American Journal of M e d i c a l Genetics 44:434-436 (1992)
Boy With a Chromosome del (3)(q12q23) and Blepharophimosis Syndrome Hiroko Fujita, Jianguo Meng, Miyako Kawamura, Noriko Tozuka, Fumiyo Ishii, and Naoko Tanaka Department of Human Development and Welfare, Faculty of the Science of Liuing, Osaka City Uniuersity, Osaka (H.F., J.M.,), Department of Pediatrics, Osaka Prefectura1 Rehabilitatwn Center, Osaka (M.K), Mitsubishi Yuka BioClinical Laboratories, Znc., Kyoto (N.T.,F.I.), and Department of Ophthalmology, Children’s Medical Center of Osaka City, Osaka (N.T.),Japan
We report on a 6-year-old boy with de novo 46,XY,del(3)(ql2q23) and bilateral blepharophimosis, ptosis, epicanthus inversus, in addition to multiple other anomalies. Since 4 previously reported cases of interstitial deletion of 3q involving 3q23 band are clinically similar, we propose this blepharophimosis sequence due to 3q23 deletion as a further “contiguous gene syndrome.” O 1882 Wiley-Lisa, Inc. KEY WORDS: interstitial deletion of chromosome 3q, blepharophimosis sequence (BPES), multiple congenital anomalies INTRODUCTION The blepharophimosis, ptosis, and epicanthus inversus sequence (BPES) is a heterogeneous clinical entity. Abnormalities occurring less frequently are malformed ears, muscular hypotonia, mental deficiencies, and cardiac defects. The existence of 2 types in BPES has recently been suggested: type 1, associated with infertility in affected females, and type 11, transmitted by males and females with incomplete penetrance (McKusick 110100). Most cases are sporadic, however, family studies have disclosed an autosomal dominant mode of inheritance for both types 1 and 11. Williamson et al. [19811reported on an 8-year-oldboy with marked blepharophimosis, ptosis, sad fixed face, joint contracture, and several other anomalies associated with a del(3)(q22.l-q24), and suspected him of having Schwartz-Jampel syndrome (McKusick 255800). Since then, severa1 other cases with a 3q interstitial deletion have been reported (Table 1). Here, we
Received for publication December 3, 1991; revision received March 31, 1992. Address reprint requests to Hiroko Fujita, M.D., Department of Human Development and Welfare, Osaka City University, Sugimotocho Sumiyoshi-ku 3-3-138, Osaka 558, Japan.
O 1992 Wiley-Liss, Inc.
report a sporadic male case of del(3Kq12q23). The patient has been followed from birth to age 6 years. CLINICAL REPORT The propositus (Fig. 1) is the first child born to a 27year-old mother and a nonconsanguineous 30-year-old father. Delivery was by cesarean section at 40 weeks gestation because of fetal distress. Birth weight was 3.1 kg, length 48.5 cm, and head circumference (OFC) 35 cm. After birth, he was treated for respiratory distress and hyper bilirubinemia. Physical examination demonstrated flat occiput, narrow and short palpebral fissures, epicanthal folds, large and odd-shaped ears, and thin lips. The patient had a short sternum, tight hips, a small penis, cryptorchidism, and long tapered fingers. There were no abnormalities of the interna1 organs including the cardiovascular system. Dermatoglyphic analysis showed whorls on al1 fingers and a bilateral simian crease. Brian CT and EEG were normal. Since age 5 months, he has been treated by a physical therapist for his stiff joints. Ophthalmologic examination showed nuclear cataract, ptosis, exotropia and nystagmus in both sides at age 3 years. Cataract extraction was performed. After that, his vision was improved with glasses. Orthopedic examination