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The Ehlers-Danlos Syndrome
J chron Dis 1970,Vol. 23,pp. 197-200.Pergamm Press. Printed in Great Britain
THE EHLERS-DANLOS REpORT
OF
TWO
SYNDROME
CASES IN MONOZYGOUS TWINS
PH[LIPPINo-AMERIcAN
GILBERT I. MARTIN,M.D. Chief Resident,Pediatrics,Montefiore Hospital and Medical Center;
AssistantInstructor,Pediatrics,Albert EinsteinCollegeof Medicine. (Received 7 August 1969; in revised form 23 January 1970)
THE Ehlers-Danlos Syndrome, one of the earliest disorders of connective tissue described, appears principally in Europeans, and persons of European extraction [l]. However, in the last several years, the syndrome has been described in other ethnic groups [24]. The disorder is usually inherited as an autosomal dominant
character [l, 5, 61. Incomplete pictures (forme frustes) and isolated cases are reported [6]. The genetic basis for the disease is far from clear. Earlier this year, a pair of Philippinc+American monozygous mirror twins presented themselves to our Emergency Room with ‘bruising into the skin’. Further examination revealed that both children manifested many of the characteristic features of this syndrome. There are no known reports of the Ehlers-Danlos Syndrome in monozygous twins; or in the PhilippinoAmerican heritage [7-g]. REPORT
OF
PATIENTS
(1) L.P., a 5 yr old Philippino-American female presented to the Emergency Room with a note from her school teacher revealing that the patient bruised easily. The mother had noticed this for many years, but attributed the bruises to ‘thin skin’. She had been assured by a physician earlier, that the child’s ‘blood picture’ was normal. The child is the product of a full term twin gestation delivered by Cesarean Section. No X-rays were taken or illnesses described during pregnancy. Diuretics were taken intermittently near term for ankle edema. Birth weight was 3 lb 9 oz. A large umbilical hernia and cutaneous hemangioma were noted at birth and she was discharged from the nursery weighing 5 lb and in excellent condition. Developmental history. Within normal limits. Re’view of systems-Occasional epistaxis. easy bruisability, eyeglasses for correction of a left strabismus. Past illnesses. Varicella 2 yr old. Surgery. Umbilical hernia repair 2 yr old. Family history. No members with cutaneous, ocular or skeletal anomalies. The father is of Philippino descent and has none of the phenotypic characteristics of Ehlers-Danlos Syndrome. The mother is a Caucasian of American descent and also is normal. A male sibling, age 8 yr, was examined and found to have no manifestations of the disease. Physical exumination. Height and weight parallel the third percentile. Pertinent physical findings include: left esotropia, decreased lid turgor. epicanthal folds, hyperelastic, velvety skin (Fig. 1) right handedness, papyraceous scars on forehead, a paper thin umbilical hernia scar, hyperextensible joints (Fig. 2), small hematomas over the anterior aspect of both legs and flat feet (Fig. 3). 197
GILBERT I. MARTIN
198 TABLE. 1.
A
B
Rh
C
BLOOD GROUPMGENS E
c
e
OF TWINS
M
N
Kell
Fya
S
s
D.P.
-
-
+
+
-
-
+
+
+
-
+
-
+
L.P.
-
-
+
+
-
-
+
+
+
-
+
-
+
Laboratory data. CBC, Urinalysis, Platlet Count, Liver Function, Tests, all normal. Coagulation factors normal. Skeletal series reveals ectopic bone formation second metacarpal right hand. Blood antigen determinations appear in Table 1. Gm phenotyping reveals a+, b+, f + factors. (2) D.P. is a 5 yr old Philippino-American female who presented to the Emergency Room with a parallel history. Birth weight 3 lb 11 oz. Past illnesses-Surgery. Right inguinal hemiorrhaphy 24 yr old. Physical examination. (Refer to previous figures.) Pertinent physical findings include: decreased lid turgor, epicanthal folds, hyperelastic, velvety skin, left handedness, papyraceous scar near right scapula, right inguinal hernia scar, hyperextensible points, hematomas over anterior aspects of both legs and flat feet. Laboratory data normal. Blood antigen determinations appear in Table 1; Gm phenotyping reveals a+, b+, f+ factors: Skeletal series reveals ectopic bone formasion second metacarpal left hand. DISCUSSION
There is an extensive literature on the genetic aspects of the Ehlers-Danlos Syndrome. Most studies dealing with large Kindreds report an Autosomal dominant transmission [5, 6, lo]. However, the trait has been transmitted by normal individuals as well [11-131. Consanguinity [5, 141, and prematurity [5], have been mentioned as contributing factors in several reports. Beighton [11], in a recent discussion, describes two families with an X-linked recessive inheritance. Differences in opinion regarding the syndrome’s mode of inheritance are probably dependent upon the gene penetrance. In many pedigrees examined, the penetrance is quite low ‘[15]. Persons possessing the gene, although phenotypically normal, can still transmit the abnormality to their offspring [6]. If the parents are normal as is the case in the twins presented, several considerations are possible. Firstly, the twins may represent a single mutant gene. As the mutation occurs in only one gamete of one parent, the child resulting from the fertilization of that gamete with a normal one will be a&&cd. Differences in clinical findings observed in patients with this syndrome may be an expression of the pleiotropism of this mutant gene. Secondly, the syndrome in these patients may be explained as an autosomal dominant with low penetrance, in either father or mother (who ever carries the gene), and strong penetrance in the offspring. Thirdly, if transmission were autosomal recessive in nature, both parents could be normal while the children might be affected. Lastly, sex-linked recessive transmission by female carriers may represent the pattern of inheritance. With this method, many generations of females might be involved before an appearance in a male member [5]. The latter explanation has no consideration in our female patients.
