Symposium on Medical Genetics

Heritable Disorders of Connective Tissue: Ehlers-Danlos Syndrome David W. Hollister, M.D.*

The heritable disorders of connective tissue fonn alarge and extremely heterogeneous group of more than 100 distinct diseases in man. Although the clinical presentations of these disorders vary widely, they share as fundamental features various alterations in the supporting structures of the body, and inheritance in a simple mendelian fashion. From a conceptual point of view, the human body may be separated into intracellular and extracellular spaces, divided at the cell membrane; normally both of these spaces are highly organized. The extracellular space is organized by the extracellular matrix which is composed primarily of fibrous proteins, such as collagen and elastin, and complex sugar compounds, the glycosaminoglycans. The specific organization of this extracellular matrix provides for a number of critical biological functions-cytoskeletal support for the included cells, tensile strength, elasticity, resistance to defonnation, and so forth-as well as certain specialized functions, such as growth. The heritable disorders of connective tissue are disorders of the extracellular matrix in which one or more of the connective tissue matrices of the body are disorganized, and hence unable to nonnally fulfill their biological roles. The ultimate consequence of this disorganization is reflected in the clinical presentations, for example, easily torn skin in Ehlers-Danlos syndromes, aneurysmal dilation and rupture of the aorta in Marfan syndrome, and dwarfism observed in the osteochondrodysplasias. Another consequence is that, with certain notable exceptions, particularly the mucopolysaccharide storage diseases, these diseases spare the parenchyma of the various organs, and thus features such as mental retardation, neuromuscular symptoms, liver or kidney failure, and endocrine or hematologic disorders are not integral features. Where organ failure does occur, as in cardiac failure in Marfan syndrome, it would appear to be secondary to the connective tissue defects. Table 1 depicts the variety of heritable disorders of connective tissue recognized at present. The majority of these diseases are the human dwarfing disorders, the osteochondrodysplasias, of which more than 70 clinically distinct varieties have been found. Substantial heterogeneity *Assistant Professor of Pediatrics and Medicine, Division of Medical Genetics, UCLA School

of Medicine, Harbor General Hospital, Torrance, California

Pediatric Clinics of North America-Vol. 25, No.3, August 1978

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Table 1. Heritable Disorders of Connective Tissue NO. OF DISTINCT DISEASE

Ehlers-Danlos syndrome Marfan syndrome Osteochondrodysplasias Pseudoxanthoma elasticum Alkaptonuria (ochronosis) Homocystin uria Weil-Marchesani Cutis laxa Osteogenesis imperfecta Mucopolysaccharidoses Menkes' syndrome

DISORDERS"

8 3 70 4 1

2 1

3 4 10

':'Recognition of heterogeneity within these disease classifications has been based primarily on differences in clinical and radiographic features, mode of inheritance, and pathologic features; in some disorders, identification of the enzymatic defects has revealed further heterogeneity.

has also been observed in mucopolysaccharide storage diseases and Ehlers-Danlos syndrome. Such classification reflects only the present incomplete understanding of these various diseases, and further heterogeneity among the various categories seems inevitable. Noteworthy by their absence are the so-called "collagen vascular" diseases, such as rheumatoid arthritis, polyarteritis, lupus erythematosus, and dermatomyositis, in which damage to the connective tissue appears to be secondary to immunologic aberrations. The heritable disorders of connective tissue are overwhelmingly pediatric diseases, usually presenting either at birth or during childhood. The role of the pediatrician is therefore paramount in recognition and accurate diagnosis, not only for the affected patient, but also for the family unit. Specific therapy is possible only in exceptional circumstances in a few conditions; nevertheless, therapy and counseling aimed at prevention or amelioration of complications may be rewarding. Of perhaps greater benefit to the young family unit will be recognition of the heritable nature of the disease, and thus the possibility of recurrence of the disorder in subsequent children, or occurrence in older or younger siblings or relatives. In some heritable disorders of connective tissue, notably the mucopolysaccharidoses, prenatal diagnosis of mid trimester pregnancies is possible, thus affording at-risk parents the option of therapeutic abortion of affected fetuses. Complete discussion of the many heritable disorders of connective tissue is beyond the scope of this review, and reference is made to the excellent monograph by McKusick for detailed information and access to the literature up to 1972. 20 The neonatal varieties of the osteochondrodysplasias are described elsewhere in this volume. The mucopolysaccharide storage diseases have been recently reviewed. 110 20, 24 Another general source is Stanbury.25

