infantile facioscapulohumeral muscular dystrophy revisited: expansion of clinical phenotypes in...

Available online at www.sciencedirect.com

ARTICLE IN PRESS

www.elsevier.com/locate/nmd

Neuromuscular Disorders xxx (2013) xxx–xxx

Infantile facioscapulohumeral muscular dystrophy revisited: Expansionof clinical phenotypes in patients with a very short EcoRI fragment

Tai-Heng Chen a,b, Yu-Hung Lai c,d, Pei-Lun Lee b, Jong-Hau Hsu b,d, Kanako Goto e,Yukiko K. Hayashi e,f, Ichizo Nishino e,f, Chin-Wen Lin g, Hsiang-Hung Shih b,Chao-Ching Huang h, Wen-Chen Liang b, Wen-Fu Wang i,j,⇑, Yuh-Jyh Jong b,d,g,⇑

a Division of Pediatric Emergency, Department of Emergency, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwanb Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

c Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwand Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

e Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japanf Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan

g Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwanh Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan

i Department of Neurology, Changhua Christian Hospital, Changhua, Taiwanj Center for General Education, Central Taiwan University of Science and Technology, Taichung, Taiwan

Received 1 August 2012; received in revised form 25 December 2012; accepted 7 January 2013

Abstract

Contrary to the classical form, infantile facioscapulohumeral muscular dystrophy (FSHD) usually denotes a severe phenotype and isfrequently associated with extramuscular involvements. To elucidate the genotype–phenotype correlation in this severe subgroup, weidentified a cohort of nine patients with infantile FSHD who also carried a very short (10–13 kb) EcoRI fragment. Their current ageranged from 8 to 33 years and age of onset ranged from 0.4 to 5 years. One patient even manifested his first FSHD-relatedsymptoms at as early as 5 months of age, including inability to smile, poor response to call, and infantile spasms. To date, fourpatients were wheelchair-bound and six patients had asymmetric weakness. Sensorineural hearing loss and abnormal fundoscopicfindings were observed in eight and all of patients respectively. Three with the smallest EcoRI fragments (10–11 kb, with normallength being 50–300 kb) had mental retardation. Two of these had epilepsy. Cardiac arrhythmias were found in five patients.Restrictive ventilatory defects were observed in seven patients, with one progressing to chronic respiratory failure. Two hadswallowing difficulties; one of these required gastrostomy. We identified several rarely reported phenotypes in infantile FSHD,including cardiac arrhythmia, respiratory insufficiency, and swallowing difficulties. There seems to be a correlation between theseverity of phenotype and the very short EcoRI fragment in the chromosome 4q35 region. We conclude that the high frequency ofmulti-organ involvements in this severe FSHD variant suggests the need for an early and multidisciplinary intervention.� 2013 Elsevier B.V. All rights reserved.

Keywords: Infantile onset; Facioscapulohumeral muscular dystrophy; EcoRI fragment; Cardiac conductive defect; Restrictive ventilatory defect

0960-8966/$ - see front matter � 2013 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.nmd.2013.01.005

⇑ Corresponding author. Address: Graduate Institute of Medicine,College of Medicine, Kaohsiung Medical University, No. 100, Shih-Chuan1st Road, Kaohsiung 80708, Taiwan. Tel.: +886 7 311 7820; fax: +886 7321 2062, Department of Neurology, Changhua Christian Hospital, No.135, Nanxiao St., Changhua City, Changhua County 500, Taiwan. Tel.:+886 4 723 8595; fax: +886 4 7232942.

E-mail addresses: [email protected] (W.-F. Wang), [email protected] (Y.-J. Jong).

