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Turner syndrome resulting from partial deletion of Y chromosome short arm: Localization of male determinants
Turner syndrome resulting from partial deletion of Y chromosome short arm." Localization of male determinants Chromosome studies performed because of the possibility of Turner syndrome in an infant girl with pedal edema and mild neck webbing revealed an X Y karyotype. Subsequent exploratory laparotomy showed dysplastic ovaries with nests of germ cells with the morphologic features of gonadoblastoma. Repeat chromosome studies from peripheral blood using high-resolution techniques, and also from skin and ovarian fibroblasts, showed an X Y karyotype but with a partial deletion of the Y short arm, which was not detected with standard techniques. These findings indicate that testis determining factors are located in this deleted region of the Y chromosome but that other gene(s) remain that induce gonadobiastoma. (J PEDIATR 105:916, 1984)
Ruth Ellen Magenis, M.D., Mark L. Tochen, M.D., Kathleen P. Holahan, M.D., Thomas Carey, M.D., Leland Allen, B.S., and Michael G. Brown, M.S. P o r t l a n d , Oregon
THE SYNDROME OF THE 46,XY PHENOTYPIC FEMALE with gonadal dysgenesis is generally diagnosed in young women with primary amenorrhea, rarely in children. Determining the presence of a Y chromosome is important for counseling the family regarding sexual development and fertility and because of the risk of malignant transformation of the dysgenetic gonad. This increased risk of ~onadal malignancy was first described in older patients ~-4 and has been extensively reviewed: Only recently has the risk in young children been reported. 6-9 W e describe features suggestive of Turner syndrome in a
From the Department of Medical Genetics, Crippled Children's Division, and University Hospital Cytogenetics Laboratory, Oregon Health Sciences University; and the Departments of Pediatrics, Pathology, and Urology, Kaiser-Permanente Medical Care Program. Supported by Grant HD-07997 from the National Institutes of Health, and by Maternal and Child Health Service Mental Retardation Training Grant MCT-O00920. Submitted for publication March 23. 1984; accepted May 18, 1984. Reprint requests: R. Ellen Magenis, M.D., Department of Medical Genetics and University Hospital Cytogenetics Laboratory, Oregon Health Sciences University, 707 S. IV. Gaines Rd.; Portland, OR 97201. 916
The Journal of P E D I A T R I C S
child with a 46,XY karyotype and deletion of the short arm of the Y chromosome, indicating that this segment is the probable location of the genes for maleness in humans. CASE REPORT This 3220 gm infant girl was born at 42 weeks gestation to a 36-year-old woman after a normal perinatal course. Pedal edema and redundant neck skinfolds were noted and indicated the possibility of Turner syndrome. The external genitalia were normal female, and a cervix was felt on rectal examination. Chromosome studies showed an XY karyotype on two occasions. Surgical exploration at 30 months of age revealed a normal proximal vagina, uterus, a~d fallopian tubes. The gonads were 1.5 and 2 cm in length, respectively, and were white, elliptical, and symmetrically placed. Frozen sections of wedge biopsies revealed foci of gonadoblastoma. Bilateral salpingo-oopherectomy was performed. The child has continued to be healthy from infancy, with growth ~along the 95th percentile for height and head circumference and 75th percentile for weight. She is of normal intellect.
METHODS Chromosomes were obtained from peripheral blood lymphocytes of the patient, parents, and siblings by routine methods. Trypsin G-banding ~~was performed on the chromosome slides of all family members. In addition, several staining techniques were used to~delineate the proband's Y
Volume 105 Number 6
Turner syndrome from Y deletion
91 7
Y
Fig. 1. Y chromosomes from patient and normal male using five different staining techniques: (left to right) Giemsa-banding, standard stain (unbanded), Giemsa-ll, quinacrine banding, and CA3/DA/DAPI R-banding. Note small size of Short arm in proband with G-, S-, and R-banding and absence of distal band with the G-banding high-resolution technique.
chromosome abnormality: standard stain for localization of the centromeric constriction of the Y, Giemsa-11 for placement Of the centromeric as well as terminal Y heterochromatin, ~ Q-banding for staining definitively the Q-bright terminal heterochromatin, ~2 R-banding with C A J D A / D A P F 3 to determine the amount of Y short arm present, and prometaphase h!gh-resolution G-banding~4for determination of break points. Chromosomes were also obtained from skin and connective tissue of both gonads by tissue culture techniques to look for a minor XO cell population.
