2. Chan TY, Critchley JA. An epidemiological study of the snakebites in the New Territories East, Hong Kong. Ann Trop MedParasitol 1994; 88: 219–21.

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5. Hardy DL Sr, Zamudio KR. Compartment syndrome,fasciotomy, and neuropathy after a rattlesnake envenomation:aspects of monitoring and diagnosis. Wilderness Environ Med2006; 17: 36–40.

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7. Weed HG. Nonvenomous snakebite in Massachusetts:prophylactic antibiotics are unnecessary. Ann Emerg Med1993; 22: 220–4.

8. Blaylock RS. Antibiotic use and infection in snakebite victims.South Afr Med J 1999; 89: 874–6.

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SUPPORTING INFORMATIONAdditional Supporting Information may be found in the on-line version of this article:

Figure S1 Superficial punctures and abrasions despite thesize of the snake.Figure S2 The locals happily playing with the poor snake incaptivity.

Please note: Wiley-Blackwell are not responsible for thecontent or functionality of any supporting materials sup-plied by the authors. Any queries (other than missing mate-rial) should be directed to the corresponding author for thearticle

Homozygous LMNA mutation R527C in atypical Hutchinson–Gilford progeriasyndrome: evidence for autosomal recessive inheritanceLili Liang, Huiwen Zhang, Xuefan Gu (guxuefan@online.sh.cn)Department of Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research,Shanghai, China

KeywordsFamilial occurrence, Inherited metabolic disorder,Mutation analysis, Skeletal dysplasia

CorrespondenceXuefan Gu, Xinhua Hospital, Kong Jiang Road1665#, Shanghai 200092, China.Tel: +86-21-65011012 |Fax: +86-21-65791316 |Email: guxuefan@online.sh.cn

Received16 December 2008; revised 20 March 2009;accepted 25 March 2009.

DOI:10.1111/j.1651-2227.2009.01324.x

Abstract

Aim: To describe two Chinese siblings of atypical Hutchinson–Gilford progeria syndrome (HGPS),

with genetic diagnosis and special clinical manifestation.

Methods: We screened the LMNA gene in four members of a consanguineous family, in which two

children were suffering from atypical HGPS. Besides general HGPS features, such as growth

retardation and characteristic appearance, special clinical phenotypes including disorders of digestive

system and severe skeletal damages were observed.

Results: Homozygous mutation 1579C>T, which predicts R527C, was identified in the exon 9 of

LMNA among the affected siblings. Heterozygous carrier status 1579C>T was detected in both of the

asymptomatic parents.

Conclusion: Homozygous mutation R527C in LMNA yields atypical HGPS, and it suggests an autosomal

recessive inheritance in this family.

INTRODUCTIONThe LMNA gene product, lamins A, is the main componentof the intermediate filamentous lamina, which lines betweenthe inner nuclear membrane and the chromatin. It is im-portant for nuclear architecture, DNA replication, mRNAtranscription and apoptosis (1).

Hutchinson–Gilford progeria syndrome (HGPS) is an ex-tremely rare genetic disorder resulted from mutations of theLMNA gene and characterized by premature ageing fea-tures. While appearing normal at birth, the affected childrenbegin to develop characteristic phenotypes within the first orsecond year, including short stature, distinctive appearance(alopecia, prominent forehead, beaked nose, micrognathia),skeletal dysplasia, loss of subcutaneous fat, atherosclerosisand cardiovascular disorders.

Most reported cases are Caucasian, and almost 90% ofthe classical cases of HGPS are caused by the dominant de novo

ª2009 Xuefan Gu/Journal Compilation ª2009 Foundation Acta Pædiatrica/Acta Pædiatrica 2009 98, pp. 1365–1367 1365

AbbreviationsHGPS, Hutchinson-Gilford progeria syndrome; MAD, mandibu-loacral dysplasia.

Liang et al. Hutchinson–Gilford progeria syndrome

single-base substitution 1824C>T, which activates a crypticsplicing site, in LMNA (2). Here we report two Chinesesiblings who bear a homozygous substitution R527C.

CASE REPORTSTheir parents are first-degree cousins. When presenting toour clinics, the affected boy was 11 years old and the youngsister was 3 years old. Otherwise, the family history indicatesno more affected relatives.

Case 1The boy was born at term after an unremarkable pregnancyand looked normal at birth. Alopecia appeared when hewas 2 months old. Meantime he suffered from diarrhoeaand itching of skin. Constipation began and continued untilnow since he was 2 years old. At the same time, skin hyper-pigmentation was apparent. Subsequently, joint mobilitydecreased in the knees and hips. He complained of precordiumpain periodically since he was 4 years old. Besides, growthretardation, loss of subcutaneous fat and skeletal deformityaggravated gradually while his intelligence and personalitymaintained normal.

