Clinical Genetics 1979: 16: 19-24
A
new presumably autosomal recessive form of the Ehlers- Danlos syndrome R. PALMER BEASLEYAND M. MICHAELCOHEN,JR.
Department of Epidemiology and Clinical Investigation, U. S. Naval Medical Research Unit No. 2, San Francisco, California and Department of Oral and Maxillofacial Surgery, School of Dentistry and Department of Pediatrics, School of Medicine, University of Washington, Seattle, Washington, U. S. A. A new form of Ehlers-Danlos syndrome is reported in two of seven sibs in a consanguineous Chinese family. Received I0 October 1978, accepted for publication 18 January 1979 K e y words: Collagen disorder; connective tissue disorder; Ehlers-Danlos syndrome.
O n the basis of clinical, genetic, and biochemical studies, many forms of the EhlersDanlos syndrome are now recognized. These have been reviewed elsewhere (Lichtenstein et al. 1973, Lord et al. 1969, McKusick 1972, McKusick & Martin 1975, Pinnell et al. 1972, Pope e t al. 1975). W e report here a Chinese family which we believe represents a previously unrecognized form of the disorder. Case Report
The family resides on Kinmen Island (Quemoy), located approximately 1 mile off the coast of mainland China in Fukien Province. The proband was ascertained by one of us (RPB), who was carrying out a prevalence survey of rheumatoid arthritis at the time. Two of seven offspring of a consanguineous marriage were affected (Fig. 1). Both were recognized by the parents as
being abnormal at birth. No other family members resemble the affected sibs and there is no family history of hyperextensible skin o r joints, fragile skin, hernias, eye disease, mental deficiency, o r deafness. Clinical findings in the affected sibs are summarized in Table 1. C u e 1 (IV-3, Fig. 1). T h e proband was a 25-year-old man who had a life-long history of hyperextensible joints. T h e product of a full-term gestation, he has had reducible bilateral inguinal hernias and lax joints since early childhood. H e never learned to talk and had not attended school. H e developed a limping gait early in life. There was n o history of easy bruisability, difficulty with wound healing, or other medical problems. Examination revealed moderate hyperelasticity of the skin and pronounced hyperextensibility of the joints, spontaneous
0009-9163/79/070019-06 $02.50/0 0 1979 Munksgaard, Copenhagen
20
BEASLEY AND COHEN
I
m v
YYY
YYY
Y
Explanot ion of Symbols &2 Dead T )'J Died in infoncy
0 No offspring Affected Fig. 1. Pedigree of new form of the Ehlers-Danlos syndrome.
genu recurvaturn, and easily demonstrable hyperextensibility of the elbows, wrists and
Table 1 Summary of clinical findings Brother Cutaneous Hyperelasticity Redundant skin (hands) Prominant veins Bruising Scarring
+
+ -
Sister
f
+
-
-
f
2
Musculoskeletal Generalized hyperextensibi Iity Hip dislocation Inguinal hernia Decreased muscle mass
+ + + +
+ + +
Craniofaclal Narrow face Small eyes Cataracts Midface deficiency Laterally protruding ears Hearing deficit
+ + + +
+ -
?
f
-
+
+
+
Gastrointestinal Diarrhea Performance Mental deficiency
fingers (Figs. 2 and 3). Although individuals fro'rn oriental populations are more hyperextensible than Caucasians, the degree of hyperextensibility in affected individuals in this family is very unusual. The muscle mass was somewhat diminished. There were bilateral marked reducible inguinal hernias and a chronically dislocated left hip. Pes
+
+ +
Fig. 2. Case 1. Marked hyperextensibility of thumb.
EHLERS-DANLOS SYNDROME
21
same physical findings as her brother, including the narrow face, small eyes and midface deficiency that differed from normal members of the family, but she did not have laterally protruding ears (Figs. 6, 7, 8 and 9). She could speak, but had an obvious hearing impairment. An audiogram revealed moderate hearing reduction at all frequencies. Her mental age was estimated to be 3-4 years. It was not possible to visualize her ocular fundi properly, despite dilatation and good cooperation. There were diffuse opacities and, except in the extreme periphery, only a red reflex but no vascular pattern could be recognized. She had apparent cataracts. Her only other medical problem was chronic diarrhea. (Only simple medical facilities were available to us and it Flg. 3. Case 1. Genu recurvatum.
