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Table of Contents    
Year : 2017  |  Volume : 65  |  Issue : 3  |  Page : 561-565

Family with Ehlers–Danlos syndrome (combined classic and vascular type) with rare presentation of progressive myopathy and unusual association of severe facial and trigeminal motor weakness

1 Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
3 Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India
4 Department of Clinical Neurosciences, National Institute of Mental Health and Neuro Sciences, Bengaluru, Karnataka, India

Date of Web Publication9-May-2017

Correspondence Address:
A Nalini
Neuromuscular Specialist, Department of Neurology, Neuroscience Faculty Block, NIMHANS, Bengaluru - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/neuroindia.NI_537_15

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 » Abstract 

We report the clinical, radiological, biochemical, muscle histology, and electron microscopic features of two members of a family with combined Ehlers–Danlos syndrome (EDS) [classic and vascular type] and progressive myopathy as the primary manifestation. A 35-year old lady presented with severe gluteal and thigh muscle pain and easy fatigability for 5 years. She developed weakness and wasting of pelvic and pectoral girdles and thighs for 3 years and severe neck flexor and truncal weakness for 6 months. She had a history of recurrent jaw dislocation, easy bruising with hyperpigmentation, hyperextensibility of joints, translucent skin, and papyraceous scars. She had high myopia with astigmatism. She had wasting of temporalis, masseters, sternocleidomastoids and trapezius. There was moderate weakness of temporalis, masseters, and facial muscles. Muscle power was Medical Research Council (MRC) grade 4 at shoulders and arms, and grade 3+ at pelvis and thighs. Serum homocysteine level was normal, and creatine kinase (CK) was 275 IU. Two dimensional echocardiogram (2D Echo) showed myxomatous degeneration of mitral valves. Electromyography (EMG) was suggestive of a myopathic pattern. Muscle magnetic resonance imaging (MR) revealed severe fatty infiltration of paraspinal muscles, gluteus maximus and medius, quadriceps, hamstrings, and gastrocnemius. Electron microscopy showed an occasional distorted fibril with mild increase in oxytalan fibers and variation in thickness of blood vessel basement membrane. Her 15-year old daughter had exertion-induced myalgias, right hemifacial hypoplasia, myopia, hyperextensible joints, hyperelastic skin, and neck muscle weakness. However, her CK and 2D Echo were normal. This report presents the rare combination of classic and vascular type of EDS primarily presenting as muscle weakness and associated with facial and trigeminal motor weakness.

Keywords: Ehlers–Danlos syndrome, facial, myopathy, trigeminal
Key Message:
Neurologic and vascular implications of Ehlers-Danlos syndrome have been largely under-recognized but may be a major contributor towards functional disability. A rare combination of classic and vascular type of Ehlers-Danlos syndrome in a lady, primarily associated with axial and proximal muscle weakness, with facial and trigeminal motor weakness, is presented. The familial association was exemplified by her daughter also suffering from the classic form of Ehlers-Danlos syndrome.

How to cite this article:
Nalini A, Devaraddi N, Gayathri N, Prasad C, Preethish-Kumar V, Polavarapu K, Shantanu S. Family with Ehlers–Danlos syndrome (combined classic and vascular type) with rare presentation of progressive myopathy and unusual association of severe facial and trigeminal motor weakness. Neurol India 2017;65:561-5

How to cite this URL:
Nalini A, Devaraddi N, Gayathri N, Prasad C, Preethish-Kumar V, Polavarapu K, Shantanu S. Family with Ehlers–Danlos syndrome (combined classic and vascular type) with rare presentation of progressive myopathy and unusual association of severe facial and trigeminal motor weakness. Neurol India [serial online] 2017 [cited 2023 Mar 26];65:561-5. Available from: https://www.neurologyindia.com/text.asp?2017/65/3/561/205933

