AUTHOR INFORMATION

Section 1 of 11

Authored by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital

Coauthored by G Bradley Schaefer, MD, Director of Hattie B Munroe Center for Human Genetics, Professor, Department of Pediatrics, University of Nebraska Medical Center; Melanie G Pepin, MS, CGC, Health Services Manager, Collagen Diagnostic Laboratory; Genetic Counselor, Department of Pathology, University of Washington

Robert D Steiner, MD, is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Medical Association, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Robert D Steiner, MD
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, May 24 2006, VOLUME 7, Number 5

INTRODUCTION

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Background: The Ehlers-Danlos family of disorders is a group of related conditions that share a common decrease in the tensile strength and integrity of the skin, joints, and other connective tissues.

In 1993, Beighton discussed the history of Ehlers-Danlos syndrome (EDS), beginning with a description of it in the fourth century BC. The first detailed clinical description of the syndrome is attributed to Tschernogobow in 1892. The syndrome derives its name from reports by Edward Ehlers, a Danish dermatologist, in 1901 and by Henri-Alexandre Danlos, a French physician with expertise in chemistry of skin disorders, in 1908. These 2 physicians combined the pertinent features of the condition and accurately delineated the phenotype of this group of disorders.

The amazing, almost unnatural, contortions that some patients with Ehlers-Danlos syndrome can perform often arouse curiosity. Historically, some patients with Ehlers-Danlos syndrome displayed the maneuvers publically in circuses, shows, and performance tours. Some achieved modest degrees of fame and bore titles such as "The India Rubber Man,The Elastic Lady," and "The Human Pretzel." Such clinical features also raise suspicion of the diagnosis when identified on physical examination.

Pathophysiology: Individuals with Ehlers-Danlos syndrome demonstrate connective tissue abnormalities as a result of defects in the inherent strength, elasticity, integrity, and healing properties of the tissues. The specific characteristics of a particular form of Ehlers-Danlos syndrome stem from the tissue-specific distribution of various components of the extracellular matrix. Each tissue and organ system expresses an array of connective proteins. The means of production and relative proportion and distribution of each protein array are unique. In addition, the specific interactions of various components of the matrix are tissue specific.

Major constituents of the extracellular matrix

Ehlers-Danlos syndrome is caused by a variety of abnormalities in the synthesis and metabolism of collagen (a component of the matrix) and other connective tissue proteins.

Collagen comprises the most abundant proteins in the body. Collagen proteins are multimeric, occurring in trimers with a central triple helical region. A minimum of 29 genes contribute to the collagen protein structure, and the genes are located on 15 of the 24 human chromosomes and form at least 19 identifiable forms of collagen molecules.

Elastic fibers are created by the association of elastin with an underlying microfibrillar array. The underlying basis of all connective tissue matrices is the microfibrillar array. (An example of a microfibrillar protein is fibrillin, which is the abnormal protein found in patients with Marfan Syndrome.) Elastin and other structural proteins are woven onto the microfibrillar array to provide the basic meshwork for the connective tissue matrix. Abnormalities of elastin have been associated with other connective tissue disorders, such as cutis laxa. Deletion of the elastin gene is involved in many of the pathophysiologic processes seen in Williams Syndrome.

Proteoglycans are core proteins that are bound to glycosaminoglycans (also commonly termed mucopolysaccharides). Essentially, proteoglycans are the glue of the connective tissue protein that seal and cement the underlying connective tissue matrix.

Macromolecular proteins include the glycoproteins of the basement membrane (type IV collagen, laminin, nidogen) and the extracellular matrix (fibronectin, tenascin).

Frequency:

• Internationally: Frequency of Ehlers-Danlos syndrome (all types combined) has been reported as 1 per 5000 to 1 per 10,000 population; however, the exact prevalence and incidence of Ehlers-Danlos syndrome are unknown.

Mortality/Morbidity:

• Reduced life expectancy is not generally a feature of Ehlers-Danlos syndrome, with the exception of the vascular form of Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV). Median life expectancy for patients with type IV Ehlers-Danlos syndrome is 50 years, because medium-sized arteries, the GI tract, and other organs tend to rupture spontaneously.

