International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571

Review Article

A Review on Ehlers-Danlos Syndrome

V. Jagadeesh Naik1, B. Aswani2, P. Yanadaiah3, K. Hemachandra4, C. Madhusudhana Shetty5

1Pharm D V Year, 2,3Assistant Professor, 4Pharm D V Year, 5Principal, Department of Pharmacy Practice, Santhiram College of Pharmacy, Nandyal, A.P. Pin -518501.

Corresponding Author: V. Jagadeesh naik

ABSTRACT

Ehlers-Danlos syndrome (EDS) is a group of inherited disorders that affect the connective tissues primarily skin, joints, and blood vessel walls. Connective tissue is a complex mixture of proteins and other substances that provides strength and elasticity to the underlying structures in the body. People who have Ehlers-Danlos syndrome usually have overly flexible joints and stretchy, fragile skin. This can become a problem if a person has a wound that requires stitches, because the skin often is not strong enough to hold them. A more severe form of the disorder, called vascular Ehlers-Danlos syndrome, can cause the walls of the blood vessels, intestines or uterus to rupture. If a person has a vascular Ehlers-Danlos syndrome, he/she may want to talk to a genetic counselor before starting a family. EDS is typically classified into six types like The Classical type (formerly types I and II), The Hyper mobility type (type III), The Vascular type (type IV), The Kyphoscoliosis type (type VI), The Arthrochalasial type (type VIIA and VIIB), The Dermatosparaxis type (type VIIC). The combined frequency of EDS is 1 in 5000 individuals worldwide. Major mutations in COL5A1 gene and COL5A2 genes are responsible for EDS. There is more chance to autosomal inheritance of EDS. There is no specific therapy to cure Ehlers-Danlos syndrome. Physical therapy is often needed. Some of the other medications are under different phases of clinical trials.

Key words: Ehlers – Danlos syndrome, connective tissues, mutations, autosomal inheritance.

INTRODUCTION  The classical type (formerly types I and EHLERS-DANLOS SYNDROME II) (EDS) is a group of disorders that affect the  The hyper mobility type (type III) connective tissues that support the skin,  The vascular type (type IV) bones, blood vessels and many other organs  The kyphoscoliosis type (type VI) and tissues. Defects in connective tissues  The arthrochalasia type (type VIIA and cause the signs and symptoms of EDS, VIIB) which vary from mildly loose joints to life [1]  The dermatosparaxis type (type VIIC) threatening complications. This six-type classification, known as Classification the villefranche nomenclature, is still Previously, there were more than 10 commonly used. The types are distinguished recognized types of EDS, differentiated by by their signs and symptoms, their roman numerical. In 1997, researchers underlying genetic causes, their patterns, of proposed a simpler classification that inheritance. [1] Sine 1997, several additional reduced the number of major types to six forms of the condition have been described. and gave them descriptive names These additional forms appear to be rare,

International Journal of Health Sciences & Research (www.ijhsr.org) 468 Vol.7; Issue: 8; August 2017 V. Jagadeesh naik t al. A Review on Ehlers-Danlos Syndrome