Ehlers–Danlos syndrome (EDS) was first recognized in the first decade of the twentieth century as a hereditary disorder with typical skin manifestations.[1],[2] This group of disorders consists of genetically heterogeneous connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. The revised classification has six major types and is based on clinical as well as biochemical features and consists of major and minor diagnostic criteria.[3] The hypermobility type is the most common form of EDS, followed by the classic type, and together, they account for approximately 90% of all cases.[4] The vascular type occurs less commonly. Muscle involvement frequently manifests as fatigue, musculoskeletal pain, and delayed gross motor development. However, muscle weakness and exercise intolerance are rarely and only sporadically described as case reports, and symptoms are generally attributed to increased distensibility of tendons or joints.[5] The diagnosis of EDS is largely based on these characteristic clinical features and the diagnostic criteria proposed by Villefranche and Brighton in 1998 and 2000.[3],[6] Most EDS subtypes are known to be caused by mutations in gene encoding collagen chains or proteins involved in their biogenesis, and overlaps are reported to occur between the various types of EDS.[7] Here, we report a 35-year-old lady with the rare combination of classic and vascular type of EDS, who presented with progressive axial and proximal myopathy along with severe involvement of facial and trigeminal cranial nerve musculature. Her daughter aged 15 years also had the classic form of EDS.

 » Case Report Top

A 35-year old lady in 2013 presented with generalized muscle pain and easy fatigability for 4–5 years. At the onset, she had continuous myalgia involving the gluteal region, which became aggravated on prolonged standing and walking. Later, she developed progressive weakness of hip girdle and thigh muscles followed by weakness of pectoral girdles for 3 years. She experienced recurrent jaw dislocation for 2 years. She also developed severe neck flexor and truncal muscle weakness and shoulder girdle wasting for 6 months. There was the presence of a thin skin with prominent veins and easy bruising of skin for many years over the arms and back of trunk, which healed leaving a dark pigmentation. She was diagnosed to be having hypothyroidism for 5 years and was on thyroid hormone supplements. Examination revealed a marfanoid habitus, micrognathia, hyperelastic skin, hyperextensible joints, and ecchymotic bruises with papyraceous scars. There was wrist and thumb sign, severe myopia, translucent skin with prominent visible veins, toe deformity (prominent 2nd and 3rd toes with same length), and severe lower motor neuron bifacial weakness. There was wasting of temporalis, masseters, sternocleidomastoid, trapezius, and pectoral girdle muscles [Figure 1] and [Figure 2]. Muscle power showed MRC grade 4- to 4 in the proximal upper limbs and grade 3 in the proximal lower limbs. Deep tendon reflexes (DTRs) were hypoactive except for hyperactive knee jerks.
Figure 1: Proband showing (a and b) severe bifacial weakness; (c and d) paperaceous scar, ecchymotic patch; (e-j) hyper extensible joints; (g and i) wrist and thumb sign; (k) second and third great toes of similar size

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Figure 2: The 15-year old daughter showing (a, f and g) hyperextensible joints; (b and c) thumb and wrist sign; (d) hyperelastic skin; (e) second and third great toes of similar size

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Investigations in Proband

Serum homocysteine level was normal, CK level was 275 IU/L. On cardiac evaluation, the electrocardiogram revealed T wave inversion in V1 and ST down sloping in V2 and aVF. 2D Echo showed a myxomatous mitral valve with mild mitral regurgitation, and an ejection fraction of 61%. She had a high myopia with astigmatism. Computed tomographic (CT) aortogram showed a normal aorta and its branches. The nerve conduction study was normal; electromyography (EMG) of the right biceps and quadriceps showed myopathic potentials. Muscle magnetic resonance imaging (MRI) showed severe fatty infiltration of paraspinal muscles, gluteus maximus, and medius. Quadriceps was more affected than the hamstrings and gastrocnemius [Figure 3]. Muscle histopathology of the left vastus lateralis revealed mild fiber size variation, an occasional fiber with rubbed out areas, and a few COX deficient fibers [Figure 4]. Immunostaining to monoclonal antibodies against α2Laminin and COL6α1 showed preserved expression in all the fibers [Figure 4]. Electron microscopy revealed an occasional distorted fibril. There was no variation either in the length or the diameter of the fibrils. Mild increase in oxytalan fibers was noted probably suggesting interruption in the successive phases in the development of elastic fibers; incompletely or spatially modified elastic fibers; or, a variant of elastic tissue that had not matured. In addition, variation in the thickness of the blood vessel basement membrane was noted [Figure 5].
Figure 3: (a-c) Axial T1, T2, and T2FS (fat saturated) images at L5–S1 level. Fat signal intensity with atrophy is involving the erector spinae (arrows) muscle. (d-f) Axial T1, T2, and T2FS images at the level of inferior pubic ramus: Minimal asymmetric atrophy and fatty infiltration of the gluteus maximus (arrow) muscle (right >left). (g-i) Axial T1, T2, and T2FS images at the level of mid-thigh. (a-d) Fatty infiltration with mild atrophic changes involving the long head of biceps, semimembranosus and semitendinosus muscle (curved arrow) and adductor longus (arrow)

