Valley Sign in Becker Muscular Dystrophy and Outliers of Duchenne and Becker Muscular Dystrophy

Original Article

Valley sign in Becker muscular dystrophy and outliers of Duchenne and Becker muscular dystrophy

Sunil Pradhan Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Valley sign has been described in patients with Duchenne volvement is an important characteristic of muscular 1 muscular dystrophy (DMD). As there are genetic and clini- dystrophies. In DMD and BMD, this selectivity is evident 2 cal similarities between DMD and Becker muscular dystro- for hypertrophy as well as wasting. In one study done on phy (BMD), this clinical sign is evaluated in this study in DMD patients, infraspinatus and deltoid muscles were found BMD and DMD/ BMD outliers. To evaluate the sign, 28 pa- to be the second and third most common hypertrophied mus- tients with Becker muscular dystrophy (BMD), 8 DMD/BMD cles after the most obvious calf muscles. On observing the outliers and 44 age-matched male controls with other neu- wasting, the muscles forming the anterior and posterior axil- romuscular diseases were studied. The sign was examined lary folds were found to be the ones most significantly wasted.3 after asking patients to abduct their arms to about 90ºwith Still finer observations revealed that in the deltoid muscle, hands directed upwards; the muscle bulk over the back of only the central fibers originating from the acromion process the shoulders was observed. The sign was considered posi- were enlarged while the anterior and posterior fibers originat- tive if the infraspinatus and deltoid muscles were enlarged ing from the clavicle and spinous process of the scapula re- and between these two muscles, the muscles forming the spectively, were wasted.3 Similarly, the inferomedial part of posterior axillary fold were wasted as if there were a valley the infraspinatus muscle was enlarged while the superolateral between the two mounts. Twenty-five BMD patients and 7 part was wasted. In other words, even though the deltoid and DMD/BMD outliers had positive valley sign. However, it was infraspinatus muscles were found enlarged, parts of these less remarkable in comparison to DMD. It was absent in all muscles which traverse through the posterior axillary fold, the 44 controls. It was concluded that the presence of valley along with other muscles such as pteres major, pteres minor sign may help in differentiating BMD from other progressive and latissimus dorsi, were wasted.3 On the other hand, subtle neuromuscular disorders of that age group. enlargement of the muscles was found to be best observable Key Words: Becker muscular dystrophy (BMD), clinical sign, when the muscles in question were under mild contraction.3 valley sign, muscle hypertrophy, muscle wasting, dystrophin Based on these findings, a clinical sign has been described in gene, muscular dystrophy patients with DMD.4 The sign which may be called the “valley sign” was observed to be present in about 90% of the DMD patients (BMD and outliers not evaluated).4 In the present clinical study, this sign was tested in BMD patients and in Introduction DMD/BMD outliers, and was compared with other neuromuscular disorders of that age group. Becker muscular dystrophy (BMD) is genetically similar to Duchenne muscular dystrophy (DMD) with gene deletion at Material and methods Xp 21 locus. The gene product dystrophin, which is a normal component of muscle cell membrane, is absent in DMD but is All the patients of BMD and DMD/BMD outliers who attended present in a small amount and in abnormal form in BMD. the outpatient clinic of a Neurology unit in this institution in the last six years and were found to have gene deletion at Xp21 locus, were Perhaps due to this reason the clinical manifestations of DMD examined for the “valley sign”. These included 28 patients with BMD and BMD are more or less similar but with a difference that from 21 families and eight DMD/BMD outliers from six families. in BMD, the age of onset is late and the progression of symp- The criteria to call a patient as having BMD included typical history toms, slow. Among the clinical features, selective muscle in- and physical findings of BMD, clinical evidence of gradual progres-

Sunil Pradhan Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226014, India. E-mail: [email protected]