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EHLERS-DANLOS SYNDROME

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EHLERS-DANLOS SYNDROME The cardinal features of Ehlers-Danlos syndrome are hyperextensible skin, hypermobilejoints, easy bruisability, and fragility of the connective tissues leading to a wide variety of clinical manifestations. Either together or in various combinations these clinical features serve as the fundamental basis for diagnosis, and, together with consideration of the pattern of inheritance, may permit subclassification into one of the presently recognized varieties of Ehlers-Danlos. The spectrum of severity varies markedly, grading imperceptibly from normal to a life-threatening condition. Although eight different varieties of Ehlers-Danlos syndrome have been delineated, it seems certain that further heterogeneity will be found; probably more than half of all patients with unequivocal signs cannot be fit easily into the present classification. Moreover, it seems likely that only a fraction of patients are ever diagnosed owing to the lack of alarming symptoms to patient or doctor. Although surely more prevalent than reported cases might indicate, the true incidence of EhlersDanlos syndrome is unknown; McKusick has suggested that it is one of the more frequent heritable disorders of connective tissue. 2o A general description of the clinical features of the Ehlers-Danlos syndrome is given below, followed by a discussion of the recognized varieties of the syndrome and their major manifestations. The descriptions are inherently biased since only the more severely affected patients come to medical attention and hence into the literature.

Skin The skin is characteristic in texture and consistency, having a velvety or soft, doughy feel, somewhat like a wet chamois or fine sponge. The skin is hyperextensible (Fig. 1) and elastic," and returns immediately to its previously normal configuration upon cessation of testing. Although the skin of the hands and feet may appear loose-fitting and somewhat redundant, elsewhere it is smooth-fitting and appears normal. Unfortunately, interpretation of both skin texture and extensibility are subjective assessments with considerable inter-observer variability, and are made more difficult by the observed variations in these important diagnostic features from case to case and normal age-related changes. In the absence of specialized equipment, the pediatrician is best advised to develop diagnostic acumen by estimations of skin texture and extensibility on normal children of various ages. Since these parameters vary with anatomic location, identical sites should be chosen; for example, the flexor aspect of the forearm for skin texture, and elbow and neck for skin extensibility. Pulling outward on the ears is another useful maneuver to ascertain skin stretchability. Also extremely helpful is direct comparison of the patient with similarly aged children; in this regard, it should be recalled that comparison with the patient's siblings may cause confusion since the comparison sibling may also be affected. The demonstrations of cutaneous hyperextensibility, as opposed to normal or lax redundant skin, ""'Elastic" is used synonymously with "stretchy" to indicate a rubberband-like property. The formal definition of "elasticity" is exactly the opposite.

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jj Figure 1. Cutaneous hyperextensibility in a 6 year old boy with Ehlers-Danlos syndrome, Figure Cutaneous hyperextensibility a 6 year old boy with Ehlers-Danlos syndrome, Type I. In1.this, and subsequent figures, thein clinical manifestations of Ehlers-Danlos syndrome Type I. In this, andwith subsequent , the clinical manifestations ofEhlers-Danlos syndrome are illustrated the samefigures patient, who presented at age 4 with extensive, recurrent bruisaarebility illustrated with the same patient, who presented at age 4 with extensive, recurrent bruisaof the shins and cutaneous fragility (easy splitting of the skin) to minor trauma. A of the shins and cutaneous fragility (easy splitting of the skin) to minor trauma. bility thorough and extensive hematologic work-up, including bone marrow, was unremarkableAsave thorough and extensive work-up , includingobservation bone marrow for a borderline low hematologic fibrinogen leveL Subsequent of, was soft, unremarkable velvety skin, save marked for cutaneous a borderline low fibrinogen level. Subsequent observation soft, velvety scarring skin, marked hyperextensibility, markedjoint hypermobility andof characteristic led to the cutaneous hyperextensibility, marked joint hypermobility and characteristic scarring led to thethis diagnosis of Ehlers-Danlos syndrome, Type I. No other affected family members with diagnosis of Ehlers-Danlos syndrome, Type I. No other affected family members with this autosomal dominant disorder were found. autosomal dominant disorder were found.

I

Figure "Papyraceous" "cigarette-paper" scarring. Note discoloration ofthe Figure 2. 2. " Papyraceous" or " or cigarette-paper" scarring. Note the the discoloration of the skinskin secondary to repeated bruising multiple scars secondary to tearing of the scars secondary to repeated bruising andand multiple scars secondary to tearing of the skin.skin. TheThe scars atrophic, shiny, exhibit a fine wrinkling. guards, provided a prosthetic are are thinthin, , atrophic , shiny, andand exhibit a fine wrinkling. ShinShin guards , provided by aby prosthetic worn continuously by this patient, have markedly reduced morbidity. unitunit, , are are worn continuously by this patient, andand have markedly reduced morbidity.