• Morbidity in Ehlers-Danlos syndrome is related to the primary pathophysiology and includes dislocations, pain, or both from chronic joint laxity as well as aberrant scarring and wound healing from abnormal tensile strength of the skin.

Race: Ehlers-Danlos syndrome affects all races equally.

Age: Ehlers-Danlos syndromes are heritable disorders. As such, the disorders are present at birth; however, symptoms may not be noticeable until later in life.

CLINICAL

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History: Although much has been learned regarding the molecular basis of some forms of Ehlers-Danlos syndrome, an accurate clinical diagnosis is the primary means of identifying affected individuals. Currently, diagnosis of relatively few of the known types of Ehlers-Danlos syndrome (vascular form [IV], lysyl hydroxylase deficiency [VI], arthrochalasia [VIIA and B], and dermatosparaxis [Ehlers-Danlos syndrome VIIC]) can be confirmed using molecular or biochemical lab testing. All forms of Ehlers-Danlos syndrome share the following primary features to varying degrees:

• Skin hyperextensibility



• Joint hypermobility and excessive dislocations



• Tissue fragility



• Poor wound healing, leading to wide thin scars (The classic description of abnormal scar formation in Ehlers-Danlos syndrome is "cigarette paper scars.")



• Easy bruising

Physical:

Clinical forms of Ehlers-Danlos syndrome

At least 6 discernible phenotypes of Ehlers-Danlos syndrome exist (see Table 1); however, a great deal of overlap exists in the phenotypes, making absolute clinical diagnosis difficult, if not impossible, at times. As many as 50% of patients with Ehlers-Danlos syndrome do not have a type or form that can be classified easily on clinical basis alone. This complicates the diagnostic process, because specific molecular diagnosis or confirmation (if available) may not be possible until a clinical subtype has been defined. Table 1 lists the identifiable forms of Ehlers-Danlos syndrome proposed by a group of clinical experts from the medical advisory board of the Ehlers-Danlos National Foundation (EDNF) in 1997. This nosology is currently used in the clinical setting.

Table 1. Types of Ehlers-Danlos Syndromes (Villefranche, 1997 classification)

Type	Inheritance	Previous Nomenclature	Major Diagnostic Criteria	Minor Diagnostic Criteria
Classic	AD*	Types I and II	Skin hyperextensibility Wide atrophic scars Joint hypermobility	Smooth, velvety skin Easy bruising Molluscoid pseudotumors Subcutaneous spheroids Joint hypermobility Muscle hypotonia Postoperative complication (hernia) Positive family history Manifestations of tissue fragility: hernia, prolapse.
Hypermobility	AD	Type III	Skin involvement (soft, smooth and velvety) Joint hypermobility	Recurrent joint dislocation Chronic joint or limb pain or both Positive family history
Vascular	AD	Type IV	Thin, translucent skin Arterial/intestinal fragility or rupture Extensive bruising Characteristic facial appearance	Acrogeria Hypermobile small joints Tendon/muscle rupture Clubfoot Early-onset varicose veins Arteriovenous, carotid-cavernous sinus fistula Pneumothorax Gingival recession Positive family history, sudden death in close relative
Kyphoscoliosis	AR†	Type VI – lysyl hydroxylase deficiency	Joint laxity Severe hypotonia at birth Scoliosis, progressive Scleral fragility or rupture of globe	Tissue fragility Easy bruising Arterial rupture Marfanoid Microcornea Osteopenia Positive family history (affected sibling)
Arthrochalasia	AD	Type VII A, B	Congenital bilateral dislocated hips Severe joint hypermobility Recurrent subluxations	Skin hyperextensibility Tissue fragility with atrophic scars Muscle hypotonia Easy bruising Kyphoscoliosis Mild osteopenia
Dermatosparaxis	AR	Type VII C	Severe skin fragility Saggy, redundant skin	Soft, doughy skin Easy bruising Premature rupture of membranes Hernias (umbilical and inguinal)
Other‡

The major diagnostic criteria are highly specific. The presence of one or more major criteria is either necessary for clinical diagnosis or highly indicative and warrant lab confirmation whenever possible. One or more minor diagnostic criteria contribute but are not sufficient for the clinical diagnosis.
   *AD = autosomal dominant
   †AR = autosomal recessive
   ‡Other forms of EDS: Type V EDS was described in a single family (XLR). Type VIII is similar to classic EDS plus periodontal disease; it is not clearly a distinct clinical entity. Type IX has been reclassified as an allelic form of Menkes (SLR). Type X was described in one family. Type XI was described as familial hypermobility syndrome and was previously removed from classifications. Ehlers-Danlos–like syndrome from tenascin-X deficiency has recently been described.