(fbcing
p. 198)
FIG. 2.
Ehlers-Danlos
syndrome.
Patient D.P. hyperextensibility
of right index finger.
FIG. 3.
Ehlers-Danlos
syndrome. Patient D.P. hematomas on aspects presenting complaint of both patients.
of legs: this was the
The Ehlers-Danlos
Syndrome : Report of two cases in monozygous
twins
199
Chromosomal studies have been done [15], and no abnormalities noted. In all the series of Kindreds studied, only two sets of twins have been reported. These were both fraternal [lo, 161. In the twins presented, blood antigens and gamma globulin Gm factors are indentical. These factors in addition to the twin’s remarkable resemblance establish that they are monozygous. The clinical manifestations of the Ehlers-Danlos Syndrome can be divided into the following categories : cutaneous, skeletal, ocular and internal [l]. The skin is usually velvety and dry with a hyperelastic texture. Most authors report retarded skin healing and sutures that hold poorly [S]. In the two presented patients, however, both surgical scars healed well. Both children do have the classical papyraceous scars over different portions of the body. Both girls also have multiple hematomas over various aspects of the body. This is often a presenting complaint before diagnosis is established. Easy bruisability does not occur because of a defect in coagulation but rather due to defective elastic tissue along the vessels [lfl. Histologic studies are far from definitive, and there is still great controversy about the basic defect in the vessel. Although many studies have investigated ‘connective tissue abnormalities’ in patients with the Ehlers-Danlos Syndrome, there is still no unified explanation regarding the defect. Jansen [18] places the defect in the collagen fibril bundles. Other authors speak of an abnormal increase in the elastic tissue of the corium [19], with a coexistant decrease in the number of collagen fibrils. Both collagen and elastic fibers are normal when examined under the electron microscope [20]. The musculoskeletal system is usually one of principal involvement. Both patients have hyperextensible, non-painful joints and flat feet. Ectopic bone formation has been described by Katz and Steiner [21] between the acetabular and femoral trochanters. It is interesting that in these patients, the ectopic bone formation is in identical places although on opposite hands. Ocular manifestations are frequently encountered, but these children do not necessarily manifest any of the characteristic abnormalities generally described : blue sclerae, ectopia lentis, microcorneas, angiod streaks and elastorrhexis [22]. Other connective tissue disorders such as Marfan’s Syndrome, and Osteogenesis Imperfecta also display much of this ocular pathology. SUMMARY
Two examples of the Ehlers-Danlos Syndrome are presented in monozygous Philippino-American twins from apparently unaffected parents. Both children manifested hyperelastic velvety skin, hy_perextensible joints, papyraceous scars, flat feet and ectopic bone formation. Since the pattern of transmission of this disorder is so variable, and the gene so pleiotropic, one may predict that the condition will appear in every population group.
1. 2. 3.
REFERENCES McKusick Victor A: Heritable Disorders of Connective Tissue. Mosby, St. Louis, 1966, p 214 Bruno NS, Narashimhan P : The Ehlers-Danlos Syndrome : a report of two cases in two generations of a Negro family. NJZJM 264 : 274, 1961 Chakraborty AN, Banerjee AK, Ghosh S: Ehlers-Danlos syndrome. J Ind Med Ass 23 : 344.1954
200
GILBERTI. MARCONI
4.