planus was evident. There was excessive wrinkling of the skin on the dorsum of the hands (Fig. 4). There were a few scars on the shins suggesting a cigarette paper appearance. The vascular pattern was not unusual and the sclerae were of normal color. The face was narrow, the eyes small, and the midface deficient compared with normal members of the family. The ears protruded laterally. A mandibular fracture had healed improperly, giving a prognathic appearance (Fig. 5). The patient was mentally deficient and possibly his hearing was impaired, although this could not be determined with certainty. (We were unable to obtain sufficient cooperation to ge consistent responses to audiogram testing, probably because of his mental deficiency.) His mental age was estimated to be between 1 and 2 years. A blood chromosome study was normal. Case 2 (IV-7, Fig. 1). The 15-year-old sister Of Case was the product Of a full-term gestation. She had most of the
Flg. 4. Case 1. Wrinkling of skin on dorsum of hand and fingers.
22
BEASLEY AND COHEN
al. 1973) of both samples were normal. In particular, there were less than 0.5 residues of x-cystine per 1,000 residues and 4.5 of hydroxylysine. These findings suggest that both procollagen peptidase and lysyl hydroxylase (Lichtenstein et al. 1973, Pinnell et al. 1972) were normal in these patients. Discussion
Fig. 5. Case 1. Laterally protruding ears, narrow face. small eves. Malunion of mandibular fracture has resulted in prognathism.
The overall pattern of abnormalities in both patients is at variance with any previously described form of the Ehlers-Danlos syndrome (McKusick & Martin 1975). Prominent features include pronounced generalized hyperextensibility of joint, moderate dermal hyperelasticity, redundant skin of the hands, mental deficiency, hearing deficit, and perhaps other features observed in one or the other patient (Table 1). Both siblings had similar faces which were different from their parents and affected
was thus not possible to undertake a workup to delineate better the nature of these problems.) A culture of leukocyte chromosomes failed to grow. Dermal punch biopsies were obtained from each patient and immediately frozen. Amino acid compositions (Lichtenstein et
Flg. 6. Case 2. Hyperextensibility at wrists and proximal interphalangeal joints.
Fig. 7. Case 2. Hyperextensible elbow.
EHLERS-DANLOS SYNDROME
Fig. 8. Case 2. Hyperelasticity of skin.
siblings. Conspicuously absent were prominent veins, easy bruisability, pseudotumors, and elastosis perforans. Scarring was minimal. We have discussed the condition with several colleagues and one further similar case - a sporadic instance - has come to light (J. G. Hall, personal communication, 1976). In addition to the known forms of the Ehlers-Danlos syndrome (McKusick & Martin 1975), one other disorder shares some similarities with the patients reported here. An autosomal recessive syndrome of hyperextensible joints, conductive deafness, keratoconus, and blue sclerae has been delineated by Greenfield et al. (1973). However, mental deficiency was not a feature of the patients tabulated by them, and our patients lacked blue sclerae and keratoconus. Mental deficiency has been reported infrequently in the classical form of the Ehlers-Danlos syndrome and is presumably
23
coincidental (Launey 1973, Lienhart 1945) or related to prematurity, which is common (Dewart 1965). The finding of two affected sibs (one male and one female) in a sibship of seven, in which consanguinity was etablished, strongly suggests that the new disorder reported here follows an autosomal recessive mode of transmission. Three forms of the Ehlers-Danlos syndrome have autosomal recessive inheritance. The enzymatic defect in two forms protocollagen lysyl hydroxylase deficiency and procollagen peptidase deficiency were not present on the basis of dermal collagen studies carried out in both of our patient. (A recent report by Steinmann and co-workers (Vogel et al. 1975) indicates that lysyl hydroxylase may be deficient even in the presence of normal amounts of hydroxylysine in dermal collagen. Enzyme activities could not be measured in the present study.) The enzymatic defect in the third autosomal recessive form (ecchymotic) is unknown, but type
Fig. 9. Case 2. Narrow face and small eyes.
BEASLEY AND COHEN
24
I11 collagen synthesis is known to b e deficient. Although we did not test for type 111 collagen synthesis in Our the clinical findings of the ecchymotic were clearly absent in the family reported here. T h e basic defect in this new, presumably autosomal recessive form of the Ehlers-Danlos syndrome remains unknown.
fect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science 182, 298-300. Lienhart, 0. (1945). La maladie d’Ehlers-Dan10s; etude clinique anatomopathologique et gtnttique. Thesis de Nancy, No. 30. Lord, J. et al. (1969). Variants of the EhlersDanlos syndrome. Clinical, biochemical, haematological, and chromosomal features of 100 patients. Ann. Rheum. Dis. 28, 228245.