Fig. 2. Chromosomeideogram depicts point of deletion in abnormal Y chromosome.
RESULTS Chromosome studies. G-banded chrbm0somes of mother and two female siblings were normal, with 46,XX in 20 cells each. The father's karyotype was 46,XY in 20 cells; no structural abnormality of the Y was detected. Segregation studies of 17 red cell enzyme, and serum protein polymorphisms revealed no inconsistencies. Initial G-banded study of the patient's peripheral blood chromosomes was interpreted as normal XY in 36 cells, with no evidence for mosaicism. One hundred G-banded cells from the skin biopsy were studied; 98 were normal 46,XY, and two, with poor morphologic characteristics, appeared to have a possible structural abnormality of the Y. One hundred three cells from the right gonad were 46,XY, as were 99 cells from the left gonad. One cell from the left gonad was missing the Y. Thus, of 339 cells examined, one was missing the Y.
Prometaphase G-banded peripheral blood chromosomes were subsequently obtained anff showed a deletion of the terminal Y short arm gray band (pl 1.2) and possibly a small deletion of the adjacent light band (Fig. 1). Giemsa11, Q-banding, and standard stain showed no evidence for a structural rearrangement; R-banding revealed that most, if not all, of the G-band light short arm region is present (Fig. 1). This interpretation is illustrated with a chromosome ideogram in Fig. 2. Pathologic findings. The specimen consisted of bilateral fallopian tubes and gonadal structures. The right and left fallopian tubes were fimbriated;!measured 3.5 and 2.2 cm in length, respectively; and were0.4 cm in average diameter. The right and lefCgonada! structures were pink-tan and measured 2 • 2 1 5 cm and 1 . 5 • 2 1 5 cm, respectively. Histologically the fallopian tubes were unre-
9 18
Magenis et al.
Fig. 3. Histologic section streak gonad: well-circumscribednests of large germ cells and primitive sex cord cells are present in spindled stroma, diagnostic of gonadoblastoma.Note characteristic laminated calcific concretions.
markable. Both gonadal structures had a spindled, cellular, ovarian-like stroma, which contained numerous wellcircumscribed nests of large germ cells and primitive sex cord cells. Hyaline bodies and laminated calcific concretions were present within some of the nests. Seminiferous tubules or ovarian follicles were not identified. No malignant elements were seen. The morphologic features were those of bilateral gonadoblastomas (Fig. 3). DISCUSSION Approximately 5% of females with Turner syndrome have been shown to have an X O / X Y mosaic chromosome constitution.~5. ~6Mosaicism of 45,XO and 46,XY in which the Y is structurally altered has also been noted in some cases.17.18 An intersex state may also result from X O / X Y mosaicism, or "mixed" gonadal dysgenesis.19,20Our patient has no convincing evidence of an XO cell population. Females with gonadal dysgenesis and an XY karyotype without mosaicism ("pure" XY gonadal dysgenesis) were first described in 1959, 2~ although the phenotype of tall
The Journal of Pediatrics December 1984
stature, primary amenorrhea, and lack of secondary sexual characteristics had been recognized earlier in two females with negative buccal smears. 22 Approximately 150 cases have been reported. 23 Pterygium colli and peripheral edema, as seen in Turner syndrome, have rarely been reported to accompany the other features of XY gonadal dysgenesis; cubitus valgus and multiple nevi are more common. This form of gonadal dysgenesis often appears to have a genetic basis. It has been described in siblings, suggesting male-limited autosomal recessive inheritance; an X-linked mode of inheritance has also been noted. 24 Further genetic heterogeneity is suggested by the finding of XY gonadal dysgenesis in campomelic dwarfismY However, many cases are sporadic; a previously undetectable partial short arm deletion, such as is present in our patient, may explain some of these. This possibility was discussed as early as 1971 by Ferguson-Smith,26 who stated that sporadic XY gonadal dysgenesis may occur in patients who have lost the male determinants carried by the Y short arm and that this could be brought about by accidental crossing over between the short arms of the X and Y chromosomes during paternal meiosis.26 One other case of Y short arm deletion without evidence for mosaicism has been described. 