.med.kyushu-u.ac.jp (S. Ohga).

0387-7604/$ - see front matter 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.10.008

Please cite this article in press as: Narazaki R et al. Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.10.008

R. Narazaki et al. / Brain & Development xxx (2012) xxxxxx

Fig. 1. (A) Fluid level attenuated inversion recovery (FLAIR)-magnetic resonance image on admission revealed multiple spotty infarctions in the bilateral frontal lobes, and a massive infarction in the right parietal lobe (arrows). (B) Posterior view of cranial magnetic resonance angiography demonstrates bilateral occlusion of the supraclinoid portions of the internal carotid arteries (arrows).

Fig. 2. Direct sequence of LMNA gene using peripheral blood lymphocyte-derived DNA determined the heterozygous mutation of G608G, GGT>GGC in the exon 11, that is specic for the diagnosis of the classical HGPS.

Patients walk at a horse-riding stance, and have normal intelligence. Because aected infants appear normal at birth, early diagnosis is challenging. HGPS arises from a de novo mutation of heterozygous lamin-A gene (LMNA), that encodes nuclear lamins lining the inner nuclear membrane. Accumulation of abnormal laminA (progerin) compromises nuclear membrane integrity and leads to aging process. HGPS is classied into laminopathies including lipodystrophy, cardiomyopathy, muscular dystrophy, and CharcotMarieTooth disease. HGPS patients die at age 13 years on average from myocardial infarction or stroke. Atherosclerosis could explain the leading cause of death. However, not all ndings may recapitulate accelerated senescence. There is little information on cerebral vasculopathy. We herein report a Japanese HGPS patient who had bilateral stenosis of carotid siphons, with reviewing literature. 2. Case report A 9 year-old male visited us because of limping and occasional headache. He was born to healthy Japanese

non-consanguineous parents at 38 gestational weeks, weighing 2580 g. Three siblings were healthy. Mother noticed his hard skin and failure to thrive 2 months after birth. At age 8 months, skin biopsy led to the diagnosis of scleroderma. Before entering an elementary school, he had boldness, prominent eyes, sparse fatty tissues, and joint stiness. The boy enjoyed school-life, and was lost to follow-up. At age 9 years, he was hospitalized because of the limping for a few days. On admission, the thin boy (height: 93.8 cm [-6.9SD], weight: 10.4 kg [-3.0SD]) showed calvities, obvious scalp veins, prominent eyes, a glyphic nose and micrognathia. Pulse (110/min) and respiration (28/min) rates were regular. Blood pressure (130/84 mmHg) was high. Narrow thorax and extremities showed rigid skin, subcutaneous fat loss, and sti joints. Cardiopulmonary sounds were normal. There was no hepatosplenomegaly. Left hemiparesis was dened. Complete blood counts showed WBC 7.10 109/L, hemoglobin concentrations 13.3 g/dL and a platelet count of 442 109/L. Blood chemistries revealed normal liver and renal functions. Lipid, endocrinological and coagulation proles were unremarkable. Brain natriuretic peptide levels were normal. There was no infection. Magnetic resonance (MR) imaging disclosed small infarctions in the bilateral frontal areas, and a large infarction in the right parietal area (Fig. 1A). MR angiography depicted bilateral obstruction of the supraclinoid portions of the internal carotid arteries (Fig. 1B). Electrocardiogram, holter records, and echocardiogram were normal. Funduscopic examination revealed no arteriosclerosis. The right 1.23 and left 1.20 ankle brachial pressure indices indicated no obstruction. Carotid echograms showed normal arterial walls without plaques or stenosis. Telomere length of peripheral blood (PB) lymphocytes of the patient (10.5, reference range: 10.120.1) and parents (father

Please cite this article in press as: Narazaki R et al. Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.10.008