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Figure 4: Transversely cut skeletal muscle tissue showing: (a) Polygonal fibers with mild variation in diameter (HE × 400); (b) rubbed-out areas (↑) (SDH × 400); (c) Cox deficient fiber(*) (COX-SDH × 400); (d and e) immunohistochemical staining to monoclonal antibodies against (d) alpha 2 laminin (merosin); (e) col6A1 shows preserved expression along the sarcolemma ×400

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Figure 5: Electron micrograph showing: (a) A portion of myofiber cut longitudinally, endomyseal collagen (*) and blood vessel (BV) ×4,800; (b) Longitudinally cut normal appearing collagen fibril with increase in oxytalan(↑) ×30,000; (c) Higher magnification of normal appearing collagen ×98,000; (d) Low ×49,000 (e) and high ×98,000 magnification of a portion of transversely cut endomyseal collagen (*) showing mild variation in diameter of collagen fibril. Presence of oxytalan(↑) is seen; (f) A portion of myofiber cut longitudinally (MF), endomyseal collagen (*), and blood vessel (BV) ×9300; (g) Note variation in the basement membrane (BM) thickness of blood vessel (↑) ×18,500

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Her 15-year old only daughter was normal until one year ago when she developed exertion induced myalgia in the lower limbs. There was no associated weakness. She was tall, had right hemifacial hypoplasia, myopia, hyperextensible joints, long slender fingers, hyperelastic skin, thumb and wrist sign, MRC grade 3 neck flexor weakness, and severe truncal muscle weakness. There was no facial or limb weakness. The deep tendon reflexes were normal. She also had a poorly responsive microcytic hypochromic anaemia (hemoglobin level: 6.4 mg/dl). The CK level was 56 IU/L, and 2D ECHO was normal [Figure 2].

 » Discussion Top

Our proband fulfilled two of the major criteria and 6 of the minor criteria for the classic type of EDS,[8] i.e., presence of skin hyperextensibility, joint hypermobility, smooth velvety skin, complications of joint hypermobility, easy bruising (manifestations of tissue extensibility and fragility), papyraceous scars “cigarette-paper” type, and also crumpled scars with a positive family history. She also had features of the hypermobility type with chronic limb pain, generalized joint hypermobility, and recurrent jaw dislocation, which is reported to occur in > 70% of the EDS-HT (hypermobility) type.[9] In addition, she also had features belonging to the vascular type with thin, translucent skin and easy bruising.

Interestingly, and unreported earlier, our proband had severe and progressive bifacial weakness and moderate trigeminal motor weakness. In a previous report, one patient of vascular type EDS among 40 cases of various types of EDS patients had mild facial weakness.[8] Our patient also had severe weakness of the neck and trunk muscles as compared to the girdle musculature, which has been reported earlier.[8] Her pelvic girdle and thigh weakness and wasting were progressive, with significant disability due to buckling. Previous reports do mention mild to moderate limb muscle weakness in a significant proportion of EDS patients;[8] however, progressive myopathic presentation as the initial and prominent symptom in EDS has rarely been reported. Further, it is proposed that the neuromuscular involvement in EDS is secondary to a direct effect of the extracellular matrix within the muscle and peripheral nerve, and may not be due to primary muscle involvement,[8] although our case undoubtedly had progressive muscle weakness as the main clinical manifestation. This weakness was well corroborated on muscle MRI, which showed significant fatty infiltration of the affected muscles in the trunk, pelvis, and thighs. Another primary muscle disorder with associated frequent facial weakness is facio-scapulo-humeral muscular dystrophy (FSHD). Our patient had skin manifestations and joint hypermobility, which are not features of FSHD. Facial weakness with joint hypermobility is known to occur in congenital myopathies (CM). Again, the skin manifestations of EDS are not features of CMs. Patient had hypothyroidism but was on adequate hormonal supplements, and hence, unlikely to have hypothyroid associated myopathy.