27 This female had multiple minor stigmata of Turner syndrome, including peripheral edema, but had normal stature, as did our patient. She had normal female genitalia and normal uterus and tubes, with 1.5 cm undifferentiated gonads. The authors concluded that genes present on the short arm of the Y chromosome determine testicutar differentiation of the primitive gonad. The small Y chromosome deletion in our patient provides strong evidence not only for localization of genes for male determination to the Y short arm but to the distal half of the Y short arm. Additional evidence for such localization is provided by the finding of the distal Y short arm translocated to the X short arm in XX males. 2s The subject of gene trait localization utilizing Y chromosome structural rearrangements has been extensively reviewed.29.30
At the time of surgery, approximately 25% of patients with Turner syndrome or gonadal dysgenesis and a Y chromosome will have an associated gonadoblastoma? Gonadoblastoma itself is not regarded as a malignant tumor, but about half of the patients with gonadoblastomas also have a component of dysgerminoma. These dysgerminomas, or seminomas, which have been described as arising in gonadoblastomas, usually have a benign clinical course if the tumor is confined to the gonad at the time of surgical excision. About 10% of gonadoblastomas will contain other germ cell components, however, including yolk sac,.tumor (endodermal sinus tumor), teratomas, and choriocarcinomas. These elements may be associated
Volume 105 Number 6
with a more m a l i g n a n t clinical course, m a y have metastases at t h e time of the initial surgery, and m a y result in eventual d e a t h from tumor, s,3~33 T h e risk of gonadal neoplasm appears to increase with age a n d approaches 50% to 70% as the third decade is reached?" In s u m m a r y , several points can be m a d e from the study of this patient. In children with features of T u r n e r synd r o m e c h r o m o s o m e studies should be performed as soon as possible. Counseling is different if a karyotype with a Y c h r o m o s o m e is found, because of the associated risk of m a l i g n a n c y a n d the preferability of early s u r g e r y . T h e presence of a Y chromosome m a y be suggested by a large baby with peripheral edema in the absence of most of the other s t i g m a t a of T u r n e r syndrome. T h e information obtained from the study of this patient, added to other evidence in the literature, supports localization of the genes for maleness to the distal short a r m of t h e Y chromosome. We thank Everett Lovrien, M.D., for performing the red cell and serum protein polymorphism measurements, Diane Tomar for help with illustrations and manuscript, and Lucy Sheehey for editing and typing.
REFERENCES
1. Frasier SD, Bashore RA, Mosier HD: Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J PEDIATR 64:740, 1964. 2. Teter J, Boczkowski K: Occurrence of tumors in dysgenetic gonads. Cancer 20:1301, 1967. 3. Teter J: Prognosis, malignancy, and curability of the germcell tumor occurring in dysgenetic gonads. Am J Obstet Gynecol 108:894, 1970. 4. Scully RE: Gonadoblastoma: A review of 74 cases. Cancer 25:1340, 1970. 5. Schellhas HF: Malignant potential of the dysgenetic gonad. I. Obstet Gynecol 44:298, 1974. II. Obstet Gynecol 44:455, 1974. 6. Santana JAM, Gardner LI, Russell JF, Neu RL: Bilateral g0nadoblastoma in a six-year old child with ambiguous genitalia and 46,XY karyotype: Gonadal histopathology before and after development of the tumor. Pediatr Res 9:317, 1975. 7. Isurugi K, Aso Y, Ishida H, et al: Prepubertal XY gonadal dysgenesis. Pediatrics 59:569, 1977. 8. Cussen L J, MacMahon RA: Germ cells a'nd ova in dysgenetic gonads of a 46,XY female dizygotic twin. Am J Dis Child 133:373, 1979. 9. MacMahon RA, Cussen L J, Walters WAW: Importance of early diagnosis and gonadectomy in 46,XY females. J Pediatr Surg 15:642, 1980. 10. Seabright M: A rapid banding technique for human chromosomes. Lancet 2:971, 1971. 11. Wyandt HE, Wysham DG, Minden SK, Anderson RS, Hecht F: Mechanisms of Giemsa banding of chromosomes. I. Giemsa-ll banding with azure and eosin. Exp Cell Res 102:85, 1976.