affecting a small numbers of families, and The hyper mobility and classical forms are most have not been well characterized. most common; the hyper mobility type may Although all types of EDS affects the joints affect as many as 1 in 10,000 to 15,000 and skin, additional features vary by type. A people, while the classical type probably usually large range of joint movement occurs in 1 in 20,000 to 40,000 people. (hyper mobility) occurs with most forms of Other forms of EDS are very rare. EDS, particularly the hyper mobility type. [2] About 30 cases of arthrochalasia type and Infants with hyper mobile joints often about 60 cases of the kyphoscoliosis type have weak muscle tone, which can delay the have been described. The vascular type is development of motor skills such as sitting, also rare, estimates vary widely, but the standing and walking. The loose joints are condition may affect about 1 in 250,000 unstable and prone to dislocation, chronic people. pain. Hyper mobility and dislocations of Genetic Changes [5] both hips at birth are characteristic features Mutations in more than a dozen in infants with arthrochalasia type of EDS. genes have been found to cause EDS. The Many people with EDS have soft, velvety classical type results more often from skin that is highly stretchy (elastic) and mutations in either the COL5A1 gene or the fragile. Affected individuals tend to bruise COL5A2 gene. Mutations in the TNXB easily, and some type of the condition also gene have been found in a very small causes abnormal scarring. [3] percentage of cases of the hypermobility People with classical form of EDS type (although in most cases, the cause of experience wounds that split open with little this type is unknown). The vascular type bleeding and leave scars that widen over results from mutations in the COL3A1 gene. time to create characteristic “cigarette PLOD1 gene mutations cause the paper” scars. The dermatosparaxis type of kyphoscoliosis type. Mutations in the the disorder is characterized by skin that COL1A1 gene or the COL1A2 result in the sags and wrinkles. Extra (redundant) folds arthrochalasia type. The dermatosparaxis of skin may be present as affected children type is caused by mutations in the get older. [3] ADAMTS2 gene. The other, less well Some forms EDS, notably the vascular characterized forms of EDS result from type and to a lesser extent the mutations in the other genes, some of which kyphoscoliosis and classical types, can have not been identified. involve serious and potentially life- Some of the genes associated with threatening complication due to EDS, including COL1A1, COL1A2, unpredictable tearing (rupture) of blood COL3A1, COL5A1 and COL5A2, provide vessels. The rupture can cause internal instructions for making pieces of several bleeding, stroke, and shock. different types of collagen. These pieces The vascular type of EDS is also assemble to form mature collagen molecules associated with an increased risk of organ that give structure and strength to rupture, including tearing of the intestine connective tissues throught the body. Other and rupture of the uterus (womb) during genes, including ADAMTS2, PLOD1 and pregnancy. People with the kyphoscoliosis TNXB, provide instructions for making form of EDS experience severe, progressive proteins that process are interact with curvature of the spine that can interfere with collagen. Mutations that cause the different breathing. [3] forms of EDS disrupt the production or Frequency [4] processing of collagen, preventing these Although it is difficult to estimate molecules from being assembled properly. the overall frequency of EDS, the combined These defects weaken connective tissues in prevalence of all types of this condition may the skin, bones, and other parts of the body, be about in 1 in 5,000 individual worldwide.

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resulting in the characteristic features of this in each cell are altered. Most often, the condition. parents of an individual with an autosomal Inheritance Pattern recessive disorder are carriers of one copy The inheritance pattern of EDS of the altered gene but don‟t show signs and varies by type. The arthrochalasia, classical, symptoms of the disorder. [6] hypermobility, and vascular forms of the Symptoms disorder have an autosomal dominant Symptoms of EDS include [6] pattern of inheritance. Autosomal dominant  Back pain inheritance means that one copy of the  Double-jointedness altered gene in each cell is sufficient to  Easily damaged, bruised, and poor cause the disorder. In some cases, an wound healing affected person inherits the mutation from  Flat feet one affected parent. Other cases result from  Increased joint mobility, joints popping, new (sporadic) gene mutations and occur in early arthritis people with no history of the disorder in  Joint dislocation their family.  Joint pain The dermatosparaxis and  Premature rupture of membranes during kyphoscoliosis types of EDS, as well as pregnancy some of the rare, less well characterized types the disorder, are inherited in an  Very soft and velvety skin autosomal recessive pattern. In autosomal  Vision problems recessive inheritance, two copies of the gene

