Ophthalmologic Manifestations of Facioscapulohumeral Dystrophy

From EyeWiki

This article will focus on ophthalmologic manifestations of facioscapulohumeral dystrophy.

Disease Entity

Facioscapulohumeral dystrophy; facio-scapulo-humeral dystrophy; facioscapulohumeral atrophy; facioscapulohumeral type progressive dystrophy; FSH muscular dystrophy; FSHD.


Facioscapulohumeral dystrophy (FSHD) is one of the most common muscular dystrophies, characterized by a progressive and descending pattern of muscle weakness and atrophy. The muscles of the face (facio-), shoulders (scapula-) and upper arms (humeral-) are affected first, followed by distal lower extremities and pelvic girdle muscles, typically with a considerable side-to-side asymmetry [1-4].

Although muscular involvement is the hallmark of the disease, other systemic manifestations such as retinal vasculopathy, hearing impairment, cardiac arrhythmia, epilepsy, cognitive disability, and chronic pain can occur [2, 4].

Two types of FSHD have been described so far: type 1 (FSHD1) and type 2 (FSHD2). Despite their different genetic mechanisms, they are clinically indistinguishable [4, 5].


FSHD is a complex genetic disorder in which a cascade of epigenetic mechanisms culminates in DNA hypomethylation and the expression of the normally silenced DUX4 gene, whose transcripts are toxic to the adult muscle cells [4-9].

FSHD1 is caused by a deletion of a variable number of tandemly repeated elements, called D4Z4, located in the subtelomeric region of the long arm of chromosome 4 (4q35). Instead of 11 to 100 D4Z4 repeat units normally present in healthy individuals, patients with FSHD1 have less than 10 D4Z4 repeat units on one of their chromosomes 4. These shortened fragments lead to DNA hypomethylation and a consequent opening of the chromatin structure, affecting the expression of the distal DUX4 gene [7, 8, 10, 11].

Patients with FSHD2, on the other hand, have a normal number of D4Z4 repeats, and DNA hypomethylation results from a mutation in the SMCHD1 gene in chromosome 18. Rare cases present with mutations in DNMT3B and LRIF1 genes [4, 12, 13]. However, DNA hypomethylation by itself is not sufficient to cause DUX4 gene derepression. Both FSHD1 and FSHD2 solely occur in the presence of a 4qA allele, a polymorphic segment, that contains a polyadenylation signal that stabilizes otherwise unstable DUX4 transcripts, resulting in translation of a toxic protein and consequent muscular disease [4, 14, 15].

The precise pathogenic mechanisms underlying the development of retinal vasculopathy in FSHD are not entirely clear. It is thought that inadequate derepression of genes involved in vascular smooth muscle or endothelial cells function (such as cellular growth and angiogenesis) plays a dominant role [2, 7, 16, 17].

Inherence pattern

FSHD1 is inherited by an autosomal dominant pattern, although sporadic disease can occur in about 10 to 30% of cases [4, 11, 18, 19]. FSHD2 is a digenic disease involving a mutation in SMCHD1 on chromosome 18 and a permissive A allele on chromosome 4q. Around 60% of FSHD2 cases are estimated to be sporadic [4, 11, 20].


FSHD is the third most frequent type of muscular dystrophy, sharing the podium with the dystrophinopathies and myotonic dystrophy [4, 7, 11]. It is estimated to affect 1 in 20 000 individuals, with a reported incidence of 0,3 per 100 000 people in a Dutch study [2, 21].

FSHD1 represents more than 95% of all cases, and a minority of patients (less than 5%) have FSHD2 [4, 11].

The age of disease onset varies, and FSHD can be diagnosed from childhood to old age. However, symptoms typically start by the second decade. Both genders are equally affected, although women are usually diagnosed later in life and appear to be less severely affected [4, 11].


The diagnosis of FSHD is suggested by typical clinical features and positive family history. The definitive diagnosis is established by genetic testing [4].

Clinical Ophthalmologic Findings

Facial muscles involvement is an early sign in patients with FSHD. Orbicularis oculi weakness hampers adequate eyelid closure especially during sleep time, resulting in potential exposure keratitis and corneal ulceration. Extra-ocular muscles are usually spared, but a few cases of progressive external ophthalmoplegia have been reported. Ptosis is rare [1, 2, 4].

Retinal vasculopathy is one of the most frequent extra-muscular findings in FSHD, affecting around 50-70% of patients [22]. Retinal vascular changes are usually bilateral and include vascular tortuosity, capillary telangiectasias and microaneurysms, commonly found in an asymptomatic patient at a screening visit [1, 2]. Most of these alterations are subtle and can be easily overlooked without a fluorescein angiogram [2]. However, a minority of FSHD patients develop a Coats-like syndrome, with significant telangiectasias and exudative retinopathy, ultimately progressing to retinal detachment, neovascularization and neovascular glaucoma [1, 2, 9, 23]. The most severe end of the clinical spectrum is typically associated with a smaller number of D4Z4 repeat units [4, 9, 11, 23].