The Online Mendelian Inheritance in Man (OMIM) database provides updated information on the clinical and molecular understanding of single gene (monogenic) disorders. The inheritance pattern, OMIM number, and original clinical descriptions of 10 major types of Ehlers-Danlos syndrome are listed below. The OMIM entries were reviewed in developing the Villefranche classification.

• Ehlers-Danlos syndrome type I (OMIM #130000, autosomal dominant) - Distinguishing features include easy bruising, mitral valve prolapse, premature rupture of the fetal membranes, and premature birth.

• Ehlers-Danlos syndrome type II (OMIM #130010, autosomal dominant) - Phenotype is similar to type 1, but the effects are milder.

• Ehlers-Danlos syndrome type III (OMIM #130020, autosomal dominant) - Features include striking joint hypermobility and minimal skin changes.

• Ehlers-Danlos syndrome type IV (OMIM #130050, autosomal dominant) - Type IV is the vascular/ecchymotic form. Patients with type IV Ehlers-Danlos syndrome have prominent venous markings, which are readily visible through the skin. Diagnostically, this type is most important, since patients are subject to spontaneous rupture of the bowel, medium-sized arteries, or both. Often, rupture leads to early death. Median life expectancy in these patients is 45-50 years.

• Ehlers-Danlos syndrome type V (OMIM #305200, X-linked recessive) - Penotype is similar to, if not indistinguishable from, type 2; however, in familial cases, type V exhibits X-linked recessive inheritance.

• Ehlers-Danlos syndrome type VI (OMIM #225400, autosomal recessive) - Patients may present with retinal detachments, microcornea, myopia, scoliosis, and neonatal hypotonia.

• Ehlers-Danlos syndrome type VII (OMIM #130060, types VIIA and VIIB, autosomal dominant; OMIM #225410, type VIIC, autosomal recessive) - Patients exhibit arthrochalasis multiplex congenita (hyperflaccidity of the joints without hyperelasticity of the skin), short stature, and micrognathia.

• Ehlers-Danlos syndrome type VIII (OMIM #130080, autosomal dominant) - In addition to the other notable features, patients with type VIII Ehlers-Danlos syndrome have multiple skin striae and significant dental problems, including early tooth loss, periodontitis, and alveolar bone loss.

• Ehlers-Danlos syndrome type IX (OMIM #304150, X-linked recessive) - Features include occipital exostoses, bladder diverticula or rupture, bony dysplasias, and decreased copper and ceruloplasmin. Ehlers-Danlos syndrome type IX is no longer a subtype. Once the gene was identified, type IX was removed from the Ehlers-Danlos syndrome classification. The gene is related to a condition termed cutis laxa or occipital horn syndrome (see Causes).

• Ehlers-Danlos syndrome type X (OMIM #225310, autosomal recessive) - Patients exhibit poor wound healing, petechiae, and a platelet aggregation defect, which can be corrected with fibronectin supplementation.

Ehlers-Danlos–like syndrome from tenascin-X deficiency (OMIM #606408, autosomal recessive) has recently been described.

Causes: Recently, the progress of the Human Genome Project and other advances in molecular genetics have provided much information regarding the molecular basis of Ehlers-Danlos syndrome. Physical positions of involved genes and their locations on chromosomal maps are provided in Table 2.