Table. No.1: Clinical manifestations and gene mutations in EDS Type Clinical manifestations Protein Gene Major criteria Minor criteria mutation Classic  Skin hyper extensibility  Easy bruising Type V procollagen COL5A1 (type I/II)  Widened atrophic scarring  Smooth and velvety skin ( nearly 50%) COL5A2  Joint hyper mobility  Molluscoid pseudo tumours  Subcutaneous spheroids  Muscular hypotonic  Complications of joint hyper mobility  Surgical complications  Positive family history Hyper mobility (type III)  Generalized joint hyper mobility  Recurring joint dislocations Tenascin X TNX-B  Mild skin involvement  Chronic joint pain (< 10%)  Positive family history Vascular (type IV)  Excessive bruising  Acrogeria Type III COL3A1  Thin, translucent skin  Early onset varicose veins procollagen  Arterial/intestinal/uterine fragility or  Hyper mobility of small joints rupture  Tendon and muscle rupture  Characteristic facial appearance  Arteriovenous or carotid- cavernous sinus fistula  Pneumo(heamo) thorax  Positive family history, sudden death in close relatives Kyphoscoliosis (type VI)  Severe muscular hypotonic at birth  Tissue fragility, including Type VIA: Lysyl LH-1  Generalized joint laxity atrophic scars hydroxylase 1 (PLOD1)  Kyphoscoliosis at birth  Easy bruising  Scelral fragility and rupture of the globe  Arterial rupture Type VIB: not  Marfanoid habitus known  Micro cornea  Osteopenia Arthrochalasia (type  Severe generalized joint Hyper mobility  Skin hyper extensibility Type 1 Procollagen COL1A1 VIIA & B) with recurrent subluxations  Tissue fragility, including COL1A2  Congenital bilateral hip dislocation atrophic scars  Easy bruising  Muscular hypotonic  Kyohoscoliosis  Mild osteopenia Dermatosparaxis(type  Severe skin fragility  Soft, doughy skin texture Procollagen-N- ADAMTS-2 VIIC)  Sagging, redundant skin  Premature rupture of proteinase  Excessive bruising membranes  Large hernia

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Exams and Tests Examination by a health care provider may Tests to diagnose EDS include: show [7]  Collagen typing (performed on a skin  Deformed surface of the eye (cornea) biopsy sample)  Excess joint looseness and joint  Collagen gene mutation testing hypermobility  Echocardiogram (heart ultrasound)  Mitral valve in the heart does not close  Lysyl hydroxylase or oxidase activity tightly (mitral valve prolapsed) (to check collagen formation)  Rupture of the intestines, uterus, or eyeball (seen only in vascular EDS, which is rare)  Soft, thin, or very stretchy skin

EDSer Pain scale Score 0-3 4-6 7-10 11-13 14+ Indication Non This is how we feel This is when our pain is This is when pain is This pain is existent every day. This is our „hightened‟ above the usual. more widespread. UNBEARABLE VERY „normal‟. Here the pain may be apparent It is apparent to overwhelming. rare Because of this we are to others but still easily hidden others. We will not want to really good at hiding it with a smile We may be quiet, move. set back, and moody We will be in tears this is our breaking point.

SUGGESTED EVALUATIONS FOR  Administration of the Epworth THE PRIMARY CARE GIVER Sleepiness scale (or similar FOLLOWING EDS [8, 9] questionnaire) may be of use. Tier I:  Formal sleep study often not useful. 1. Assess musculoskeletal pain and joint 4. Evaluate for depression and/or anxiety. stability  Consider mental health referral  Gait abnormalities (many well especially for cognitive behavioral benefit from shoe orthotics). therapy.  Temporomandibular joint 5. Offer educational and support resources dysfunction.  Suggest use of patient advocate or  If present, craniofacial pain case manager if applicable. specialist referral recommended  Patient Advocate Foundation,  Physical therapy referral. www.patientadvocate.org.  Orthopedic referral if indicated for Tier II: recurrent instability. 6. Assess activities of daily living and  Pain management is often best tiered ergonomic habits. using physical therapy, localized  Consider occupational therapy pain relief and behavioral therapy. referral. For significant pain, consider 7. Address quality of life concerns. referral to pain management 8. Baseline echocardiogram for structural specialist. anomalies and possible aortic dilation 2. Evaluate for fainting or light-headedness  Refer as indicated especially due to low blood pressure/ 9. Evaluate for gastrointestinal orthostatic intolerance. signs/symptoms.  Consider tilt table testing and/or  Constipation ECG if appropriate.  Irritable bowel 3. Assess for sleep disorders, excessive  Persistent heart burn including daytime sleepiness, and/or chronic gastroparesis and/or hiatal hernia fatigue

