eMedicine Specialties > Neurology > Pediatric Neurology

Facioscapulohumeral Dystrophy

Naganand Sripathi, MD, Director, Neuromuscular Clinic, Department of Neurology, Henry Ford Hospital

Updated: Feb 23, 2007

Introduction

Background

Facioscapulohumeral dystrophy (FSHD) is one of the most common types of muscular dystrophy. It has distinct regional involvement and progression. FSHD is an autosomal dominant disorder in as many as 90% of affected patients. Landouzy and Dejerine first described FSHD in 1884. Tyler and Stephens described an extensive family from Utah in which 6 generations were affected. Walton and Nattrass established FSHD as a distinct muscular dystrophy with specific diagnostic criteria.

Pathophysiology

It is an autosomal dominant disease in 70-90% of patients and is sporadic in the rest. One of the FSHD genes has been localized to chromosome band 4q35, but the gene or genes that are affected in FSHD are still unknown. Patients with FSHD have a shorter Eco RI digestion fragment detected by the chromosome-4qter DNA marker p13E-11. About 2% of FSHD patients are not linked to the locus at 4q35.

The probe p13E-11 identifies 2 polymorphic loci at 4q35 and 10q26. The Eco R1 fragment of 4q is composed of repetitive DNA sequences that are 3.3-kilobase (kb) Kpn I tandem repeats identified as D4Z4. In control subjects, the D4Z4 repeat consists of 11-100 KpnI units, each 3.3 kb, whereas in FSHD this is shortened; the shortened Eco RI fragment in FSHD is 1-10 units. Diagnostic difficulties arise as these fragments also may come from chromosome 10, as already described. 4-Type units are resistant to Bln I and 10-type units are resistant to Xap I. The combined use of EcoRI, BlnI, and XapI in pulsed-field gel electrophoresis–based DNA separation techniques allows detection of 4q fragments.

• At least one copy of D4Z4 is required to develop FSHD.
• Mosaic males are mostly affected, where as mosaic females with an equal complement of affected cells are more often asymptomatic carriers.
• A bi-allelic variation of chromosome 4qter is known, designated as 4qA and 4qB. FSHD alleles are exclusively of the 4qter type.
• Although the genetic lesion is well described in FSHD, the causal gene and the protein products are not known.
• The most extensively studies candidate genes for FSHD on 4q35 are ANT1, PDLIM3, FRG1, TUBB4q, FRG2, and DUX4.

Disease mechanisms

The actual genetic defect in FSHD is unknown. Possible disease mechanisms include the following:

• Position variegation effect on a proximal candidate gene or genes
• Direct and indirect evidence points to epigenetic modifications in the DNA. A local deficit of a repressor complex due to the contraction of D4Z4 may cause inappropriate expression of genes. This may account for upregulation of FRG2, FRG1, and ANT1 in FSHD muscle.
• The most common modification of mammalian DNA is cytosine methylation that is necessary for many regulatory processes. D4Z4 was found to be hypomethylated in FSHD.
• Myoblasts from patients with FSHD also demonstrate increased susceptibility to oxidative stress.

Frequency

United States

FSHD is the third most common muscular dystrophy. Estimated prevalence of FSHD is 1 case in 20,000 persons.

Mortality/Morbidity

Most of the patients have normal life expectancy.

Sex

Frequency is higher in males; however, asymptomatic cases are more common in females.

Age

• The usual presentation is between the first and third decades. Ninety-five percent of patients show clinical features before age 20 years. As many as one third of patients are asymptomatic.
• Infantile onset has been described, but is rare.

Clinical

Physical

• Initial weakness is seen in facial muscles, starting in the orbicularis oculi, orbicularis oris, and zygomaticus.
  • Patients may have difficulty with labial sounds, whistling, or drinking through a straw.
  • Weakness may be asymmetric.
  • Extraocular and pharyngeal muscles are spared.
• Shoulder weakness is the presenting symptom in more than 82% of patients with symptoms.
  • Scapular fixation is weak from the onset. Winging of the scapula is the most characteristic sign. The scapula is placed more laterally than normal. It moves upwards in shoulder abduction.
  • The deltoid muscle usually is spared, and shoulder abduction weakness is predominantly due to weak scapula fixation.
  • If the scapula is stabilized manually against the chest wall, the patient may experience improved movement. Upward slope of the anterior axillary fold results from weakness of the pectoralis major.
• Truncal weakness is early. Lower abdominal muscles are weaker than upper abdominal muscles, resulting in the Beevor sign, a physical finding very specific for FSHD.
• Weakness of foot dorsiflexion follows shoulder weakness.
  • Tibialis anterior muscle weakness is highly characteristic, whereas posterior muscles of the leg are spared.
  • In a few patients, a foot-drop gait is the presenting complaint. In more than 50% of patients, the pelvic girdle muscles are never involved.
• Atypical phenotypes in patients with FSHD
  • Scapulohumeral dystrophy (SHD) or facial-sparing SHD with or without myalgia
  • FSHD with chronic progressive external ophthalmoplegia (CPEO)
  • Limb-girdle muscular dystrophy syndrome
  • Distal myopathy
  • Asymmetric brachial weakness
• Extramuscular manifestations are as follows:
  • High-frequency hearing loss in almost 75%
  • Retinal telangiectasias in about 60%
  • Atrial arrhythmias in 5%
  • Restrictive respiratory disease in 1%
  • Mental retardation
  • Seizures