showed mild generalized hypotonia, joint contractures, and pes valgus. Bone films showed a normal appearance including a bone age of 6 years as expected. Standard electromyographic (EMG) examination also showed no abnormal discharges. Fbutine laboratory examinations in blood and urine were normal. The patient was given a urinary screening test for orotic aciduria after Rogers and Porter [19681, as the orotic aciduria locus is mapped to the proximal portion of chromosome 3q (3cen+3q21). The result showed a normal density peak. Psychomotor development is as follows; head control a t 12 months, sat alone a t 18 months, and walked without support at 6 years. He speaks in single words with unclear articulation. His present I Q is estimated to be 22. At age 6 years, height is normal but weight and OFC are -2 SD below the mean. Talipes equinovarus requires orthopedic shoes and walked slowly with an ataxic gait. The face was long and flat with fixed expres-
A Boy With de1(3)(q12q23)
435
TABLE 1. Clinical Manifestations of 6 Patients With Interstitial Deletion of 3q
Chromosome del(3) Sex Age (years) Birth weight (g)/weeks Birth length (cm) Craníofacial Microcephaly Defects of skull Blepharophimosis Ptosis Epicanthal folds Strabismus Cataract Low nasal bridge Malformed or large ears Limbs Equino varus or valgus Joint contractures Syndactyly of 11-111 toes Simian line Whorls on al1 fingers Absence of digital creases Trunk Scoliosis or kyphosis Abnormal genitalia Defect of inner organ Development Mental retardation Short stature Walk alone (years) Few words with meaning (vears)
Resent case q12q23 M 6 3,140140 48.5
++ + + + +
+ + +
++ +-
+
Okada et al. [19871 q12q21 F 8 2,600/40 47
Williamson et al. U9811 q22.iq24
+
+ + +
+
+ + -
+
-
-
-
Kidney"
+-
+ +
6 5
7 Not vet
M 8 2,039136 42
+ + f + + + +
Martsolf et al. [19831 q23q25 F 1 2,041139
Al-Awadi et al. 119861 q23q25
+ + + + + + +
+
+
+ + +
+ + +
+ + + +-
-
+ +
6 Not vet
M 3 1,900
+
+ + +
Alvarado et al. [1987]q23q25 F 7112 2,280 36
+
-
+ -
-
VSDb
VSD
VSD
+
+ +
+ +
2 6/12 3 6/12
"Kidney, incomplete duplication of collecting system. bVSD,Ventricular septal defect.
sion. The eyes showed marked blepharophimosis, ptosis, and epicanthus inversus. A funnel chest was present. He has a weak grip, and he has had severe constipation since infancy. There were mild contractures at most joints. The genitalia were normal and testes were palpable in the inguinal canals.
CYTOGENETIC FINDINGS Chromosome studies of peripheral blood lymphocytes using standard GTG banding techniques showed an interstitial deletion of 3q. Usíng hígh resolution banding, the deleted portion was found to be q12q23. The karyotype is of 46,XY,de1(3)(pter-ql2:: q23-qter) (Fig. 2). Parents and a younger sister have normal chromosome.
Fig. 1. "he patient. A and B, at age 2 years, C, at age 6 years.
DISCUSSION With the addition of our patient, there have been at least 6 patients with an interstitial del(3q). Clinical data from the present report and those from previous reports [Williamson et al., 1981; Martsolf et al., 1983; Al-Awadi et al., 1986; Alvarado et al., 1987; Okada et al., 19871 are in Table 1. Five of the 6 patients had a de novo interstitial deletion of 3q. One remaining patient had a 3q deleted chromosome derived from mother's balanced insertion. Notwithstanding the apparent dif-
436
Fujita et al.
3 Fig. 2. High-resolution G-banded chromosomes 3 of the patient. The left shows de1(3)(q12q23). Two arrows on a diagram of normal chromosome 3 indicate breakpoints, 3q12 and 3q23.
