Download Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome (EDS) is a heterogeneous hereditary disorder of connective tissue affecting skin, ligaments,
joints, blood vessels, and internal organs. EDS is characterized
by skin extensibility, joint hpermobility, and tissue fragility.
The prevalence of EDS is estimated to be about 1 in 5000
births.
a. Autosomal dominant inheritance
b. EDS VIIA caused by mutations in the genes for type
I collagen (COL1A1)
c. EDS VIIB caused by mutations in the genes for type
I collagen (COL1A2), mapped at 7q22.1
6. Dermatospraxis type (EDS type VIIC)
a. Autosomal recessive inheritance
b. Caused by homozygous mutations in the ADAMTS2
gene (5q23) encoding procollagen I N-terminal peptidase resulting in procollagen peptidase deficiency
7. Other types
a. EDS type V
i. X-linked recessive inheritance
ii. Described in only two families with clinical features similar to EDS II
iii. Molecular basis unknown
b. EDS type VIII
i. A rare type
ii. Autosomal dominant inheritance
iii. Similar to classic type except the presence of
periodontal friability
c. EDS type IX
i. Previously redefined as occipital horn syndrome
(X-linked cutis laxa)
ii. An X-linked recessive condition allelic to Menkes
syndrome
iii. Abnormal copper utilization secondary to defective copper transport resulting in decreased
activity of lysyl oxidase, an important copperdependent enzyme required for cross-linking in
collagen biosynthesis and elastin fibers
d. EDS type X
i. Autosomal recessive inheritance
ii. Described only in a single family
iii. Associated platelet aggregation due to a defect in
fibronectin
e. EDS type XI
i. Termed familial joint hypermobility syndrome
ii. Autosomal dominant inheritance
iii. Previously removed from the EDS classification
GENETICS/BASIC DEFECTS
1. Classic type (includes EDS type I, gravis type and EDS
type II, mitis type)
a. Autosomal dominant inheritance
b. Mutations in the COL5A1 gene (mapped at 9q34.2q34.3), COL5A2 (mapped at 2q31), and COL1A1
(mapped at 17q21.31-q22) genes result in EDS I
c. Mutations in the COL5A1 and COL5A2 genes result
in EDS II
2. Hypermobile type (EDS type III)
a. Autosomal dominant inheritance in the classic form
of type III EDS
b. Mutations in COL3A1, typically cause EDS IV, also
cause EDS III
c. Mutations in the TNXB gene that encodes tenascin-X
(neither a collagen nor a collagen-modifying protein)
result in a variation of the classic form of the EhlersDanlos syndrome
i. Autosomal recessive disorder
ii. Clinical findings (joint hypermobility, soft
hyperextensible skin, and easy bruising without
skin scars) are compatible with Beighton’s
description of Ehlers-Danlos syndrome type III
or “benign familial hypermobility”
3. Vascular type (EDS type IV, arterial-ecchymotic type)
a. Autosomal dominant inheritance
b. COL3A1 locus: 2q31
c. Caused by mutations in the gene that encodes type
III procollagen (COL3A1), which is the major component of blood vessels, viscera and the uterus.