Acknowledgments
We would like t o thank Peter H. Byers, M.D. of the Departments of Medicine and Biochemistry of the University of Washington for carrying out the biochemical analyses of the dermal tissue. This project was supported in part by USPHS Grant No. 1 R 0 1 DE04502-02. References
Dewart, P. (1965). Maladie d’Ehlers-Danlos. Arch. Derm. Syph. 21, 397-402. Greenfield, G., A. Romano, R. Stein & R. M. Goodman (1973). Blue sclerae and keratoconus: Key features of a distinct heritable disorder of connective tissue. Clin. Genet. 4, 8-16.
Launay, C. (1973). Chez un g a r ~ o nde onze ans, associt a une arrikration mentale. Bull. Soc. MLd. H6p. (Paris) 56, 709-715. Lichtenstein, J. R., G. R. Martin, L. D. Kohn, P. H. Byers & V. A. McKusick (1973). De-
McKusick, V. A. (1972). Heritable Disorders of Connective Tissue. 4th Ed. St. Louis, C. V. Mosby Co. McKusick, V. A. & G. R. Martin (1975). Molecular defects in collagen. Ann. Intern. Med. 82, 585-586. Pinnell, S. R., S. M. Krane, J. E. Kenzora .& M. J. Glimcher (1972). A heritable disorder of connective tissue; hydroxylysine deficient collagen disease. New Engl. J . Med. 286, 1013-1020. Pope, F. M., G. R. Martin, J . R. Lichtenstein et al. (1975). Patients with Ehlers-Danlos syndrome type IV lack type I11 collagen. Pror. Nat. Acad. Sci. (Wash.) 7 2 , 1314-1319. Vogel, A. et al. (1975). Ehlers-Danlos syndrome in two siblings with deficient lysyl hydroxylase activity in cultured skin-fibroblasts but only mild hydroxylysine deficit in skin. Helv. Paediat. Acta 30, 255-260. Address: M . Michael Cohen, Jr., D.M.D. Health Sciences Building, SB-24 University of Washington Seattle, Washington 98195
A
new presumably autosomal recessive form of the Ehlers- Danlos syndrome R. PALMER BEASLEYAND M. MICHAELCOHEN,JR.
Department of Epidemiology and Clinical Investigation, U. S. Naval Medical Research Unit No. 2, San Francisco, California and Department of Oral and Maxillofacial Surgery, School of Dentistry and Department of Pediatrics, School of Medicine, University of Washington, Seattle, Washington, U. S. A. A new form of Ehlers-Danlos syndrome is reported in two of seven sibs in a consanguineous Chinese family. Received I0 October 1978, accepted for publication 18 January 1979 K e y words: Collagen disorder; connective tissue disorder; Ehlers-Danlos syndrome.
O n the basis of clinical, genetic, and biochemical studies, many forms of the EhlersDanlos syndrome are now recognized. These have been reviewed elsewhere (Lichtenstein et al. 1973, Lord et al. 1969, McKusick 1972, McKusick & Martin 1975, Pinnell et al. 1972, Pope e t al. 1975). W e report here a Chinese family which we believe represents a previously unrecognized form of the disorder. Case Report
The family resides on Kinmen Island (Quemoy), located approximately 1 mile off the coast of mainland China in Fukien Province. The proband was ascertained by one of us (RPB), who was carrying out a prevalence survey of rheumatoid arthritis at the time. Two of seven offspring of a consanguineous marriage were affected (Fig. 1). Both were recognized by the parents as
being abnormal at birth. No other family members resemble the affected sibs and there is no family history of hyperextensible skin o r joints, fragile skin, hernias, eye disease, mental deficiency, o r deafness. Clinical findings in the affected sibs are summarized in Table 1. C u e 1 (IV-3, Fig. 1). T h e proband was a 25-year-old man who had a life-long history of hyperextensible joints. T h e product of a full-term gestation, he has had reducible bilateral inguinal hernias and lax joints since early childhood. H e never learned to talk and had not attended school. H e developed a limping gait early in life. There was n o history of easy bruisability, difficulty with wound healing, or other medical problems. Examination revealed moderate hyperelasticity of the skin and pronounced hyperextensibility of the joints, spontaneous