The cardiac evaluation in the proband showed myxomatous changes in the mitral valve. This feature is known to occur in the vascular form.[10] CK has been reported to be normal (170–220IU/L) in a large series studied by Voermans et al.[8] Both our patients had normal CK levels. Muscle biopsy in three patients reported earlier with the classic type EDS had shown short collagen fragments at the sarcolemma.[8] Our proband did not show abnormal collagen on electron microscopy, except for a variation in the blood vessel wall thickness.

It is a common phenomenon that the female subjects are more frequently and, possibly, more severely affected than males, and in familial cases, the disease is known to more frequently be transmitted by an affected mother.[11] Our family with the affected mother and daughter signifies the same. It is well accepted by many authors that neurologic implications of EDS have been largely neglected or under recognized in the past. It is immensely important to identify these cases because the effect on the neuromuscular system is recognized to be a major contributor for functional disability in EDS. As EDS presents with protean constellation of symptoms and signs, it is imperative to identify the subtle neuromuscular aspects, make an early diagnosis, and thus offer better rehabilitation measures to prevent disabling complications. It is also important to type them as there could be devastating complications with the associated vascular type.

In the absence of a readily available method of genetic testing, EDS remains a clinical diagnosis and neuromuscular manifestations should be identified early to improve the quality of life.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Ehlers E, Cutis L. Neigung zu Haemorhagien in der Haut, Lockerung mehrerer Artikulationen. Dermatologische Zeitschrift 1901;8:173-4.  Back to cited text no. 1
Danlos HA. Un cas de cutis laxa avec tumeurs par contusion chronique des coudes et des genoux (xanthome juvenile pseudodiabétique de MM, Halloepau et Macé de Lépinay). Bulletin de la Société Française de Dermatologie et de Syphiligraphie 1908;39:1252-56.  Back to cited text no. 2
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers–Danlos syndromes: Revised nosology, Villefranche, 1997. Ehlers–Danlos National Foundation (USA) and Ehlers–Danlos Support Group (UK). Am J Med Genet 1998;77:31-7.  Back to cited text no. 3
Steinmann B, Royce PM, Superti-Furga A. The Ehlers–Danlos syndrome. In: Royce PM, Steinmann B, editors. Connective Tissue and Its Heritable Disorders. 2nd edition. New York: Wiley-Liss; 2002. p. 431-524.  Back to cited text no. 4
Pretorius ME, Butler IJ. Neurologic manifestations of Ehlers–Danlos syndrome. Neurology 1983;33:1087-9.  Back to cited text no. 5
Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol 2000;27:1777-9.  Back to cited text no. 6
Castori M. Ehlers–Danlos syndrome, hypermobility type: An underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol 2012;2012:751768.  Back to cited text no. 7
Voermans NC, van Alfen N, Pillen S, Lammens M, Schalkwijk J, Zwarts MJ, et al. Neuromuscular involvement in various types of Ehlers–Danlos syndrome. Ann Neurol 2009;65:687-97.  Back to cited text no. 8
De Coster PJ, Martens LC, Van den Berghe L. Prevalence of temporomandibular joint dysfunction in Ehlers–Danlos syndromes. Orthod Craniofac Res 2004;7:237-40.  Back to cited text no. 9
Takano H, Miyamoto Y, Sawa Y, Fukushima N, Matsumiya G, Fujita T, et al. Successful mitral valve replacement in a patient with Ehlers–Danlos syndrome type VI. Ann Thorac Surg 2005;80:320-2.  Back to cited text no. 10
Castori M, Camerota F, Celletti C, Grammatico P, Padua L. Ehlers–Danlos syndrome hypermobility type and the excess of affected females: Possible mechanisms and perspectives. Am J Med Genet A 2010;152A: 2406-8.  Back to cited text no. 11


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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