Please cite this article in press as: Chen T-H et al., Infantile facioscapulohumetients with a very short EcoRI fragment, Neuromuscul Disord (2013), http://

1. Introduction

With a worldwide prevalence of 1 in 15,000–20,000,facioscapulohumeral muscular dystrophy (FSHD;MIM158900) accounts for the third most common formof muscular dystrophy [1]. In the majority of patients,

ral muscular dystrophy revisited: Expansion of clinical phenotypes in pa-dx.doi.org/10.1016/j.nmd.2013.01.005


mailto:[email protected]

mailto:yjjong@kmu. edu.tw

mailto:yjjong@kmu. edu.tw



2 T.-H. Chen et al. / Neuromuscular Disorders xxx (2013) xxx–xxx

ARTICLE IN PRESS

FSHD is dominantly inherited with a causative genopathymapped in the chromosome 4q35 region, where variabledeletions occur on a 3.3 kb tandem repeat (D4Z4) arrayvisualized by EcoRI/BlnI digested DNA fragment onSouthern blot. Normal individuals have 11 or morerepeats (50–300 kb) on each copy of 4q35, whereasindividuals with FSHD have 1–10 repeats (10–39 kb) onone copy of 4q35 [2]. Clinical symptoms of classicalFSHD include descending weakness from the facial andshoulder girdle muscles to lower extremities in slowprogression, which most starts in the second decade.With the relatively spared involvements of bulbar,respiratory, and cardiac muscles, FSHD patients usuallyhave a normal life expectancy [1].

A genotype-phenotype correlation in FHSDpathogenesis has been proposed based on the observationthat the size of EcoRI fragment is reported to beassociated with age of onset, rate of progression, and ageat loss of ambulation [3]. In most FSHD patients, theEcoRI fragment ranges from 15 to 38 kb; whereaspatients with the very short fragments (usually 10–14 kb)usually delineate the most severe phenotype and highfrequency of extramuscular manifestations [4–6].

In contrast to classical form, the infantile variant ofFSHD, first identified by Brook in 1977 [7], uniformlydenotes a severe phenotype with initial presentation offacial weakness before the age of 5 years and shouldergirdle weakness before the age of 10 years [8]. Theseseverely affected patients often become wheelchair-dependent by the end of the first decade, with asignificant association of other neurological symptomssuch as hearing, visual, and cognitive impairments[5,8–10]. However, the link between the extremelycontracted size of EcoRI fragment and infantile FSHD isstill elusive. Very short EcoRI fragments (10–14 kb) arefound in the majority of infantile FSHD patients but notall [6,9–11]. With the increasing case recognitions and theadvent in genetic diagnostics, recent studies haveconcluded that infantile variant of FSHD is not agenetically separate entity but a part of the FSHDspectrum [8,12].

In this study, we followed a cohort of nine patientswith the clinical diagnosis of infantile FSHD, whosegenetic results revealed very short EcoRI fragments.Through such comprehensive data acquisition, wereport a genotype-phenotype correlation betweenneurological symptoms and the size of EcoRIfragments. We also broaden the clinical spectrum ofthis severe FSHD variant.

2. Patients and methods

2.1. Enrollment of study subjects

An extensive chart review was performed between 1978and 2011 under the approval of the Institutional ReviewBoard (IRB) of Kaohsiung Medical University Hospital.


Informed consents were obtained from all patients ortheir parents. The case histories were reviewed, and allfamilies and patients were asked to fill out a clinicalquestionnaire. In this study, the ascertainment of caseswith infantile FSHD was made by those who fulfilled thefollowing two criteria: (1) the clinical criteria made byBrouwer et al. [8], including facial weakness manifestedbefore 5 years of age or shoulder girdle weakness before10 years of age; and (2) genetic confirmation on amolecular basis showing a pathognomonic contraction of4q35 fragment. Furthermore, for the purpose of thisstudy, we defined a severely affected FSHD subgroup ashaving an EcoRI fragment 10–14 kb [5].

2.2. Clinical assessments

Clinical history and family members sharing the samesymptoms as the index cases were reviewed. The clinicalhistories, particularly for those with subtle presentations,were mainly extracted from parents’ reports or frompatients’ previous facial photographs taken in infancyand young childhood.