0009-9163/79/070019-06 $02.50/0 0 1979 Munksgaard, Copenhagen
20
BEASLEY AND COHEN
I
m v
YYY
YYY
Y
Explanot ion of Symbols &2 Dead T )'J Died in infoncy
0 No offspring Affected Fig. 1. Pedigree of new form of the Ehlers-Danlos syndrome.
genu recurvaturn, and easily demonstrable hyperextensibility of the elbows, wrists and
Table 1 Summary of clinical findings Brother Cutaneous Hyperelasticity Redundant skin (hands) Prominant veins Bruising Scarring
+
+ -
Sister
f
+
-
-
f
2
Musculoskeletal Generalized hyperextensibi Iity Hip dislocation Inguinal hernia Decreased muscle mass
+ + + +
+ + +
Craniofaclal Narrow face Small eyes Cataracts Midface deficiency Laterally protruding ears Hearing deficit
+ + + +
+ -
?
f
-
+
+
+
Gastrointestinal Diarrhea Performance Mental deficiency
fingers (Figs. 2 and 3). Although individuals fro'rn oriental populations are more hyperextensible than Caucasians, the degree of hyperextensibility in affected individuals in this family is very unusual. The muscle mass was somewhat diminished. There were bilateral marked reducible inguinal hernias and a chronically dislocated left hip. Pes
+
+ +
Fig. 2. Case 1. Marked hyperextensibility of thumb.
EHLERS-DANLOS SYNDROME
21
same physical findings as her brother, including the narrow face, small eyes and midface deficiency that differed from normal members of the family, but she did not have laterally protruding ears (Figs. 6, 7, 8 and 9). She could speak, but had an obvious hearing impairment. An audiogram revealed moderate hearing reduction at all frequencies. Her mental age was estimated to be 3-4 years. It was not possible to visualize her ocular fundi properly, despite dilatation and good cooperation. There were diffuse opacities and, except in the extreme periphery, only a red reflex but no vascular pattern could be recognized. She had apparent cataracts. Her only other medical problem was chronic diarrhea. (Only simple medical facilities were available to us and it Flg. 3. Case 1. Genu recurvatum.
planus was evident. There was excessive wrinkling of the skin on the dorsum of the hands (Fig. 4). There were a few scars on the shins suggesting a cigarette paper appearance. The vascular pattern was not unusual and the sclerae were of normal color. The face was narrow, the eyes small, and the midface deficient compared with normal members of the family. The ears protruded laterally. A mandibular fracture had healed improperly, giving a prognathic appearance (Fig. 5). The patient was mentally deficient and possibly his hearing was impaired, although this could not be determined with certainty. (We were unable to obtain sufficient cooperation to ge consistent responses to audiogram testing, probably because of his mental deficiency.) His mental age was estimated to be between 1 and 2 years. A blood chromosome study was normal. Case 2 (IV-7, Fig. 1). The 15-year-old sister Of Case was the product Of a full-term gestation. She had most of the
Flg. 4. Case 1. Wrinkling of skin on dorsum of hand and fingers.
22
BEASLEY AND COHEN
al. 1973) of both samples were normal. In particular, there were less than 0.5 residues of x-cystine per 1,000 residues and 4.5 of hydroxylysine. These findings suggest that both procollagen peptidase and lysyl hydroxylase (Lichtenstein et al. 1973, Pinnell et al. 1972) were normal in these patients. Discussion
Fig. 5. Case 1. Laterally protruding ears, narrow face. small eves. Malunion of mandibular fracture has resulted in prognathism.
The overall pattern of abnormalities in both patients is at variance with any previously described form of the Ehlers-Danlos syndrome (McKusick & Martin 1975). Prominent features include pronounced generalized hyperextensibility of joint, moderate dermal hyperelasticity, redundant skin of the hands, mental deficiency, hearing deficit, and perhaps other features observed in one or the other patient (Table 1). Both siblings had similar faces which were different from their parents and affected
was thus not possible to undertake a workup to delineate better the nature of these problems.) A culture of leukocyte chromosomes failed to grow. Dermal punch biopsies were obtained from each patient and immediately frozen. Amino acid compositions (Lichtenstein et
Flg. 6. Case 2. Hyperextensibility at wrists and proximal interphalangeal joints.
Fig. 7. Case 2. Hyperextensible elbow.