Turner syndrome from Y deletion
9 19
12. Caspersson T, Zech L, Johansson C, Modest E J: Identification of human chromosomes by DNA reacting fluorescent agents. Chromosoma 30:215, 1970. 13. Schweizer D: Simultaneous fluorescent staining of R-bands and specific heterochromatic regions (DA-DAPI bands) in human chromosomes. Cytogenet Cell Genet 27:190, 1980. 14. Yunis J J: High resolution of human chromosomes. Science 191:1268, 1976. 15. Ferguson-Smith MA: Karyotype-phenotype correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations. J Med Genet 2:141, 1965. 16. Magenis RE, Breg WR, Clark KA, et al: Distribution of sex chromosome complements in 651 patients with Turner's syndrome. Am J Hum Genet 32:79A, 1980. 17. Fryns JP, Pederson JC, Goddeeris P, Berghe H van den: Non-fluorescent Y chromosome in mixed gonadal dysgenesis with 45,X/46,XY mosaicism. Ann Genet 23:54, 1980. 18. Magenis RE, Donlon T: Non-fluorescent Y chromosomes: Cytologic evidence of origin. Hum Genet 60:133, 1982. 19. Sohval AR: Hermaphroditism with "atypical" or "mixed" gonadal dysgenesis. Am J Med 36:281, 1964. 20. Simpson JL: Disorders of sexual differentiation. New York, 1976, Academic Press, p 194. 21. Harnden DG, Stewart JS: The chromosomes in a case of pure gonadal dysgenesis. Br Med J 2:1285, 1959. 22. Swyer GIM: Male pseudohermaphroditism: A hitherto undescribed form. Br Med J 2:709, 1955. 23. Simpson JL, Christakos AC, Horwith M, Silverman FS: Gonadal dysgenesis in individuals with apparently normal chromosomal complements: Tabulation of cases and compilation of genetic data. Birth Defects 12:215, 1971. 24. Simpson JL, Blagowidow N, Martin A: XY gonadal dysgenesis: Genetic heterogeneity based on clinical observations, H-Y antigen status and segregation analysis. Hum Genet 58:91, 1981. 25. Hovm611er ML, Osuna A, Ekl6f E, et al: Campomelic dwarfism: A genetically determined mesenchymal disorder combined with sex reversal. Hereditas 86:51, 1977. 26. Ferguson-Smith MA: Abnormal gonadal differentiation in XY females and XX males. Birth Defects 7:204, 1971. 27. Rosenfeld RG, Luzzatti L, Hintz RL, et al: Sexual and somatic determinants of the human Y chromosome: Studies in a 46,XYp- phenotypic female. Am J Hum Genet 31:458, 9 1979. 28. 'Magenis RE, Webb M J, McKean RS, et al: Translocation (X;Y) (p23.33; pl 1.2) in XX males." Etiology of male phenotype. Hum Genet 62:271, 1982. 29. Biihler E: A synopsis of the human Y chromosome. Hum Genet 55:145, 1980. 30. Davis RM: Localization of male determining factors in man: A thorough review of structural anomalies of the Y chromosome. J Med Genet 18:161, 1981. 31. Talerman A: Gonadoblastoma associated with embryonal carcinoma. Obstet Gynecol 43:138, 1973. 32. Gallager HS, Lewis RP: Sequential gonadoblastoma and choriocarcinoma. Obstet Gynecol 41:123, 1973. 33. Luzzatto R, Murray JM, Gallager HS: Gonadoblastoma associated with malignant teratoma. So Med J 72:624, 1979. 34. Donahoe PK, Crawford JD, Hendyen WH: Mixed gonadal dysgenesis, pathogenesis, and management. J Pediatr Surg 14:287, 1979.