ferences in the extent of clinical and cytogenetic evaluaACKNOWLEDGMENTS tions, these 6 patients share many common manifestaWe thank Dr. J.M. Opitz, Professor at Shodair Chiltions. Five had BPES and at least a deletion of 3q23 dren’s Hospital, and Dr. N. Niikawa, Professor at band. The other patient, who had deletion of 3q12-q21, Nagasaki University School of Medicine, for their rehad normal eyelids. Recently, Fukushima et al. [1991] view of this manuscript. reported a boy with BPES and an apparently balanced de novo reciprocal translocation with break points at REFERENCES 3q23 and 4 ~ 1 5 . 2They . suggested that a break in the Al-Awadi SA, Naguib KK, Farag TI, Teebi AS, Cuschieri A, Al-Othman 3q23 band had damaged of the putative gene responsible SA, Sundareshan TS (1986): Complex translocation involving chromosomes Y, 1 and 3 resulting in deletion of segment 3 q 2 h q 2 5 . for autosomal dominant BEPS. We corroborate this asJ Med Genet 23:91-92. sociation between BPES and a deletion of 3q23. M, Bocian M, Walker AP (1987): Interstitial deletion of the Furthermore, our patient has joint contractures and a Alvarado long arm of chromosome 3: Case report, review, and definition of a fixed facial appearance similar to that of the patient phenotype. Am J Med Genet 27:781-786. described by Williamson et a1.[19811, who was suspected Fukushima Y, Wakui K, Nishida T, Ueoka Y (1991):Blepharophimosis of having the Schwartz-Jampel syndrome. Diagnostic sequence and de novo balanced autosomal translocation [46,XY, t(3;4)(q23;p15.2)1: Possible assignment of the trait to 3q23. Am J criteria of this syndrome are myotonia confirmed by Med Genet 40:485-487. EMG, dwarfism with skeletal anomalies, and characterMartsolf JT, Ray M (1983): Interstitial deletion of the long arm of istic facial and ocular anomalies. Since their and our chromosome 3. Ann GBnbt 26:98-99. patients had normal EMG findings and our patient had Okada N, Hasegawa T, Osawa M, Fukuyama Y (1987): A case of de novo normal bone films and an average stature, the diagnosinterstital deletion 3q. J Med Genet 24:305-308. tic criteria were insufficient for Schwartz-Jampel syn- Rogers LE, Porter FS (1968): Hereditary orotic aciduria 11. A urinary drome. screening test. Pediatrics 42:423-428. Thus, patients with an interstitial deletion of 3q23 Williamson RA, Donlan MA, Dolan CR, Thuline HC, Harrison MT, Hall J G (1981):Familial insertional translocation of a portion of 3q have a contiguous gene syndrome expressing the cliniinto 1l q resulting in duplication and deletion of region 3q22.l-+q24 cal picture of BPES. in different offspring. Am J Med Genet 9:105-111.
Boy With a Chromosome del (3)(q12q23) and Blepharophimosis Syndrome Hiroko Fujita, Jianguo Meng, Miyako Kawamura, Noriko Tozuka, Fumiyo Ishii, and Naoko Tanaka Department of Human Development and Welfare, Faculty of the Science of Liuing, Osaka City Uniuersity, Osaka (H.F., J.M.,), Department of Pediatrics, Osaka Prefectura1 Rehabilitatwn Center, Osaka (M.K), Mitsubishi Yuka BioClinical Laboratories, Znc., Kyoto (N.T.,F.I.), and Department of Ophthalmology, Children’s Medical Center of Osaka City, Osaka (N.T.),Japan
We report on a 6-year-old boy with de novo 46,XY,del(3)(ql2q23) and bilateral blepharophimosis, ptosis, epicanthus inversus, in addition to multiple other anomalies. Since 4 previously reported cases of interstitial deletion of 3q involving 3q23 band are clinically similar, we propose this blepharophimosis sequence due to 3q23 deletion as a further “contiguous gene syndrome.” O 1882 Wiley-Lisa, Inc. KEY WORDS: interstitial deletion of chromosome 3q, blepharophimosis sequence (BPES), multiple congenital anomalies INTRODUCTION The blepharophimosis, ptosis, and epicanthus inversus sequence (BPES) is a heterogeneous clinical entity. Abnormalities occurring less frequently are malformed ears, muscular hypotonia, mental deficiencies, and cardiac defects. The existence of 2 types in BPES has recently been suggested: type 1, associated with infertility in affected females, and type 11, transmitted by males and females with incomplete penetrance (McKusick 110100). Most cases are sporadic, however, family studies have disclosed an autosomal dominant mode of inheritance for both types 1 and 11. Williamson et al. [19811reported on an 8-year-oldboy with marked blepharophimosis, ptosis, sad fixed face, joint contracture, and several other anomalies associated with a del(3)(q22.l-q24), and suspected him of having Schwartz-Jampel syndrome (McKusick 255800). Since then, severa1 other cases with a 3q interstitial deletion have been reported (Table 1). Here, we
Received for publication December 3, 1991; revision received March 31, 1992. Address reprint requests to Hiroko Fujita, M.D., Department of Human Development and Welfare, Osaka City University, Sugimotocho Sumiyoshi-ku 3-3-138, Osaka 558, Japan.