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is tantamount to diagnosing Ehlers-Danlos syndrome, yet it is not uncommon for even the most striking hyperextensibility to go unnoticed. Absence of hyperextensibility per se does not rule out Ehlers-Danlos syndrome, since several varieties display minimal elasticity of skin. Cutaneous fragility, manifested by splitting ofthe dermis to relatively minor trauma, may be a prominent feature. These wounds typically occur over pressure points, such as knees and elbows, and areas prone to trauma, such as the shins, forehead, and chin. They tend to bleed little and often, owing to retraction ofadjacent skin, present a gaping, "fish-mouth" appearance. Sutures may hold poorly, and dehiscence may occur; in this regard, the use of adhesive tape has proved advantageous. Healing may be slow, necessitating prolonged fixation of the wound edges, and may result in so-called "cigarette-paper" or "papyraceous" scarring. These scars appear atrophic, thin, and shiny, are often hyperpigmented, and are usually corrugated by fine wrinkles (Fig. 2). Although usually observed over the knees, elbows, and shins, similar changes occur elsewhere and may give the impression that the scaris wider than, for example, the usual appendectomy scar. Easy bruisability is common, and is frequently the presenting complaint to the pediatrician. Other manifestations of a bleeding tendency are bleeding from the gums following brushing of the teeth or following dental extractions, or, rarely, gastrointestinal bleeding or hemoptysis. These features may lead to an extensive (and expensive) search for a coagulopathy should the diagnosis of Ehlers-Danlos syndrome escape

Figure 3. Easy bruisability. No antecedent trauma was recalled prior to this large bruise on the left arm. Similar bruises occurred elsewhere, and an organizing subcutaneous hematoma, presenting as an irregular mass beneath the skin, was found on the right lateral thigh .

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notice (Fig. 3). Although a variety of plasma clotting factors or platelet abnormalities have been reported in Ehlers-Danlos syndrome,20 most patients will be normal, although the Rumpel-Leede test may be positive. Most authorities have concluded that the bruisability and other bleeding manifestations are the result of factors other than platelets or clotting factors. 9. 20. 29 Easy bruisability and cutaneous fragility probably account for the majority of presentations to pediatricians, and, in this regard, several prophylactic measures may prove useful. Particularly for the active, younger child, knee pads or athletic shin guards protect these vulnerable areas; the older child should be counseled to avoid heavy contact sports or similar avocations. Additional cutaneous manifestations are the presence of subcutaneous masses of varying size and consistency. So-called molluscoid pseudotumors may develop at pressure points, such as the heel, knees, and elbows. Irregular masses may result elsewhere from organization or calcification of subcutaneous hematomas, and small fat-containing cysts, called spherules, may be noted. The latter may calcify and form the basis for radiologic diagnosis of Ehlers-Danlos syndrome.

Joint Manifestations Joint hypermobility is a cardinal feature, but, as in the case of the cutaneous manifestations, varies depending on the specific type of EhlersDanlos syndrome. As arule,jointhyperextensibilityis generalized, affecting both large and small joints, and frequent dislocations of hips, patella, shoulders, and elbows may occur. The elbow can be extended past 180 degrees as can the knees (genu recurvatum) (Fig. 4). The thumb can be apposed to the forearm when the wrist is flexed, and the fingers dorsifiexed past 90 degrees with the palm on a flat surface (Fig. 5). Quite often the questions, "Are you double-jointed?" and, "Can you do tricks with your fingers?" will elicit a remarkable display of finger contortions (Fig. 6). Similar feats ofhyperfiexibility include placing the ankle behind

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/ Figure Figure 5. 5. Joint Joint hypermobility hypermobility permitting permitting apposition apposition of of the the thumb thumb to to the the radius radius and and hyperextension hyperextension of of the the finger. finger.

the the neck, neck, or or the the head head between between the the knees knees while while bending bending backward. backward. Ligamentous Ligamentous laxity laxity may may be be observed observed at at multiple multiple joints; joints; pulling pulling on on the the distal distal phalanx phalanx of of aa finger finger may may result result in in considerable considerable lengthening lengthening of of the the finger, finger, aa phenomenon phenomenon known known as as telescoping telescoping (Fig. (Fig. 7). 7). Several Several grading grading 5 30 systems systems for for semiquantitation semiquantitation of ofjoint joint hypermobility hypermobility have have been been devised, devised, 5.20 ' and and offer offer objective objective methods methods for for ascertainment ascertainment ofhyperflexibility. ofhyperfiexibility. Joint effusions fusions are are frequent, frequent, especially especially at at the knee, and hemarthrosis may occur. Kyphoscoliosis Kyphoscoliosis may may also also be be present, and spondylolisthesis spondylolisthesis may be a source of back pain. Congenital dislocations of the of back pain. Congenital dislocations the hip and elsewhere are not unusual, unusual, and and clubfoot clubfoot has has been been reported. reported. Apparent hypotonia and muscular lar underdevelopment underdevelopment suggestive suggestive of of neuromuscular disease has been observed served in in young young children. children.