Consequently, individuals with this type often experience life-threatening vascular and gastrointestinal
complications
4. Kyphoscoliosis type (EDS type VI, ocular-scoliotic type)
a. Autosomal recessive inheritance
b. PLOD gene mapped to 1p36.3-p36.2
c. Caused by mutations in the PLOD gene encoding
lysyl hydroxylase
d. Caused by deficient activity of the enzyme procollagen lysyl hydroxylase
e. EDS VIA: reduced activity of lysyl hydroxylase
f. EDS VIB: normal enzyme level
5. Arthrochalasis type (EDS types VIIA and VIIB,
arthrochalasis multiplex congenita)
CLINICAL FEATURES
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1. Classic type (EDS I and II)
a. Major diagnostic criteria: the presence of scars with
joint hypermobility suggests the classical type
i. Skin hyperextensibility
ii. Widened atrophic scars (the hallmark “cigarettepaper” scars, a manifestation of tissue fragility)
iii. Joint hypermobility
iv. Positive family history
b. Minor diagnostic criteria
i. Smooth, velvety skin
EHLERS-DANLOS SYNDROME
ii. Molluscoid pseudotumors
a) Fresh lesions associated with scars
b) Frequently found over pressure points such
as elbows and knees
iii. Subcutaneous spheroids
a) Small subcutaneous spherical hard bodies
b) Frequently mobile and palpable on the forearms and shins
c) May be calcified and detectable radiologically
iv. Complications of joint hypermobility
a) Sprains
b) Dislocations
c) Recurrent joint subluxations in the shoulder,
patella, and temporomandibular joints
d) Pes planus
v. Muscle hypotonia
vi. Delayed gross motor development
vii. Easy bruising
viii. Manifestations of tissue extensibility and fragility
a) Hiatal hernia
b) Anal prolapse in childhood
c) Cervical insufficiency
ix. Surgical complications (postoperative hernias)
x. Positive family history
c. Other features
i. Families with variable severity (mild, moderate,
and severe) of the skin manifestations
ii. Dyspareunia and sexual dysfunction: occasional
complaints
iii. Fatigue: a frequent complaint
2. Hypermobile type (EDS III)
a. Major diagnostic criteria
i. Skin involvement (variable hyperextensibility
and/or smooth, velvety skin)
ii. Generalized joint hypermobility (dominant clinical feature)
b. Minor diagnostic criteria
i. Recurrent joint dislocations (particularly shoulder, patella, and temporomandibular joints)
ii. Chronic joint/limb pain (early onset, chronic,
and possibly debilitating)
iii. Positive family history
c. Other features
i. Early-onset, chronic, and possibly debilitating
musculoskeletal pain
ii. Aggravation of joint symptoms during pregnancy
but a complete return to the former status is possible
3. Vascular type (EDS IV)
a. Major diagnostic criteria: the presence of any 2 or
more major criteria is highly indicative of diagnosis
of EDS IV; biochemical testing is strongly recommended to confirm the diagnosis
i. Thin translucent skin (especially noticeable on
the chest or abdomen)
ii. Arterial/intestinal/uterine fragility or rupture
(presenting signs in 70% of adults with vascular
type of EDS)
a) Spontaneous arterial rupture peaks in the 3rd
or 4th decade but may occur earlier, most
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commonly involves midsized arteries, and is
the most common cause of sudden death.
The sites of arterial rupture are the thorax
and abdomen (50%), head and neck (25%),
and extremities (25%)
b) Intrapartum uterine rupture and pre/postpartum arterial rupture result in 15% mortality.
Vaginal and perineal tears may complicate
pregnancies during delivery
c) Gastrointestinal ruptures occur in about 25%
of patients, most common in the sigmoid
colon
d) Ruptures of the small bowel and stomach are
rare. The rupture may present as an acute
abdomen
iii. Easy bruising
a) Life long history
b) Spontaneous or with minimal trauma
iv. Characteristic facial appearance in some affected
patients due to a decrease in the subcutaneous
adipose tissue
a) Thin lips and philtrum
b) Small chin
c) Thin nose
d) Large eyes
v. Family history of the vascular type of EDS
b. Minor diagnostic criteria: the presence of one or more