O 1992 Wiley-Liss, Inc.
report a sporadic male case of del(3Kq12q23). The patient has been followed from birth to age 6 years. CLINICAL REPORT The propositus (Fig. 1) is the first child born to a 27year-old mother and a nonconsanguineous 30-year-old father. Delivery was by cesarean section at 40 weeks gestation because of fetal distress. Birth weight was 3.1 kg, length 48.5 cm, and head circumference (OFC) 35 cm. After birth, he was treated for respiratory distress and hyper bilirubinemia. Physical examination demonstrated flat occiput, narrow and short palpebral fissures, epicanthal folds, large and odd-shaped ears, and thin lips. The patient had a short sternum, tight hips, a small penis, cryptorchidism, and long tapered fingers. There were no abnormalities of the interna1 organs including the cardiovascular system. Dermatoglyphic analysis showed whorls on al1 fingers and a bilateral simian crease. Brian CT and EEG were normal. Since age 5 months, he has been treated by a physical therapist for his stiff joints. Ophthalmologic examination showed nuclear cataract, ptosis, exotropia and nystagmus in both sides at age 3 years. Cataract extraction was performed. After that, his vision was improved with glasses. Orthopedic examination showed mild generalized hypotonia, joint contractures, and pes valgus. Bone films showed a normal appearance including a bone age of 6 years as expected. Standard electromyographic (EMG) examination also showed no abnormal discharges. Fbutine laboratory examinations in blood and urine were normal. The patient was given a urinary screening test for orotic aciduria after Rogers and Porter [19681, as the orotic aciduria locus is mapped to the proximal portion of chromosome 3q (3cen+3q21). The result showed a normal density peak. Psychomotor development is as follows; head control a t 12 months, sat alone a t 18 months, and walked without support at 6 years. He speaks in single words with unclear articulation. His present I Q is estimated to be 22. At age 6 years, height is normal but weight and OFC are -2 SD below the mean. Talipes equinovarus requires orthopedic shoes and walked slowly with an ataxic gait. The face was long and flat with fixed expres-
A Boy With de1(3)(q12q23)
435
TABLE 1. Clinical Manifestations of 6 Patients With Interstitial Deletion of 3q
Chromosome del(3) Sex Age (years) Birth weight (g)/weeks Birth length (cm) Craníofacial Microcephaly Defects of skull Blepharophimosis Ptosis Epicanthal folds Strabismus Cataract Low nasal bridge Malformed or large ears Limbs Equino varus or valgus Joint contractures Syndactyly of 11-111 toes Simian line Whorls on al1 fingers Absence of digital creases Trunk Scoliosis or kyphosis Abnormal genitalia Defect of inner organ Development Mental retardation Short stature Walk alone (years) Few words with meaning (vears)
Resent case q12q23 M 6 3,140140 48.5
++ + + + +
+ + +
++ +-
+
Okada et al. [19871 q12q21 F 8 2,600/40 47
Williamson et al. U9811 q22.iq24
+
+ + +
+
+ + -
+
-
-
-
Kidney"
+-
+ +
6 5
7 Not vet
M 8 2,039136 42
+ + f + + + +
Martsolf et al. [19831 q23q25 F 1 2,041139
Al-Awadi et al. 119861 q23q25
+ + + + + + +
+
+
+ + +
+ + +
+ + + +-
-
+ +
6 Not vet
M 3 1,900
+
+ + +
Alvarado et al. [1987]q23q25 F 7112 2,280 36
+
-
+ -
-
VSDb
VSD
VSD
+
+ +
+ +
2 6/12 3 6/12
"Kidney, incomplete duplication of collecting system. bVSD,Ventricular septal defect.
sion. The eyes showed marked blepharophimosis, ptosis, and epicanthus inversus. A funnel chest was present. He has a weak grip, and he has had severe constipation since infancy. There were mild contractures at most joints. The genitalia were normal and testes were palpable in the inguinal canals.
