The Clinical Presentation of Ehlers-Danlos Syndrome

Elizabeth J. Lawrence, RNC, MSN, NNP

Adv Neonatal Care. 2005;5(6):301-314.

Understanding the Genetics of EDS

Genes exist in pairs and are the blueprints for the development and function of every cell in the body.^[2,46] A developing fetus receives one half of each gene pair from each parent, creating a new set of gene pairs that determine the infant's traits. There are 23 pairs of chromosomes: 22 pairs known as autosomes and a pair of chromosomes that determines the sex of an infant.^[2]

The classical, hypermobile, vascular, and arthrochalasia types of EDS are inherited in an autosomal dominant manner.^[1,7,10,25] Each affected infant has an affected parent. The altered gene is found on an autosome rather than the sex chromosome; therefore, males and females are equally affected.^[2] The EDS gene is dominant, requiring only 1 gene to express EDS characteristics.^[2,7] If 1 parent has EDS and 1 parent does not, they have a 50% chance of having a child with EDS and 50% chance of having an unaffected child.

Inheritance with the kyphoscoliosis and dermatosparaxis types of EDS is autosomal recessive; therefore, 2 copies of the altered gene must be present for EDS to occur.^[1,7,35] Couples who have an affected child have a 25% chance of having another affected child with each subsequent pregnancy.^[35,46]

The patterns of inheritance and the type of EDS remain consistent within a family.^[2,3,46] A family with classical-type EDS will not develop vascular-type EDS without the introduction of those genes into the family. However, variations in the severity of EDS can occur within a family.

Vascular-type EDS can be identified by mutations in the COL3A1 gene.^[1,4,9,29] The COL3A1 gene is 1 of several genes that provide instructions for making the components of collagen. Type III collagen is found in tissues such as the skin, lungs, intestinal walls, and the walls of blood vessels.^[29] Currently, there are 320 mutations of the COL3A1 gene identified in vascular EDS.^[29]

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Cite this: The Clinical Presentation of Ehlers-Danlos Syndrome - Medscape - Dec 01, 2005.