At presentation, he had extreme short stature (height:87cm; weight: 9.95 kg), alopecia, prominent forehead, con-vex nasal ridge, micrognathia, narrow shoulder and a horse-riding stance (Fig. 1A). His skin was thin, dry and taut.Freckle-like hyperpigmentation spread over the whole body.His neck was fastened to left (Fig. 1A). Contrary to typicalHGPS, he had still full cheeks. Dry gangrene and calcifica-tion lesions could be seen on skin over joints (Fig. 1B). Thenails were short and dystrophic. Clavicles were impalpable.

His teeth were crowed and maloccluded as for preservationof baby teeth.

Case 2This patient was the younger sister of case 1. She was bornby unremarkable delivery. She seemed recapitulating herbrother’s history. Her hair appeared sparse since she was4 months old (Fig. 1C). At the age of 6 months, she pre-sented with diarrhoea. One year later, constipation beganand itching of skin started to afflict her. Mobility of fingersdecreased since the second year of life. There was no com-plaint of precordium pain yet. She was short (height: 80 cm;weight: 8.65 kg). Hyperpigmentation was widely distributedand more intense in the abdomen. The fingernails were dys-trophic (Fig. 1D).

Hepatic function, renal function, blood calcium, bloodphosphonium, blood free T3, free T4, TSH, serum choles-terol, triglyceride, lipoproteins and fasting blood glucose hadbeen tested for both the siblings and were all within the nor-mal range. For the brother, X-ray showed severe scoliosis,absent clavicles (Fig. 1E) and delayed bone age. The poste-rior fontanel of the brother was unusually wide with the twoparietal bones arching over the occipital bone, which mea-sured 10 cm in length at the arch base and 2 cm in height.Elevated ST segment in lead II of the electrocardiogram pro-vided evidence of myocardial ischaemia in the inferior wallof heart. For the younger sister, hypoplastic clavicles, slightscoliosis and delayed bone age were noted on radiography.Her electrocardiogram was still normal. Neither of themever had fracture.

The parents are healthy, having no relative sign or symp-tom.

Figure 1 (A) Case 1 with facial characteristics, loss of subcutaneous tissue and muscle atrophy. (B) Feet of case 1 showing dry gangrene and calcification on toes.

(C) Case 2 with facial characteristics. Note alopecia, visible scalp vein, prominent forehead and micrognathia. (D) Hand of case 2. Note the broadened, short distal

phalanges and flexion of the fingers. (E) Orthotopic radiograph of case 1 revealing severe scoliosis and absent clavicle. (F) Sequence at position 1579 of case. (G)

Sequence at position 1579 of parents.

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Hutchinson–Gilford progeria syndrome Liang et al.

Genomic DNA was extracted from blood, and LMNAmutation analysis was performed by the sequencing ofpolymerase chain reaction products. Among the four sam-ples, the only genomic sequence variation detected was a1579C>T missense mutation in exon 9 resulting in a R527Csubstitution. The two children are homozygous while boththe parents are heterozygous (Figs. 1F, G).

DISCUSSIONHGPS has been known for its variable phenotypes. How-ever, several features in our cases are special. First, disordersof digestive system had not been mentioned before. Second,skeletal damages were particularly severe, especially in case1. The absence of clavicles, persistence of both the anteriorand the posterior fontanelles and pronounced scoliosis in-dicated that bone changes were more severe than classicalHGPS. In combination with the feature of full cheeks, thecase could be categorized as atypical HGPS.

Many mutations have been confirmed to contribute toHGPS. Giovannoli et al. first described the heterozygousmutation 1824C>T in LMNA in two children affected withHGPS (3). Eriksson et al. confirmed the same de novo sub-stitution in LMNA, 1824C>T, and certified that it was themost common cause for classical HGPS (2). Recurrentheterozygous de novo point mutations in the LMNA genesupport the prevailing hypothesis that HGPS is a sporadic dom-inant disorder. However, in some cases, recurrence of HGPSin siblings from parental consanguineous families and com-pound heterozygous probands born by unaffected carrierparents suggested the alternative pattern of autosomal re-cessive inheritance (4–7). Our patients were affected by thelatter mode.

Naturally occurring mutations in human LMNA havebeen confirmed to be responsible for at least 12 diseases.They are collectively called laminopathies (8). The rela-tionship between genotype and phenotype was far fromclear. Mutations in different locations may cause differentlaminopathies. Even at the same site, different amino acidsubstitution may induce great clinical heterogeneity, such asin the case of mutation of codon 527. So far, three differentsubstitutions have been documented at this codon. R527Pwas associated with autosomal dominant Emery–Dreifussmuscular dystrophy (9). Homozygous R527H was the mostcommon mutation in mandibuloacral dysplasia (MAD) (10).R527C was described in a compound heterozygote patientwith the R471C, causing MAD in a 28-year-old female(11). MAD is characterized by postnatal growth retarda-tion, skeletal malformations and mottled cutaneous pig-mentation, showing considerable overlapping with HGPS.However, as for MAD, growth retardation, alopecia andlipodystrophy are less severe while osteolysis is usually moresevere than HGPS (6).

