American J o u r n a l of Medical Genetics 41:216-220 (1991)
Monozygotic Twins Discordant for the Major Signs of McCune-Albright Syndrome Machiko Endo, Yutaka Yamada, Nobuo Matsuura, and Norio Niikawa Department of Pediatrics, Hakodate Chuoh Hospital, Hakodate (M.E., Y.Y.),Department of Pediatrics, Hokkaido University School of Medicine, Sapporo (N.M.),and Department of Human Genetics Nagasaki University School of Medicine, Nagasaki (N.N.),Japan
We describe a girl, one of monozygotic (MZ) twins, with endocrine dysfunction with precocious puberty, cafe-au-lait nevi and polyostotic fibrous dysplasia (PFD), McCuneAlbright syndrome (MAS). After treatment with cyproterone acetate for 7 years the precocious puberty and excess growth improved but the bone-age still remain advanced. The co-twin had an advanced bone-age and a small cafe-au-lait spot, but showed neither endocrinopathy nor fibrous dysplasia of bone. On the basis of the findings in these twins, together with those in previously reported familial cases of MAS, including two pairs of MZ twins, a 2-hit mutation hypothesis is proposed: a dominant mutation may be inherited and leads to PFD in offspring as the primary defect of MAS; the second mutation may occur in somatic cells leading to mosaicism and thus resulting in MAS. This concept explains not only sporadic cases of MAS but also reported familial cases. If we assume that the second mutation occurred in an early somatic division, it would explain the discrepancy of clinical manifestations between MZ twins. KEY WORDS: polyostotic fibrous dysplasia, endocrine dysfunction, precocious puberty INTRODUCTION The McCune-Albright syndrome (MAS)is a clinically defined disorder characterized by endocrine dysfunction with precocious puberty, patchy cutaneous pigmentation, and fibrous dysplasia of bone. MAS is also called polyostotic fibrous dysplasia (PFD) as a histopathological entity. Cause and pathogenesis of MAS remain obReceived for publication October 22, 1990; revision received March 1, 1990. Address reprint requests to Machiko Endo, M.D., Department of Pediatrics, Hakodate Chuoh Hospital, Honcho 33-2, Hakodate 040, Japan.
0 1991 Wiley-Liss, Inc.
scure and controversial. Although most MAS patients are sporadic, 6 familial cases of MAS or PFD have been reported [Hibbs and Rush, 1952; Firat and Stutzman, 1968; Reitzik and Lownie, 1975; Lemli, 1977; AlvarezArratia et al., 1983; Fukazawa et al., 19901, suggesting that the disorder is genetically determined. However, clinical manifestations of the affected relatives other than the propositi in these families, were much less severe, showing only bone lesions andlor pigmented nevi, i.e., not MAS in the sense of its classic definition. Two of the 6 families contained monozygotic (MZ) twins who were discordant for the classic signs of MAS [Lemli, 1977; Fukazawa et al., 19901. These observations seem to speak against a simple monogenic inheritance. We report herein another pair of MZ twins, one with typical MAS with the other lacking bone lesions and endocrinopathy.
