Clinical Genetics 1977: 12: 97-100
Male with 45,X karyotype A. FORABOSCO~, A. CARRATU~, M. A s s m z , A. DE POL^, B. DUTRILLAUXS 1 Cattedra
AND
E. CHELI~
di Istologia ed Embriologia Gen., I” Cattedra di Anatomia Umana Normale,
Universiti di Modena, di Puericultura, Universith di Sassari, Italy and 3Institut de Progenkse, rue de 1’Ecole de Medicine, Paris, France 3 Istituto
A 5-month-old male child with the clinical stigmata of Turner syndrome, bilateral testes and a non-mosaic 45,X karyotype in blood and skin tissue is presented. This is the second case reported in the literature of an “XO-male” with normal external genitalia. Received 20 January, revised 24 February, accepted f o r publication 23 March 1977
The development of secondary male sex characteristics is strictly dependent on testicular differentiation of the embryonic gonads (Jost 1970). Cytogenetic investigations have also demonstrated that, for such differentiation, the presence of the Y chromosome is necessary (Hamerton 1968). However, some apparent exceptions to this rule have been revealed. The first and most important of these exceptions concerns the so-called “XXmales”: individuals with testicles, normal male external genitalia and a 46,XX karyotype. Although rare, this condition has been described in more than 45 cases. In many of these cases it has not been possible to discover the Y chromosome, even after the Q-band technique, which permits the specific identification of the long arm of the Y chromosome (De la Chapelle 1972). The second exception is the “XX-true hermaphrodite: individuals with basically masculine phenotype and a mixture of testicular and ovarian tissues in the gonads. In these patients the karyotype is also 46,XX (Pfeiffer 1974).
Other exceptions to the above-stated rule are subjects with testicles, normal male external genitalia and a 45,X karyotype. This condition, also referred to as “XOmale” or “XO with testicles”, seems to be very rare. Only one such case has been reported in the literature previous to this case (Lo Curto et al. 1974). Case Report
The propositus is the second-born male child of healthy, non-consanguineous parents, who were both 36 years of age at the time of the birth of the child. H e was born at term, after a normal pregnancy during which the mother had not been exposed to drugs, radiation or infectious disease. Cyanosis at birth prompted immediate hospitalization in a special care unit. Clinical findings showed: weight 3,450 g, length 50 cm, head circumference 37 cm, thoracic circumference 36 cm; macro-dolicocephaly; wide forehead; eyes with antimongoloid slant, long palpebral fissures and hypertelorism; low-set ear! with large and pro-
98
FORABOSCO ET A L
The dermatoglyphic pattern displayed a total ridge count of 170, and in each palm there was a bilateral dislocation of axial triradii in t”. Cytogenetic Observations
Fig. 1. The propositus at 5 months of age.
minent auricles; macrostomia; short and large neck with a redundant, wide nucal cutaneous fold (cutis laxa); shield chest with increased intermammillary distance; normally rounded abdomen; male genital organs with a small, curved penis, partially enclosed by the scrotum; left testicle in position, right testicle at the level of the external inguinal orifice; muscular tone normal and neonatal reflexes normal; no lymphedema present. ECG, EEG, otoneurological and ophthalmological examinations gave normal results. Routine biochemical examinations of the blood and urine were normal. No abnormalities of the skeletal system were found by radiographic surveys. Renal and urinary tracts were also normal.
Female sex-chromatin was absent in buccal smear as well as in hair-root preparations stained with quinacrine mustard. Blood cultures from the propositus and his parents were prepared according to standard techniques. Skin cultures from the propositus were also obtained. Chromosome analysis was performed on slides stained with quinacrine mustard or processed according to the R-banding and C-banding methods (Dutrillaux 1975). One hundred cells of the propositus were examined from successive blood cultures and 50 cells from skin cultures. The chromosome number was 45, and all examined cells contained a single X chromosome. The Q-bands (Fig. 2), R-bands and C-bands on all chromosomes had normal distributions. The parents had normal karyotypes; in the father the Y-chromosome was of normal size and pattern. Discussion
The main clinical features of the child can be summarized as follows: normal male sexual development, in spite of hypoplasia of the penis; presence of some Turner-like stigmata (i.e., nucal cutis laxa, short neck, shielded-chest and Turner-like dermatoglyphics); a 45,X karyotype with no evidence of mosaicism in the two tissues examined. This combination of clinical signs is very similar to that described by Lo Curto et al. (1974) in a 45,X male, although their case also had signs of chondrosteodysplasia. Lo Curto et al. (1974) reexamined a few XO-males previously reported without banding studies; all these individuals were
MALE WITH 45,X KARYOTYPE
99
Fig. 2. Karyotype of blood culture, stained with Q.M.. showing 45.X chromosomes without any evidence of a fluorescent pattern characteristic of the Y long-arm chromosome.