Figure Figure 6. 6. Joint Joint hypermobility hypermobility demondemonstrated by by finger finger contortions. contortions. strated

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J Figure 7. "Telescoping" of the index finger. The examiner is pulling outward on the index finger which, at rest, is shorter than the middle finger. Considerable lengthening occurs, as may be noted by the displacement of the distal and proximal interphalangeal joints and nail bed.

Additional Features The facies are often slightly abnormal with epicanthic folds and apparent ocular hypertelorism which usually proves to be lateral displacement of the inner canthi (telecanthus or distopia canthorum). The palate may be high-arched. Frequently, patients can extend the tongue to touch the tip of the nose-the Gorlin tongue sign. 13 Internal manifestations of connective tissue weakness may present in a number of ways. Umbilical and inguinal herniae are common, and hiatal hernia or eventration of the diaphragm may occur. Diverticulae of hollow viscerum have been observed in the stomach, duodenum, colon, and bladder. 6 , 20 Rectal bleeding may occur and, in children below about fi ve years, repeated rectal prolapse. 6 Abnormalities of the renal collecting system or cystic lesions of the kidney may be observed by pyelography, and renal tubular acidosis may occur.17 Occasionally, spontaneous pneumothorax occurs, and may be due to subpleural blebs. Cardiovascular manifestations may include the "floppy mitral valve" syndrome, or the combination of mitral and tricuspid insufficiency due to redundant chordae tendineae, or valve CUSpS.19 Although rare, dilation and dissection of the aorta or other arteries is also a recognized complication of Ehlers-Danlos syndrome. 2o (The arterial and gastrointestinal disasters associated with Ehler-DanIos, Type IV, are described below.) Pregnancy, with its associated generalized "loosening" of connective tissue,28 poses hazards to the mother with Ehlers-Danlos syndrome; among these are the risks of abdominal herniation, severe varicosities, increased joint laxity, premature and precipitous labor, excessive bleeding following episiotomy, postpartum hemorrhage, uterine or bladder prolapse, and dehiscence of sutured incisions of skin, mucosa, or uterine wall. 7 Cutaneous striae are rare in Ehlers-Danlos syndrome. Striae are focal tears in dermal collagen occurring perpendicularly to the direction of stress, but without disruption of the overlying epidermis; these wounds, like full thickness defects, heal by scarring. Presumably the cutaneous hyperextensibility prevents this sequence of events. The fetus with Ehlers-Danlos syndrome is also at-risk since the fetal membranes share the fragility of other connective tissues. Thus prema-

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ture rupture of membranes, leading to premature delivery, may occur.3 Congenital dislocations and hypotonia have been previously mentioned. Ehlers-Danlos syndrome should be considered in the differential diagnosis of bleeding tendencies in the newborn period. Varieties of Ehlers-Danlos Syndrome At present, eight more or less distinct varieties of Ehlers-Danlos syndrome have been recognized on the basis of clinical and genetic differences; in four of these varieties, biochemical studies have both identified a fundamental defect and confirmed at a molecular level the heterogeneity observed clinically. Tables 2 and 3 display the salient features of Types I to VIII, and the variations of the principal features and modes of inheritance should be noted. This classification originated with Beighton 7 as modified by McKusick,20 and has been further modified by addition of the recently described Type VIII. Several of these types have characteristic abnormalities beyond the usual features of Ehlers-Danlos syndrome, and these will be described under the relevant type. In Type I, the gravis variety, skin hyperextensibility, joint hypermobility, bruisability, and tissue friability are marked, and joint hypermobility is generalized. Prematurity is frequent due to precocious rupture of friable fetal membranes. Mild epicanthal folds, broadening of the nasal root, and configuration about the eyes often yield a peculiar appearance that has been described as "parrot-like" facies?" Tissue fragility may present surgical difficulties. Type II, the mitis variety, has mildly stretchy skin and mild joint hypermobility, which may be limited to hands and feet. Type III, the benign hypermobile variety, is characterized by severe, generalizedjoint hypermobility, and the sequelae thereof, such as dislocations, hemarthroses, and precocious arthritis. Skin manifestations are minimal. Patients with this type are thought to be at increased risk of developing the "floppy mitral valve" syndrome. 2 " Type IV, the ecchymotic (arterial) type, probably carries the most ominous prognosis owing to a liability to catastrophic bleeding from major arteries 4 and spontaneous perforation of the gastrointestinal tract.!' 2, 20 Joint hypermobility is limited to the digits, and skin stretchability is absent or minimal. Unlike the other varieties, in Type IV the skin is thin and semitransparent, and prominent venous networks may be easily observed. Bruisability is extremely severe, and minor trauma leads to extensive ecchymoses. Large varicose veins may be present. Arterial rupture of major vessels (aortic. femoral. popliteal, cervical. brachial, splenic,