minor criteria contribute to the diagnosis of the vascular type of EDS, but are not sufficient to establish the
diagnosis
i. Acrogeria (an aged appearance of the extremities, particularly the hands)
ii. Hypermobility of small joints (usually limited to
the digits)
iii. Tendon and muscle rupture (knee)
iv. Talipes equinovarus (clubfoot) (12%)
v. Early-onset varicose veins
vi. Arteriovenous, carotid-cavernous sinus fistula
vii. Pneumothorax/pneumohemothorax (common in
childhood)
viii. Chronic joint subluxations/dislocations
a) TMJ
b) Patella
c) Ankles
ix. Congenital dislocation of the hips
x. Gingival recession
xi. A positive family history consistent with autosomal dominant inheritance with sudden death in
close relatives
c. Other features
i. An uncommon subtype: diagnosis often made
only after a catastrophic complication or at postmortem examination
ii. Acute abdominal and flank pain (diffuse or
localized): a common manifestation of arterial or
intestinal rupture
iii. Subcutaneous venous pattern particularly apparent over the chest and abdomen
iv. Hypermobility of large joints and hyperextensibility of the skin: unusual in the vascular type
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EHLERS-DANLOS SYNDROME
v. The teenage boys: at higher risk for arterial rupture
possibly due to further weakening of the defective
collagen during the prepubertal growth spurt
vi. Patients undergoing surgery: prone to have arterial rupture in the postoperative period, possibly due to increased collagenase activity after
surgical trauma
vii. Aneurysms (if present) resulting from arterial tears
with walled-in hematomas or pseudoaneurysms
viii. Danger of varicose-vein surgery in unrecognized cases since the extreme fragility of all
blood vessels can lead to a loss of a limb or even
loss of life
4. EDS V
a. An extremely rare X-linked, recessively inherited
disorder
b. Clinically similar to EDS II
i. Joint hyperextensibility
ii. Slightly hyperelastic skin
iii. Skin subject to mildly abnormal scarring
c. Normal life span
d. Asymptomatic female carriers
5. Kyphoscoliosis type (EDS VI)
a. Major diagnostic criteria: presence of 3 major criteria
is suggestive of diagnosis of EDS, kyphoscoliosis type
i. Generalized joint laxity (recurrent joint dislocations common in adults)
ii. Severe muscle hypotonia at birth
iii. Kyphoscoliosis, present at birth or within the
first year of life, progressive (adults with severe
kyphoscoliosis are at risk for restrictive lung
disease and pneumonia)
iv. Scleral fragility and rupture of the ocular globe
b. Minor diagnostic criteria
i. Tissue fragility, including atrophic scars
ii. Easy bruising
iii. Marfanoid habitus
iv. Microcornea (most patients)
v. Radiologically considerable osteopenia (osteoporosis)
vi. Family history (e.g., affected sibs)
c. Other features
i. Pronounced muscular hypotonia leading to
delayed gross motor development
ii. Severe phenotype often results in loss of ambulation in the second or third decade
iii. Scleral fragility leading to rupture of the ocular
globe after minor trauma
iv. Cardiovascular complications
a) Vascular rupture: the major life-threatening
complication
b) Both aortic dilatation/dissection and rupture
of medium-sized arteries may occur
c) Mitral valve prolapse common
v. Differential diagnosis: severe neonatal form of
Marfan syndrome
6. Arthrochalasia type (EDS VIIA and VIIB)
a. Major diagnostic criteria:
i. Severe generalized joint hypermobility, with
recurrent subluxations
ii. Congenital bilateral hip dislocation (present in
all biochemically proven individuals, may lead
to short stature)
b. Minor diagnostic criteria:
i. Skin hyperextensibility
ii. Tissue fragility, including atrophic scars
iii. Easy bruising
iv. Muscle hypotonia
v. Kyphoscoliosis (may lead to short stature)
vi. Radiologically mild osteopenia
c. Other features
i. Short stature resulting from complication of severe
kyphoscoliosis and/or hip dislocation
ii. Differential diagnosis: Larsen syndrome
7. Dermatosparaxis type (EDS VIIC)
a. Major diagnostic criteria:
i. Severe skin fragility (wound healing not impaired,
scars not atrophic)
