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Facioscapulohumeral muscular dystrophy as a genetic cause of pectus excavatum
European Journal of Medical Genetics 58 (2015) 203e204
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Letter to the editor
Facioscapulohumeral muscular dystrophy as a genetic cause of pectus excavatum Table 1 Clinical clues for FSHD. Keywords: Pectus excavatum Facioscapulohumeral muscular dystrophy (FSHD)
Dear editor, With great interest we read the review on pectus excavatum and pectus carinatum by Cobben et al. in your journal [Cobben et al., 2014]. The authors explain that the pathogenesis of these morphological chest wall abnormalities is largely unknown and that they may occur in isolation or as part of a genetic syndrome. Although many genetic syndromes are associated with pectus excavatum, most of them are very rare [Jones, 2013]. The authors discuss some of the most frequent monogenic syndromes and chromosomal disorders that are associated with pectus excavatum. For an extensive overview, they refer to a genetic review on the etiology of chest wall deformities [Kotzot and Schwabegger, 2009]. They also present a practical table with diagnostic recommendations that can be helpful in the differential diagnosis of genetic causes of pectus excavatum. This table focuses mostly on features of inherited connective tissue disorders and dysmorphias occurring in various monogenic and chromosomal disorders. It would be helpful for geneticists also to look for features of facioscapulohumeral muscular dystrophy (FSHD) which has a relatively high incidence of pectus excavatum of 5e16% [Padberg, 1982; Patijn, 1983]. FSHD is one of the most common muscular dystrophies with an estimated prevalence of 1 in 8.000 [Deenen et al., 2014] and is caused by inefficient repression of the D4Z4 macrosatellite array in the subtelomeric region of chromosome 4q. This results in expression of the DUX4 retrogene which is a double homeobox transcription factor. Its targets include FRG1 and FRG2, genes with unknown function, and WNT proteins, which have embryonic functions such as body axis patterning, cell fate specification, cell proliferation and cell migration in tissues such as bone and muscle. This fits the clinical picture of FSHD being a combination of an asymmetrical facial muscle dysplasia, a progressive limb and truncal muscle dystrophy and lower frequencies of retinal vasculopathy, hearing loss and pectus excavatum [Nagasao et al., 2014]. Overall, assessment of symptoms and signs of FSHD is straightforward (Table 1). However, recognizing more subtle signs may be difficult, especially in cases of mild facial weakness. Next, because of the high proportion of de novo mutations and marked variability of symptoms within families, the family history does not always reveal a diagnosis of FSHD. http://dx.doi.org/10.1016/j.ejmg.2015.02.007 1769-7212/Ó 2015 Elsevier Masson SAS. All rights reserved.
Face Upper extremity Lower extremity Trunk
(Asymmetrical) facial weakness: difficulty in closing eyelids and pursing lips, whistling, blowing cheeks Winging of scapula (frequently asymmetrical) Asymmetrical weakness of shoulder girdle (shoulder abduction, anteflexion, endo- and exorotation) (Asymmetrical) weakness of foot dorsiflexors, knee flexors and hip adductors (Asymmetrical) atrophy of m. pectoralis major Weakness of neck extension and flexion Abdominal muscle weakness with positive Beevor sign (upward movement of the umbilicus on flexing the neck) Lumbar hyperlordosis
Fig. 1. Lateral chest radiograph of a patient with FSHD and severe pectus excavatum.