Ruth Ellen Magenis, M.D., Mark L. Tochen, M.D., Kathleen P. Holahan, M.D., Thomas Carey, M.D., Leland Allen, B.S., and Michael G. Brown, M.S. P o r t l a n d , Oregon
THE SYNDROME OF THE 46,XY PHENOTYPIC FEMALE with gonadal dysgenesis is generally diagnosed in young women with primary amenorrhea, rarely in children. Determining the presence of a Y chromosome is important for counseling the family regarding sexual development and fertility and because of the risk of malignant transformation of the dysgenetic gonad. This increased risk of ~onadal malignancy was first described in older patients ~-4 and has been extensively reviewed: Only recently has the risk in young children been reported. 6-9 W e describe features suggestive of Turner syndrome in a
From the Department of Medical Genetics, Crippled Children's Division, and University Hospital Cytogenetics Laboratory, Oregon Health Sciences University; and the Departments of Pediatrics, Pathology, and Urology, Kaiser-Permanente Medical Care Program. Supported by Grant HD-07997 from the National Institutes of Health, and by Maternal and Child Health Service Mental Retardation Training Grant MCT-O00920. Submitted for publication March 23. 1984; accepted May 18, 1984. Reprint requests: R. Ellen Magenis, M.D., Department of Medical Genetics and University Hospital Cytogenetics Laboratory, Oregon Health Sciences University, 707 S. IV. Gaines Rd.; Portland, OR 97201. 916
The Journal of P E D I A T R I C S
child with a 46,XY karyotype and deletion of the short arm of the Y chromosome, indicating that this segment is the probable location of the genes for maleness in humans. CASE REPORT This 3220 gm infant girl was born at 42 weeks gestation to a 36-year-old woman after a normal perinatal course. Pedal edema and redundant neck skinfolds were noted and indicated the possibility of Turner syndrome. The external genitalia were normal female, and a cervix was felt on rectal examination. Chromosome studies showed an XY karyotype on two occasions. Surgical exploration at 30 months of age revealed a normal proximal vagina, uterus, a~d fallopian tubes. The gonads were 1.5 and 2 cm in length, respectively, and were white, elliptical, and symmetrically placed. Frozen sections of wedge biopsies revealed foci of gonadoblastoma. Bilateral salpingo-oopherectomy was performed. The child has continued to be healthy from infancy, with growth ~along the 95th percentile for height and head circumference and 75th percentile for weight. She is of normal intellect.
METHODS Chromosomes were obtained from peripheral blood lymphocytes of the patient, parents, and siblings by routine methods. Trypsin G-banding ~~was performed on the chromosome slides of all family members. In addition, several staining techniques were used to~delineate the proband's Y
Volume 105 Number 6
Turner syndrome from Y deletion
91 7
Y
Fig. 1. Y chromosomes from patient and normal male using five different staining techniques: (left to right) Giemsa-banding, standard stain (unbanded), Giemsa-ll, quinacrine banding, and CA3/DA/DAPI R-banding. Note small size of Short arm in proband with G-, S-, and R-banding and absence of distal band with the G-banding high-resolution technique.
chromosome abnormality: standard stain for localization of the centromeric constriction of the Y, Giemsa-11 for placement Of the centromeric as well as terminal Y heterochromatin, ~ Q-banding for staining definitively the Q-bright terminal heterochromatin, ~2 R-banding with C A J D A / D A P F 3 to determine the amount of Y short arm present, and prometaphase h!gh-resolution G-banding~4for determination of break points. Chromosomes were also obtained from skin and connective tissue of both gonads by tissue culture techniques to look for a minor XO cell population.