Comparing and Contrasting Types of Ehlers-Danlos Syndrome ^{[1,2,3,4,5,6,7,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]}
Current Classification EDS Type	Prevalence	Inheritance Pattern	Gene(s) Mutation Responsible	Gene Function	Diagnosis Confirmed By	Clinical Features	Maternal/Pregnancy Complications
Classical (Formerly known as Type I Severe classic type, gravis type Type II Mild classic type, mitis type)	Affects 20,000 to 40,000 people	Autosomal dominant	Chromosome 17 COL1A1 (collagen, type 1, alpha 1)	Provides the genetic instructions to make collagen	Family history and clinical examination Targeted mutation analysis for a specific mutation, available only in research labs	• Skin hyperextensibility • Intrauterine growth restriction • Joint hypermobility • Redundant skin folds, eyelids • Skin scarring (fish mouth or cigarette paper scars) • Congenital diverticula of the bladder (typically males; rare but reported in females) • Inguinal hernias (males)	• Preterm labor • Scoliosis (problems with anesthesia) • PROM • Atonic uterus at cesarean birth
			Chromosome 7 COL1A2 (collagen, type 2, alpha 2)	Same
			Chromosome 9 COL5A1 (collagen, type 5 alpha 1)	Same
			Chromosome 2 COL5A2 (collagen, type 5, alpha 2)	Same
Hypermobility (Formerly known as Type III)	Most common type Affects 1 in 10,000 to 15,000 people	Autosomal dominant	No known gene Diagnosis is by clinical examination only A small subgroup of individuals have been found with TNCB (tenascin XB) located on chromosome 6	Same as above Provides the instructions for making the protein tenascin-X	Family history and clinical examination and presenting symptoms such as recurrent joint dislocations, chronic joint and limb pain	• Smooth, velvety skin • Easy bruising • Joint hypermobility with unusual range of motion • Inguinal hernias (males)	• Preterm labor • Postpartum hemorrhage
Vascular (Formerly known as Type IV Ecchymotic type, arterial type)	Affects 1 in 100,000 to 200,000 people Most serious form of EDS due to arterial or major organ rupture. Risk of sudden death in the 3rd or 4th decade of life	Autosomal dominant	Chromosome 2 COL3A1 (collagen, type 3, alpha 1) 320 mutations of this gene have been identified	Creating procollagen for strength in the connective tissues of skin, lungs, intestinal walls, and blood vessel walls	Skin biopsy for collagen analysis for abnormal electrophoretic mobility Sequence analysis testing to identify mutations available for genetic counseling	• Distinctive facial features • Thin translucent skin over the chest and abdomen • Acrogeria • Lobeless ears • Respiratory distress suggestive of pneumothorax • Short stature	• Uterine fragility or rupture • Postpartum arterial bleeding • Vaginal or perineal tears during delivery • Wound dehiscence possible after a cesarean birth • High maternal mortality (25%) • Pneumothorax
Kyphoscoliosis (Formerly known as Type VI Ocular-scoliotic)	<60 cases reported worldwide	Autosomal recessive	Chromosome 1 PLOD (procollagen-lysine, -2-oxoglutarate 5-dioxygenase)	Lysyl hydroxylase adds hydroxyl groups to lysines (amino acids) in collagen	Urine test to detect increased ratio of deoxypyridinoline to pyridinoline cross-links	• Joint laxity and severe muscle hypotonia at birth • Kyphoscoliosis is present at birth • Scleral fragility and rupture of the ocular globe • Marfan-like appearance	• Scoliosis • Measurement of lysyl hyroxylase in the amniotic fluid may predict the outcome of an infant
Arthrochalasia (Formerly known as Type VIIA Type VIIB)	30 cases reported worldwide	Autosomal dominant	Chromosome 17 COL1A1 Chromosome 7 COL1A2 Most cases occur with no family history (spontaneous mutations)	Genetic instructions to make collagen	Electrophoresis and mutation analysis	• Congenital bilateral hip dislocation • Severe generalized joint hypermobility with recurrent subluxations
Dermatosparaxis (Formerly known as Type VIIC)	Rarest form; only 10 cases reported worldwide	Autosomal recessive	Chromosome 5 ADAMTS-2 (a disintegrin-like and metalloprotease reprolysin type with thrombospondin type 1 motif, 2)	Initiates the production of several procollagen proteins	Electrophoresis	• Severe skin fragility and bruising • Doughy, sagging, redundant skin (especially facial) • Large umbilical hernia • Blue sclera • Short stature, dwarfism	• PROM
Other (Formerly known as Type V)	Rare, only described in 1 family	X-linked recessive	Unknown	Unknown	Family history		• Tissue fragility • Scoliosis
Type VIII	Rare	Autosomal dominant	Similar to classical type	Unknown	Uncertain	• Periodontal friability, loss of teeth by age 30
Type IX (occipital horn syndrome)	Rare	X-linked recessive allelic to Menkes syndrome	Unknown	Abnormal copper utilization	Decreased copper and ceruloplasmin levels	• Mildly extensive skin, occipital horn-like exostosis short humeri, short clavicles, bowed long bones, chronic diarrhea, bladder diverticulae
Type X	Rare, only described in 1 family	Autosomal recessive	Unknown	Unknown	Family history	• Joint hypermobility • Poor wound healing • Platelet aggregation defect

PROM, premature rupture of membranes.