204
Letter to the editor / European Journal of Medical Genetics 58 (2015) 203e204
The exact pathophysiology of pectus excavatum in FSHD is currently unknown. In those cases where the pectoral muscles are not yet severely involved a genetic/metabolic explanation is favored; it also explains why not all FSHD patients develop pectus excavatum. Another hypothesis suggests that weak major pectoral muscles are not able to counteract the negative intra-thoracic pressure on inspiration. As a consequence, the relatively flexible anterior chest wall is pulled inwards on every inspiration resulting in repetitive mechanical stress finally leading to pectus excavatum [Nagasao et al., 2014]. Pectus excavatum can be severe in a proportion of patients with FSHD and may even be the presenting symptom. Moreover, severe pectus excavatum in FSHD is a risk factor for ventilator dependency due to compression of the lungs, especially in case of weakness of accessory respiratory muscles [Wohlgemuth et al., 2004]. We therefore think it is important to add FSHD as a genetic cause to the extensive list of etiologies of chest wall deformities referred to by Cobben et al., and to add these clinical clues to the presented diagnostic recommendations. Because of its complex genetic mechanism FSHD cannot be detected by whole exome sequencing and therefore early clinical recognition of FSHD as cause of pectus excavatum will prevent unnecessary genetic tests and diagnostic delay. (see Fig. 1) References Cobben JM, Oostra RJ, van Dijk FS. Pectus excavatum and carinatum. Eur J Med Genet 2014;57:414e7.
d.C.C.M Jones KL. Smith’s Recognizable Patterns of Human Malformation. Seventh ed. Philadelphia (PA): WB Saunders; 2013. 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;83:1056e9. Kotzot D, Schwabegger AH. Etiology of chest wall deformitiesea genetic review for the treating physician. J Pediatr Surg 2009;44:2004e11. Nagasao T, Shimizu Y, Morotomi T, Takano N, Jiang H, Kishi K. Irregular location of major pectoral muscle can be a causative factor of pectus excavatum. Med Hypotheses 2014;82:512e7. Padberg G. Facioscapulohumeral Disease. Thesis. University of Leiden; 1982. Patijn J. De ziekte van Landouzy-Dejerine. Een computer-tomografische studie van de skeletmusculatuur. Thesis. University of Amsterdam.; 1983. Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 2004;63:176e8.
Karlien Mul, George W. Padberg, Nicol C. Voermans* Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands * Corresponding
author. Department of Neurology (935), Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: þ31 24 3616600; fax: þ31 24 3618837. E-mail address: [email protected] (N.C. Voermans). 12 February 2015 Available online 25 February 2015
Contents lists available at ScienceDirect
European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg
Letter to the editor
Facioscapulohumeral muscular dystrophy as a genetic cause of pectus excavatum Table 1 Clinical clues for FSHD. Keywords: Pectus excavatum Facioscapulohumeral muscular dystrophy (FSHD)
Dear editor, With great interest we read the review on pectus excavatum and pectus carinatum by Cobben et al. in your journal [Cobben et al., 2014]. The authors explain that the pathogenesis of these morphological chest wall abnormalities is largely unknown and that they may occur in isolation or as part of a genetic syndrome. Although many genetic syndromes are associated with pectus excavatum, most of them are very rare [Jones, 2013]. The authors discuss some of the most frequent monogenic syndromes and chromosomal disorders that are associated with pectus excavatum. For an extensive overview, they refer to a genetic review on the etiology of chest wall deformities [Kotzot and Schwabegger, 2009]. They also present a practical table with diagnostic recommendations that can be helpful in the differential diagnosis of genetic causes of pectus excavatum. This table focuses mostly on features of inherited connective tissue disorders and dysmorphias occurring in various monogenic and chromosomal disorders. It would be helpful for geneticists also to look for features of facioscapulohumeral muscular dystrophy (FSHD) which has a relatively high incidence of pectus excavatum of 5e16% [Padberg, 1982; Patijn, 1983]. FSHD is one of the most common muscular dystrophies with an estimated prevalence of 1 in 8.000 [Deenen et al., 2014] and is caused by inefficient repression of the D4Z4 macrosatellite array in the subtelomeric region of chromosome 4q. This results in expression of the DUX4 retrogene which is a double homeobox transcription factor. Its targets include FRG1 and FRG2, genes with unknown function, and WNT proteins, which have embryonic functions such as body axis patterning, cell fate specification, cell proliferation and cell migration in tissues such as bone and muscle. This fits the clinical picture of FSHD being a combination of an asymmetrical facial muscle dysplasia, a progressive limb and truncal muscle dystrophy and lower frequencies of retinal vasculopathy, hearing loss and pectus excavatum [Nagasao et al., 2014]. Overall, assessment of symptoms and signs of FSHD is straightforward (Table 1). However, recognizing more subtle signs may be difficult, especially in cases of mild facial weakness. Next, because of the high proportion of de novo mutations and marked variability of symptoms within families, the family history does not always reveal a diagnosis of FSHD. http://dx.doi.org/10.1016/j.ejmg.2015.02.007 1769-7212/Ó 2015 Elsevier Masson SAS. All rights reserved.