adult male pseudohermaphrodites and did not display Turner stigmata. The development of a male phenotype in the absence of any detectable Y chromosome material could be explained as follows (Rios et al. 1975): 1) The male sexual development is the consequence of an undetected mosaicism or an early elimination of the Y chromosome. This model assumes the presence of a stemline containing the Y chromosome at an early embryonic stage, triggering testicular differentiation. Subsequently, this stem-line could have been lost or become indetectable because of extreme reduction. 2) The Y chromosome, or at least part of it, could have been translocated to another chromosome. This hypothesis could be verified by the use of Q- and C-banding
techniques, but the possibility of detecting translocations involving the short arm or the paracentromeric regions, only, of the Y , which appear to contain the testis-determining factor(s), is remote at present. 3) The development of testes in the absence of Y-chromosome material has been explained in terms of a mutation of one of the genes responsible for sexual determination. An autosomal gene, called sex-reversal (Sxr), in the mouse induces the immature gonads of a genetic female to differentiate into a testis rather than into an ovary. This observation has led to the suggestion that a gene homologous to “Sxr” causes the sex reversal condition in all mammalian species (Cattanach 1974). None of these hypotheses has been proved as yet, but both human XX-males and
100
F O R A B O S C O E T AL
XX true hermaphrodites are positive t o H-Y antigen (Wachtel et al. 1976), which favours the Y-translocation hypothesis. In fact, t h e human H-Y gene has been assigned to a region close to the centromere, linked to the testis-determining gene(s), and most probably is the male-determining gene itself (Koo et al. 1976).
References Cattanach, B. M. (1974). Genetic disorders of sex determination in mice and other mammals. Birth Defects: Proceedings of the Fourth International Conference, ed. Motulsky, G. & W. Lenz, Amsterdam, Excerpta Medica. De la Chapelle, A. (1972). Nature and origin of males with XX sex chromosome. Amer. J . hum. Genet. 24, 71-105. Dutrillaux, B. (1975). Sur la Nature et I’Origine des Chromosomes Humains. Paris, Expansion Scientifique. Hamerton, J. L. (1968). Significance of sex chromosome derived heterochromatin in mammals. Nature (Lond.) 219, 910-914.
Jost A. (1970). Hormonal factors in the sex differentiation of the mammalian foetus. Phil. Trans. B 259, 119-130. Lo Curto, F., E. Pucci, S. Scappaticci, S. Scotta, F . Severi, G. B. Burgio & M. Fraccar0 (1974). XO and male phenotype. Amer. J. Dis. Child. 128, 90-91. Pfeiffer, R. A. (1974). True hermaphroditism. Helv. paediat. Acta, Suppl. 34, 99-110. Rios, M. E., R. L. Kaufman, G. S. Sekhan, J. G. Bucy, J. E. Bauman & L. S. Jacobs (1975). An XX-male: Cytogenetic and endocrine studies. Clin. Genet. 7 , 155-162. Koo, G. C . , S. S. Wachtel, W. R. Breg et al. (1976). Mapping the locus of the H-Y antigen. Birth Defects: Original Article Series X I I , NO. 7, 175-180. Wachtel, S. S., G . C. Koo, W. Roy Breg et al. (1976). Serologic detection of a Y-linked gene in XX males and XX true hermaphrodites. New Engl. J. Med. 295, 750-754. Address: Prof. Antonino Forabosco Cattedra di Istologia ed Embriologia Generale Istituto di Anatomia U . Normale Universitci di Modena Italy
Male with 45,X karyotype A. FORABOSCO~, A. CARRATU~, M. A s s m z , A. DE POL^, B. DUTRILLAUXS 1 Cattedra
AND
E. CHELI~
di Istologia ed Embriologia Gen., I” Cattedra di Anatomia Umana Normale,
Universiti di Modena, di Puericultura, Universith di Sassari, Italy and 3Institut de Progenkse, rue de 1’Ecole de Medicine, Paris, France 3 Istituto
A 5-month-old male child with the clinical stigmata of Turner syndrome, bilateral testes and a non-mosaic 45,X karyotype in blood and skin tissue is presented. This is the second case reported in the literature of an “XO-male” with normal external genitalia. Received 20 January, revised 24 February, accepted f o r publication 23 March 1977