Table 2. Characteristics of Eight Variants ofEhle rs-Danlos Syndrome SKIN TYPES

(gravis) II (mitis) III (benign hypermobile) IV (ecchymotic)

V (X-linked) VI (ocular) VII (procollagen peptidase deficiency) Vln (periodontitis)

HYPEREX-

JOINT

SKIN

TENSIBILITY

HYPERMOBILITY

FRAGrLrry

BRUISING

Marked Moderate Minimal

Marked Moderate Marked

Marked Moderate Minimal

Marked Moderate Minimal

Minimal or absent Marked Marked Moderate

Limited to digits Minimal Marked Marked

Marked

Marked

Moderate Minimal Moderate

Moderate Minimal Moderate

Minimal

Moderate

Moderate

Minimal

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Table 3. Characteristics of Eight Variants of Ehlers-Dan los Syndrome TYPES

MAJOR COMPLICATIONS

INHERITANCE

Musculoskeletal deformities common; varicose veins, prematurity due to ruptured membranes

Autosomal dominant

Unknown

Autosomal dominant Autosomal dominant Autosomal recessive

Unknown

X-linked

Lysyl oxidase deficiency

Autosomal recessive Autosomal recessive Autosomal dominant

Lysyl hydroxylase deficiency Procollagen peptidase deficiency Unknown

II III

Arthritis

IV

Death from arterial rupture, aortic dissection, intestinal perforation; musculoskeletal abnormalities absent Musculoskeletal disorders common Fragility of cornea and sclera; musculoskeletal disorders Marked short stature and multiple joint dislocations Advanced generalized periodontitis

v VI VII VIII

BASIC DEFECT

Unknown Type III collagen deficiency

etc.) may occur without antecedent trauma, or with minimal trauma, and lead to massive hemorrhage or death. Although aneurysmal dilation and dissection may occur, it is also clear that slit-like defects in normal caliber arteries may also occur. Operative attempts at vascular repair have been almost uniformly unsuccessful due to the friability of the vessel walls and other tissues (characterized as similar to wet blotting paper); usually, after a prolonged interoperative struggle to achieve hemostasis, the artery is simply ligated. Conservative treatment, whenever possible, is recommended. 4 A patient may survive one bleed, only to suffer recurrent bleeds at the same or different sites months or years later. Because of the extreme vascular fragility of these patients, angiographic studies should be attempted in only the most dire circumstances. Spontaneous rupture of the bowel, primarily large bowel, also occurs, and may recur repeatedly." 2, 6 There is some evidence to suggest intramural bleeding into the bowel wall, together with tissue friability, are important in the pathogenesis?O Transient intestinal obstruction without perforation may occur. The patient with Type IV presenting with abdominal pain often poses a considerable diagnostic and management problem since obstruction, perforation, and arterial bleeding must be considered as well as other pathologies. In Type V, the X-linked variety, the skin hyperextensibility is striking, but joint hypermobility is mild. Cutaneous fragility, bruising, and scarring are moderate. Since this condition is inherited on the X chromosome, the disease is virtually limited to males. Type VI, the ocular variety, has marked hyperextensibility of skin and hypermobility of joints , but, in addition, has ocular abnormalities in excess and of greater severity than those observed in other varieties. '6, 21 A number of ocular findings have been noted in Ehlers-Danlos syndrome, such as blue sclera, microcornea, glaucoma, keratoconus, megalocornea, occasional retinal detachment, and rarely, ectopia lentis. In Type VI, however, these are regular features, particularly microcornea, glaucoma, and retinal detachment, and, in addition, there is severe scleral fragility leading to rupture of the globe with mild trauma. Repair is usually unsuccessful, leading to enucleation; the risk of loss of both eyes is substantial. Severe kyphoscoliosis may be more prevalent in this variety. At present, it is uncertain whether Type VI Ehlers-Danlos syndrome and a syndrome known as "fragilitas oculi," which shows many ocular and joint similarities, and autosomal recessive inheritance are distinct disorders. 20