Auditory evaluations were performed by directotoscopic examination, audiometry, and auditory-evokedbrainstem responses (ABR). Ophthalmologicalexaminations were done by the ophthalmologist (Y-HLai), who performed fundoscopic examination andretinography. We also delivered a questionnaire focusedon personal history of clinical risk factors for deafness asrecurrent or chronic ear infections, previously relevantear trauma, and chronic exposure to ototoxic substances.

In all patients, muscle involvement was assessedaccording to their age of onset, distribution, andprogression of weakness, neurological examination, serumcreatine kinase (CK) and muscular imaging by computedtomography (CT). When cerebral involvement wassuspected as an association, intellectual testing,electroencephalography (EEG), and brain CT or magneticresonance imaging were subsequently performed.Cardiopulmonary involvements were assessed by: (1)parameters of lung function via spirometry testing; and (2)cardiac assessments via 12-lead electrocardiogram (ECG),24-h Holter ECGs, and echocardiography. The whole-spine standing anteroposterior and lateral plainradiographs were used for evaluation of kyphoscoliosis.Feeding disorders or swallowing difficulties were evaluatedclinically and via questionnaire survey by the collaborativegastroenterologist (H-H Shih).

2.3. Molecular diagnosis

Briefly, genomic DNA was extracted from peripheralblood leukocytes using a standard technique. DNA wasinitially digested with EcoRI then double-digested withEcoRI and BlnI restriction enzymes according to themanufacturer’s instructions (Roche Cat.No.10703737001and 11558161001 respectively). The digested DNA was



T.-H. Chen et al. / Neuromuscular Disorders xxx (2013) xxx–xxx 3

ARTICLE IN PRESS

then transferred by southern blotting. Hybridization wasperformed using the probe p13E-11, labeled withradioactive 32P-dCTP. The products were visualized todetermine the size of 4q35 fragment on autography byusing a BAS2500 image analyzer (Fuji Photo Film,Japan).

3. Results

3.1. Clinical features and genetic analysis

We enrolled nine eligible patients (5 males and 4females) who fulfilled the clinical criteria of infantileFSHD. Their initial genetic reports showed a very shortEcoRI fragment ranging from 10 to 13 kb. They havebeen followed in our clinic, a tertiary referral center, forthe duration between 3 and 32 years. Their main clinicalfeatures are summarized in Tables 1 and 2. Thesepatients were from seven families with mean age of20.0 ± 8.3 years (ranging from 8 to 33). Six patients werefamilial and three were sporadic. There was aconsanguineous marriage in the parents of cases 2 and 3.The mean age of onset of FSHD symptoms was3.2 ± 1.7 years. The mean age of patients receivingdefinitive diagnosis was 12.3 ± 2.3 years. The mostfrequent symptom was facial weakness. However, twocases manifested their first FSHD-related symptoms withextramuscular features during infancy, including hearingloss and infantile spasms.

Table 1Clinical and genetic characteristics of nine patients with infantile FSHD.

Patientno., sex

Age (y) at Onset symptoms EcoRI(kb)Current Onsetc Diagnosis Wheelchair-

bound

1, M 27 5 15 25 Facial weakness 13

2a, M 17 5 14 � Facial weaknessshoulder weakness

13

3a, M 15 4 13 � Facial weakness 13

4, M 33 0.4 12 15 Epilepsyd facialweakness hearing loss

10

5b, F 16 4 14 15 Facial weaknessshoulder weakness

11

6b, F 14 4 12 � Facial weaknessshoulder weakness

11

7, M 20 2 11 � Facial weakness 13

8, F 8 0.9 7 � Facial weaknesshearing loss

13

9, F 30 3.5 13 13 Facial weaknessshoulder weakness

13

M, male; F, female; CK, creatine kinase; UL, upper limbs; LL, lower limbs; ya Sibling brothers and consanguinity of their parents.b Sibling sisters.c First recognizable abnormality/first symptom.d Infantile spasms.


