SHORT REPORT ABSTRACT: We describe a patient with facioscapulohumeral musculardystrophy (FSHD) associated with Mobius syndrome and congenital oph-thalmoplegia. This 7-year-old girl had profound limitation of extraocularmovements since birth, congenital facial diplegia, neonatal hypotonia, andprogressive limb-girdle weakness. FSHD genetic testing revealed a patho-genic haplotype with a D4Z4 repeat of 30 kb. The father carries the sameallele, although is minimally affected. This unusual case expands the geno-typic–phenotypic spectrum of FSHD.

Muscle Nerve 37: 526–529, 2008

ATYPICAL FACET OF MOBIUS SYNDROME: ASSOCIATION WITHFACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

HANNA K. KOLSKI, MD,1 NORMA J. LEONARD, MD,2 RICHARD J.L.F. LEMMERS, PhD,3

and JOHN S. BAMFORTH, MD2

1 Department of Pediatrics, Room 7313A, Aberhart Centre 1, 11402 University Avenue,University of Alberta, Edmonton, Alberta T6G 2J3, Canada

2 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada3 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

Accepted 22 October 2007

Mobius syndrome is characterized by congenitalfacial weakness, typically bilateral, and impairmentof ocular abduction.12 Since the 1960s it has becomeclear that Mobius syndrome might be secondary toprogressive myopathic diseases, including myotonicdystrophy. The first description of congenital facialdiplegia associated with a progressive myopathy re-sembling facioscapulohumeral dystrophy (FSHD)was in 1971.3 Since then, a molecular marker forFSHD has become available, with many diverse phe-notypes being recognized in the FSHD clinical spec-trum.6,10 This includes five children originally diag-nosed with Mobius syndrome or congenital facialdiplegia (albeit with normal extraocular move-ments) who were later clinically and molecularlyconfirmed to have FSHD.2,5

FSHD is caused by a contraction of the macrosat-ellite repeat D4Z4 on chromosome 4qter. The D4Z4repeat can also be found on chromosome 10qterand on two equally common chromosome 4qter vari-ants (4qA and 4qB), but only D4Z4 contractions onchromosome 4qA cause the disease.7 Molecular di-

agnosis for FSHD is performed by Southern analysison EcoRI-digested DNA. Control individuals haveD4Z4 repeat arrays that are larger than 40 kb; pa-tients carry one repeat between 10 and 40 kb.

We report a child with features of Mobius syn-drome, congenital complete ophthalmoplegia andfacial diplegia, and severe muscle weakness associ-ated with the characteristic FSHD mutation.

CASE REPORT

This girl was born to a healthy woman, gravida 1,para 1, woman following a term pregnancy remark-able only for polyhydramnios. Delivery was uncom-plicated. Even as a neonate the patient could notmove her eyes laterally or vertically. There was ab-sence of facial movements. She was hypotonicthroughout. Development was delayed in all areas.She sat at 10 months and first walked at 2 years,never crawling. By 6 years of age she walked inde-pendently and climbed stairs without rail support,but in the following year her gait deteriorated andshe fell often. She frequently dropped objects. Herspeech was barely comprehensible. Cognitive statuswas judged to be that of a 2-year-old.

Past surgeries included cosmetic eye reconstruc-tion, gastric-tube insertion for swallowing dysfunc-tion, and insertion of thoracic rods for scoliosis.Ophthalmology assessments found no retinal abnor-malities and hearing was normal bilaterally. Echocar-diogram and electrocardiogram were normal.

Abbreviations: CPEO, chronic progressive external ophthalmoplegia; EMG,electromyography; FSHD, facioscapulohumeral dystrophy; PBL, peripheralblood lymphocytes; PFGE, pulsed-field gel electrophoresisKey words: facial diplegia; facioscapulohumeral muscular dystrophy; Mo-bius syndrome; ophthalmoplegiaCorrespondence to: H. Kolski; e-mail: Hanna.Kolski@capitalhealth.ca

© 2007 Wiley Periodicals, Inc.Published online 4 December 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20941