R. Narazaki et al. / Brain & Development xxx (2012) xxxxxx Table 1 Reported patients with HGPS who developed cerebral infarction associated with bilateral stenosis of carotid siphon. Pt Sex LMNA G608G 1 2 3 4 5 6 7 8 9 10 m m f m m m m m f m NR NR NR NR NR Yes Yes Yes Yes Yes Age at diagnosis HGPS NR 4m NR NR NR NR 3y 2y 1y 8m CVAa 17 y 11 y 7y 7y 4y 5y 5y 9y 6y 9y Concurrent vascular lesions Angina 17 y 11 y 9y 8y No No No No 9y No Acral nec. No No No No No No No No No No Others No No No No No No No No No No Calcied microvessel walls (aut.) Bilateral ICA pinhole stenosis (aut.) Left ICA complete occlusion (ang.) Left ICA complete occlusion (ang.) Bilateral ICA occlusion Bilateral ICA complete occlusion Bilateral ICA severe stenosis Bilateral ICA occlusion Left ! Bilateral ICA stenosis Bilateral ICA occlusion Heart failure at 17 y Sudden death at 11 y Alive at 14 y Alive at 9 y NR Alive at 8 y Alive at 5 y Sudden death at 15 y Alive at 12 y CVA at 10 y Cerebral vasculopathy assessed by MRI/ MRA (or angiogram/autopsy) Cause of death at years of age Reportsb

Reichel (1970) Shozawa (1984) Dyck (1987) Naganuma (1990) Smith (1993) Merideth (2008) Rosman (2001) Nagakura (2010) Kato (2011) Our case

Pt: patient, NR: not recorded, nec: necrosis, ICA: internal carotid artery, MRA: magnetic resonance imaging, MRA: magnetic resonance angiography, aut.: autopsy, ang.: angiography, m: month(s) of age, y: year(s) of age. a Cerebro-vascular accidents (CVA) include transient ischemic attack and cerebral infarction. b Reports were collected from Reichel et al. Am J Clin Pathol 1970;53:24353, Shozawa et al. Acta Pathol Jpn 1984;34:797811, Dyck et al. J Pediatr 1987;111:40710, Naganuma et al. No To Hattatsu 1990;22:716, Smith et al. Am J Neuroradiol 1993;14:4413, Merideth et al. N Engl J Med 2008;358:592604, Rosman et al. J Child Neurol 2001;16:2125, Nagakura et al. J Jpn Pediatr Soc 2010;114:193 (abstract), and Kato et al. J Jpn Pediatr Soc 2011;115:380 (abstract).

9.5, mother 8.1; Ref. range: 7.018.0) were normal assessed by ow-FISH analysis. Direct sequence of LMNA using PB-derived DNA identied the heterozygous mutation, p.G608G (Fig. 2B). Hemiparesis gradually improved with aspirin therapy, although transient ischemic attacks recurred 2 and 5 months after discharge. One year later, he fell down from a school chair, and developed subdural hematoma. Following a transient stop of aspirin, he died suddenly at age 10 years. 3. Discussion LMNA G608G is an exclusive genotype of HGPS. The incidence is 1 per 4 million live births. WS occurs at a higher incidence of 1 per 0.11 million population, and about 80% of cases were reported from Japan. We reviewed 20 HGPS cases in previous reports of Japan, but not more than half met with the phenotype. LMNA G608G was only determined in one Japanese case [2], and 3 cases recently presented in Annual Meetings of Japanese Pediatric Society. In our patient, neonatal scleroderma portended the premature aging. HGPS shares the features of rigid skin, skeletal anomalies, and joint stiness with restrictive dermopathy (RD; OMIM 275210) or mandibulo-acral dysplasia (MAD;

OMIM 248370). These syndromes arise from the dierent mutations in LMNA, or those in ZMPSTE24 that encodes a metalloproteinase involved in the post-translational processing of prelamin-A to mature lamin-A. Atypical HGPS and WS are associated with nonG608G mutations of LMNA [35]. Chen et al. [5] found 4 patients having heterozygous missense mutations in LMNA (A57P, R133L, and L140R) and wild-type WRN, among 26 patients diagnosed with atypical WS. They showed lipodystrophy but no alopecia or growth failure, indicating a distinct laminopathy from progeria. Telomere dysfunction occurs in progeria syndromes and segmental progerias such as dyskeratosis congenita. Telomere length is shortened in broblasts but not lymphocytes of HGPS [6]. Early diagnosis is required for farnesyltransferase inhibitor therapy. In this line, combined study on LMNA G608G and telomere length could eectively screen progeria in early infancy. The life-span of HGPS patients depends on the vascular senescence. Table 1 summarizes HGPS patients having carotid siphon stenosis. Atherosclerosis with calcication was found in 2 reports of autopsy. On the other hand, the remaining 8 had transient ischemic attacks as the rst manifestation of vasculopathy at around age 6 years. No other vasculopathy preceded cerebrovascular accidents. The pathological ndings in