Fig. 2. Chromosomeideogram depicts point of deletion in abnormal Y chromosome.
RESULTS Chromosome studies. G-banded chrbm0somes of mother and two female siblings were normal, with 46,XX in 20 cells each. The father's karyotype was 46,XY in 20 cells; no structural abnormality of the Y was detected. Segregation studies of 17 red cell enzyme, and serum protein polymorphisms revealed no inconsistencies. Initial G-banded study of the patient's peripheral blood chromosomes was interpreted as normal XY in 36 cells, with no evidence for mosaicism. One hundred G-banded cells from the skin biopsy were studied; 98 were normal 46,XY, and two, with poor morphologic characteristics, appeared to have a possible structural abnormality of the Y. One hundred three cells from the right gonad were 46,XY, as were 99 cells from the left gonad. One cell from the left gonad was missing the Y. Thus, of 339 cells examined, one was missing the Y.
Prometaphase G-banded peripheral blood chromosomes were subsequently obtained anff showed a deletion of the terminal Y short arm gray band (pl 1.2) and possibly a small deletion of the adjacent light band (Fig. 1). Giemsa11, Q-banding, and standard stain showed no evidence for a structural rearrangement; R-banding revealed that most, if not all, of the G-band light short arm region is present (Fig. 1). This interpretation is illustrated with a chromosome ideogram in Fig. 2. Pathologic findings. The specimen consisted of bilateral fallopian tubes and gonadal structures. The right and left fallopian tubes were fimbriated;!measured 3.5 and 2.2 cm in length, respectively; and were0.4 cm in average diameter. The right and lefCgonada! structures were pink-tan and measured 2 • 2 1 5 cm and 1 . 5 • 2 1 5 cm, respectively. Histologically the fallopian tubes were unre-
9 18
Magenis et al.
Fig. 3. Histologic section streak gonad: well-circumscribednests of large germ cells and primitive sex cord cells are present in spindled stroma, diagnostic of gonadoblastoma.Note characteristic laminated calcific concretions.
markable. Both gonadal structures had a spindled, cellular, ovarian-like stroma, which contained numerous wellcircumscribed nests of large germ cells and primitive sex cord cells. Hyaline bodies and laminated calcific concretions were present within some of the nests. Seminiferous tubules or ovarian follicles were not identified. No malignant elements were seen. The morphologic features were those of bilateral gonadoblastomas (Fig. 3). DISCUSSION Approximately 5% of females with Turner syndrome have been shown to have an X O / X Y mosaic chromosome constitution.~5. ~6Mosaicism of 45,XO and 46,XY in which the Y is structurally altered has also been noted in some cases.17.18 An intersex state may also result from X O / X Y mosaicism, or "mixed" gonadal dysgenesis.19,20Our patient has no convincing evidence of an XO cell population. Females with gonadal dysgenesis and an XY karyotype without mosaicism ("pure" XY gonadal dysgenesis) were first described in 1959, 2~ although the phenotype of tall
The Journal of Pediatrics December 1984
stature, primary amenorrhea, and lack of secondary sexual characteristics had been recognized earlier in two females with negative buccal smears. 22 Approximately 150 cases have been reported. 23 Pterygium colli and peripheral edema, as seen in Turner syndrome, have rarely been reported to accompany the other features of XY gonadal dysgenesis; cubitus valgus and multiple nevi are more common. This form of gonadal dysgenesis often appears to have a genetic basis. It has been described in siblings, suggesting male-limited autosomal recessive inheritance; an X-linked mode of inheritance has also been noted. 24 Further genetic heterogeneity is suggested by the finding of XY gonadal dysgenesis in campomelic dwarfismY However, many cases are sporadic; a previously undetectable partial short arm deletion, such as is present in our patient, may explain some of these. This possibility was discussed as early as 1971 by Ferguson-Smith,26 who stated that sporadic XY gonadal dysgenesis may occur in patients who have lost the male determinants carried by the Y short arm and that this could be brought about by accidental crossing over between the short arms of the X and Y chromosomes during paternal meiosis.26 One other case of Y short arm deletion without evidence for mosaicism has been described. 