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10. Assess for pelvic floor insufficiency v. 1. Beighton B, De Paepe A, Steinmann B, prolapsed. Tsipouras P, Wenstrup RJ. Ehlers-Danlos  If present, offer gynecologic or Support Group (UK). Am J Med Genet. urologic referral. 1998 Apr 28; 77 (1):31-7. 2. Byers PH, Murray ML. Heritable collagen 11. Offer preconception counseling disorders: the paradigm of the Ehlers- regarding genetic risks and pregnancy Danlos syndrome. J Invest Dermatol. 2012 complications. Nov 15; 132 (E1):E6-11. 12. Consider genetic counseling referral. 3. De Paepe A, Malfait F. The Ehlers-Danlos [10] Treatment syndrome, a disorder with many faces. Clin There is no specific cure for Ehlers- Genet. 2012 Jul; 82 (1):1-11. Danlos Syndrome. Individual problems and 4. Malfait F, De Paepe A. The Ehlers-Danlos symptoms are evaluated and cared for syndrome. Adv Exp Med Biol. 2014; appropriately. 802:129-43. Physical therapy or evaluation by a doctor 5. Sobey G. Ehlers-Danlos syndrome – a specializing in rehabilitation medicine is commonly misunderstood group of conditions. Clin Med (Lond). 2014 Aug; often needed. Some of the therapies are 14(4):432-6. under clinical trials, they are 6. Vanakker O, Callewaert B, Malfait F, (1) Beta-blockers (celiprolo) are the drug Coucke P. The Genetics of Soft Connective used under the phase-IV clinical trials. Dose Tissue Disorders. Annu Rev Genomics Hum ranging from 100-400 mg BID Genet. 2015; 16:229-55. (2) Angiotensin-II receptor blockers like 7. Krakow D. Heritable diseases of connective Irbesartan used under phase-III clinical tissue. In: Firestein GS, Budd RC, Gabriel trials. Apart from these therapies, mind- SE, Mclnnes IB, O‟Dell JR, eds. Kelly and th body therapy for pain in EDS is under Firestein‟s Textbook of Rheumatology. 10 phase-II clinical trials. ed. Philadelphia, PA: Elsevier; 2017: chap 105. 8. “Ehlers-Danlos Syndrome, Hypermobility PATIENT EDUCATION PROGRAM Type,” by Howerd Levy (2010) In: Gene AND EDS (PREDUSED) Reviews, www.genetests.org/ The French association of the 9. “Ehlers-Danlos Syndrome,” by C Atzinger Ehlers-Danlos Syndromes and the and B Tinkle (2010). In: Management of rehabilitation center of the „Croix-Rouge Genetic Syndromes, 3rd ed. (S Cassidy, Francaise des Massues‟ propose a patient Allanson, edd.), Wiley Publications. education program for the patients with a 10. Pyeritz RE. Inherited diseases of connective hyper mobility type SED (the PrEduSED tissue. In: Goldman L, Schafer AI, eds. th program). This education program us open Goldman-Cecil Medicine. 25 ed. to patients and their caregivers located in Philadelphia, PA: Elsevier Saunders; 2016: France. chap 260.

BIBLIOGRAPHY

How to cite this article: Naik VJ, Aswani B, Yanadaiah P. A review on ehlers-danlos syndrome. Int J Health Sci Res. 2017; 7(8):468-472.

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International Journal of Health Sciences & Research (www.ijhsr.org) 472 Vol.7; Issue: 8; August 2017