All patients harbored a very short EcoRI fragment witha mean size being 12 ± 1.2 kb. Three mutations were denovo, two sisters inherited their mutation from theirasymptomatic mother who had somatic mosaicism, twoinherited their mutation from a parent who had verymild phenotype, and two brothers inherited theirmutation from their affected father who had classicaladult phenotype. Some parts of clinical data regardingpatterns of muscle weakness in six cases (cases No. 1, 2,3, 5, 6, and 7) have been described in a previouslypublished study [13].

3.2. Muscular involvements and progression

Muscle weakness showed progressive course in all cases.Their mean serum CK level was 607.3 IU/L. There was nosignificant correlation between the CK values and the ageof disease onset, ambulatory status, or the size of EcoRIfragment. Delayed development of gross motormilestones in early childhood was recorded in cases 4 and8. Four patients have been wheelchair-bound to datewith mean age of loss of ambulation being 17 ± 5.4 years.Prominent asymmetric wasting of shoulder or pelvicgirdle muscles was observed in five patients, which wasconfirmed by muscle CT (Fig. 1). Degeneration of tibialisanterior muscle resulting in foot drop was noted in fivepatients. Four patients had received muscle biopsypreviously which revealed several common pathologicalfeatures seen in FSHD. These included variations in

Affected parentsand phenotypes

CK(IU/L)

Asymmetricweakness

Footdrop

Musclebiopsy

Kyphoscoliosis

Mother, 13 kb,subtle phenotype

193 UL + + Moderate

Father, 13 kb,adult phenotype

1066 LL � � �

Father, 13 kb,adult phenotype

1391 UL, LL � + �

De novo 62 � + + Mild

Mother, mosaic,no phenotype

430 LL + � Moderate

Mother, mosaic,no phenotype

1109 � + � Mild

Father, 13 kb,subtle phenotype

517 LL � � �

De novo 628 � � � �

De novo 70 UL, LL + + Moderate

, years.



Table 2Extramuscular features of nine patients with infantile FSHD.

Patientno.

Hearingloss

Retinalabnormalities

Mentalretardation

Epilepsy Standard or HolterECG

Echocardiography Lungfunction

Swallowingdifficulties

1 Bilateral Tortuous vessels N � IRBBB N MR �2 Right Tortuous vessels N � IRBBB N MR �3 Bilateral Tortuous vessels N � N N N �4 Bilaterala Optic atrophy Profound + IRBBB N SRb +c

(DQ = 5) 1st AV block5 Bilateral Tortuous vessels Moderate + N N MR +

(IQ = 40)6 Bilateral Tortuous vessels Moderate � N N MR �

(IQ = 55)7 N Tortuous vessels N � IRBBB N MR �

RVHSinus bradycardia

8 Bilaterala Tortuous vessels N � N N N �9 Bilateral Tortuous vessels N � Left posterior

hemiblockN SR �

Right atrialenlargement

DQ, developmental quotient; IQ, intelligence quotient; ECG, electrocardiogram; IRBBB, incomplete right-bundle branch block; AV; atrioventricular;RVH, right ventricular hypertrophy; N, normal; MR, moderate restrictive; SR, severe restrictive.

a Required hearing aids.b Under home ventilator support.c Required gastrostomy.


ARTICLE IN PRESS

muscle fiber size with hypertrophy of predominantly typeII fibers, scattered small angular fibers, and endomysialinflammatory cellular infiltration. The total spinal X-rayshowed that all patients had various degrees ofhyperlordosis. Five of these also had mild-to-moderatedegrees of kyphoscoliosis.

Fig. 1. Muscle CT findings at the levels of chest and upper arms of patient 1 (A(D). Note the significant muscular wasting in an asymmetric distribution shmaximus (arrow in B), and hamstring muscles (arrows in C and D).