Rosa N. et al reported that patients with FSHD have thinner central corneas and lower intraocular pressure measurements in comparison with healthy controls [24].

Differential diagnosis

More common diseases such as diabetic retinopathy, venous occlusive disease, hypertensive retinopathy or sickle-cell anemia, should be included in the differential diagnosis of a retinal microvascular disorder [2]. Also, familial exudative vitreoretinopathy, retinopathy of prematurity, Norrie’s disease, hemangioma and Eales’ disease can all lead to retinal telangiectasias and exudation and should be considered when such findings are present.


There is no curative treatment for FSHD and disease management is based on supportive care focusing on screening, rehabilitation and symptomatic control [4, 25]. An ophthalmological exam with dilated fundus examination is recommended for all patients with FSHD at the time of diagnosis to screen for reversible and potentially sight-threatening complications. When identified in an early stage, Coats-like syndrome manifestations can be treated with photocoagulation and/or intravitreal injections of anti-angiogenic agents, preventing further retinal damage [2, 4, 25]. The regularity of subsequent follow-up visits varies according to the severity of initial eye findings. Adults without retinal vasculopathy at the first visit should be evaluated again by an ophthalmologist if they develop visual complaints. Patients with the smallest D4Z4 repeats, as well as children with the infantile form of the disease should have at least an annual ophthalmological examination [2, 23, 25].


Classically, FSHD is a slowly progressive disease and patients usually have a normal lifespan [4, 11]. However, it can lead to significant disability and morbidity, ultimately resulting in wheelchair dependence in about 20% of patients. On the other hand, some patients can persist with mild or no symptoms for their entire lives [4, 5, 11]. It seems to be an association between the number of D4Z4 units and the severity of disease progression and phenotype, with patients with smaller repeat units (between 1 to 3 elements), having a faster progression to more severe manifestations [4, 9, 11, 23]. Men seem to have a more severe clinical phenotype [4].


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2. Matos R, Beato J, Silva M, Silva S, Brandão E, Falcão-Reis F, et al. Combined treatment with intravitreal bevacizumab and laser photocoagulation for exudative maculopathy in facioscapulohumeral muscular dystrophy. Ophthalmic Genet. 2017;38(5):490-3.

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9. Ricci G, Mele F, Govi M, Ruggiero L, Sera F, Vercelli L, et al. Large genotype-phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis. Sci Rep. 2020;10(1):21648.

10. van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35(4):315-7.

11. Lemmers RJ MD, van der Maarel SM Facioscapulohumeral muscular dystrophy. : GeneReviews; 1999 [updated February 6, 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1443/.

12. Hamanaka K, Šikrová D, Mitsuhashi S, Masuda H, Sekiguchi Y, Sugiyama A, et al. Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy. Neurology. 2020;94(23):e2441-e7.

13. van den Boogaard ML, Lemmers R, Balog J, Wohlgemuth M, Auranen M, Mitsuhashi S, et al. Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. Am J Hum Genet. 2016;98(5):1020-9.

14. Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, et al. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002;32(2):235-6.

15. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010;329(5999):1650-3.

16. Wuebbles RD, Hanel ML, Jones PL. FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy. Dis Model Mech. 2009;2(5-6):267-74.

17. Fitzsimons RB. Retinal vascular disease and the pathogenesis of facioscapulohumeral muscular dystrophy. A signalling message from Wnt? Neuromuscul Disord. 2011;21(4):263-71.

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19. Köhler J, Rupilius B, Otto M, Bathke K, Koch MC. Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis. Hum Genet. 1996;98(4):485-90.

20. de Greef JC, Lemmers RJ, Camaño P, Day JW, Sacconi S, Dunand M, et al. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010;75(17):1548-54.

21. Deenen JC, Arnts H, van der Maarel SM, Padberg GW, Verschuuren JJ, Bakker E, et al. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology. 2014;83(12):1056-9.

22. Osborne RJ, Welle S, Venance SL, Thornton CA, Tawil R. Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy. Neurology. 2007;68(8):569-77.

23. Statland JM, Sacconi S, Farmakidis C, Donlin-Smith CM, Chung M, Tawil R. Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size. Neurology. 2013;80(13):1247-50.

24. Rosa N, Lanza M, de Bernardo M, Cecio MR, Passamano L, Politano L. Intraocular pressure in patients with muscular dystrophies. Ophthalmology. 2013;120(6):1306-7.e1.

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