Interestingly, the different assembly of R527C and R471Cseems to yield distinct phenotypes. Besides the heterzygosityof R527C and R471C in MAD described above and the ho-mozygosity of R527C in our atypical HGPS patients, Zirn etal. described a patient with a distinct phenotype combining

muscular dystrophy, MAD and atypical progeria, which wascaused by a homozygous R471C (12).

R527 is situated within a hot region for mutations causingprogeria-like diseases, which consists of adjacent residuesR471, R527, T528, M540 and K542 (7). R527 is located atthe external surface of the domain and is involved in theformation of salt bridges (13). Arginine is a basic aminoacid while cysteine is neutral; therefore, R527C substitutionwould disrupt the surface structure of the protein and haveglobal effects on the lamin structure.

The patients we described here expanded the mutationspectrum of HGPS and provided further recognition of newphenotypic variations among HGPS patients.

ACKNOWLEDGEMENTSThis work has been approved by institutional ethics commit-tee and supported by Hi-Tech Research and DevelopmentProgram (2007AA02Z447) and National Science and Tech-nology Program (2006BAI05A05).

References

1. Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, SpannTP. Nuclear lamins: building blocks of nuclear architecture.Genes Dev 2002; 16: 533–47.

2. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J,Scott L, et al. Recurrent de novo point mutations in lamin Acause Hutchinson–Gilford progeria syndrome. Nature 2003;423: 293–8.

3. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, AmielJ, Boccaccio I, et al. Lamin: a truncation inHutchinson–Gilford progeria. Science 2003; 300: 2055.

4. Khalifa MM. Hutchinson–Gilford progeria syndrome: reportof a Libyan family and evidence of autosomal recessiveinheritance. Clin Genet 1989; 35: 125–32.

5. Plasilova M, Chattopadhyay C, Pal P, Schaub NA, BuechnerSA, Mueller H, et al. Homozygous missense mutation in thelamin A ⁄ C gene causes autosomal recessiveHutchinson–Gilford progeria syndrome. J Med Genet 2004;41: 609–14.

6. Hennekam RC. Hutchinson–Gilford progeria syndrome:review of the phenotype. Am J Med Genet A 2006; 140:2603–24.

7. Verstraeten VL, Broers JL, van Steensel MA, Zinn-Justin S,Ramaekers FC, Steijlen PM, et al. Compound heterozygosityfor mutations in LMNA causes a progeria syndrome withoutprelamin A accumulation. Hum Mol Genet 2006; 15: 2509–22.

8. McClintock D, Ratner D, Lokuge M, Owens DM, Gordon LB,Collins FS, et al. The mutant form of lamin A that causesHutchinson–Gilford progeria is a biomarker of cellular agingin human skin. Plos One 2007; 2: e1269.

9. Bonne G, Di Barletta MR, Varnous S, Becane HM,Hammouda EH, Merlini L, et al. Mutations in the geneencoding lamin A ⁄ C cause autosomal dominantEmery–Dreifuss muscular dystrophy. Nat Genet 1999; 21:285–8.

10. Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D’ApiceMR, Massart C, et al. Mandibuloacral dysplasia is caused by amutation in LMNA-encoding lamin A ⁄ C. Am J Hum Genet2002; 71: 426–31.

11. Pollex RL, Hegele RA. Hutchinson–Gilford progeria syndrome.Clin Genet 2004; 66: 375–81.

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Liang et al. Hutchinson–Gilford progeria syndrome

12. Zirn B, Kress W, Grimm T, Berthold LD, Neubauer B,Kuchelmeister K, et al. Association of homozygous LMNAmutation R471C with new phenotype: mandibuloacraldysplasia, progeria, and rigid spine muscular dystrophy. Am JMed Genet A 2008; 146A: 1049–54.