27 This female had multiple minor stigmata of Turner syndrome, including peripheral edema, but had normal stature, as did our patient. She had normal female genitalia and normal uterus and tubes, with 1.5 cm undifferentiated gonads. The authors concluded that genes present on the short arm of the Y chromosome determine testicutar differentiation of the primitive gonad. The small Y chromosome deletion in our patient provides strong evidence not only for localization of genes for male determination to the Y short arm but to the distal half of the Y short arm. Additional evidence for such localization is provided by the finding of the distal Y short arm translocated to the X short arm in XX males. 2s The subject of gene trait localization utilizing Y chromosome structural rearrangements has been extensively reviewed.29.30
At the time of surgery, approximately 25% of patients with Turner syndrome or gonadal dysgenesis and a Y chromosome will have an associated gonadoblastoma? Gonadoblastoma itself is not regarded as a malignant tumor, but about half of the patients with gonadoblastomas also have a component of dysgerminoma. These dysgerminomas, or seminomas, which have been described as arising in gonadoblastomas, usually have a benign clinical course if the tumor is confined to the gonad at the time of surgical excision. About 10% of gonadoblastomas will contain other germ cell components, however, including yolk sac,.tumor (endodermal sinus tumor), teratomas, and choriocarcinomas. These elements may be associated
Volume 105 Number 6
with a more m a l i g n a n t clinical course, m a y have metastases at t h e time of the initial surgery, and m a y result in eventual d e a t h from tumor, s,3~33 T h e risk of gonadal neoplasm appears to increase with age a n d approaches 50% to 70% as the third decade is reached?" In s u m m a r y , several points can be m a d e from the study of this patient. In children with features of T u r n e r synd r o m e c h r o m o s o m e studies should be performed as soon as possible. Counseling is different if a karyotype with a Y c h r o m o s o m e is found, because of the associated risk of m a l i g n a n c y a n d the preferability of early s u r g e r y . T h e presence of a Y chromosome m a y be suggested by a large baby with peripheral edema in the absence of most of the other s t i g m a t a of T u r n e r syndrome. T h e information obtained from the study of this patient, added to other evidence in the literature, supports localization of the genes for maleness to the distal short a r m of t h e Y chromosome. We thank Everett Lovrien, M.D., for performing the red cell and serum protein polymorphism measurements, Diane Tomar for help with illustrations and manuscript, and Lucy Sheehey for editing and typing.
REFERENCES
1. Frasier SD, Bashore RA, Mosier HD: Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J PEDIATR 64:740, 1964. 2. Teter J, Boczkowski K: Occurrence of tumors in dysgenetic gonads. Cancer 20:1301, 1967. 3. Teter J: Prognosis, malignancy, and curability of the germcell tumor occurring in dysgenetic gonads. Am J Obstet Gynecol 108:894, 1970. 4. Scully RE: Gonadoblastoma: A review of 74 cases. Cancer 25:1340, 1970. 5. Schellhas HF: Malignant potential of the dysgenetic gonad. I. Obstet Gynecol 44:298, 1974. II. Obstet Gynecol 44:455, 1974. 6. Santana JAM, Gardner LI, Russell JF, Neu RL: Bilateral g0nadoblastoma in a six-year old child with ambiguous genitalia and 46,XY karyotype: Gonadal histopathology before and after development of the tumor. Pediatr Res 9:317, 1975. 7. Isurugi K, Aso Y, Ishida H, et al: Prepubertal XY gonadal dysgenesis. Pediatrics 59:569, 1977. 8. Cussen L J, MacMahon RA: Germ cells a'nd ova in dysgenetic gonads of a 46,XY female dizygotic twin. Am J Dis Child 133:373, 1979. 9. MacMahon RA, Cussen L J, Walters WAW: Importance of early diagnosis and gonadectomy in 46,XY females. J Pediatr Surg 15:642, 1980. 10. Seabright M: A rapid banding technique for human chromosomes. Lancet 2:971, 1971. 11. Wyandt HE, Wysham DG, Minden SK, Anderson RS, Hecht F: Mechanisms of Giemsa banding of chromosomes. I. Giemsa-ll banding with azure and eosin. Exp Cell Res 102:85, 1976.