Ota M, Yasusda Y: Erster Fall van Syndrom d’Ehlers-Danlos in Japan. Zb Taut Gescblechtskr 66: 120, 1941 Johnson SAM, Falls HF: Ehlers-Danlos syndrome : a clinical and genetic study. ArcIs Derm Syph 60 : 82,1949 Husebye Kjeld 0, Getz Kaare: Ehlers-Danlos syndrome : correlation of clinical and histopathologic findings. Arch Derm 78 : 732-739, 1958 McKusick Victor A : Personal communication Dawis-Lawis : Personal communication Beighton Peter : Personal communication Papp John P, Paley Richard G: Ehlers-Danlos syndrome. Post Grad Med 40: 586,1966 Beighton Peter : X-linked recessive inheritance in the Ehlers-Danlos syndrome. Brit Med J. (3), 409-411, 1968. Stewart AM: Three cases exhibiting the Ehlers-Danlos syndrome. Proc Roy Sot Med 30 : 984. 1937 Porter Ian H : Heredity and Disease. New York, McGraw-Hill, 1968, p 283 Summer George K : The Ehlers-Danlos syndrome. AJDC 91: 419,1956 Pommerening Robert A, Antonius John I: Normal chromosomes in a family with Ehlers-Danlos syndrome. Arch Derm 94 : 425-429, 1966 Dorsch HH: Euber das Ehlers-Danlos Syndrom, Veroffentlichung Eines Falles bein Sinem Zwillingskind. Kinderaerti Prax 21: 49, 1953 Samuels ML, Schwartz ML, Meister MM: The Ehlers-Danlos syndrome. U.S. Armed Forces MJ 4:737-742, 1953 Jansen LH: The structure of the connective tissue: an explanation of the symptoms in the Ehlers-Danlos syndrome. Dermstologica 110 : 10 8,1955 Tobias N: Ehlers-Danlos syndrome associated with con. lipomatosis, Arch Derm Syph 40: 135, 1949 Wechsler I-IL, Fisher E : Ehlers-Danlos syndrome. Pathologic, histochemical and electronmicroscopic observations. Arch Path 77 : 613, 1964 Katz I, Steiner K: Ehlers-Danlos syndrome with ectopic bone formation. Radiology 65 : 352, 1955 Percival SPB : Angiod streaks and elastorrhexis. Brit J Opthal 52 : 97, 1968.
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
THE EHLERS-DANLOS REpORT
OF
TWO
SYNDROME
CASES IN MONOZYGOUS TWINS
PH[LIPPINo-AMERIcAN
GILBERT I. MARTIN,M.D. Chief Resident,Pediatrics,Montefiore Hospital and Medical Center;
AssistantInstructor,Pediatrics,Albert EinsteinCollegeof Medicine. (Received 7 August 1969; in revised form 23 January 1970)
THE Ehlers-Danlos Syndrome, one of the earliest disorders of connective tissue described, appears principally in Europeans, and persons of European extraction [l]. However, in the last several years, the syndrome has been described in other ethnic groups [24]. The disorder is usually inherited as an autosomal dominant
character [l, 5, 61. Incomplete pictures (forme frustes) and isolated cases are reported [6]. The genetic basis for the disease is far from clear. Earlier this year, a pair of Philippinc+American monozygous mirror twins presented themselves to our Emergency Room with ‘bruising into the skin’. Further examination revealed that both children manifested many of the characteristic features of this syndrome. There are no known reports of the Ehlers-Danlos Syndrome in monozygous twins; or in the PhilippinoAmerican heritage [7-g]. REPORT
OF
PATIENTS
(1) L.P., a 5 yr old Philippino-American female presented to the Emergency Room with a note from her school teacher revealing that the patient bruised easily. The mother had noticed this for many years, but attributed the bruises to ‘thin skin’. She had been assured by a physician earlier, that the child’s ‘blood picture’ was normal. The child is the product of a full term twin gestation delivered by Cesarean Section. No X-rays were taken or illnesses described during pregnancy. Diuretics were taken intermittently near term for ankle edema. Birth weight was 3 lb 9 oz. A large umbilical hernia and cutaneous hemangioma were noted at birth and she was discharged from the nursery weighing 5 lb and in excellent condition. Developmental history. Within normal limits. Re’view of systems-Occasional epistaxis. easy bruisability, eyeglasses for correction of a left strabismus. Past illnesses. Varicella 2 yr old. Surgery. Umbilical hernia repair 2 yr old. Family history. No members with cutaneous, ocular or skeletal anomalies. The father is of Philippino descent and has none of the phenotypic characteristics of Ehlers-Danlos Syndrome. The mother is a Caucasian of American descent and also is normal. A male sibling, age 8 yr, was examined and found to have no manifestations of the disease. Physical exumination. Height and weight parallel the third percentile. Pertinent physical findings include: left esotropia, decreased lid turgor. epicanthal folds, hyperelastic, velvety skin (Fig. 1) right handedness, papyraceous scars on forehead, a paper thin umbilical hernia scar, hyperextensible joints (Fig. 2), small hematomas over the anterior aspect of both legs and flat feet (Fig. 3). 197