Face Upper extremity Lower extremity Trunk
(Asymmetrical) facial weakness: difficulty in closing eyelids and pursing lips, whistling, blowing cheeks Winging of scapula (frequently asymmetrical) Asymmetrical weakness of shoulder girdle (shoulder abduction, anteflexion, endo- and exorotation) (Asymmetrical) weakness of foot dorsiflexors, knee flexors and hip adductors (Asymmetrical) atrophy of m. pectoralis major Weakness of neck extension and flexion Abdominal muscle weakness with positive Beevor sign (upward movement of the umbilicus on flexing the neck) Lumbar hyperlordosis
Fig. 1. Lateral chest radiograph of a patient with FSHD and severe pectus excavatum.
204
Letter to the editor / European Journal of Medical Genetics 58 (2015) 203e204
The exact pathophysiology of pectus excavatum in FSHD is currently unknown. In those cases where the pectoral muscles are not yet severely involved a genetic/metabolic explanation is favored; it also explains why not all FSHD patients develop pectus excavatum. Another hypothesis suggests that weak major pectoral muscles are not able to counteract the negative intra-thoracic pressure on inspiration. As a consequence, the relatively flexible anterior chest wall is pulled inwards on every inspiration resulting in repetitive mechanical stress finally leading to pectus excavatum [Nagasao et al., 2014]. Pectus excavatum can be severe in a proportion of patients with FSHD and may even be the presenting symptom. Moreover, severe pectus excavatum in FSHD is a risk factor for ventilator dependency due to compression of the lungs, especially in case of weakness of accessory respiratory muscles [Wohlgemuth et al., 2004]. We therefore think it is important to add FSHD as a genetic cause to the extensive list of etiologies of chest wall deformities referred to by Cobben et al., and to add these clinical clues to the presented diagnostic recommendations. Because of its complex genetic mechanism FSHD cannot be detected by whole exome sequencing and therefore early clinical recognition of FSHD as cause of pectus excavatum will prevent unnecessary genetic tests and diagnostic delay. (see Fig. 1) References Cobben JM, Oostra RJ, van Dijk FS. Pectus excavatum and carinatum. Eur J Med Genet 2014;57:414e7.
d.C.C.M Jones KL. Smith’s Recognizable Patterns of Human Malformation. Seventh ed. Philadelphia (PA): WB Saunders; 2013. 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;83:1056e9. Kotzot D, Schwabegger AH. Etiology of chest wall deformitiesea genetic review for the treating physician. J Pediatr Surg 2009;44:2004e11. Nagasao T, Shimizu Y, Morotomi T, Takano N, Jiang H, Kishi K. Irregular location of major pectoral muscle can be a causative factor of pectus excavatum. Med Hypotheses 2014;82:512e7. Padberg G. Facioscapulohumeral Disease. Thesis. University of Leiden; 1982. Patijn J. De ziekte van Landouzy-Dejerine. Een computer-tomografische studie van de skeletmusculatuur. Thesis. University of Amsterdam.; 1983. Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 2004;63:176e8.
Karlien Mul, George W. Padberg, Nicol C. Voermans* Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands * Corresponding
author. Department of Neurology (935), Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: þ31 24 3616600; fax: þ31 24 3618837. E-mail address: [email protected] (N.C. Voermans). 12 February 2015 Available online 25 February 2015