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CMYK 203 Pradhan S: Valley sign in BMD and outliers sion of the disease, medical records showing raised serum creatine 11-18 years. All of them presented for the first time at a stage kinase (CK) levels and myopathic pattern on concentric needle elec- when they had significant weakness in their proximal muscles tromyography. Family history of typical progression of the disease but all were managing their independent daily routine activ- and typical histopathological findings in patients or affected siblings, ity. Their serum creatine kinase (CK) values ranged between were taken as the definitive evidences whenever present. Gene deletion studies were performed in all patients by the method described 510 IU and 3570 IU. Electromyography (EMG) showed a in earlier reports.3-5 As the muscle biopsy could not be done in all myopathic pattern in all of them. Nineteen out of the 28 pa- cases and the gene deletion studies yielded positive results in only tients had gene deletion at the hotspot, which centered around about two-thirds of the patients, the gold standard for the selection exon 45 to 51; the rest of them had deletion at other sites in of patients was the positive test for gene deletion at the Xp 21 locus; the same Xp21 locus. The valley sign was positive in 25 out of the rest of them were excluded to avoid any possible contamination 28 BMD patients including the two with inconspicuous calves. from other muscular dystrophies. In the group from which the pa- All the 25 patients showed enlargement of the deltoid and tients for the present study were selected, about one-third were non- infraspinatus muscles but the wasting of the posterior axil- deletional cases6 who were excluded. The patients who were above 16 years of age with no crippling, were included in BMD while those lary fold was less remarkable as compared to the earlier re- between 12 and 16 years of age who could walk and get up from a ported DMD cases. The regional topography however, was sitting position with great difficulty but were not yet chair-bound, conspicuous enough to be noticed by an experienced observer were considered as DMD/BMD outliers. as a distinct sign. Out of the 3 BMD cases with negative sign, To view the sign, the back of the patient was exposed. He was obesity masked the sign in one, lack of significant wasting of asked to abduct the shoulders to 90o or thereabouts, with 90o flexion the posterior axillary fold masked it in another and lack of of the elbow, so that the hands were directed upwards. In patients significant enlargement of the infraspinatus muscle masked with positive sign, two bulges were visible on either side of a depres- it in the third patient. sion on the back of the shoulder, like a valley between the two mounts.4 The depression or groove ran from the spinous process of the scapula All the eight DMD/BMD outliers were males with the age to the axilla; it was due to the wasting of the muscles forming the range of 13-15 (mean + SD = 13.8 + 0.8) years. The age at posterior axillary fold, such as pteres major, pteres minor, latissimus onset ranged between 6 and 10 years. All of them were able to dorsi and small parts of the deltoid, infraspinatus and long head of walk slowly with a waddling gait but had great difficulty in triceps muscles. Inferomedial to this depression was the bulge (the getting up from a sitting position. All of them appeared to be mount) due to hypertrophy or relatively preserved bulk of the on the verge of becoming chair-bound at the time of examina- inferomedial two-thirds of the infraspinatus muscle. Superolateral tion. EMG showed myopathic pattern in all. Genetic study to the depression was the bulge (the second mount) due to hypertro- revealed deletion at the central hotspot in the region of exon phy or the relatively preserved bulk of the central fibers of the deltoid muscle. 45 to 52 in all the eight cases. The valley sign was positive in All the 3 components of the clinical sign were analyzed in the pa- seven out of eight cases. In the remaining patient, the wast- tients and the controls. Forty-four patients in the age group of 11-48 ing of the posterior axillary fold was not significant enough to (mean + SD = 21.95 + 5.95) years who were suffering from neu- produce a depression between the two bulges and the bulge romuscular diseases other than DMD/BMD, were also studied for formed by the infraspinatus muscle was less remarkable. this sign. These included 9 patients with limb girdle muscular dys- Patients of muscular dystrophy other than DMD/BMD and trophy (LGMD), 8 with spinal muscular atrophy Type III (SMA- those with SMA-III did not show all the 3 components that III), 9 with chronic polymyositis, 11 with facioscapulohumeral dys- were essential to call it a positive sign. However, infraspina- trophy (FSHD) and 7 with myotonia dystrophica. The diagnosis of these patients was supported by clinical, biochemical, tus hypertrophy was observed in two patients with SMA, in electrophysiological and/or histopathological evidences. The sign one with LGMD and in all the 11 with FSHMD. Also, deltoid observed in DMD/BMD patients was compared with the findings enlargement was seen in five patients with SMA-III, one with seen in these patients. The sign was considered positive only when LGMD, in eight patients with FSHD and in four patients two independent observers working in Neurology as trainee resident with myotonic dystrophy. doctors after post-graduation in internal medicine, who were well versed with the sign, agreed with the author’s observation. Discussion