3.3. Hearing and ophthalmologic assessments

As shown in Table 2, eight patients had high frequencysensorineural hearing loss identified by clinical andinstrumental evaluations. Two of them required hearingaids for the correction of speech delay. Three patients

), hip and upper thighs of patient 3 (B and C), and lower thighs of patient 7owing most severely at the bilateral triceps brachii (arrow in A), gluteal



Fig. 2. Fundus photographs of patients with infantile FSHD: (A) right eye of patient 6 showing tortuous retinal arteries and arterioles. (B) Right eye ofpatient 4 showing optic atrophy but with no tortuosity of retinal vessels.

Fig. 3. Arrhythmogenic abnormalities in patients with infantile FSHD: (A–C) Standard 12-lead ECG of patients Nos. 1, 4, and 7, respectively, showingvariable degrees of conductive defect with a persistent IRBBB (rSr’ pattern in lead V1 or V2, arrows). (D) In comparison with the normal ECG record ofpatient 5.


ARTICLE IN PRESS

(cases 3, 5 and 6) had a history of dysarthria and languagedevelopment delay during young childhood.

Under direct fundoscopic examination, eight patientshad variable degrees of tortuous retinal vessels and onehad an unusual presentation of optic atrophy withouttortuous vasculopathy (Fig. 2). None of our patients hadtrue ocular telangiectasia or visual impairment to date,though retinal fluoroscein angiography was not routinelyundertaken.

3.4. Additional findings of extramuscular involvements

In three patients, mental retardation and delayedpsychomotor milestones were documented in early


childhood. Case 4 had infantile spasms diagnosed at theage of 5 months. His epileptic seizure evolved intolocalization-related epilepsy at the 3-year-old stage andthen was well controlled by carbamazepine andphenytoin from 8 years of age. Antiepileptic drugs werestopped at 13 years of age. Case 5 experienced her firstepisode of generalized tonic-clonic seizure at 12 years ofage and is currently being treated with valproic acid. Allof above three patients had normal neuroimaging.

The abnormalities of surface12-lead ECG or HolterECGs were reported in five patients. None had otherassociated cardiovascular risk factors. The cardiacproblems included mostly minor conductiveabnormalities, particularly incomplete right-bundle




ARTICLE IN PRESS

branch block (IRBBB), and usually appeared in the sameindividual (Fig. 3). Their results of echocardiographywere normal, and so far, there have been no overt heartsymptoms in all cases.

Swallowing difficulties were reported in two patientswith one of them needing gastrostomy. Seven patientshad moderate-to-severe restrictive ventilatory defect onspirometry testing. Case 4 manifested signs of nocturnalhypoventilation and progressive daily ventilatory failurerequiring in-home support of non-invasive ventilationwith mechanical in-exsufflation cough assist since 28 yearsof age.

4. Discussion

Several studies have proposed that the size of EcoRlfragment correlates roughly but inversely with the clinicalseverity of FSHD. So far, the great majority of reportedinfantile FSHD patients for which genetic data areavailable have a very short EcoRI fragment. The presentstudy provides additional evidence for this correlation. Ofnote, we found that extramuscular features, such ashearing loss and epilepsy, could manifest the firstsymptoms with an association of infantile FSHD.Furthermore, except for auditory and ophthalmologicalinvolvements, several rarely reported clinicalmanifestations in FSHD, such as cardiac conductivedefects, respiratory insufficiency, and swallowingdifficulties, seem more prevalent in patients with infantileFSHD. This information provides opportunities for earlyintervention in these patients.

Rapid progression in lower limb weakness resulting inloss of ambulation, as seen in four of our cases, has beenwell recognized in patients with infantile FSHD [10,11].Previously, asymmetric muscle weakness has beenregarded as an exclusion criterion for infantile form ofFSHD [10]. However, we observed that 67% of ourpatients presented with asymmetry of weakness,suggesting that this is, in fact, a common feature ofinfantile FSHD. Moreover, we provide the first evidenceof asymmetric muscle wasting, using muscle CT, in apatient with infantile FSHD.