GILBERT I. MARTIN
198 TABLE. 1.
A
B
Rh
C
BLOOD GROUPMGENS E
c
e
OF TWINS
M
N
Kell
Fya
S
s
D.P.
-
-
+
+
-
-
+
+
+
-
+
-
+
L.P.
-
-
+
+
-
-
+
+
+
-
+
-
+
Laboratory data. CBC, Urinalysis, Platlet Count, Liver Function, Tests, all normal. Coagulation factors normal. Skeletal series reveals ectopic bone formation second metacarpal right hand. Blood antigen determinations appear in Table 1. Gm phenotyping reveals a+, b+, f + factors. (2) D.P. is a 5 yr old Philippino-American female who presented to the Emergency Room with a parallel history. Birth weight 3 lb 11 oz. Past illnesses-Surgery. Right inguinal hemiorrhaphy 24 yr old. Physical examination. (Refer to previous figures.) Pertinent physical findings include: decreased lid turgor, epicanthal folds, hyperelastic, velvety skin, left handedness, papyraceous scar near right scapula, right inguinal hernia scar, hyperextensible points, hematomas over anterior aspects of both legs and flat feet. Laboratory data normal. Blood antigen determinations appear in Table 1; Gm phenotyping reveals a+, b+, f+ factors: Skeletal series reveals ectopic bone formasion second metacarpal left hand. DISCUSSION
There is an extensive literature on the genetic aspects of the Ehlers-Danlos Syndrome. Most studies dealing with large Kindreds report an Autosomal dominant transmission [5, 6, lo]. However, the trait has been transmitted by normal individuals as well [11-131. Consanguinity [5, 141, and prematurity [5], have been mentioned as contributing factors in several reports. Beighton [11], in a recent discussion, describes two families with an X-linked recessive inheritance. Differences in opinion regarding the syndrome’s mode of inheritance are probably dependent upon the gene penetrance. In many pedigrees examined, the penetrance is quite low ‘[15]. Persons possessing the gene, although phenotypically normal, can still transmit the abnormality to their offspring [6]. If the parents are normal as is the case in the twins presented, several considerations are possible. Firstly, the twins may represent a single mutant gene. As the mutation occurs in only one gamete of one parent, the child resulting from the fertilization of that gamete with a normal one will be a&&cd. Differences in clinical findings observed in patients with this syndrome may be an expression of the pleiotropism of this mutant gene. Secondly, the syndrome in these patients may be explained as an autosomal dominant with low penetrance, in either father or mother (who ever carries the gene), and strong penetrance in the offspring. Thirdly, if transmission were autosomal recessive in nature, both parents could be normal while the children might be affected. Lastly, sex-linked recessive transmission by female carriers may represent the pattern of inheritance. With this method, many generations of females might be involved before an appearance in a male member [5]. The latter explanation has no consideration in our female patients.
(fbcing
p. 198)
FIG. 2.
Ehlers-Danlos
syndrome.
Patient D.P. hyperextensibility
of right index finger.
FIG. 3.
Ehlers-Danlos
syndrome. Patient D.P. hematomas on aspects presenting complaint of both patients.