The development of secondary male sex characteristics is strictly dependent on testicular differentiation of the embryonic gonads (Jost 1970). Cytogenetic investigations have also demonstrated that, for such differentiation, the presence of the Y chromosome is necessary (Hamerton 1968). However, some apparent exceptions to this rule have been revealed. The first and most important of these exceptions concerns the so-called “XXmales”: individuals with testicles, normal male external genitalia and a 46,XX karyotype. Although rare, this condition has been described in more than 45 cases. In many of these cases it has not been possible to discover the Y chromosome, even after the Q-band technique, which permits the specific identification of the long arm of the Y chromosome (De la Chapelle 1972). The second exception is the “XX-true hermaphrodite: individuals with basically masculine phenotype and a mixture of testicular and ovarian tissues in the gonads. In these patients the karyotype is also 46,XX (Pfeiffer 1974).
Other exceptions to the above-stated rule are subjects with testicles, normal male external genitalia and a 45,X karyotype. This condition, also referred to as “XOmale” or “XO with testicles”, seems to be very rare. Only one such case has been reported in the literature previous to this case (Lo Curto et al. 1974). Case Report
The propositus is the second-born male child of healthy, non-consanguineous parents, who were both 36 years of age at the time of the birth of the child. H e was born at term, after a normal pregnancy during which the mother had not been exposed to drugs, radiation or infectious disease. Cyanosis at birth prompted immediate hospitalization in a special care unit. Clinical findings showed: weight 3,450 g, length 50 cm, head circumference 37 cm, thoracic circumference 36 cm; macro-dolicocephaly; wide forehead; eyes with antimongoloid slant, long palpebral fissures and hypertelorism; low-set ear! with large and pro-
98
FORABOSCO ET A L
The dermatoglyphic pattern displayed a total ridge count of 170, and in each palm there was a bilateral dislocation of axial triradii in t”. Cytogenetic Observations
Fig. 1. The propositus at 5 months of age.
minent auricles; macrostomia; short and large neck with a redundant, wide nucal cutaneous fold (cutis laxa); shield chest with increased intermammillary distance; normally rounded abdomen; male genital organs with a small, curved penis, partially enclosed by the scrotum; left testicle in position, right testicle at the level of the external inguinal orifice; muscular tone normal and neonatal reflexes normal; no lymphedema present. ECG, EEG, otoneurological and ophthalmological examinations gave normal results. Routine biochemical examinations of the blood and urine were normal. No abnormalities of the skeletal system were found by radiographic surveys. Renal and urinary tracts were also normal.
Female sex-chromatin was absent in buccal smear as well as in hair-root preparations stained with quinacrine mustard. Blood cultures from the propositus and his parents were prepared according to standard techniques. Skin cultures from the propositus were also obtained. Chromosome analysis was performed on slides stained with quinacrine mustard or processed according to the R-banding and C-banding methods (Dutrillaux 1975). One hundred cells of the propositus were examined from successive blood cultures and 50 cells from skin cultures. The chromosome number was 45, and all examined cells contained a single X chromosome. The Q-bands (Fig. 2), R-bands and C-bands on all chromosomes had normal distributions. The parents had normal karyotypes; in the father the Y-chromosome was of normal size and pattern. Discussion
The main clinical features of the child can be summarized as follows: normal male sexual development, in spite of hypoplasia of the penis; presence of some Turner-like stigmata (i.e., nucal cutis laxa, short neck, shielded-chest and Turner-like dermatoglyphics); a 45,X karyotype with no evidence of mosaicism in the two tissues examined. This combination of clinical signs is very similar to that described by Lo Curto et al. (1974) in a 45,X male, although their case also had signs of chondrosteodysplasia. Lo Curto et al. (1974) reexamined a few XO-males previously reported without banding studies; all these individuals were
MALE WITH 45,X KARYOTYPE
99
Fig. 2. Karyotype of blood culture, stained with Q.M.. showing 45.X chromosomes without any evidence of a fluorescent pattern characteristic of the Y long-arm chromosome.