Please cite this article in press as: Narazaki R et al. Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.10.008

R. Narazaki et al. / Brain & Development xxx (2012) xxxxxx

coronaries and aorta of HGPS patients resemble those of elderly persons, but are much more limited. Gerhard-Herman et al. [7] performed the cardiovascular assessment in the cohort of 26 HGPS patients, and demonstrated that accelerated vascular stiening was an early and pervasive mechanism of vasculopathy. Olive et al. [8] reported that adventitial brosis was representative of HGPS arteries, but was less prominent in noncardiovascular circulation. Vascular smooth muscle cells were defective in human iPS [9] and rodent model of HGPS. Occlusive carotid siphons are reported in patients with moyamoya disease, sickle cell disease and thalassemia. Functionally compromised vascular smooth muscle cells may predispose the crooked portion to circulatory stress. HGPS infants result in a progressive foreshortening of the distance between optic chiasm and bony orbit, leading to optic nerve redundancy and kinking [10]. Cranial remodeling might also aect the cerebrovascular formations. Symmetrical siphon stenosis may occur as a unique cerebral vasculopathy of HGPS, compounded by accelerated senescence. Contributions to authorship N.R. and O.S. treated the patient, and wrote the manuscript. M.M., I.K., D.S. and K.S. completed the genetic studies and the measurement of telomere length. S.M., Y.K., F.S., and A.H. supported clinical management. H.T. and O.S. organized the study and supported to complete the manuscript. Conict of interest There is no conict of interest required on the study. Acknowledgments We thank Dr. Eiko Kato (Div. Pediatr, Tosei General Hosp, Aichi, Japan), Dr. Masahiro Kamouchi (2nd Dept. Int. Med. Kyushu Univ. Hosp., Fukuoka,

Japan) and Dr. Kensuke Akiyoshi (Dept. Pediatr, Oita Univ. Hosp., Oita, Japan) for the helpful discussion. This work was supported by a Grant-in-Aid for Scientic Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a grant from research on intractable diseases for Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan. References
[1] Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, et al. Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 2008;358:592604. [2] Nakamura S, Makita Y, Takagi A, Hashimoto Y, Takahashi H, Ishida-Yamamoto A, et al. Hutchinson-Gilford progeria syndrome with severe skin calcinosis. Clin Exp Dermatol 2007;32:5258. [3] Fukuchi K, Katsuya T, Sugimoto K, Kuremura M, Kim HD, Li L, et al. LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome. J Med Genet 2004;41:e67. [4] Lehwalda LM, Renauda DL, Campeaub NG, Babovic-Vuksanovicc D. Novel LMNA mutation in a patient with progeroid phenotype. J Pediatr Neurol 2007;5:1438. [5] Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, et al. LMNA mutations in atypical Werners syndrome. Lancet 2003;362:4405. [6] Decker ML, Chavez E, Vulto I, Lansdorp PM. Telomere length in Hutchinson-Gilford progeria syndrome. Mech Ageing Dev 2009;130:37783. [7] Gerhard-Herman M, Smoot LB, Wake N, Kieran MW, Kleinman ME, Miller DT, et al. Mechanisms of premature vascular aging in children with Hutchinson-Gilford progeria syndrome. Hypertension 2012;59:927. [8] Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, et al. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol 2010;30:23019. [9] Zhang J, Lian Q, Zhu G, Zhou F, Sui L, Tan C, et al. A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 2011;8:3145. [10] Ullrich NJ, Silvera VM, Campbell SE, Gordon LB. Craniofacial Abnormalities in Hutchinson-Gilford Progeria Syndrome. AJNR Am J Neuroradiol 2012;33:14128.

Please cite this article in press as: Narazaki R et al. Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.10.008