Differential Diagnoses

Other Problems to Be Considered

Scapuloperoneal dystrophy
Spinal muscular dystrophy with scapuloperoneal phenotype
Scapuloperoneal neuropathy

Workup

Laboratory Studies

• Serum creatine kinase levels are elevated.

Imaging Studies

• Imaging studies show a selective destructive process involving the anterior compartment muscles of the leg. Hypertrophy of the psoas muscles also is observed occasionally.

Other Tests

• FSHD gene testing
• Electrodiagnostic studies; these may reveal myopathic potentials. Focal neuropathies and occasionally a brachial plexopathy may be seen as a result of stretch injury.

Procedures

• Muscle biopsy: If results of genetic testing for FSHD are negative, a muscle biopsy is strongly recommended to rule out other conditions that mimic FSHD.

Histologic Findings

• Muscle
  • Multifocal distribution
  • Fiber size variation with central nuclei
  • Endomysial connective tissue proliferation
  • Regenerating, moth-eaten fibers and muscle fibers undergoing phagocytosis
  • Isolated angular atrophic fibers
  • Rimmed vacuoles
  • Focal inflammation in perivascular and perimysial distributions
  • Muscle fibers expressing membrane attack complex
  • Muscle fibers expressing class 1 major histocompatibility antigen

Treatment

Medical Care

• No definitive therapy is available for FSHD.
• A pilot trial of sustained-release albuterol taken PO (16 mg/d) for 3 months increased lean body mass. A modest 12% increase in muscle strength was noted.
• A double-blind placebo-controlled trail randomizing the patients to placebo, 8 mg albuterol twice daily, or 16 mg albuterol twice daily showed no improvement in global strength. However, albuterol improved grip strength and muscle mass.
• In a randomized, double-blinded, cross-over trial in a mixed population of dystrophies (12 with FSHD), a creatine monohydrate value of 10 g/d demonstrated a slight improvement in overall strength.
• Aerobic training may improve exercise performance (Olsen, 2005). Twelve weeks of low-intensity aerobic exercises (on a cycle ergometer at a heart rate corresponding to a work intensity of 65% of VO₂ max for 35-min weekly sessions and increased to 5-times weekly in 4 wk) improved maximal oxygen uptake and work load with no signs of muscle damage.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Beta2-adrenergic agonists

By activating cyclic AMP, this agent stimulates the ATPase pump, thereby activating the beta-adrenergic pathway. Albuterol reportedly improves muscle strength in FSHD patients through its nonspecific anabolic properties.

Scapulothoracic arthrodesis may be attempted in selected patients with preserved deltoid function. An improved functional range of abduction can be achieved if the scapula is fixed in 15-20° of rotation. In a series by Bunch and Siegel, 11 of 12 patients improved with this procedure.

Albuterol (Ventolin, Proventil)

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility.

Dosing

Adult

16 mg/d PO in divided doses

Pediatric

Not established

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, tricyclic antidepressants, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Follow-up

Complications

• Coats syndrome: This syndrome, a retinal vasculopathy with telangiectasia, exudation, and retinal detachment, is seen in 49-75% of affected individuals. If detected early, retinal photocoagulation may prevent serious consequences.
• Hearing loss: Sensorineural deafness is observed in 64% of patients; it may be unilateral.
• Mental impairment and epilepsy: These are seen in the early onset group. Mental retardation is observed in about 40% of patients with early onset 4q35-FSHD. Epilepsy also is observed often in this subset of patients.
• Labile hypertension
• Cardiac complications: Atrial arrest, bundle branch block, and dilated cardiomyopathy have been reported.