CLINICAL REPORT Twin 1 Patient S.Y., one of twins, was a 1011/iz year old girl. The parents stated that the twins were dizygotic, and since they appeared so, only S.Y. was first examined when she was 25/12 years old. She was admitted to our hospital because of breast enlargement, vaginal bleeding, and early development of pubic hair. She was born at 40 weeks of gestation with a weight of 2,350 g. The mother had no history of infections, X-ray, or drug exposures during the pregnancy. Father and mother were both 29 years old at the time of the twins' birth. When she was 6 months old, the mother noted vaginal bleeding. Since then, it had occurred 3 times. Breast development was noticed a t age one year. On admission at age 25/12 years, the height was 90.3 cm (normal: 86.1 + 3.2 cm) and weight 13.2 kg (normal: 11.7 + 1.3 kg). Skeletal maturation was accelerated with a bone-age of 53/i2 years. Breasts were enlarged, the areolae pigmented (Tanner grade 1111, and the public hair scanty. Cafe-au-laitnevi were present on the skin of the abdomen, neck, arms, and buttock. A roentgenogram of the skull showed thickening of the base and the frontal bone. Computerized tomographic scans of the brain and the abdominal cavity did not show any abnormalities. A 99"rc-MDP scintigram of the bone showed accumulation on the basal skull, frontal bones, and the
McCune-Albright Syndrome in One of Monozygotic Twins
217
serum LH and follicle stimulating hormone (FSH) were low for age (Table I). Serum estradiol level (33 pg/ml) was high for age, and serum estrone and estriol levels were low (below 10 pg/ml). Cytological examination of a vaginal smear disclosed an estrogen effect with the karyopyknotic index a t 62%. These findings indicated precocious puberty. She was finally diagnosed as havin MAS.Treatment with cyproterone acetate (100 mg/mFI day) was then initiated. After treatment for 7 years, the breast enlargement gradually decreased, pubic hair disappeared, and the vaginal bleeding improved. She measured 106.8 cm ( + 2.7 S.D.) at age 3%2 years and 149.4 cm ( + 1.9 S.D.) a t lO%2 years, and was much taller than her co-twin (Fig. 2).
Twin 2 F.Y. is a co-twin. Her birth weight was 2,700 g. When examined by us at age 3%2 years, her height was 99.8 cm ( + 0.9 S.D.) and bone-age 57/iz years. Her facial appearance was quite different from that of twin 1(Fig. 2). She had no signs of precocious puberty but a cafe-aulait spot (1 x 1 cm) on the right thigh. An X-ray survey of the skeleton and a bone scintigram showed no detectable abnormalities (Fig. 1). Results of endocrine examinations are shown in Tables I and 11. Gonadotropin values after loading LH-RH a t age 31°/12 years were slightly high, but the values a t 6 and 8 years were not increased. Serum alkaline phosphatase level (226 U/ml) was at the normal upper limit for age. Results of other
Fig. 1: Bone scintigrams at age 3 % ~years show abnormal accumulation ofg9Tcin the basal skull, the frontal bone, and the left upper arm oftwin 1 (right),but a normal pattern in twin 2 (left).High density in the right arm is due to injection of the radioisotope.
left arm (Fig. l),suggesting PFD. Biopsy ofthe bone was not available. Complete blood count, liver function, and urinalysis were normal. Serum levels of calcium and phosphorus were 9.6 mg/dl and 5.7 mg/dl, respectively. Serum alkaline phosphatase level (716 U/1: Bassey Lawrey method) was high for age (normal: 60-160 U/l). Serum concentrations of thyroxin (7.8 ngldl) and triiodothyronine (145.7 ng/dl) were normal. Response of thyroid stimulating hormone (TSH) to TSH-releasing hormone (TRH) stimulation (Table I) and lZ3I up-take scintigram of the thyroid gland were both normal. Serum concentrations of adrenocorticotropic hormone (ACTH) and cortisol were normal, and cortisol was suppressed by an administration of 1mg dexamethasone. Urinary excretion levels of 17OHCS (1.7 mg/day) and 17KS (0.9 mg/day) were normal, and responded well to a dose of metyrapone. Blood glucose and insulin responses to an intake of glucose (1.75 g k g weight) were slightly high, and growth hormone was suppressed normally (Table 11). Thus she was denied from gigantism. Serum growth hormone responses after arginine, insulin, and TRH loading were all normal. After injection of luteinizing hormone-releasing hormone (LH-RH), responses of
Fig. 2: Twin 1 (right) and twin 2 (left) at age 4 years.