adult male pseudohermaphrodites and did not display Turner stigmata. The development of a male phenotype in the absence of any detectable Y chromosome material could be explained as follows (Rios et al. 1975): 1) The male sexual development is the consequence of an undetected mosaicism or an early elimination of the Y chromosome. This model assumes the presence of a stemline containing the Y chromosome at an early embryonic stage, triggering testicular differentiation. Subsequently, this stem-line could have been lost or become indetectable because of extreme reduction. 2) The Y chromosome, or at least part of it, could have been translocated to another chromosome. This hypothesis could be verified by the use of Q- and C-banding
techniques, but the possibility of detecting translocations involving the short arm or the paracentromeric regions, only, of the Y , which appear to contain the testis-determining factor(s), is remote at present. 3) The development of testes in the absence of Y-chromosome material has been explained in terms of a mutation of one of the genes responsible for sexual determination. An autosomal gene, called sex-reversal (Sxr), in the mouse induces the immature gonads of a genetic female to differentiate into a testis rather than into an ovary. This observation has led to the suggestion that a gene homologous to “Sxr” causes the sex reversal condition in all mammalian species (Cattanach 1974). None of these hypotheses has been proved as yet, but both human XX-males and
100
F O R A B O S C O E T AL
XX true hermaphrodites are positive t o H-Y antigen (Wachtel et al. 1976), which favours the Y-translocation hypothesis. In fact, t h e human H-Y gene has been assigned to a region close to the centromere, linked to the testis-determining gene(s), and most probably is the male-determining gene itself (Koo et al. 1976).
References Cattanach, B. M. (1974). Genetic disorders of sex determination in mice and other mammals. Birth Defects: Proceedings of the Fourth International Conference, ed. Motulsky, G. & W. Lenz, Amsterdam, Excerpta Medica. De la Chapelle, A. (1972). Nature and origin of males with XX sex chromosome. Amer. J . hum. Genet. 24, 71-105. Dutrillaux, B. (1975). Sur la Nature et I’Origine des Chromosomes Humains. Paris, Expansion Scientifique. Hamerton, J. L. (1968). Significance of sex chromosome derived heterochromatin in mammals. Nature (Lond.) 219, 910-914.
Jost A. (1970). Hormonal factors in the sex differentiation of the mammalian foetus. Phil. Trans. B 259, 119-130. Lo Curto, F., E. Pucci, S. Scappaticci, S. Scotta, F . Severi, G. B. Burgio & M. Fraccar0 (1974). XO and male phenotype. Amer. J. Dis. Child. 128, 90-91. Pfeiffer, R. A. (1974). True hermaphroditism. Helv. paediat. Acta, Suppl. 34, 99-110. Rios, M. E., R. L. Kaufman, G. S. Sekhan, J. G. Bucy, J. E. Bauman & L. S. Jacobs (1975). An XX-male: Cytogenetic and endocrine studies. Clin. Genet. 7 , 155-162. Koo, G. C . , S. S. Wachtel, W. R. Breg et al. (1976). Mapping the locus of the H-Y antigen. Birth Defects: Original Article Series X I I , NO. 7, 175-180. Wachtel, S. S., G . C. Koo, W. Roy Breg et al. (1976). Serologic detection of a Y-linked gene in XX males and XX true hermaphrodites. New Engl. J. Med. 295, 750-754. Address: Prof. Antonino Forabosco Cattedra di Istologia ed Embriologia Generale Istituto di Anatomia U . Normale Universitci di Modena Italy