Although previously reported, the precise prevalence ofretinovascular alterations in infantile FSHD patients mightbe underestimated because retinal fluorescenceangiography was not generally performed particularly inthe children [5,6,10]. A recent report, though lackinggenetic background, suggests a correlation between theretinovascular abnormalities and the severity of muscularinvolvement [14]. We further report a genotype-phenotypecorrelation of retinovascular alteration in infantile FSHDpatients. Intriguingly, one male patient with the mostsevere phenotype (case 4) presented with optic atrophy,which has not been reported in infantile-onset FSHD. Asevere retinal vasculopathy might have contributed to theoptic atrophy. Nevertheless, the tortuosity of retinalvessels could represent a possible carrier state or a mild


manifestation of Coats’ disease [15]. Given that Coat’sdisease and visual loss in FSHD both can be preventableby early laser photocoagulation [16], screening allinfantile FSHD patients with indirect ophthalmoscopymight be essential. Fluorescence angiography should beconsidered if any symptoms of visual deterioration arereported [10].

Rarely, FSHD can be associated with abnormal brainfunctions in childhood, particularly in those with a veryshort EcoRI fragment [6,17]. Epilepsy could present ininfantile FSHD and our patient with infantile spasms inthe current cohort is the fourth reported so far [6,12,18].In line with previous studies, we found that epilepsyfrequently occurred with mental retardation and bothwere only observed in patients with the very shortestEcoRI fragments (10–12 kb) [5,6]. Moreover, it should beemphasized that early childhood onset facial weaknessand auditory or visual disturbance could be obscured bythe presence of profound mental retardation [19].

Our observation in infantile FSHD patients confirms theprevious finding of cardiac arrhythmia in FSHD [20,21].Similar to a previous large cohort of classical FSHD, wefound a minor abnormality IRBBB accounting for themost conductive abnormality in our patient group [21].In the pathophysiological aspect, the rSr’ pattern inIRBBB may be attributed to a change in the position ofthe heart as a result of the decrease in the anteroposteriordiameter of the distorted chest, such as pectus excavatumand straight back syndrome [22]. Hence a high incidenceof kyphoscoliosis and hyperlordosis among our patientsalso could be relevant. In a study that followed aCaucasian cohort with IRBBB, subjects were suggestedto be at greater risk of developing in morbid, completeform [23]. Noteworthily, the complete RBBB has alsoreported an association in 60% of classical FSHDpatients who manifested significant cardiac symptoms[21]. Therefore, given a high incidence of IRBBBpresenting at a relatively younger age in our group, aregular cardiac follow-up including an annual ECG testshould be suggested for all infantile FSHD patients. Wealso provide the possible genotype-phenotype correlationof cardiac involvement in infantile FSHD patients.

Respiratory insufficiency in FSHD is rare, representingapproximately only 1% of the Dutch FSHD population[24]. The prevalence of respiratory failure in infantileFSHD is presumed to be higher given that severe muscleweakness, wheelchair dependence, and kyphoscoliosis arerisk factors for compromised respiratory functions. Toour knowledge, eight patients with infantile FSHD havebeen reported to be associated with respiratory failure.However, the sizes of their EcoRI fragments were notfully elaborated [4,25–28]. Although assessments byspirometry have been suggestively doubtable in FSHDpatients [10], as high as 78% of our patients showedrestrictive ventilatory defect, with one progressing tochronic respiratory failure. Therefore we recommend thata high possibility of ventilatory insufficiency should be




ARTICLE IN PRESS

warranted for patients with infantile FSHD, followed by acareful symptom history and spirometry assessment.

Nevertheless, there are still difficulties in establishing asubstantial genotype–phenotype association in FSHD,mainly due to the significant phenotype variability, evenamong affected family members [29]. Indeed, most of ourpatients inherited the disease from parents who haveeither a mild or an adult onset phenotype. Thisdiscrepancy may be resulted from largely undetectedsomatic mosaicism in the parents by standard testingusing liquid DNA in the present study [30]. On the otherhand, our finding also suggests the possibility that severalunknown (epi)genetic mechanisms or modifying genes/factors could be involved in the unexpected or moresevere phenotypes [31].