Table 2. Molecular Basis of Ehlers-Danlos Syndrome

Type of EDS	Old Nomenclature	Protein Abnormality	Gene Abnormality	Chromosome Locus
Classic	Type I/II	Type V collagen	( COL5A1 ) ( COL5A2 )	9q34.2-34.3 2q31
Hypermobility	Type III	Unknown	Unknown
Vascular	Type IV	Type III collagen	COL3A1	2q31
Kyphoscoliosis	Type VI	Lysyl hydroxylase deficiency (some)	PLOD1	1p36.3-36.2
Arthrochalasia	Type VII A/B	Type I collagen	COL1A1 COL1A2	17q31-22.5 7q22.1
Dermatospraxis	Type VIIC	N-proteinase	ADAMST2	5q23-24

DIFFERENTIALS

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Williams Syndrome

Other Problems to be Considered:

Stickler syndrome
Cutis laxa
TGFBR-related phenotype
Ehlers-Danlos–like syndrome from tenascin-X deficiency (OMIM #606408)

WORKUP

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Lab Studies:

• To confirm the diagnosis of the vascular form of Ehlers-Danlos syndrome, (Ehlers-Danlos syndrome type IV) and for arthrochalasia (Ehlers-Danlos syndrome type VIIA and VIIB) and dermatosparaxis (Ehlers-Danlos syndrome VIIC), biochemical studies can detect alterations in collagen molecules in cultured skin fibroblasts. Molecular (DNA-based) testing is available for Ehlers-Danlos syndrome types IV and VII as well. With the exception of kyphoscoliotic type (Ehlers-Danlos syndrome type VI), which can be identified by urinary analyte assay, the most common and remaining forms of Ehlers-Danlos syndrome are identified by clinical examination.

Procedures:

• Skin biopsy findings (performed for histopathologic analysis) are nondiagnostic.

TREATMENT

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Medical Care:

• A correct diagnosis is critical and must be determined if possible. Confirmation using biochemical studies on collagen molecules is possible with cultured skin fibroblasts for the vascular form (Ehlers-Danlos syndrome type IV), for arthrochalasia (Ehlers-Danlos syndrome type VIIA and VIIB), and for dermatosparaxis (Ehlers-Danlos syndrome type VIIC). A diagnostic assay of urinary pyridinoline cross-links identifies the kyphoscoliosis type (Ehlers-Danlos syndrome type VI) Therefore, if the clinical diagnosis is type IV, type VI, and some of the forms of type VII Ehlers-Danlos syndrome, perform biochemical or molecular studies. Once a diagnosis of Ehlers-Danlos syndrome has been made, preventative measures should be undertaken. Wearing a MedicAlert bracelet may be helpful in case of life-threatening events.



• In the event of skin lacerations or other injuries, take extreme care with the use of sutures. Seriously consider alternatives to sutures, including adhesive strips and wound glues.



• Monitor patients for scoliosis and instruct them to avoid excessive or repetitive lifting and other activities that produce undue strain or stress on their already hypermobile joints.



• Pay careful attention to cardiac auscultation and evaluation. The murmur of mitral valve prolapse (particularly in classic and hypermobile Ehlers-Danlos syndrome) should be noted; if indicated, perform an echocardiogram. In the presence of mitral valve prolapse, monitoring and screening are indicated, as is the use of subacute bacterial endocarditis (SBE) precautions. As adults with vascular Ehlers-Danlos syndrome are at risk for arterial aneurysm and rupture, noninvasive visualization of the arterial tree may be indicated. Initial echocardiogram including the aortic arch is recommended for adults with classic Ehlers-Danlos syndrome, as recent studies indicate possible risk for thoracic aortic enlargement. There is not enough current evidence to guide the approach to monitoring for this potential complication.



• High-dose (1-4 g/d) ascorbic acid therapy has been tried and, in theory, has a potential effect. Clinical studies suggest that wound healing, even in patients not deficient in vitamin C, can be improved with supplementation above the recommended daily allowance. In patients with type VI Ehlers-Danlos syndrome, bleeding time, wound healing, and muscle strength seemed to improve after 1 year of high-dose vitamin C therapy; however, high-dose vitamin C therapy is not the standard of care.

Consultations:

• Consultation with an ophthalmologist may be necessary. Patients with Ehlers-Danlos syndrome should be screened for myopia, retinal tears, and keratoconus. Recommend regular eye examinations.