526 Short Reports MUSCLE & NERVE April 2008

On examination at 71/2 years she displayed amajor open bite deformity of the lower jaw causingthe tongue to protrude. Cranial nerve examinationwas remarkable for absence of horizontal and verti-cal extraocular movements. There was profound fa-cial weakness involving both the upper and lowerparts of the face, including eye closure. She hadbilateral ptosis midway across the pupils with absenteyelid creases. She drooled and speech was dysar-thric. All tongue movements were limited. There wasno tongue atrophy. There was a severe fixed lumbarlordosis at the lumbosacral angle and mild thoracicscoliosis. Her hips were markedly flexed in indepen-dent standing. There was striking pelvic obliquitydue to a tight tensor fascia lata on the left. Mildcontractures were present only at the heel cords(right more than left). She was hypotonic through-out, with head lag. She demonstrated prominentsymmetrical scapular winging, decreased bulkaround the shoulders, and horizontal clavicles. Shecould not raise her hands above her shoulders norindependently stand up from the floor. Strength wasmildly decreased in the biceps, triceps, hip flexors,hamstrings, and dorsiflexors; she could barely over-come gravity in the deltoids, hip extensors, andquadriceps, with mild asymmetries. Gait was charac-terized by bilateral hip abductor weakness (wad-dling), knee hyperextension, and mild foot drop.Tendon reflexes were absent. Both plantar re-sponses were flexor. Cerebellar function and sensa-tion were intact. A gastric tube was in situ. Theremainder of the examination was normal.

Family History. All relatives were asymptomatic.However, the father’s examination findings were re-markable only for mildly decreased strength bilater-ally in the deltoids (grade 5 on the Medical ResearchCouncil scale) and biceps (grade 4). He had diffi-culty in doing sit-ups. There was no Beevor’s sign.There was no facial or scapular weakness and eyemovements were normal. He displayed an elevationin serum creatine kinase (CK) level shortly afterweight lifting (4,118 IU/L; normal 40–200 IU/L),although repeat value at rest was normal (156 IU/L). The patient’s mother was asymptomatic and hada normal clinical examination.

Investigations. The child’s CK, at age 5 months, was681 IU/L. Muscle biopsy at age 14 months from theleft paraspinal and gastrocnemius muscles revealednonspecific myopathic abnormalities includingperivascular chronic inflammatory infiltrates, rarenecrotic and regenerating fibers, mild to moderatevariability in fiber size and shape, increased endomy-

sial connective tissue, and perimysial fibrous thick-ening. The patient’s head magnetic resonance imag-ing showed small extraocular muscles. There wereno brainstem abnormalities.

The molecular diagnosis from the affected childand both parents was performed on DNA isolatedfrom peripheral blood lymphocytes (PBLs). PBLswere embedded in agarose plugs and treated withpronase as described previously.7 For D4Z4 arraysizing, DNA samples were double-digested withEcoRI/HindIII, EcoRI/BlnI, and with XapI. In orderto determine the distal 4qA/4qB variation at 4qter,DNA was digested with HindIII. Subsequently, di-gested DNA was separated in a 22-h run by pulsedfield gel electrophoresis (PFGE) and transferred to anylon membrane by Southern blotting as describedpreviously.7 Membranes for D4Z4 sizing were hybrid-ized with probe p13E-11 (D4F104S1) and for A/Btyping sequentially with probes 4qA or 4qB.

The child’s genetic testing revealed a 4qA-typeD4Z4 repeat of 30 kb, confirming FSHD (Fig. 1).The allele was further characterized as the 4qA161haplotype. This FSHD allele was inherited from thefather, who displayed no signs of somatic mosaicism.Chromosomes and myotonic dystrophy genetic test-ing were normal.

DISCUSSION

This child’s clinical features were atypical, both fromthe point of view of Mobius syndrome and, in manyrespects, of infantile FSHD. When ocular motility islimited in Mobius presentations this typically in-volves horizontal eye movements.9,12 Mobius syn-drome in rare instances has been associated withcomplete ophthalmoplegia, but in one case this waspresumed to be due to a supranuclear lesion.9 Fur-thermore, our patient exhibited generalized facialdiplegia, which differs from the pattern of relativesparing of lower facial muscles characteristic of Mo-bius syndrome.12

Although cases of congenital facial diplegia withearly onset shoulder-girdle weakness have been re-ported in conjunction with the FSHD phenotypeand 4q35 deletion,2,5 it is generally accepted thatFSHD spares the extraocular muscles.10 Unlike somepatients with FSHD, there was no evidence of senso-rineural deafness or Coat’s syndrome (bilateral reti-nal exudative telangiectasia).5

The presence of polyhydramnios and profoundhypotonia at birth suggests that the process startedin utero, in contrast to typical infantile FSHD,wherein limb-girdle weakness typically declares itselfin childhood or adolescence.3 However, it has been

Short Reports MUSCLE & NERVE April 2008 527

suggested that FSHD cases with early onset facialweakness may have severe neuromuscular disabilityand premature demise.1

One question that arises, in relation to our pa-tient, is whether FSHD was responsible for the Mo-bius syndrome and ophthalmoparesis, or whether

there were two separate processes occurring simul-taneously in this child. The demonstration of a D4Z4repeat of 30 kb in 4qA (pathogenic allele) supportsthe belief that FSHD was the underlying etiology.7Furthermore, there are some overlapping featuresreported in the clinical literature. Hurwitz et al.4