In conclusion, our current study identified, in infantileFSHD, a higher incidence of auditory andophthalmologic symptoms than previously reported, insubjects with similar genetic background. We furtherreport some clinical features that have never beenreported in patients with infantile FSHD. Cardiac andrespiratory abnormalities can be detected in patientsyounger than 30 years of age. This severe FSHD variantfollows a progressive disease course. The high frequencyof multi-organ involvement necessitates an earlydiagnosis and multidisciplinary intervention.

Conflict of interest

All authors of this article declare no conflict of interest.

Acknowledgments

We are sincerely grateful to Dr. Mana Leung(Kaohsiung Municipal United Hospital); Dr. Chien-HuaWang and Tysh-Jyi Hsieh (Kaohsiung MedicalUniversity Hospital) for their invaluable comments. Thisstudy received a grant from Changhua Christian Hospitaland Kaohsiung Medical University (100-CCH-KMU-004).

References

[1] Tawil R. Facioscapulohumeral muscular dystrophy. Curr NeurolNeurosci Rep 2004;4:51–4.

[2] Wijmenga C, Hewitt JE, Sandkuijl LA, et al. Chromosome 4q DNArearrangements associated with facioscapulohumeral musculardystrophy. Nat Genet 1992;2:26–30.

[3] Ricci E, Galluzzi G, Deidda G, et al. Progress in the moleculardiagnosis of facioscapulohumeral muscular dystrophy and correlationbetween the number of KpnI repeats at the 4q35 locus and clinicalphenotype. Ann Neurol 1999;45:751–7.

[4] Nakagawa M, Matsuzaki T, Higuchi I, et al. Facioscapulohumeralmuscular dystrophy: clinical diversity and genetic abnormalities inJapanese patients. Intern Med 1997;36:333–9.

[5] Trevisan CP, Pastorello E, Tomelleri G, et al. Facioscapulohumeralmuscular dystrophy: hearing loss and other atypical features ofpatients with large 4q35 deletions. Eur J Neurol 2008;15:1353–8.


[6] Funakoshi M, Goto K, Arahata K. Epilepsy and mental retardationin a subset of early onset 4q35-facioscapulohumeral musculardystrophy. Neurology 1998;50:1791–4.

[7] Brooke MH. A clinician’s view of neuromuscular diseases. Baltimore,Md: Williams & Wilkins; 1977.

[8] Brouwer OF, Padberg GW, Wijmenga C, Frants RR.Facioscapulohumeral muscular dystrophy in early childhood. ArchNeurol 1994;51:387–94.

[9] Brouwer OF, Padberg GW, Bakker E, Wijmenga C, Frants RR.Early onset facioscapulohumeral muscular dystrophy. Muscle Nerve1995;2:S67–72.

[10] Klinge L, Eagle M, Haggerty ID, Roberts CE, Straub V, BushbyKM. Severe phenotype in infantile facioscapulohumeral musculardystrophy. Neuromuscul Disord 2006;16:553–8.

[11] Jardine PE, Koch MC, Lunt PW, et al. De novo facioscapulohumeralmuscular dystrophy defined by DNA probe p13E-11 (D4F104S1).Arch Dis Child 1994;71:221–7.

[12 Miura K, Kumagai T, Matsumoto A, et al. Two cases of chromosome4q35-linked early onset facioscapulohumeral muscular dystrophy withmental retardation and epilepsy. Neuropediatrics 1998;29:239–41.

[13] Wang CH, Leung M, Liang WC, Hsieh TJ, Chen TH, Jong YJ.Correlation between muscle involvement, phenotype and D4Z4fragment size in facioscapulohumeral muscular dystrophy.Neuromuscul Disord 2012;22:331–8.