Comparing and Contrasting Types of Ehlers-Danlos Syndrome ^{[1,2,3,4,5,6,7,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]}
Current Classification EDS Type	Prevalence	Inheritance Pattern	Gene(s) Mutation Responsible	Gene Function	Diagnosis Confirmed By	Clinical Features	Maternal/Pregnancy Complications
Classical (Formerly known as Type I Severe classic type, gravis type Type II Mild classic type, mitis type)	Affects 20,000 to 40,000 people	Autosomal dominant	Chromosome 17 COL1A1 (collagen, type 1, alpha 1)	Provides the genetic instructions to make collagen	Family history and clinical examination Targeted mutation analysis for a specific mutation, available only in research labs	• Skin hyperextensibility • Intrauterine growth restriction • Joint hypermobility • Redundant skin folds, eyelids • Skin scarring (fish mouth or cigarette paper scars) • Congenital diverticula of the bladder (typically males; rare but reported in females) • Inguinal hernias (males)	• Preterm labor • Scoliosis (problems with anesthesia) • PROM • Atonic uterus at cesarean birth
			Chromosome 7 COL1A2 (collagen, type 2, alpha 2)	Same
			Chromosome 9 COL5A1 (collagen, type 5 alpha 1)	Same
			Chromosome 2 COL5A2 (collagen, type 5, alpha 2)	Same
Hypermobility (Formerly known as Type III)	Most common type Affects 1 in 10,000 to 15,000 people	Autosomal dominant	No known gene Diagnosis is by clinical examination only A small subgroup of individuals have been found with TNCB (tenascin XB) located on chromosome 6	Same as above Provides the instructions for making the protein tenascin-X	Family history and clinical examination and presenting symptoms such as recurrent joint dislocations, chronic joint and limb pain	• Smooth, velvety skin • Easy bruising • Joint hypermobility with unusual range of motion • Inguinal hernias (males)	• Preterm labor • Postpartum hemorrhage
Vascular (Formerly known as Type IV Ecchymotic type, arterial type)	Affects 1 in 100,000 to 200,000 people Most serious form of EDS due to arterial or major organ rupture. Risk of sudden death in the 3rd or 4th decade of life	Autosomal dominant	Chromosome 2 COL3A1 (collagen, type 3, alpha 1) 320 mutations of this gene have been identified	Creating procollagen for strength in the connective tissues of skin, lungs, intestinal walls, and blood vessel walls	Skin biopsy for collagen analysis for abnormal electrophoretic mobility Sequence analysis testing to identify mutations available for genetic counseling	• Distinctive facial features • Thin translucent skin over the chest and abdomen • Acrogeria • Lobeless ears • Respiratory distress suggestive of pneumothorax • Short stature	• Uterine fragility or rupture • Postpartum arterial bleeding • Vaginal or perineal tears during delivery • Wound dehiscence possible after a cesarean birth • High maternal mortality (25%) • Pneumothorax
Kyphoscoliosis (Formerly known as Type VI Ocular-scoliotic)	<60 cases reported worldwide	Autosomal recessive	Chromosome 1 PLOD (procollagen-lysine, -2-oxoglutarate 5-dioxygenase)	Lysyl hydroxylase adds hydroxyl groups to lysines (amino acids) in collagen	Urine test to detect increased ratio of deoxypyridinoline to pyridinoline cross-links	• Joint laxity and severe muscle hypotonia at birth • Kyphoscoliosis is present at birth • Scleral fragility and rupture of the ocular globe • Marfan-like appearance	• Scoliosis • Measurement of lysyl hyroxylase in the amniotic fluid may predict the outcome of an infant
Arthrochalasia (Formerly known as Type VIIA Type VIIB)	30 cases reported worldwide	Autosomal dominant	Chromosome 17 COL1A1 Chromosome 7 COL1A2 Most cases occur with no family history (spontaneous mutations)	Genetic instructions to make collagen	Electrophoresis and mutation analysis	• Congenital bilateral hip dislocation • Severe generalized joint hypermobility with recurrent subluxations
Dermatosparaxis (Formerly known as Type VIIC)	Rarest form; only 10 cases reported worldwide	Autosomal recessive	Chromosome 5 ADAMTS-2 (a disintegrin-like and metalloprotease reprolysin type with thrombospondin type 1 motif, 2)	Initiates the production of several procollagen proteins	Electrophoresis	• Severe skin fragility and bruising • Doughy, sagging, redundant skin (especially facial) • Large umbilical hernia • Blue sclera • Short stature, dwarfism	• PROM
Other (Formerly known as Type V)	Rare, only described in 1 family	X-linked recessive	Unknown	Unknown	Family history		• Tissue fragility • Scoliosis
Type VIII	Rare	Autosomal dominant	Similar to classical type	Unknown	Uncertain	• Periodontal friability, loss of teeth by age 30
Type IX (occipital horn syndrome)	Rare	X-linked recessive allelic to Menkes syndrome	Unknown	Abnormal copper utilization	Decreased copper and ceruloplasmin levels	• Mildly extensive skin, occipital horn-like exostosis short humeri, short clavicles, bowed long bones, chronic diarrhea, bladder diverticulae
Type X	Rare, only described in 1 family	Autosomal recessive	Unknown	Unknown	Family history	• Joint hypermobility • Poor wound healing • Platelet aggregation defect