218
Endo et al. TABLE I. Results of LH-RH and TRH Tests in the Twins Twin 2 Twin 1 TRH test LH-RH test LH-RH test TRH test TSH LH FSH TSH LH FSH Time (min) (mIU/ml) (mIU/ml) (pU/ml) (mIU/ml) (mIU/ml) (pU/ml)
Age at
examination (years)
3.2 4.6 2.5 3.2 2.0 2.2
0 15 30 60 90 120
2 5/12
(twin 1)
3 10/12
(twin 2)
Monozygotic Twins Discordant for the Major Signs of McCune-Albright Syndrome Machiko Endo, Yutaka Yamada, Nobuo Matsuura, and Norio Niikawa Department of Pediatrics, Hakodate Chuoh Hospital, Hakodate (M.E., Y.Y.),Department of Pediatrics, Hokkaido University School of Medicine, Sapporo (N.M.),and Department of Human Genetics Nagasaki University School of Medicine, Nagasaki (N.N.),Japan
We describe a girl, one of monozygotic (MZ) twins, with endocrine dysfunction with precocious puberty, cafe-au-lait nevi and polyostotic fibrous dysplasia (PFD), McCuneAlbright syndrome (MAS). After treatment with cyproterone acetate for 7 years the precocious puberty and excess growth improved but the bone-age still remain advanced. The co-twin had an advanced bone-age and a small cafe-au-lait spot, but showed neither endocrinopathy nor fibrous dysplasia of bone. On the basis of the findings in these twins, together with those in previously reported familial cases of MAS, including two pairs of MZ twins, a 2-hit mutation hypothesis is proposed: a dominant mutation may be inherited and leads to PFD in offspring as the primary defect of MAS; the second mutation may occur in somatic cells leading to mosaicism and thus resulting in MAS. This concept explains not only sporadic cases of MAS but also reported familial cases. If we assume that the second mutation occurred in an early somatic division, it would explain the discrepancy of clinical manifestations between MZ twins. KEY WORDS: polyostotic fibrous dysplasia, endocrine dysfunction, precocious puberty INTRODUCTION The McCune-Albright syndrome (MAS)is a clinically defined disorder characterized by endocrine dysfunction with precocious puberty, patchy cutaneous pigmentation, and fibrous dysplasia of bone. MAS is also called polyostotic fibrous dysplasia (PFD) as a histopathological entity. Cause and pathogenesis of MAS remain obReceived for publication October 22, 1990; revision received March 1, 1990. Address reprint requests to Machiko Endo, M.D., Department of Pediatrics, Hakodate Chuoh Hospital, Honcho 33-2, Hakodate 040, Japan.
0 1991 Wiley-Liss, Inc.
scure and controversial. Although most MAS patients are sporadic, 6 familial cases of MAS or PFD have been reported [Hibbs and Rush, 1952; Firat and Stutzman, 1968; Reitzik and Lownie, 1975; Lemli, 1977; AlvarezArratia et al., 1983; Fukazawa et al., 19901, suggesting that the disorder is genetically determined. However, clinical manifestations of the affected relatives other than the propositi in these families, were much less severe, showing only bone lesions andlor pigmented nevi, i.e., not MAS in the sense of its classic definition. Two of the 6 families contained monozygotic (MZ) twins who were discordant for the classic signs of MAS [Lemli, 1977; Fukazawa et al., 19901. These observations seem to speak against a simple monogenic inheritance. We report herein another pair of MZ twins, one with typical MAS with the other lacking bone lesions and endocrinopathy.