[14] Longmuir SQ, Mathews KD, Longmuir RA, Joshi V, Olson RJ,Abramoff MD. Retinal arterial but not venous tortuosity correlateswith facioscapulohumeral muscular dystrophy severity. J AAPOS2010;14:240–3.

[15] Small RG. Coats’ disease and muscular dystrophy. Trans Am AcadOphthalmol Otolaryngol 1968;72:225–31.

[16] Fitzsimons RB, Gurwin EB, Bird AC. Retinal vascular abnormalitiesin facioscapulohumeral muscular dystrophy. A general associationwith genetic and therapeutic implications. Brain 1987;110(Pt 3):631–48.

[17] Hobson-Webb LD, Caress JB. Facioscapulohumeral musculardystrophy can be a cause of isolated childhood cognitivedysfunction. J Child Neurol 2006;21:252–3.

[18] Akiyama C, Suzuki H, Nonaka I. A case of facioscapulohumeralmuscular dystrophy with infantile spasms, sensorineural deafness andretinal vessel abnormality. No To Hattatsu 1991;23:395–9.

[19] Saito Y, Miyashita S, Yokoyama A, et al. Facioscapulohumeralmuscular dystrophy with severe mental retardation and epilepsy.Brain Dev 2007;29:231–3.

[20] Stevenson WG, Perloff JK, Weiss JN, Anderson TL.Facioscapulohumeral muscular dystrophy: evidence for selective,genetic electrophysiologic cardiac involvement. J Am Coll Cardiol1990;15:292–9.

[21] Laforet P, de Toma C, Eymard B, et al. Cardiac involvement ingenetically confirmed facioscapulohumeral muscular dystrophy.Neurology 1998;51:1454–6.

[22] Surawicz B, Knilans TK. Right bundle branch block. Chou’selectrocardiography in clinical practice. Philadelphia, PA: Saunders;2008, pp. 95-107.

[23] Liao YL, Emidy LA, Dyer A, et al. Characteristics and prognosis ofincomplete right bundle branch block: an epidemiologic study. J AmColl Cardiol 1986;7:492–9.

[24] Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der MaarelSM, Padberg GW. Ventilatory support in facioscapulohumeralmuscular dystrophy. Neurology 2004;63:176–8.

[25] Yasukohchi S, Yagi Y, Akabane T, Terauchi A, Tamagawa K,Mizuno Y. Facioscapulohumeral dystrophy associated withsensorineural hearing loss, tortuosity of retinal arterioles, and anearly onset and rapid progression of respiratory failure. Brain Dev1988;10:319–24.

[26] Bailey RO, Marzulo DC, Hans MB. Infantile facioscapulohumeralmuscular dystrophy: new observations. Acta Neurol Scand1986;74:51–8.




ARTICLE IN PRESS

[27] McGarry J, Garg B, Silbert S. Death in childhood due to facio-scapulo-humeral dystrophy. Acta Neurol Scand 1983;68:61–3.

[28] Nakagawa M, Higuchi I, Yoshidome H, et al. Familialfacioscapulohumeral muscular dystrophy: phenotypic diversity andgenetic abnormality. Acta Neurol Scand 1996;93:189–92.

[29] Sakellariou P, Kekou K, Fryssira H, et al. Mutation spectrum andphenotypic manifestation in FSHD Greek patients. NeuromusculDisord 2012;22:339–49.


[30] Lemmers RJ, van der Wielen MJ, Bakker E, Padberg GW, FrantsRR, van der Maarel SM. Somatic mosaicism in FSHD often goesundetected. Ann Neurol 2004;55:845–50.

[31] Richards M, Coppee F, Thomas N, Belayew A, Upadhyaya M.Facioscapulohumeral muscular dystrophy (FSHD): an enigmaunravelled? Hum Genet 2012;131:325–40.



infantile facioscapulohumeral muscular dystrophy revisited: expansion of clinical phenotypes in...

Documents