ii. Sagging, redundant skin (redundancy of the
facial skin resulting in an appearance resembling
cutis laxa) analogous to the animal disease
dermatosparaxia
b. Minor diagnostic criteria:
i. Soft, doughy skin texture
ii. Easy bruising (substantial)
iii. Premature rupture of fetal membranes
iv. Large hernias (umbilical, inguinal)
c. Other features
i. Blue sclera
ii. Palmar creases
iii. Micrognathia
iv. Joint laxity without subluxations
8. EDS VIII
a. Chronically inflamed, heavily pigmented, discrete, pretibial plaques (granulomatous collagen
degeneration)
b. Premature periodontal disease
c. Premature loss of teeth
d. Hypermobile joints
e. Thin, soft, hyperextensible skin
f. Easy bruising skin
g. Skin prone to abnormal scarring
h. No consistent biochemical or structural changes
detectable
9. Occipital horn syndrome (EDS IX)
a. Also called X-linked cutis laxa
b. Skeletal dysplasia
i. Occipital horns
ii. Broad clavicles
iii. Deformed radii, ulnae, and humeri
iv. Narrow rib cage
v. Undercalcified long bones
vi. Coxa valga
c. Unusual facial appearance
d. Hypermobility of finger joints
e. Limitation of extension of elbows
f. Chronic diarrhea
g. Genitourinary abnormalities
i. Bladder diverticulae
ii. Susceptible to rupture of the bladder
EHLERS-DANLOS SYNDROME
h. Vascular complications
i. Splenic artery aneurysm
ii. Hepatic artery aneurysm
i. Neuropathologic findings
i. Neovascularization and extreme reduplication of
the cerebral arteries with cystic medial degeneration
ii. Cerebellar hypoplasia
iii. Focal cortical dysplasia
iv. Cerebellar heterotopias
j. Abnormal copper utilization
i. Depleted serum copper level
ii. Depleted serum ceruloplasmin level
10. Ehlers-Danlos syndrome with fibronectin deficiency
(EDS X)
a. A mild, recessively inherited variant of Ehlers-Danlos
syndrome
b. Resembling EDS types II and III
c. Thin, fragile, easily scarred skin
d. Joint hypermobility
e. Excessive bruising
f. Abnormal platelet aggregation but correctable with
normal fibronectin
DIAGNOSTIC INVESTIGATIONS
1. Classic type
a. Ultrastructural studies
i. Disturbed collagen fibrillogenesis
ii. A characteristic “cauliflower” deformity of collagen fibrils
b. Abnormal electrophoretic mobility of the proα1(V) and
proα2(V) chains of collagen type V in some patients
c. Demonstration of a mutation in COL5A1 and/or
COL5A2 genes. Mutations in the COL1A1 are not a
major cause of classic EDS.
d. Echocardiogram to measure aortic root size
2. Vascular type
a. Demonstration of structurally abnormal collagen type
III produced by cultured skin fibroblasts
b. Demonstration of a mutation in the COL3A1 gene
c. Surveillance of aneurysm by MRI or CT scan without
contrast material or venous subtraction angiography
3. Kyphoscoliosis type
a. Demonstration of deficient activity of the enzyme procollagen lysine hydroxylase in affected individuals,
diagnosed by biochemical testing of the urine and
enzyme assay of cultured fibroblasts
b. Demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in the urine measured by HPLC, a highly sensitive and specific test
c. Demonstration of mutations of the PLOD gene that
encodes the enzyme procollagen lysyl hydroxylase
d. Echocardiogram to measure aortic root size
4. Arthrochalasis type
a. Electrophoretic demonstration of pNα1(I) or pNα2(I)
chains extracted from dermal collagen or harvested
from cultured skin fibroblasts
b. Mutation analysis (complete or partial exon 6 skipping in cDNAs of COL1A1 or COL1A2 respectively)
5. Dermatospraxis type: electrophoretic demonstration of
pNα1(I) or pNα2(I) chains from collagen type I extract-
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ed from dermis in the presence of protease inhibitors, or
obtained from cultured skin fibroblasts
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib
i. Autosomal recessive: 25% risk of having an
affected sib
ii. Autosomal dominant: risk low (1–5%) unless the
parent is affected or having somatic mosaicism
or germline mosaicism
iii. X-linked recessive: 50% risk of having an affected
brother if the mother is a carrier
b. Patient’s offspring
i. Autosomal recessive: risk not increased unless