• Consultation with a dentist may be necessary. Patients with connective tissue disorders should practice meticulous dental care, which should be monitored. Treat periodontitis aggressively. In particular, good dental care is important in patients with type VI Ehlers-Danlos syndrome.



• Accurate genetic counseling is one of the most critical issues in the treatment of patients with Ehlers-Danlos syndrome.


• • Provide the family with detailed information regarding the inheritance pattern, recurrence risks, and identification of at-risk family members. Screen pertinent individuals in the family for subtle signs and symptoms of the condition regardless of whether signs or symptoms are suggested by the family history. Discuss the prognosis and natural history of the particular Ehlers-Danlos syndrome type in detail with the family.
  
  
  
  • A key element in the genetic counseling process includes triage toward indicated medical services and, most importantly, resource identification. Identify support group resources and provide other information to the family, such as the Ehlers-Danlos National Foundation.
  
  
  

Activity: Instruct patients with Ehlers-Danlos syndrome to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on the already hypermobile joints. However, careful weight training with relatively low weight may be therapeutic. Advise patients to avoid (preventable) significant trauma.

MEDICATION

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High-dose ascorbic acid has been used, although it is not considered the standard of care (see Treatment).

FOLLOW-UP

Section 8 of 11

In/Out Patient Meds:

• Wound healing may be improved with vitamin C supplementation above the recommended daily allowance (see Medical Care).



• SBE prophylaxis may be appropriate in the presence of mitral valve prolapse.

Complications:

• Complications are related to the primary pathophysiology and include joint dislocations, wound healing problems, and scarring. Individuals with vascular Ehlers-Danlos syndrome are at risk for spontaneous arterial rupture and bowel perforation, particularly the sigmoid colon, as well as other hollow organ perforation or rupture.

Prognosis:

• Median life expectancy for patients with type IV Ehlers-Danlos syndrome is 50 years. In patients with other Ehlers-Danlos syndrome types, life expectancy is usually normal.

Patient Education:

• Genetic counseling: The diversity and complexity of Ehlers-Danlos syndrome serve to highlight several important principles of clinical human genetics. That these principles be accurately relayed to and understood by the family during counseling is critical.


• • Genetic heterogeneity refers to the fact that mutations in different genes can produce the same phenotype. For example, type I Ehlers-Danlos syndrome can result from mutations in 2 collagen genes, either COL5A1 (chromosome bands 9q34.2-34.3) or COL5A2 (band 2q31).
  
  
  
• Variable expression (ie, variability in severity of disease expression) is a hallmark of autosomal dominant conditions. Autosomal dominant Ehlers-Danlos syndrome exhibits both intrafamilial and interfamilial variability, which is a critical counseling issue in regard to recurrences. In addition, examining families closely for members who may not have been diagnosed in the past is important because of the mild degree of expression.



• Overlap of phenotypes: An indeterminate diagnosis of a clinical subtype of Ehlers-Danlos syndrome may not be possible in as many as 50% of patients. The clinician must tell patients when the diagnosis is either unknown or unclear, rather than guess and provide incorrect information. Important implications clearly exist for the subtypes of Ehlers-Danlos syndrome regarding the differences in modes of inheritance and long-term prognoses.



• Availability of diagnostic and laboratory studies: Currently, the diagnosis of only a few subtypes of Ehlers-Danlos syndrome can be confirmed using the practical laboratory studies available. Note the prevailing misconception that specific findings exist in skin biopsy specimens that can confirm or exclude the specific diagnosis of Ehlers-Danlos syndrome. No specific histopathologic findings exist in skin biopsy specimens from patients with Ehlers-Danlos syndrome; therefore, skin biopsies should not be performed to confirm or exclude the diagnosis. A skin biopsy may be indicated to obtain cultured skin fibroblasts for specific biochemical and molecular studies, but most patients and clinicians must simply rely on clinical diagnosis.



• Elucidating the pathophysiology of a specific clinical disorder often leads to rethinking the phenotypic classification. For example, the previously designated type IX Ehlers-Danlos syndrome is now known to be the result of a mutation in a copper transport gene and is an allelic variant to Menkes (kinky hair) disease.