Results Clinical signs have always played a major role in the diagnosis and management of patients as these cost nothing and All the 28 BMD patients were male in the age range of 17- depending on specificity, help physicians in reaching the cor- 41 (mean + SD = 26.5 + 4.2) years. All belonged to the rect diagnosis with fair accuracy. The valley sign is classically central and eastern districts of the Uttar Pradesh province of described in patients with DMD.4 The present study is the India. Twenty-six of them had mild to moderate calf muscle first to show its presence in BMD and the outliers, which are enlargement and pure motor gradually progressive proximal the milder forms of the same genetic disorder. The value of its muscle weakness; 2 patients had no appreciable calf hyper- presence lies in the fact that several muscular dystrophies and trophy. The age of onset as told by the patients, was between spinal muscular atrophies clinically manifest for the first time

204 Neurology India June 2004 Vol 52 Issue 2 204 CMYK Pradhan S: Valley sign in BMD and outliers in adolescence and early adult life and the presence of the our previous studies, this constitutes about two-thirds of all valley sign may help in differentiating BMD or the outliers phenotypic cases.9 In the absence of immunohistochemical from other related disorders. Though the pattern of muscle studies other cases could not be included but the sign is ex- involvement helps in clinical differentiation of these disorders, pected to be positive in some of them also. proximal muscle weakness is common to most of them with Another important observation was the enlargement of both an exception of myotonia dystrophica. Calf muscle enlarge- deltoid and infraspinatus muscles in control cases with FSHD. ment also helps in differentiating BMD from other disorders, However, the topography in these patients after adoption of but occasionally, a few patients of LGMD or SMA-III may the same posture, was so different that this was described also demonstrate calf enlargement. Mildly raised CK values separately as a “poll-hill sign”.10 In FSHD, the trapezius and also don’t help in differentiating these disorders. In this situ- biceps muscles were found significantly wasted and this was ation, the valley sign may be quite useful in differentiating also the case with myotonic dystrophy, but not with BMD or BMD and outliers from other neuromuscular disorders of that the outliers. Similarly, the observations on the medial border age group. of the scapula were also remarkable. In FSHD, it was di- In DMD/BMD, the selectivity in muscle involvement is so rected inferomedially due to inverse rotation and there was marked that both hypertrophy and wasting could be observed winging, predominantly of the inferior angle. In myotonic in the same region i.e., on the back of the shoulder.4 The posi- dystrophy, there was no winging or abnormal rotation of the tive sign which is described as a valley between the two mounts, scapula. In BMD, in spite of minimal winging, there was no has three components and all the three must be present to call inverse rotation and the medial border was directed it a positive sign - (1) Bulge due to hypertrophy or relatively inferolaterally. If the relatively preserved bulk of the trape- preserved bulk of the deltoid muscle fibers of acromion origin; zius, biceps and triceps muscles, and normal inclination and (2) Linear or oval depression due to wasting of the posterior slight or no winging of the medial border of scapula, are taken axillary folds including parts of the deltoid and infraspinatus into account, the ‘valley sign’ may be quite useful in differen- muscles which traverse the fold and (3) Bulge due to hyper- tiating BMD or the outliers from other neuromuscular disor- trophy or relatively preserved bulk of the infraspinatus