PROM, premature rupture of membranes.

Comparing and Contrasting the Major and Minor Diagnostic Criteria for Ehlers Danlos Syndrome By Type ^{[1,2,10,25,28,35]}
EDS Type	Major Diagnostic Criteria	Minor Diagnostic Criteria
Classical	Skin hyperextensibility, widened atrophic scars, joint hypermobility	• Positive family history
Classical		• Physical findings include smooth velvety skin, mulluscoid pseudotumors, subcutaneous spheroids, complications of joint hypermobility (sprains, dislocations/subluxations), muscle hypotonia, delayed gross motor development, easy bruising, tissue extensibility, fragility, surgical complications
Hypermobility	Skin involvement (either smooth/velvety skin or hyperextensibility), generalized joint hypermobility	• Positive family history
Hypermobility		• Physical findings include recurring joint dislocations, chronic joint/limb pain
Vascular	Thin translucent skin, arterial/intestinal/uterine fragility or rupture, extensive bruising, characteristic facial appearance	• Positive family history, specifically sudden death of a close relative(s)
Vascular		• Physical findings include acrogeria, hypermobility of small joints, tendon and muscle rupture, clubfoot, early onset varicose veins, arteriovenous, carotid-cavernous sinus fistula, pneumothorax/pneumohemothorax, gingival recession
Kyphoscoliosis	Generalized joint laxity, severe muscle hypotonia at birth, scoliosis at birth, scleral fragility, rupture of the ocular globe	• Positive family history (e.g., affected siblings)
Kyphoscoliosis		• Physical findings include tissue fragility, atrophic scars, easy bruising, arterial rupture, marfanoid habitus (Marfan-like), microcornea, osteopenia on radiograph
Arthrochalasis	Severe generalized joint hypermobility with recurrent subluxations, congenital bilateral hip dislocation	• Physical findings include skin hyperextensibility, tissue fragility, atrophic scars, easy bruising, muscle hypotonia, kyphoscoliosis, osteopenia on radiograph
Dermatosparaxis	Severe skin fragility, sagging redundant skin	• Physical findings include soft, doughy skin, easy bruising, premature rupture of fetal membranes, large hernias (umbilical or inguinal)

Beighton's Criteria for Joint Hypermobility ^[1,2,46]
Joint Assessment	One Extremity	Both Extremities
Passive dorsiflexion of the little finger >90°	1	2
Passive flexion of thumbs to the forearm	1	2
Hyperextension of the elbows beyond 10°	1	2
Hyperextension of the knees beyond 10°	1	2
Forward flexion of the trunk with knees fully extended and palms resting on the floor	1	NA

NOTE. Beighton's Criteria is used in both children and adults to assess 5 different joint mobility performances with a maximum score of 9. A score of 5 is the minimum score suggestive of joint hypermobility.