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Type VII, the multiple congenital dislocation variety, exhibits marked joint hypennobility with dislocations, moderate cutaneous hyperextensibility and bruisability, and short stature. The multiple congenital dislocations observed make this variety similar to (identical?) the condition known as arthrochalasis multiplex congenita,zo The infants are floppy, apparently due to extreme ligamentous laxity, and surgical plication is frequently required for joint re-articulation. In Type VIII, the periodontitis variety, skin stretchability, bruisability, and joint mobility are mild, but cutaneous fragility is moderate, leading to moderate scarring. The characteristic feature is severe and generalized periodontitis, resulting in extensive resorption of alveolar bone and premature loss of teeth. 20• 26

Molecular Defects The seemingly protean manifestations of Ehlers-Danlos syndrome can be related to a fundamental theme: disorganization of the connective tissues resulting in loss of biomechanical integrity. Considerable insight into the causation of a number of varieties of Ehlers-Dan los syndrome has been obtained in recent years, and for the most part these insights have been based on advancing understanding of the chemistry and biology of collagen. Collagen Heterogeneity Collagen, a fibrous protein, is the most abundant protein in the body. Like the Ehlers-Danlos syndrome, collagen has been found to be heterogeneous, and comprises a family of closely related proteins; at least five varieties of human collagen are now known (Table 4).8.27 Each of these collagen types is closely similar in size and shape, and each is composed of three protein chains, or subunits, tightly coiled about each other to form a long, thin, "triple-helical" rod-like molecule (Fig. 8, bottom); they differ by virtue of containing different subunit chains, and particularly by virtue of strikingly different distribution in various tissues. Type I collagen, for example, seems to occur wherever great tensile strength is required, is virtually the only collagen type found in bone and tendon, and comprises 80 per cent of skin collagen. Type III collagen, on the other hand, occurs in tissues that normally undergo mild to moderate distention, and is thus a major constituent of blood vessels and hollow viscerum such as gut, uterus, lung, and so forth. Table 4. Varieties of Collagen SUBUNIT(S)"

STRUCTUREt

,,1(I), ,,2(1)

[,,1(1)]2,,2(1)

II III

"l(n) "l(III)

[al(n)]3 [al(III)]3

IV

al(IV)

[al(IV)]3

V?

"A,,,B

"A["B],?

TYPE

DISTRIBUTION

Bone, tendon, skin, other Cartilage, vitreous Blood vessels, gut, uterus, skin Glomerulus, lens capsule Basement membranes

*By convention, the subunit protein chains of collagen are called "a" chains, and are distinguished from each other by Arabic numerals where more than one chain occurs in a given collagen type; Roman numerals are used to distinguish collagen type. tThis shorthand notation designates the number and variety of subunit chains; note that all collagens contain three protein chains.

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...- - - - - - 3 0 0 0 A OH

OH

OH



OH

OH



OH

15A

OH

OH

OH

OH

OH

OH

OH



Figure S. Abbreviated biosynthesis of collagen (see text). Above, Initiation of synthesis of a procollagen chain from a ribosome and hydroxylation of proline and lysine residues to hydroxyproline and hydroxylysine, respectively. Center, Completed procollagen molecule with triple-helical central region and non-helical end segments (saw-tooth lines). Below, Collagen molecule. An approximate model of this molecule is a length of % inch rope 52 inches long. (Modified from McKusick, V . A.: Heritable Disorders of Connective Tissue. Edition 4. St. Louis, C . V. Mosby Co., 1972.)

COLLAGEN

Ehlers-Danlos Type IV, the ecchymotic variety, has been shown to lack Type III collagen. 22 Since Type III collagen is a prominent component of blood vessel and gut, the major complications of this variety (ecchymoses, perforation of bowel, rupture of arteries) are at least partially explained by absence of this collagen type. Since this disease is inherited as an autosomal recessive and affected patients have essentially no Type III collagen, obligate carriers (parents of an affected child) would be expected to have reduced levels of Type III collagen, and this proves to be the case. 23 Collagen Synthesis In order for the collagens to subserve their biological roles, they must be synthesized, secreted, modified, assembled, and cross-linked with other collagen molecules to form fibrils, bundles, and larger aggregates that are the ultimate structural units and provide tensile strength to the tissues. Aberrations in this orderly, multi-step process would result in defective structural units, and several such defects have been identified in Ehlers-Danlos syndrome. Although a complete description of collagen synthesis and assembly is beyond the scope ofthis review, 12 an ou tline of this process is provided in Figure 8. Like many other proteins destined for extracellular transport, collagen is initially synthesized as a larger, higher molecular weight precursor called "procollagen." Procollagen differs from collagen by virtue of extra lengths of protein (which are not coiled in the triple-helical configuration) at both ends. The process of collagen biogenesis begins with synthesis of pro collagen chains on the ribosomes (Fig. 8, top). As the protein chain is being elongated on the ribosome, certain of the incorporated proline and lysine residues are enzymatically hydroxylated and become hydroxyproline and hydroxylysine respectively. These modified amino acids occur virtually exclusively in collagen, and assays for hydroxyproline have traditionally provided a convenient measure of collagen.' These hydroxylation reac-