Turner syndrome from Y deletion
9 19
12. Caspersson T, Zech L, Johansson C, Modest E J: Identification of human chromosomes by DNA reacting fluorescent agents. Chromosoma 30:215, 1970. 13. Schweizer D: Simultaneous fluorescent staining of R-bands and specific heterochromatic regions (DA-DAPI bands) in human chromosomes. Cytogenet Cell Genet 27:190, 1980. 14. Yunis J J: High resolution of human chromosomes. Science 191:1268, 1976. 15. Ferguson-Smith MA: Karyotype-phenotype correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations. J Med Genet 2:141, 1965. 16. Magenis RE, Breg WR, Clark KA, et al: Distribution of sex chromosome complements in 651 patients with Turner's syndrome. Am J Hum Genet 32:79A, 1980. 17. Fryns JP, Pederson JC, Goddeeris P, Berghe H van den: Non-fluorescent Y chromosome in mixed gonadal dysgenesis with 45,X/46,XY mosaicism. Ann Genet 23:54, 1980. 18. Magenis RE, Donlon T: Non-fluorescent Y chromosomes: Cytologic evidence of origin. Hum Genet 60:133, 1982. 19. Sohval AR: Hermaphroditism with "atypical" or "mixed" gonadal dysgenesis. Am J Med 36:281, 1964. 20. Simpson JL: Disorders of sexual differentiation. New York, 1976, Academic Press, p 194. 21. Harnden DG, Stewart JS: The chromosomes in a case of pure gonadal dysgenesis. Br Med J 2:1285, 1959. 22. Swyer GIM: Male pseudohermaphroditism: A hitherto undescribed form. Br Med J 2:709, 1955. 23. Simpson JL, Christakos AC, Horwith M, Silverman FS: Gonadal dysgenesis in individuals with apparently normal chromosomal complements: Tabulation of cases and compilation of genetic data. Birth Defects 12:215, 1971. 24. Simpson JL, Blagowidow N, Martin A: XY gonadal dysgenesis: Genetic heterogeneity based on clinical observations, H-Y antigen status and segregation analysis. Hum Genet 58:91, 1981. 25. Hovm611er ML, Osuna A, Ekl6f E, et al: Campomelic dwarfism: A genetically determined mesenchymal disorder combined with sex reversal. Hereditas 86:51, 1977. 26. Ferguson-Smith MA: Abnormal gonadal differentiation in XY females and XX males. Birth Defects 7:204, 1971. 27. Rosenfeld RG, Luzzatti L, Hintz RL, et al: Sexual and somatic determinants of the human Y chromosome: Studies in a 46,XYp- phenotypic female. Am J Hum Genet 31:458, 9 1979. 28. 'Magenis RE, Webb M J, McKean RS, et al: Translocation (X;Y) (p23.33; pl 1.2) in XX males." Etiology of male phenotype. Hum Genet 62:271, 1982. 29. Biihler E: A synopsis of the human Y chromosome. Hum Genet 55:145, 1980. 30. Davis RM: Localization of male determining factors in man: A thorough review of structural anomalies of the Y chromosome. J Med Genet 18:161, 1981. 31. Talerman A: Gonadoblastoma associated with embryonal carcinoma. Obstet Gynecol 43:138, 1973. 32. Gallager HS, Lewis RP: Sequential gonadoblastoma and choriocarcinoma. Obstet Gynecol 41:123, 1973. 33. Luzzatto R, Murray JM, Gallager HS: Gonadoblastoma associated with malignant teratoma. So Med J 72:624, 1979. 34. Donahoe PK, Crawford JD, Hendyen WH: Mixed gonadal dysgenesis, pathogenesis, and management. J Pediatr Surg 14:287, 1979.