CLINICAL REPORT Twin 1 Patient S.Y., one of twins, was a 1011/iz year old girl. The parents stated that the twins were dizygotic, and since they appeared so, only S.Y. was first examined when she was 25/12 years old. She was admitted to our hospital because of breast enlargement, vaginal bleeding, and early development of pubic hair. She was born at 40 weeks of gestation with a weight of 2,350 g. The mother had no history of infections, X-ray, or drug exposures during the pregnancy. Father and mother were both 29 years old at the time of the twins' birth. When she was 6 months old, the mother noted vaginal bleeding. Since then, it had occurred 3 times. Breast development was noticed a t age one year. On admission at age 25/12 years, the height was 90.3 cm (normal: 86.1 + 3.2 cm) and weight 13.2 kg (normal: 11.7 + 1.3 kg). Skeletal maturation was accelerated with a bone-age of 53/i2 years. Breasts were enlarged, the areolae pigmented (Tanner grade 1111, and the public hair scanty. Cafe-au-laitnevi were present on the skin of the abdomen, neck, arms, and buttock. A roentgenogram of the skull showed thickening of the base and the frontal bone. Computerized tomographic scans of the brain and the abdominal cavity did not show any abnormalities. A 99"rc-MDP scintigram of the bone showed accumulation on the basal skull, frontal bones, and the
McCune-Albright Syndrome in One of Monozygotic Twins
217
serum LH and follicle stimulating hormone (FSH) were low for age (Table I). Serum estradiol level (33 pg/ml) was high for age, and serum estrone and estriol levels were low (below 10 pg/ml). Cytological examination of a vaginal smear disclosed an estrogen effect with the karyopyknotic index a t 62%. These findings indicated precocious puberty. She was finally diagnosed as havin MAS.Treatment with cyproterone acetate (100 mg/mFI day) was then initiated. After treatment for 7 years, the breast enlargement gradually decreased, pubic hair disappeared, and the vaginal bleeding improved. She measured 106.8 cm ( + 2.7 S.D.) at age 3%2 years and 149.4 cm ( + 1.9 S.D.) a t lO%2 years, and was much taller than her co-twin (Fig. 2).
Twin 2 F.Y. is a co-twin. Her birth weight was 2,700 g. When examined by us at age 3%2 years, her height was 99.8 cm ( + 0.9 S.D.) and bone-age 57/iz years. Her facial appearance was quite different from that of twin 1(Fig. 2). She had no signs of precocious puberty but a cafe-aulait spot (1 x 1 cm) on the right thigh. An X-ray survey of the skeleton and a bone scintigram showed no detectable abnormalities (Fig. 1). Results of endocrine examinations are shown in Tables I and 11. Gonadotropin values after loading LH-RH a t age 31°/12 years were slightly high, but the values a t 6 and 8 years were not increased. Serum alkaline phosphatase level (226 U/ml) was at the normal upper limit for age. Results of other
Fig. 1: Bone scintigrams at age 3 % ~years show abnormal accumulation ofg9Tcin the basal skull, the frontal bone, and the left upper arm oftwin 1 (right),but a normal pattern in twin 2 (left).High density in the right arm is due to injection of the radioisotope.
left arm (Fig. l),suggesting PFD. Biopsy ofthe bone was not available. Complete blood count, liver function, and urinalysis were normal. Serum levels of calcium and phosphorus were 9.6 mg/dl and 5.7 mg/dl, respectively. Serum alkaline phosphatase level (716 U/1: Bassey Lawrey method) was high for age (normal: 60-160 U/l). Serum concentrations of thyroxin (7.8 ngldl) and triiodothyronine (145.7 ng/dl) were normal. Response of thyroid stimulating hormone (TSH) to TSH-releasing hormone (TRH) stimulation (Table I) and lZ3I up-take scintigram of the thyroid gland were both normal. Serum concentrations of adrenocorticotropic hormone (ACTH) and cortisol were normal, and cortisol was suppressed by an administration of 1mg dexamethasone. Urinary excretion levels of 17OHCS (1.7 mg/day) and 17KS (0.9 mg/day) were normal, and responded well to a dose of metyrapone. Blood glucose and insulin responses to an intake of glucose (1.75 g k g weight) were slightly high, and growth hormone was suppressed normally (Table 11). Thus she was denied from gigantism. Serum growth hormone responses after arginine, insulin, and TRH loading were all normal. After injection of luteinizing hormone-releasing hormone (LH-RH), responses of
Fig. 2: Twin 1 (right) and twin 2 (left) at age 4 years.
218
Endo et al. TABLE I. Results of LH-RH and TRH Tests in the Twins Twin 2 Twin 1 TRH test LH-RH test LH-RH test TRH test TSH LH FSH TSH LH FSH Time (min) (mIU/ml) (mIU/ml) (pU/ml) (mIU/ml) (mIU/ml) (pU/ml)
Age at
examination (years)
3.2 4.6 2.5 3.2 2.0 2.2
0 15 30 60 90 120
2 5/12
(twin 1)
3 10/12
(twin 2)