of legs: this was the
The Ehlers-Danlos
Syndrome : Report of two cases in monozygous
twins
199
Chromosomal studies have been done [15], and no abnormalities noted. In all the series of Kindreds studied, only two sets of twins have been reported. These were both fraternal [lo, 161. In the twins presented, blood antigens and gamma globulin Gm factors are indentical. These factors in addition to the twin’s remarkable resemblance establish that they are monozygous. The clinical manifestations of the Ehlers-Danlos Syndrome can be divided into the following categories : cutaneous, skeletal, ocular and internal [l]. The skin is usually velvety and dry with a hyperelastic texture. Most authors report retarded skin healing and sutures that hold poorly [S]. In the two presented patients, however, both surgical scars healed well. Both children do have the classical papyraceous scars over different portions of the body. Both girls also have multiple hematomas over various aspects of the body. This is often a presenting complaint before diagnosis is established. Easy bruisability does not occur because of a defect in coagulation but rather due to defective elastic tissue along the vessels [lfl. Histologic studies are far from definitive, and there is still great controversy about the basic defect in the vessel. Although many studies have investigated ‘connective tissue abnormalities’ in patients with the Ehlers-Danlos Syndrome, there is still no unified explanation regarding the defect. Jansen [18] places the defect in the collagen fibril bundles. Other authors speak of an abnormal increase in the elastic tissue of the corium [19], with a coexistant decrease in the number of collagen fibrils. Both collagen and elastic fibers are normal when examined under the electron microscope [20]. The musculoskeletal system is usually one of principal involvement. Both patients have hyperextensible, non-painful joints and flat feet. Ectopic bone formation has been described by Katz and Steiner [21] between the acetabular and femoral trochanters. It is interesting that in these patients, the ectopic bone formation is in identical places although on opposite hands. Ocular manifestations are frequently encountered, but these children do not necessarily manifest any of the characteristic abnormalities generally described : blue sclerae, ectopia lentis, microcorneas, angiod streaks and elastorrhexis [22]. Other connective tissue disorders such as Marfan’s Syndrome, and Osteogenesis Imperfecta also display much of this ocular pathology. SUMMARY
Two examples of the Ehlers-Danlos Syndrome are presented in monozygous Philippino-American twins from apparently unaffected parents. Both children manifested hyperelastic velvety skin, hy_perextensible joints, papyraceous scars, flat feet and ectopic bone formation. Since the pattern of transmission of this disorder is so variable, and the gene so pleiotropic, one may predict that the condition will appear in every population group.
1. 2. 3.
REFERENCES McKusick Victor A: Heritable Disorders of Connective Tissue. Mosby, St. Louis, 1966, p 214 Bruno NS, Narashimhan P : The Ehlers-Danlos Syndrome : a report of two cases in two generations of a Negro family. NJZJM 264 : 274, 1961 Chakraborty AN, Banerjee AK, Ghosh S: Ehlers-Danlos syndrome. J Ind Med Ass 23 : 344.1954
200
GILBERTI. MARCONI
4.
Ota M, Yasusda Y: Erster Fall van Syndrom d’Ehlers-Danlos in Japan. Zb Taut Gescblechtskr 66: 120, 1941 Johnson SAM, Falls HF: Ehlers-Danlos syndrome : a clinical and genetic study. ArcIs Derm Syph 60 : 82,1949 Husebye Kjeld 0, Getz Kaare: Ehlers-Danlos syndrome : correlation of clinical and histopathologic findings. Arch Derm 78 : 732-739, 1958 McKusick Victor A : Personal communication Dawis-Lawis : Personal communication Beighton Peter : Personal communication Papp John P, Paley Richard G: Ehlers-Danlos syndrome. Post Grad Med 40: 586,1966 Beighton Peter : X-linked recessive inheritance in the Ehlers-Danlos syndrome. Brit Med J. (3), 409-411, 1968. Stewart AM: Three cases exhibiting the Ehlers-Danlos syndrome. Proc Roy Sot Med 30 : 984. 1937 Porter Ian H : Heredity and Disease. New York, McGraw-Hill, 1968, p 283 Summer George K : The Ehlers-Danlos syndrome. AJDC 91: 419,1956 Pommerening Robert A, Antonius John I: Normal chromosomes in a family with Ehlers-Danlos syndrome. Arch Derm 94 : 425-429, 1966 Dorsch HH: Euber das Ehlers-Danlos Syndrom, Veroffentlichung Eines Falles bein Sinem Zwillingskind. Kinderaerti Prax 21: 49, 1953 Samuels ML, Schwartz ML, Meister MM: The Ehlers-Danlos syndrome. U.S. Armed Forces MJ 4:737-742, 1953 Jansen LH: The structure of the connective tissue: an explanation of the symptoms in the Ehlers-Danlos syndrome. Dermstologica 110 : 10 8,1955 Tobias N: Ehlers-Danlos syndrome associated with con. lipomatosis, Arch Derm Syph 40: 135, 1949 Wechsler I-IL, Fisher E : Ehlers-Danlos syndrome. Pathologic, histochemical and electronmicroscopic observations. Arch Path 77 : 613, 1964 Katz I, Steiner K: Ehlers-Danlos syndrome with ectopic bone formation. Radiology 65 : 352, 1955 Percival SPB : Angiod streaks and elastorrhexis. Brit J Opthal 52 : 97, 1968.
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.