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tions are mediated by the specific enzymes, prolyl hydroxylase and lysyl hydroxylase. Following synthesis and hydroxylation, three completed procollagen chains align in a side-by-side fashion, and spontaneously twist into the procollagen molecule (Fig. 8, center). This molecule is subsequently transported through various cell compartments, and finally secreted into the extracellular space. Once outside the cell, procollagen is converted to collagen by the action of procollagen peptidases. At least two separate peptidase enzymes are responsible for removing the extra segments from procollagen and producing the final collagen molecule of the correct size (Fig. 8, bottom). The newly formed collagen molecule has a marked tendency to aggregate spontaneously with other collagen molecules, a social proclivity that may be easily demonstrated in vitro, and is termed "selfassembly." Individual collagen molecules align themselves in a specific side-by-side, overlapping fashion (the so-called "quarter-stagger" alignment in which each molecule is displaced by roughly one-quarter of its length as compared with the adjacent molecule). The result, both in vitro and in vivo, is the formation of a long collagen fibril that exhibits the characteristic cross-banding pattern of collagen fibrils in electron micrographs. The process of collagen biogenesis is, however, incomplete at this point since the newly formed fibril has two properties not found in mature collagen fibrils: it is easily dissolved, and it has no tensile strength, and therefore, no biological utility.

Collagen Cross-Linking The process of self-assembly places each collagen molecule in a defined position with respect to adjacent molecules; as a consequence, certain lysine and hydroxylysine residues are placed "in register" with each other (Fig. 9). One of these amino acids is then converted by the enzyme lysyl oxidase to an "active aldehyde" (Fig. 9, right) which spontaneously reacts with the adjacent amino (NH 2 ) group to form a covalent cross-link between adjacent collagen molecules. Alternatively, both adjacent amino acids may be converted to "active aldehydes" by lysyl oxidase, but since these also react with each other, the result is the same-a cross-link between adjacent molecules. Both lysine and hydroxylysine participate in cross-link formation, and both can be converted into "active aldehydes" by lysyl oxidase. This process of cross-linking, repeated again and again, yields very large insoluble aggregations of hundreds or thousands of molecules all tightly linked together in the form of fibrils and bundles. Of ultimate biological significance is the fact that cross-linked collagen possesses great tensile strength. Type V Ehlers-Danlos appears to be due to the diminished activity of the enzyme lysyl oxidase. 10 This enzyme, as noted above, converts certain lysine and hydroxylysine residues to "active aldehydes" in the first step of cross-link formation. As a result, cross-link formation is impaired. Total failure of cross-linking would be incompatible with life, suggesting either that the observed residue activity of the enzyme suffices for a modest degree of cross-link formation, or that other, currently unidentified, processes of cross-linking may occur.

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ACTIVE ALDEHYDE

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Figure 9. Cross-linking of collagen. Depicted are two collagen molecules, indicated by cylinders, in precise alignment within afibril. The epsilon-amino groups (NH 2) of lysine (orhydroxylysine) from each molecule are in close proximity. Oxidative deamination by the enzyme, lysyl oxidase, yields an "active aldehyde" that spontaneously reacts with the adjacent amino group to form a covalent cross-link.

Type VI is due to diminished activity of the enzyme lysine hydroxylase. 16 As a consequence, hydroxylysine levels are diminished, and lysine elevated in analysis of collagen from affected patients. 21 The role of hydroxylysine as a participant of cross-link formation has been previously noted, and defective cross-linkage of hydroxylysine-deficient collagen has been demonstrated. The exact explanation for the striking ocular problems in this recessive disease is presently unclear. Type VII is reportedly due to defective conversion of pro collagen to collagen by one or more enzymes known as pro collagen peptidases. 18 These enzymes are responsible for the cleavage, from each end of the procollagen molecule, of the extra segments. Patients with this variety cannot properly trim procollagen to the correct size; the presumed result is impairment of the normal process of self-assembly, which may in turn impair cross-link formation. The molecular defects causing Ehlers-Danlos Types I, II, III, and VIII are presently unknown, but the clear demonstration that collagen biogenesis is defective in Types IV to VII makes it virtually certain that defects of collagen will be ultimately implicated as well in the unknown varieties.