Prognosis

• Size of deletion affects disease severity and thus prognosis.
  • Ricci studied 122 Italian families affected by FSHD and 230 healthy control subjects. An Eco RI fragment shorter than 30 kb that was resistant to Bln I restriction was found in 114 of 122 families (93%) with FSHD. Fifteen percent of the control group showed Eco RI fragments smaller than 30 kb that were Bln I sensitive, suggesting that these were 10 qter alleles. Prognosis varied with the length of the fragment size and the remaining Kpn I units. The probabilities of developing the severe form of the disease were as follows:
    • 100% with very short segment length of 10-13 kb (1-2 Knp I repeats left)
    • 54% in patients with fragment length of 16-20 kb (3-4 Knp I repeats left)
    • 19% in patients with fragment length greater than 21 kb (more than 4 Knp I repeats left)
• Age of onset is variable. The disease tends to progress from the face downwards. Asymmetry and selective muscle group involvement distinguish FSHD from other muscular dystrophies. Many authors describe stepwise deterioration with prolonged periods of apparent arrest. Extraocular muscles, bulbar muscles, deltoids, and respiratory muscles usually are spared. Ventilatory impairment is seen in fewer than 10% of patients.
• Approximately 20% of patients may require wheelchair assistance.
• Life expectancy is normal in most patients.

References

1. Bunch WH, Siegel IM. Scapulothoracic arthrodesis in facioscapulohumeral muscular dystrophy. Review of seventeen procedures with three to twenty-one-year follow-up. J Bone Joint Surg Am. Mar 1993;75(3):372-6. [Medline].

2. Faustmann PM, Farahati J, Rupilius B, et al. Cardiac involvement in facio-scapulo-humeral muscular dystrophy: a family study using Thallium-201 single-photon-emission-computed tomography. J Neurol Sci. Dec 1996;144(1-2):59-63. [Medline].

3. Funakoshi M, Goto K, Arahata K. Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy. Neurology. Jun 1998;50(6):1791-4. [Medline].

4. Gilchrist JM. Other muscular dystrophies. In: Gilchrist JM, ed. Prognosis in Neurology. Butterworth-Heinemann;1998:347-9.

5. Griggs RC, Mendell JR, Miller RG. The muscular dystrophies. In: Evaluation and Treatment of Myopathies. Philadelphia: FA Davis Co;1995:122-8.

6. Kissel JT, McDermott MP, Natarajan R, et al. Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology. May 1998;50(5):1402-6. [Medline].

7. Kissel JT, McDermott MP, Mendell JR, et al. Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology. Oct 23 2001;57(8):1434-40. [Medline].

8. Krasnianski M, Eger K, Neudecker S, et al. Atypical phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35 deletion. Arch Neurol. Oct 2003;60(10):1421-5. [Medline].

9. Laoudj-Chenivesse D, Carnac G, Bisbal C, et al. Increased levels of adenine nucleotide translocator 1 protein and response to oxidative stress are early events in facioscapulohumeral muscular dystrophy muscle. J Mol Med. Mar 2005;83(3):216-24. [Medline].

10. Neudecker S, Krasnianski M, Bahn E, Zierz S. Rimmed vacuoles in facioscapulohumeral muscular dystrophy: a unique ultrastructural feature. Acta Neuropathol (Berl). Sep 2004;108(3):257-9. [Medline].

11. Olsen DB, Orngreen MC, Vissing J. Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology. Mar 22 2005;64(6):1064-6. [Medline].

12. Ricci E, Galluzzi G, Deidda G, et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol. Jun 1999;45(6):751-7. [Medline].

13. Tawil R, Forrester J, Griggs RC, et al. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. Jun 1996;39(6):744-8. [Medline].

14. Tawil R, Figlewicz DA, Griggs RC, Weiffenbach B. Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium. Ann Neurol. Mar 1998;43(3):279-82. [Medline].

15. Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve. Jul 2006;34(1):1-15. [Medline].

16. Walter MC, Lochmuller H, Reilich P, et al. Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology. May 9 2000;54(9):1848-50. [Medline].

17. Winokur ST, Barrett K, Martin JH, et al. Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress. Neuromuscul Disord. May 2003;13(4):322-33. [Medline].

Keywords

FSHD, muscular dystrophy, Eco RI digestion fragment, Eco RI restriction enzyme, DUX1 protein, adenine nucleotide translocator 1 protein, scapulohumeral dystrophy, SHD, facial-sparing SHD with or without myalgia, chronic progressive external ophthalmoplegia, CPEO, limb-girdle muscular dystrophy syndrome, distal myopathy, asymmetric brachial weakness

Contributor Information and Disclosures

Author

Naganand Sripathi, MD, Director, Neuromuscular Clinic, Department of Neurology, Henry Ford Hospital
Naganand Sripathi, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, Michigan State Medical Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

James J Riviello Jr, MD, Professor of Pediatrics, Division of Neurology, Baylor College of Medicine; Chief of Neurophysiology, Texas Children's Hospital
James J Riviello Jr, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic
Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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