the spouse is a carrier
ii. Autosomal dominant: 50% risk of having an
affected offspring
iii. X-linked recessive: none of the sons will be
affected; all daughters will be carriers
2. Prenatal diagnosis
a. Possible by demonstrating the disease causing mutation in the fetal cells from CVS or amniocentesis or
by linkage analysis for families in which linkage has
been established
b. Possible by biochemical assay on cultured fetal cells
for demonstrating biochemical defect in the specific
type of collagen
3. Management
a. General approach: conservative and preventive management of most skin and joint problems
i. Avoid tension when sutures are applied
ii. Leave removable sutures in place for twice the
usual time
iii. Physical therapy to strengthen the muscles that
need to provide support for the loose ligaments
b. Classic type
i. Medical intervention limited to symptomatic
therapy and prophylactic measures
ii. Wear protection pads or stocking
iii. Avoid contact sports
iv. Physiotherapy for children with hypotonia and
delayed motor development
v. Antimicrobial prophylaxis for patients with
mitral valve prolapse
vi. Ascorbic acid helps avoid easy bruising but does
not change the basic clinical picture
c. Kyphoscoliotic type
i. Orthopedic management of kyphoscoliosis
ii. Physical therapy for older children, adolescents,
and adults
iii. Antimicrobial prophylaxis for patients with
mitral valve prolapse
iv. Aggressive control of blood pressure
v. Improve with large doses of ascorbic acid
because vitamin C is a cofactor for the enzyme
that is deficient
a) Improve urinary excretion of hydroxylysine
b) Improve muscle strength and wound healing
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EHLERS-DANLOS SYNDROME
d. Vascular type
i. Prompt recognition of the major complications
ii. Difficult to repair ruptured arteries because of the
pronounced vascular fragility
iii. Avoid elective surgery
iv. Rupture of the bowel, a surgical emergency
v. Avoid pregnancy because the risk of vascular rupture is especially high during pregnancy
vi. Minimize risk of trauma by avoiding contact sport,
heavy lifting, and weight training
vii. Treat high blood pressure aggressively
viii. Patient education
a) Possible complications
b) Need for close monitoring
c) Attention to sudden unexplained pain
REFERENCES
Beighton P: The Ehlers-Danlos syndrome. In: Beighton P (ed): McKusick’s
Heritable Disorders of Connective Tissue. St Louis: Mosby, 1992:189–251.
Beighton P, Curtis D: X-linked Ehlers-Danlos syndrome type V: The next generation. Clin Genet 27:472–478, 1985.
Beighton P, De Paepe A, Danks D, et al.: International nosology of heritable
disorders of connective tissue, Berlin, 1986, 29:581, 594, 1988.
Beighton P, De Paepe A, Steinmann B, et al.: Ehlers-Danlos syndromes:
Revised nosology, Villefranche, 1997. Am J Med Genet 77:31–37, 1998.
Burrows NP: The molecular genetics of the Ehlers-Danlos syndrome. Clin Exp
Dermatol 24:99–106, 1999.
Byers PH: Ehlers-Danlos syndrome type IV: a genetic disorder in many guises.
J Invest Dermatol 105:311–313, 1995.
Byers PH: An exception to the rule. N Engl J Med 345:1203–1204, 2001.
Byers PH: Disorders of collagen biosynthesis and structure. In: Scriver CR,
Beaudet al., Sly WS, Valle D (eds): The Metabolic and Molecular Bases of
Inherited Disease. 8th ed. Vol 4. New York: McGraw-Hill, 2001:5241– 5285.
Byers PH, Duvic M, Atkinson M, et al.: Ehlers-Danlos syndrome type VIIA
and VIIB result from splice-junction mutations or genomic deletions that
involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am
J Med Genet 72:94–105, 1997.
De Paepe A, Nuytinck L, Hausser I, et al.: Mutations in the COL5A1 gene are
causal in the Ehlers-Danlos syndromes I and II. Am J Hum Genet
60:547–554, 1997.
Giunta C, Superti-Furga A, Spranger S, et al.: Ehlers-Danlos syndrome type
VII: clinical features and molecular defects. J Bone Joint Surg Am
81:225–238, 1999.
Mao JR, Bristow J: The Ehlers-Danlos syndrome: on beyond collagens. J Clin
Invest 107:1063–1069, 2001.
McKusick VA: Heritable Disorders of Connective Tissue. Saint Louis, CV
Mosby Co., 1972.