Comparing and Contrasting the Major and Minor Diagnostic Criteria for Ehlers Danlos Syndrome By Type ^{[1,2,10,25,28,35]}
EDS Type	Major Diagnostic Criteria	Minor Diagnostic Criteria
Classical	Skin hyperextensibility, widened atrophic scars, joint hypermobility	• Positive family history
Classical		• Physical findings include smooth velvety skin, mulluscoid pseudotumors, subcutaneous spheroids, complications of joint hypermobility (sprains, dislocations/subluxations), muscle hypotonia, delayed gross motor development, easy bruising, tissue extensibility, fragility, surgical complications
Hypermobility	Skin involvement (either smooth/velvety skin or hyperextensibility), generalized joint hypermobility	• Positive family history
Hypermobility		• Physical findings include recurring joint dislocations, chronic joint/limb pain
Vascular	Thin translucent skin, arterial/intestinal/uterine fragility or rupture, extensive bruising, characteristic facial appearance	• Positive family history, specifically sudden death of a close relative(s)
Vascular		• Physical findings include acrogeria, hypermobility of small joints, tendon and muscle rupture, clubfoot, early onset varicose veins, arteriovenous, carotid-cavernous sinus fistula, pneumothorax/pneumohemothorax, gingival recession
Kyphoscoliosis	Generalized joint laxity, severe muscle hypotonia at birth, scoliosis at birth, scleral fragility, rupture of the ocular globe	• Positive family history (e.g., affected siblings)
Kyphoscoliosis		• Physical findings include tissue fragility, atrophic scars, easy bruising, arterial rupture, marfanoid habitus (Marfan-like), microcornea, osteopenia on radiograph
Arthrochalasis	Severe generalized joint hypermobility with recurrent subluxations, congenital bilateral hip dislocation	• Physical findings include skin hyperextensibility, tissue fragility, atrophic scars, easy bruising, muscle hypotonia, kyphoscoliosis, osteopenia on radiograph
Dermatosparaxis	Severe skin fragility, sagging redundant skin	• Physical findings include soft, doughy skin, easy bruising, premature rupture of fetal membranes, large hernias (umbilical or inguinal)

Ehlers-Danlos Syndrome Resource List for Parents and Professionals
Resource	Description of Contents
Canadian Ehlers-Danlos Association www.ehlersdanlos.ca 88 De Rose Ave Bolton, Ontario, Canada L7E 1A8 Phone: 905-951-7559 Fax: 905-761-7567	Information about EDS, list serves, personal web pages, links to other sites and a forum for posting questions.
Ehlers-Danlos National Foundation www.ednf.org 3200 Wilshire Blvd. Suite 1601, South Tower Los Angeles, Calif 90010 Phone: 800-956-2902 Fax: 213-427-0057	General information about EDS with a well-developed guide for educators and parents. Numerous links to other websites. Publishes a quarterly newsletter titled Loose Connections that provides current information on medical advances in EDS, updates on the activities of the Foundation, and valuable information on living with EDS.
Ehlers-Danlos Support Group www.ehlers-danlos.org PO Box 335 Farnham Surrey GU101XJ, England Phone: (44) 1252-690-940	A registered charity, run by volunteers, many of whom are affected by EDS. The website is designed to share medical information about EDS, to provide links to various support groups, and opportunities to share coping strategies and personal experiences. They also highlight the latest research and offer a variety of publications.
Online Mendelian Inheritance in Man www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM	Search for EDS: this site gives detailed and highly technical genetic descriptions for origins of various EDS types with an emphasis on the current progress related to gene mapping of these disorders.
EDS Today www.edstoday.org	A nonprofit organization that provides a wealth of information, article links, and support group information aimed at individuals and the medical community.
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases www.niams.nih.gov/hi/topics/connective/connective.htm 1 AMS Circle Bethesda, Md 20892-3675 Phone: 301-496-8188 or 877-226-4267	Easy-to-read fact sheets written for consumers with detailed information about connective tissue diseases. A government publication, freely accessible and without copyright restrictions.
National Organization for Rare Diseases www.rarediseases.org 55 Kenosia Ave PO Box 1968 Danbury, Conn 06813-1968 Phone: 203-744-0100 Fax: 203-798-2291	Listings and descriptions of EDS of all types. Houses a database of >2000 organizations and sources of help for patients with rare diseases and searchable data base of >1150 rare diseases. Also accepts e-mail queries from patients who are having problems accessing services, or those who have questions related to genetic inheritance.
National Institutes of Health www.genetests.com or www.geneclinics.org	Contains the link to GeneReviews, which provides peer-reviewed information about all types of EDS as well as links to lab analysis through Gene tests.