13. Burke B, Stewart CL. Life at the edge: the nuclear envelope andhuman disease. Nat Rev Mol Cell Biol 2002; 3: 575–85.

Ulcerative colitis associated with Takayasu’s arteritis in a childNecati Balamtekin (drbalamtekin@yahoo.com)1, Figen Gürakan1, Seza Ozen2, Bena Oguz3, Beril Talim4

1.Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Hacettepe University, Medical Faculty, Ankara, Turkey2.Department of Pediatrics, Hacettepe University, Medical Faculty, Ankara, Turkey3.Department of Radiology, Hacettepe University, Medical Faculty, Ankara, Turkey4.Department of Pediatric Pathology, Hacettepe University, Medical Faculty, Ankara, Turkey

KeywordsChild report, Takayasu arteritis, Ulcerative colitis

CorrespondenceNecati Balamtekin, MD, Department of Pediatrics,Section of Gastroenterology, Hepatology and Nutri-tion, Hacettepe University, Medical Faculty, Ankara0610, Turkey.Tel: +90-(312)305-1993Fax: +90-(312)305-4157Email: drbalamtekin@yahoo.com

Received26 December 2008; revised 11 February 2009;accepted 31 March 2009.

DOI:10.1111/j.1651-2227.2009.01330.x

Abstract

Takayasu’s arteritis (TA) and ulcerative colitis (UC) are chronic inflammatory diseases of unknown

aetiology, and their coexistence is very rare.

A 14-year-old Turkish girl presented with abdominal pain, nausea, vomiting and weight loss. UC was

diagnosed based on physical examination and laboratory investigations and was confirmed by

colonoscopic biopsies. TA developed approximately 1 year later, and was diagnosed with angiography

performed for ongoing severe abdominal pain in spite of well-controlled UC.

Patients suffering from chronic inflammatory diseases such as UC must be investigated for other

inflammatory diseases such as TA, especially if the response to immunosuppressant therapy is

unsatisfactory.

Conclusion: Findings from our patients suggest that paediatricians must remain alert to the possibility of abdom-

inal vasculitis in patients with UC and unresolved abdominal pain in spite of clinical remission.

INTRODUCTIONTakayasu’s arteritis (TA) and ulcerative colitis (UC) are un-common chronic inflammatory diseases, and their aetiolo-gies remain unknown. TA is more prevalent in Japan andSoutheast Asia, whereas UC is more common in NorthAmerica and Europe. The coexistence of these two diseasesis very rare, with only some 50 cases, mostly adults, reportedworldwide and more than half of them from Japan. This as-sociation has not been reported previously in Turkey.

We report herein a female adolescent patient with anoverlapping syndrome of TA and UC.

CASE REPORTA 14-year-old Turkish girl admitted to our outpatient unitin January 2008 with abdominal pain, nausea, vomiting andweight loss of 12 kg. Her previous medical and family his-tory was unremarkable. Her complaints had started approx-imately 1 year before. She suffered from abdominal pain,fatigue and vomiting. She was diagnosed as anorexia ner-vosa and treated with risperidone and sertraline. There wasno regression in her complaints after 4 months and irondeficiency anaemia developed. After 8 months, she was referredto our hospital because of unresponsiveness to ironsupplementation and ongoing complaints.

Her physical examination on admission revealed a bodytemperature of 37.4�C, pulse rate 80 ⁄ min, weight 35.2 kg

(<3rd percentile) and height 155 cm (50th percentile).Blood pressure was 110 ⁄ 70 mmHg. She seemed apathic andmoderately pale with severe abdominal pain. No other ab-normality was detected on physical examination.

Laboratory data showed: haemoglobin 11.5 g ⁄ dL (range:12–18), white blood count 15 600 ⁄ mm3 (range: 4100–11 200), thrombocyte count 578 000 ⁄ m3 (range: 159 000–388 000), mean corpuscular volume (MCV) 66 femtolitre(fl) (range: 80.4–95.9), erythrocyte sedimentation rate (ESR)67 mm ⁄ h (range: 3–20), fibrinogen 690 mg ⁄ dL (range: 144–430) and C-reactive protein (CRP) 12.5 mg ⁄ dL (range: 0–0.8). Biochemical tests revealed normal liver enzymes. Totalprotein and albumin levels were 7.78 g ⁄ dL (range: 6.0–8.0)and 3.68 g ⁄ dL (range: 3.8–5.4), respectively. Renal functiontests were normal. Faecal calprotectin level was high at316.5 mg ⁄ L (range: <50) and p-ANCA was negative. Serumimmunoglobulin IgA was 326 mg ⁄ dL, and antiendomysiumantibody IgA and antitissue transglutaminase IgA were nega-tive. Tuberculin test was negative. Occult blood in stoolwas positive. Mutational analysis for familial Mediterraneanfever was negative. Abdominal ultrasonography showed wallthickening in the ascending colon, caecum and terminalileum. There were a few enlarged mesenteric lymph nodes.Barium radiography of the small intestine and colon werenormal. Upper gastrointestinal endoscopy and histopatho-logical examination of the biopsy samples were normal.Colonoscopy demonstrated erythematous, granular mucosa

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Ulcerative colitis associated with Takayasu’s arteritis in a child Balamtekin et al.