Mentzel HJ, Seidel J, Vogt S, et al.: Vascular complications (splenic and hepatic
artery aneurysms) in the occipital horn syndrome: report of a patient and
review of the literature. Pediatr Radiol 29:19–22, 1999.
Michalickova K, Susic M, Willing MC, et al.: Mutations of the alpha2(V) chain
of type V collagen impair matrix assembly and produce Ehlers-Danlos
syndrome type I. Hum Mol Genet 7:249–255, 1998.
Myllyharju J, Kivirikko KI: Collagens and collagen-related disease. Ann Med
33:7–21, 2001.
Nuytinck L, Freund M, Lagae L, et al. Classical Ehlers-Danlos syndrome
caused by a mutation in type I collagen. Am J Hum Genet 66:1398–1402,
2000.
Pepin M, Byers PH: Ehlers-Danlos syndrome, vascular type. Gene Reviews,
2002. http://www.genetests.org
Pope FM, Burrow NP: Ehlers-Danlos syndrome has varied molecular mechanisms. J Med Genet 34:400–410, 1997.
Pyeritz RE: Ehlers-Danlos syndrome. N Engl J Med 342:730–732, 2000.
Schalkwijk J, Zweers MC, Steijlen PM, et al.: A recessive form of the EhlersDanlos syndrome caused by tenascin-X deficiency. N Engl J Med
345:1167–1175, 2001.
Smith LT, Wertelecki W, Milstone LM, et al.: Human Dermatosparaxis: a form
of Ehlers-Danlos syndrome that results from failure to remove the
aminoterminal propeptide of type I procollagen. Am J Hum Genet
51:235–244, 1992.
Sorokin Y, Johnson MP, Rogowski N, et al.: Obstetric and gynecologic dysfunction in the Ehlers-Danlos Syndrome. J Reprod Med 39:281–284,
1994.
Steinmann B, Royce PM, Superti-Furga A: The Ehlers-Danlos syndrome. In
Royce PM, Steinmkann B (eds): Connective Tissue and Its Heritable
Disorders. Molecular, Genetic, and Medical Aspects. New York, WileyLiss, 1993:351–408.
Tiller GE, Cassidy SB, Wensel C, et al.: Aortic root dilatation in Ehlers-Danlos
syndrome types I, II and III. A report of five cases. Clin Genet 53:460–465,
1998.
Wenstrup RJ: Ehlers-Danlos syndrome, kyphoscoliotic form. Gene Reviews,
2003. http://www.genetests.org
Wenstrup RJ, Paepe AD: Ehlers-Danlos syndrome, Classic type. Gene
Reviews, 2003. http://www.genetests.org
Wenstrup RJ, Florer JB, Willing MC, et al.: COL5A1 Haploinsufficiency is a
common molecular mechanism underlying the classical form of EDS.
Am J Hum Genet 66:1766–1776, 2000.
Wenstrup RJ, Meyer RA, Lyle JS, et al.: Prevalence of aortic root dilatation in
the Ehlers-Danlos syndrome. Genet Med 4:112–117, 2002.
Yeowell HN, Pinnell Skelet Radiol: The Ehlers-Danlos syndromes. Semin
Dermatol 12:229–240, 1993.
Yeowell HN, Walker LC: Mutations in the lysyl hydroxylase 1 gene that result
in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab 71:212–224, 2000.
EHLERS-DANLOS SYNDROME
Fig. 1. Hyperextensible joints enable a girl and two sisters with EDS
to exhibit difficult hyperextensible joint maneuvers.
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EHLERS-DANLOS SYNDROME
Fig. 2. Familial Ehlers-Danlos syndrome in the son (A–D), the daughter
(E), and the father (F–H) exhibiting hyperextensible joints and hyperelastic skin. The son also has fascia weakness presenting as a hernia
on the lower chin.
EHLERS-DANLOS SYNDROME
349
Fig. 4. Typical EDS showing easy bruises and scars of the skin
Fig. 3. A male and a female with EDS showing hyperextensible joints
and hyperelastic skin.