Pathogenetic Mechanisms The known defects in collagen biogenesis in Types IV to VII indicate that two or possibly three different pathogenetic mechanisms are involved. The absence of Type III collagen in Type IV Ehlers-Danlos is reminiscent of the thalassemia syndromes in which lack of protein synthesis (in this case, the alpha or beta globin chains of hemoglobin) is observed. The absence of Type III collagen may be due to absence of the relevant genes, absence of synthesis, or the production of a defective molecule; in any event, Type III collagen does not accumulate normally in

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the extracellular matrix. By contrast, the defects in Ehlers-Danlos Types V (lysyl oxidase deficiency) and VI (lysyl hydroxylase deficiency) directly interfere with the process of collagen cross-linking, thus producing a mechanically incompetent connective tissue matrix. Ehlers-Danlos Type VIII (procollagen peptidase deficiency) appears to indirectly impede collagen cross-linking by interfering with the normal "self-assembly" of collagen. Thus the known abnormalities of collagen biogenesis include absence of a specific collagen type, defective cross-linking, and defective assembly of collagen.

Approach to the Patient The diagnosis of Ehlers-Danlos syndrome is usually readily made by clinical examination once this diagnosis is entertained, and the appropriate diagnostic maneuvers performed, leading to the observation of unusual skin texture, cutaneous hyperextensibility, joint hypermobility, bruisability, evidence oftissue friability, or a combination thereof. Careful estimation ofthe extent and severity of these features, together with a careful search for coexistent abnormalities, forms one basis for subclassification into a particular type. The other basis for subclassification is determination of the probable mode of inheritance, based on careful examination of parents, siblings, or other relatives. Observation of an affected parent of an affected child will restrict consideration to the autosomal dominant types of Ehlers-Danlos (I, II, III, VIII), whereas absence of an affected parent but presence of the disorder in a sibling will indicate the presence of a recessive variety (Types IV, V, VI, and VII). Since Type V is a sex-linked disorder, virtually only males are affected. Isolated cases present obvious difficulties since these may represent either a new dominant mutation or a recessive disorder; clinical criteria alone must be used with corresponding reduction in confidence that a correct subclassification has been made. Consideration of both the clinical features and probable mode of inheritance is essential. As previously mentioned, perhaps half of all patients with unequivocal manifestations of Ehlers-Danlos syndrome cannot be easily fit into the present classification; for such patients, the diagnosis of "Ehlers-Danlos, Type Unknown" is preferred, and indicates that either the clinical features or the inheritance pattern differ from previously described types. Accumulation of such cases will permit further definition of heterogeneity in EhlersDanlos syndrome in the future. Biochemical confirmation of the diagnosis of a type of Ehlers-Danlos syndrome for which the molecular defect is known remains a specialized research endeavor, and is beyond the capabilities of the usual clinical laboratory. The author would be happy to assist physicians in arranging for such confirmation.

SUMMARY The Ehlers-Danlos syndrome is a relatively common heritable disorder of connective tissue. The cardinal features are cutaneous hyperextensibility, joint hypermobility, bleeding diathesis, and tissue fragility, and

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these features lead to a large variety of additional manifestations. Of the eight presently described types, four varieties have been found to be caused by defects in the biogenesis of collagen, the major structural protein of the body. Consideration of the clinical features and probable mode of inheritance will permit subclassification of many patients into specific types, and biochemical confirmation is possible for several varieties.

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27. Trelstad, R. L.: The developmental biology of vertebrate collagens. J. Histochem. Cytol., 21 :521-528, 1973. 28. Wenzel, H. G.: Untersuchunger iiber die Dehnbarkeit und Zerreissbarkeit der Haut. Zentralbl. Allg. Pathol., 85:117,1949. 29. Wigzell, F. W., and Ogston, D.: The bleeding tendency in Ehlers-Danlos syndrome. Ann. Phys. Med., 7:55, 1963. 30. Wynne-Davies, R.: Acetabular dysplasia and familial jOint laxity: two etiological factors in congenital dislocation of the hip. A review of589 patients and their families. J. Bone Joint Surg., 52B:704, 1970. Division of Medical Genetics UCLA School of Medicine Harbor General Hospital 1000 West Carson Street Torrance, California 90509

Heritable disorders of connective tissue: Ehlers-Danlos syndrome.

Symposium on Medical Genetics Heritable Disorders of Connective Tissue: Ehlers-Danlos Syndrome David W. Hollister, M.D.* The heritable disorders of...
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