CYTOGENETIC FINDINGS Chromosome studies of peripheral blood lymphocytes using standard GTG banding techniques showed an interstitial deletion of 3q. Usíng hígh resolution banding, the deleted portion was found to be q12q23. The karyotype is of 46,XY,de1(3)(pter-ql2:: q23-qter) (Fig. 2). Parents and a younger sister have normal chromosome.
Fig. 1. "he patient. A and B, at age 2 years, C, at age 6 years.
DISCUSSION With the addition of our patient, there have been at least 6 patients with an interstitial del(3q). Clinical data from the present report and those from previous reports [Williamson et al., 1981; Martsolf et al., 1983; Al-Awadi et al., 1986; Alvarado et al., 1987; Okada et al., 19871 are in Table 1. Five of the 6 patients had a de novo interstitial deletion of 3q. One remaining patient had a 3q deleted chromosome derived from mother's balanced insertion. Notwithstanding the apparent dif-
436
Fujita et al.
3 Fig. 2. High-resolution G-banded chromosomes 3 of the patient. The left shows de1(3)(q12q23). Two arrows on a diagram of normal chromosome 3 indicate breakpoints, 3q12 and 3q23.
ferences in the extent of clinical and cytogenetic evaluaACKNOWLEDGMENTS tions, these 6 patients share many common manifestaWe thank Dr. J.M. Opitz, Professor at Shodair Chiltions. Five had BPES and at least a deletion of 3q23 dren’s Hospital, and Dr. N. Niikawa, Professor at band. The other patient, who had deletion of 3q12-q21, Nagasaki University School of Medicine, for their rehad normal eyelids. Recently, Fukushima et al. [1991] view of this manuscript. reported a boy with BPES and an apparently balanced de novo reciprocal translocation with break points at REFERENCES 3q23 and 4 ~ 1 5 . 2They . suggested that a break in the Al-Awadi SA, Naguib KK, Farag TI, Teebi AS, Cuschieri A, Al-Othman 3q23 band had damaged of the putative gene responsible SA, Sundareshan TS (1986): Complex translocation involving chromosomes Y, 1 and 3 resulting in deletion of segment 3 q 2 h q 2 5 . for autosomal dominant BEPS. We corroborate this asJ Med Genet 23:91-92. sociation between BPES and a deletion of 3q23. M, Bocian M, Walker AP (1987): Interstitial deletion of the Furthermore, our patient has joint contractures and a Alvarado long arm of chromosome 3: Case report, review, and definition of a fixed facial appearance similar to that of the patient phenotype. Am J Med Genet 27:781-786. described by Williamson et a1.[19811, who was suspected Fukushima Y, Wakui K, Nishida T, Ueoka Y (1991):Blepharophimosis of having the Schwartz-Jampel syndrome. Diagnostic sequence and de novo balanced autosomal translocation [46,XY, t(3;4)(q23;p15.2)1: Possible assignment of the trait to 3q23. Am J criteria of this syndrome are myotonia confirmed by Med Genet 40:485-487. EMG, dwarfism with skeletal anomalies, and characterMartsolf JT, Ray M (1983): Interstitial deletion of the long arm of istic facial and ocular anomalies. Since their and our chromosome 3. Ann GBnbt 26:98-99. patients had normal EMG findings and our patient had Okada N, Hasegawa T, Osawa M, Fukuyama Y (1987): A case of de novo normal bone films and an average stature, the diagnosinterstital deletion 3q. J Med Genet 24:305-308. tic criteria were insufficient for Schwartz-Jampel syn- Rogers LE, Porter FS (1968): Hereditary orotic aciduria 11. A urinary drome. screening test. Pediatrics 42:423-428. Thus, patients with an interstitial deletion of 3q23 Williamson RA, Donlan MA, Dolan CR, Thuline HC, Harrison MT, Hall J G (1981):Familial insertional translocation of a portion of 3q have a contiguous gene syndrome expressing the cliniinto 1l q resulting in duplication and deletion of region 3q22.l-+q24 cal picture of BPES. in different offspring. Am J Med Genet 9:105-111.