Sidebar 1: Putting a Face to Vascular Type EDS: A Mother's Story. By: Cathy Bowen

Editor's Note
The following story illustrates the importance of both taking a complete family history, and of really listening to the details of the story. David's pictures (Figs 7A-F) illustrate the changing face of EDS. David's history, as recounted by his mother, also provides some very important clues to the diagnosis of EDS. We thank this mother for her insights, and we heed her important reminder to look and listen ever so carefully to our patients and their parents.MBF

David Daniel Bowen III was born March 31, 1982 after my water broke prematurely and I went into labor at 36 weeks gestation. He weighed 4 lbs 5 oz (1956 grams), was 17 ½ inches long, and his head measured 12 ¾ inches. The doctors evaluated David and decided that because of his head size he was actually small for gestational age and closer to 39 weeks. David was born with thin, translucent skin on his chest and abdomen that persisted throughout his life. He had bilateral inguinal hernias, cryptorchidism, bilateral hydroceles, and hypospadias. His hips were also rotated inward at birth later causing him to toe-in when he learned to walk. David also had a small mouth with a high arched palate, cross bite, and crowded teeth.

David was active in all sports; he especially loved hockey, karate, and basketball. However, he seemed to have a propensity for injuries. He had stitches in his scalp that would not hold. A dog bite under his right eye took 40 internal and external stitches. This wound healed without problems. Later an elbow wound developed into a deep cigarette paper scar. When he was 10 years old he tore his anterior cruciate ligament and had to wear a knee brace.

David had bowel problems. He could only stool every 2 to 3 days and would pass blood and mucous with large formed stools. At 13 ½ years of age he had a spontaneous sigmoid colon rupture and developed peritonitis and marked inflammation of the small bowel. This required a colostomy repair. His surgeon said this perforation was unusual; he had not seen it before and he did not understand the cause. Unfortunately, because of the perforation, the surgeon raised the question of abuse and a social worker conducted a child abuse investigation. Needless to say, no evidence was found. Although 5 different physicians were consulted no one gave David a diagnosis; he was treated like a normal healthy boy.

David recovered slowly after his surgery. On his eighth postoperative day when the intern was removing the staples from his incision, the skin spread apart and bled like a fresh wound. They placed adhesive strips on the wound edges and David was discharged home a day later. Postoperatively, David returned to the surgeon's office 3 times in the first 2 weeks because of complaints of extreme gas pain, loss of appetite, weight loss, pain under his right rib area, a pulling sensation, and right lower chest discomfort that interfered with taking a deep breath. The 5.5-inch vertical incision spread to 1.5 inches wide, and required recurrent cauterization to the wound edges. It took a long time to heal; however, these symptoms were not recognized as atypical. Four months later, David returned to surgery for an end-to-end reanastomosis that was complicated by multiple adhesions. The reanastomosis failed; David developed septic shock and was transferred to another facility for emergency surgery. On July 8, 1996, David died.

Shortly before his death David was first examined by a geneticist. She felt that he had a connective tissue disorder called Ehlers-Danlos syndrome type IV (now reclassified to EDS vascular type). David had a skin biopsy done confirming that this was a spontaneous "new" mutation of vascular-type EDS.

We remain completely devastated by David's loss even years later. Every day remains a struggle. No one can fathom the magnitude of these feelings unless they have lost a child this way. Our family tries to use our grief for David in a positive way, to bring education and awareness to others. Our hope is that we can prevent another family from having to endure what happened to us.

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The Clinical Presentation of Ehlers-Danlos Syndrome

Understanding the Genetics of EDS

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Sidebar 1: Putting a Face to Vascular Type EDS: A Mother's Story. By: Cathy Bowen

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