• Encourage patients to protect their joints and avoid undue trauma. Instruct patients to avoid entertaining other persons by performing maneuvers "showing off" their joint laxity. Continued excessive stretching of the joints may further exacerbate the underlying disorder.



• Instruct patients to avoid excessive or repetitive heavy lifting and other movements that produce undue strain or stress on already hypermobile joints.

• Instruct patients with connective tissue disorders to practice meticulous dental care. Monitor dental hygiene and treat periodontitis aggressively. This advice is particularly important for patients with type VI Ehlers-Danlos syndrome.

• Instruct patients with Ehlers-Danlos syndrome to visit the ophthalmologist regularly for myopia, retinal tears, and keratoconus screening.



• Instruct patients with Ehlers-Danlos syndrome to avoid undue trauma to the skin and other organ systems because of poor wound healing and skin fragility. In particular, the primary care physician should strongly discourage potentially traumatic recreational activities.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Of particular note is vascular Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV). An accurate diagnosis must be made, and it is critical to follow this with biochemical or molecular testing. Counseling must include detailed information regarding a variety of important issues, including emergent action, surgical options, effects of pregnancy (which may be life threatening), and risk for arterial, bowel, and other organ complications. Surgeons and others looking after these patients should not underestimate the difficulty and complications with trauma and surgery these patients face.

Special Concerns:

• Pregnancy represents a special issue in patients with certain types of Ehlers-Danlos syndrome. The critical elements clearly are prepregnancy identification of the syndrome and anticipation of potential complications or problems. Ehlers-Danlos syndrome presents a specific set of risks for both mother and baby.


• • Risks for the mother include uterine prolapse, uterine tear, poor wound healing during the postpartum period, and excessive bleeding both during and after delivery.
  
  
  
  • Risks for the baby include premature rupture of membranes with secondary premature delivery and all inherent complications. In addition, significant joint laxity already present in the newborn period may be mistaken for hypotonia, resulting in a misdirected diagnostic evaluation.
  
  
  

TEST QUESTIONS

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CME Question 1: Which of the following features is not a major sign or symptom of Ehlers-Danlos syndrome?

A: Cardiac valvular dysfunction
B: Skin hyperextensibility
C: Joint hypermobility and excessive dislocations
D: Tissue fragility
E: Poor wound healing

The correct answer is A: Although mitral valve prolapse occurs in some patients with types III and IV Ehlers-Danlos syndrome, it is not a cardinal feature.

CME Question 2: Which of the following types of Ehlers-Danlos syndrome is associated with a shortened life expectancy from spontaneous vascular rupture, GI tract rupture, or both?

A: Type I
B: Type II
C: Type III
D: Type IV
E: Type V

The correct answer is D: Ehlers-Danlos syndrome type IV is the only form with a significant reduction in life expectancy. Median life expectancy for patients with type IV Ehlers-Danlos syndrome is 50 years.

Pearl Question 1 (T/F): Diagnostic confirmation by molecular studies is available in patients with all types of Ehlers-Danlos syndrome.

The correct answer is False: Molecular testing is available for a few types only (types IV and VI and some forms of type VII). Diagnosis is made clinically.

Pearl Question 2 (T/F): Typical skin biopsy findings exist for Ehlers-Danlos syndrome.

The correct answer is False: Ehlers-Danlos syndrome cannot be diagnosed or excluded using histopathologic findings.

Pearl Question 3 (T/F): Recommendations for the care of patients with Ehlers-Danlos syndrome include prophylactic use of beta-blockers.

The correct answer is False: Patients should avoid trauma and undue wear and tear on the skin and joints. Beta-blockers are not indicated.

Pearl Question 4 (T/F): Ehlers-Danlos syndrome best fits in the category of collagen vascular disorders.

The correct answer is False: Ehlers-Danlos syndrome is a connective tissue disorder that is distinct from, and not synonymous with, collagen vascular disorders.

BIBLIOGRAPHY

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• Beighton P, De Paepe A, Steinmann B, et al: Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 1998 Apr 28; 77(1): 31-7[Medline].
• Bristow J, Carey W, Egging D, Schalkwijk J: Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet 2005 Nov 15; 139(1): 24-30[Medline].
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