mus- ders of that age group. As has been described in patients with cle. Thus, wasted posterior axillary fold forms the valley. DMD,11 the sign attains greater value by its presence in two Superolateral to this valley is seen the deltoid mount and BMD patients who had inconspicuous calves. inferomedial to this, the infraspinatus mount. The present study deals with BMD and the DMD/BMD outliers and is an Acknowledgements extension of the work done earlier in DMD. Most of the BMD patients were examined at the stage when they were not much The author gratefully acknowledges the help of Dr. B. Mittal, PhD, crippled. The presence of a positive sign even at this early Department of genetics, for performing gene deletion studies. stage of the disease indicates that the regional topography of the muscles behind the shoulder remains the same in two simi- References lar genotypic diseases, i.e., DMD and BMD. However, in BMD the changes in the muscle bulk were less remarkable in the 1. Emery AEH. Duchenne muscular dystrophy New York: Oxford University Press 1987:25-42. early stage and it reflected in the valley sign, which was also 2. Walton J, Gardner-Medwin D. The muscular dystrophies. In: Walton J, (Ed). less remarkable in BMD as compared to DMD patients. In Disorders of voluntary muscle. 5th (Ed). London: Churchill Livingstone this context, we did observe that the valley sign was more re- 1988:519-68. 3. Pradhan S, Mittal B. Infraspinatus muscle hypertrophy and axillary folds wast- markable in DMD/BMD outliers whom we examined at the ing as the important signs in Duchenne muscular dystrophy. Clin Neurol stage of significant disability. Neurosurg 1995;91:134-8. 4. Pradhan S. New Clinical sign in Duchenne muscular dystrophy. Pediatr Neurol In an analytical account on this new clinical sign, a com- 1994;11:298-300. parison has been made between this and the Gower’s sign.7 5. Sinha S, Pradhan S, Mittal RD, Mittal B. Detection of gene deletion in patients of Duchenne muscular dystrophy/Becker muscular dystrophy using According to this review, the Gower’s sign is based on selec- polymerase chain reaction. Indian J Med Res (B) 1992;96:297-301. tivity in the loss of muscle power in certain groups of muscles 6. Chaturvedi LS, Srivastava S, Mukherjee M, Mittal RD, Phadke SR, Pradhan S, et al. Carrier detection in non-deletional Duchenne/Becker muscular dystro- so that the patient makes best use of relatively preserved phy families using polymorphic dinucleotide (CA) repeat loci of dystrophin gene. muscle power (in spared groups of muscles) which can be ap- Indian J Med Res 2001;113:19-25. 7. Stockman JA, (Ed). The Year Book of Pediatrics. Mosby, New York, 1996;304- preciated in the peculiar way the patient gets up from a squat- 6. ting position. Thus, one can infer that the Gower's sign high- 8. Jayaraman KS, (Ed). The Pradhan sign in Duchenne muscular dystrophy. In- dia: Nature - News; 2001:6. lights selectivity in the loss of muscle power while the valley 9. Singh V, Sinha S, Misra S, Chaturvedi LS, Pradhan S, Mittal RD, et al. Pro- sign highlights selectivity in the loss of (or the increase in) portion and pattern of dystrophin gene deletions in North Indian Duchenne muscle bulk.7 The simplicity in eliciting the valley sign has led and Becker muscular dystrophy patients. Hum Genet 1997;99:206-8. 10. Pradhan S. Poly-hill sign in fascioscapulohumeral dystrophy. Muscle & Nerve to its universal acceptance in DMD7,8 and the present study 2002;25:754-5. extends its utility to BMD and DMD/BMD outliers. 11. Pradhan S. “Valley sign” in Duchenne muscular dystrophy: Importance in patients with inconspicuous calves. Neurol India 2002. The present study deals only with the gene deletion positive cases of BMD and DMD/BMD outliers. According to one of Accepted on 15.12.2002

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