EHLERS-DANLOS SYNDROME
Fig. 8. Case 2. Hyperelasticity of skin.
siblings. Conspicuously absent were prominent veins, easy bruisability, pseudotumors, and elastosis perforans. Scarring was minimal. We have discussed the condition with several colleagues and one further similar case - a sporadic instance - has come to light (J. G. Hall, personal communication, 1976). In addition to the known forms of the Ehlers-Danlos syndrome (McKusick & Martin 1975), one other disorder shares some similarities with the patients reported here. An autosomal recessive syndrome of hyperextensible joints, conductive deafness, keratoconus, and blue sclerae has been delineated by Greenfield et al. (1973). However, mental deficiency was not a feature of the patients tabulated by them, and our patients lacked blue sclerae and keratoconus. Mental deficiency has been reported infrequently in the classical form of the Ehlers-Danlos syndrome and is presumably
23
coincidental (Launey 1973, Lienhart 1945) or related to prematurity, which is common (Dewart 1965). The finding of two affected sibs (one male and one female) in a sibship of seven, in which consanguinity was etablished, strongly suggests that the new disorder reported here follows an autosomal recessive mode of transmission. Three forms of the Ehlers-Danlos syndrome have autosomal recessive inheritance. The enzymatic defect in two forms protocollagen lysyl hydroxylase deficiency and procollagen peptidase deficiency were not present on the basis of dermal collagen studies carried out in both of our patient. (A recent report by Steinmann and co-workers (Vogel et al. 1975) indicates that lysyl hydroxylase may be deficient even in the presence of normal amounts of hydroxylysine in dermal collagen. Enzyme activities could not be measured in the present study.) The enzymatic defect in the third autosomal recessive form (ecchymotic) is unknown, but type
Fig. 9. Case 2. Narrow face and small eyes.
BEASLEY AND COHEN
24
I11 collagen synthesis is known to b e deficient. Although we did not test for type 111 collagen synthesis in Our the clinical findings of the ecchymotic were clearly absent in the family reported here. T h e basic defect in this new, presumably autosomal recessive form of the Ehlers-Danlos syndrome remains unknown.
fect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science 182, 298-300. Lienhart, 0. (1945). La maladie d’Ehlers-Dan10s; etude clinique anatomopathologique et gtnttique. Thesis de Nancy, No. 30. Lord, J. et al. (1969). Variants of the EhlersDanlos syndrome. Clinical, biochemical, haematological, and chromosomal features of 100 patients. Ann. Rheum. Dis. 28, 228245.
Acknowledgments
We would like t o thank Peter H. Byers, M.D. of the Departments of Medicine and Biochemistry of the University of Washington for carrying out the biochemical analyses of the dermal tissue. This project was supported in part by USPHS Grant No. 1 R 0 1 DE04502-02. References
Dewart, P. (1965). Maladie d’Ehlers-Danlos. Arch. Derm. Syph. 21, 397-402. Greenfield, G., A. Romano, R. Stein & R. M. Goodman (1973). Blue sclerae and keratoconus: Key features of a distinct heritable disorder of connective tissue. Clin. Genet. 4, 8-16.
Launay, C. (1973). Chez un g a r ~ o nde onze ans, associt a une arrikration mentale. Bull. Soc. MLd. H6p. (Paris) 56, 709-715. Lichtenstein, J. R., G. R. Martin, L. D. Kohn, P. H. Byers & V. A. McKusick (1973). De-
McKusick, V. A. (1972). Heritable Disorders of Connective Tissue. 4th Ed. St. Louis, C. V. Mosby Co. McKusick, V. A. & G. R. Martin (1975). Molecular defects in collagen. Ann. Intern. Med. 82, 585-586. Pinnell, S. R., S. M. Krane, J. E. Kenzora .& M. J. Glimcher (1972). A heritable disorder of connective tissue; hydroxylysine deficient collagen disease. New Engl. J . Med. 286, 1013-1020. Pope, F. M., G. R. Martin, J . R. Lichtenstein et al. (1975). Patients with Ehlers-Danlos syndrome type IV lack type I11 collagen. Pror. Nat. Acad. Sci. (Wash.) 7 2 , 1314-1319. Vogel, A. et al. (1975). Ehlers-Danlos syndrome in two siblings with deficient lysyl hydroxylase activity in cultured skin-fibroblasts but only mild hydroxylysine deficit in skin. Helv. Paediat. Acta 30, 255-260. Address: M . Michael Cohen, Jr., D.M.D. Health Sciences Building, SB-24 University of Washington Seattle, Washington 98195