-144-

-96-

-48-

-27-

-10-

p13E-11

BE M

4qA 4qB

BE BE HH H HH HX X X

Y

Y

FSHDallele

FIGURE 1. Southern blot of DNA derived from proband and her parents. Membranes for D4Z4 sizing were hybridized with probe p13E-11(D4F104S1) and for A/B typing sequentially with probes 4qA or 4qB. Note that the affected child’s pathogenic 30-kB 4qA allele is paternaland 40-kB 4qA allele is maternal. E means EcoRI and HindIII double digestion (all 4 and 10 alleles intact). B means EcoRI and BlnI doubledigestion (digest only 10-type alleles). X means XapI digestion (digest only 4-type alleles). H means HindIII digestion (for A/B typing).

528 Short Reports MUSCLE & NERVE April 2008

described a sibship with congenital hypotonia andpartial ophthalmoparesis (marked limitation of ab-duction, elevation, and depression), one of whomdisplayed myopathic features on recti EMG and mus-cle histopathology. Their cases, however, differedfrom ours due to bilateral preservation of eye adduc-tion, lack of ptosis or profound facial involvement,presence of mild deafness, and a later onset of limb-girdle distribution weakness. Miura et al.8 reportedan individual with FSHD and acquired limitation ofupgaze, tongue atrophy, and mental retardation.

Krasnianski et al.6 described a father and twochildren with atypical FSHD, confirmed molecularly,with “chronic progressive external ophthalmople-gia” (CPEO). The father developed arm and shoul-der-girdle weakness around 25 years of age. He ex-perienced slowly progressive ptosis throughout hislife. He displayed limited upward and lateral gaze inthe right eye. His children showed progressive bilat-eral ptosis beginning in infancy and delayed grossmotor development, similar to our case. At age 7years, they underwent surgical correction of strabis-mus.

With more widespread availability and use of de-letion testing, the clinical spectrum of early onsetFSHD is clearly widening. Our case also highlightsprevious observations that there is variability in bothclinical severity and age of onset of FSHD between,as well as within, families.2,11 Whereas FSHD oftenpresents as a mild, slowly progressive myopathy,10

there are also families with severely affected infantswho have one asymptomatic or minimally affectedparent.1 In some familial cases, although the size ofthe inherited fragment remains constant, FSHD maybe more severe in offspring when parents carry thedeletion in a somatic mosaic state.11 Remarkably,detailed PFGE analysis showed that the minimallyaffected father was not mosaic for the FSHD allele.

We conclude that FSHD should be considered inthe differential diagnosis of a child presenting withclinical features of Mobius syndrome and congenitalophthalmoparesis, even in the absence of a positive

family history. Establishing a correct diagnosis hasgreat prognostic significance for the child as well asgenetic implications for the whole family.

Presented at the 25th annual Carrell-Krusen Symposium, Dallas,Texas, February, 2003.

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3. Hanson PA, Rowland LP. Mobius syndrome and facioscapu-lohumeral muscular dystrophy. Arch Neurol 1971;24:31–39.

4. Hurwitz LJ, Maguire CJF, Fannin T. Congenital ophthalmo-plegia. A myopathic aetiology in two siblings. J Neurol Neu-rosurg Psychiatry 1968;31:372–378.

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7. Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GJ, van Om-men GJB, Frants RR, et al. Facioscapulohumeral musculardystrophy is uniquely associated with one of the two variantsof the 4q subtelomere. Nat Genet 2002;32:235–236.

8. Miura K, Kumagai T, Matsumoto A, Iriyama E, Watanabe K,Goto K, et al. Two cases of chromosome 4q35-linked earlyonset facioscapulohumeral muscular dystrophy with mentalretardation and epilepsy. Neuropediatrics 1998;29:239–241.

9. Van Allen MW, Blodi FC. Neurologic aspects of the Mobiussyndrome. A case study with electromyography of the extraoc-ular and facial muscles. Neurology 1960;10:249–259.

10. van der Kooi AJ, Visser MC, Rosenberg N, van den Berg-VosR, Wokke JH, Bakker E, et al. Extension of the clinical rangeof facioscapulohumeral dystrophy: report of six cases. J Neu-rol Neurosurg Psychiatry 2000;69:114–116.

11. van der Maarel SM, Deidda G, Lemmers RJ, van Overveld PG,van der Wielen M, Hewitt JE, et al. De novo facioscapulo-humeral muscular dystrophy: frequent somatic mosaicism,sex-dependent phenotype, and the role of mitotic transchro-mosomal repeat interaction between chromosomes 4 and 10.Am J Hum Genet 2000;66:26–35.

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