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Hypogonadism in Chromatin-Negative Phenotypic Male Subjects
THE JOURNAL OF UROLOGY
Vol. 103, May Printed in U.S.A.
Copyright© 1970 by The Williams & Wilkins Co.
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS JOHN P. DONOHUE From the Department of Urology, Indiana University Medical Center, Indianapolis, Indiana
Herein are reported 3 distinct forms of hypogonadism in true chromatin-negative male subjects with normal male karyotypes. These patients are to be distinguished from hypogonadal patients with Klinefelter's syndrome whose buccal smears are chromatin-positive and karyotypes are abnormal. In other words, patients with Klinefelter's syndrome are chromatin-positive and have an extra X chromosome. (A variety of other abnormal chromosomal constitutions, involving at least 2 X chromosomes and 1 Y, have since been found in Klinefelter's syndrome 1). TABLE
1.
normal (fig. 1). Biopsy of the testis revealed considerable peritubular fibrosis. Diagnosis would have been Klinefelter's syndrome if a normal male buccal smear and karyotype had not been found. The testis tubules were lined only with sustentacular cells (Sertoli cells) and no germinal epithelium was seen (fig. 2). This case represents primary testicular deficiency characterized by germinal cell aplasia, in that the testis tubules are lined only by Sertoli cells. This is called del Castillo or the "Sertoli only" syndrome. 2 The clinical and laboratory features of this syndrome
Clinical evaluations
Case 1 Del Castillo's Syndrome Age/Race/Sex Complaint Beard Habitus Breasts Phallus Testes Escutcheon Vasography Ejaculation Sperm count Height Family history Other finding
22, white, male No ejaculation Sparse, much decreased Slim male Normal Normal, 8 cm. Slightly small and soft, 2 cm. Decreased male Normal None 0
5'9" Normal
Case 2 Kallmann's Syndrome
Case 3 Reifenstein's Syndrome
16, white, male Small testes Much decreased Slim male Normal Small, 3 cm. Small, 1 cm.
17, colored, male Breast enlargement Much decreased (absent) Eunuchoid o+ Markedly enlarged Small, 3 to 4 cm. Normal size
o+
o+
Yes 0 5'10½" 2 sisters, irregular menses, cleft lip Anosmia
Yes 1,000,000
The purpose of this paper is to distinguish from Klinefelter's syndrome with its specific defect of aneuploidy, those hypogonadal male subjects with normal karyotypes (euploidy).
2 brothers with gynecomastia Congenital hypospadias
as previously described, were present. The only variant was low gonadotropin (FSH) urinary excretion whereas usually this syndrome has gonadotropins normal to slightly elevated. This is thought to be an X-linked recessive or sex limited autosomal dominant inheritance. The patient in case 2 would appear to have Kallmann's syndrome (figs. 3 and 4). The marked decrease in testicular and phallic size, secondary sexual characteristics, infantile and dysgenetic seminiferous tubules, decreased to absent Leydig cells, decreased ketosteroids,
CASE REPORTS
The essential clinical and laboratory findings of the 3 cases are summarized in tables 1 and 2. The patient in case 1 became aware of the absence of nocturnal emission and ejaculate when he was a college student. The patient's growth, development and family history were otherwise Accepted for publication June 21, 1969. Read at North Central Section, American Urological Association, Rochester, Minnesota, September 18-21, 1968. 1 Jacobs, P. A. and Strong, J. A.: A case of human intersexuality having a possible XXY sexdetermining mechanism. Nature, 183: 302,.19,,59.
5'8½"
'Del Castillo, E. B., Trabucco, A. and de la Baize, F. A.: Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells. J. Clin. Endocrinol., 7: 493, 1947. 645
646
DONOHUE
TABLE
2. Laboratory studies
Case 1 Del Castillo's Syndrome 17 OH-urinary (normal range 5-15 mg./24 hr.) 17 ketosteroids-urinary (normal range 5-25 mg./24 hr.) Pregnanetriol-urinary (normal range 0-4 mg./24 hr.) Follicle stimulating hormone-urinary (normal range 6-60 mu./24 hr.) T3 resin sponge uptake Growth hormone assay Estrogen-urinary (normal range 4-25 mg./24 hr.) Protein bound iodine (normal range 3.5-9.6 Y%) Buccal smear Chromosome map (normal range 46XY) Testis biopsy
7.7 mg./24 5.8 mg./24 3.2 mg./24 3.4 mg./24 1. 7 mg./24
hr. hr. hr. hr. hr.
Case 2 Kallmann's Syndrome Normal 2.5 mg./24 hr. 3.6 mg./24 hr. Normal 6-16 mu./24 hr.
6 mu./24 hr.
Case 3 Reifenstein1 s Syndrome 14.3 mg./24 hr. 15.7 mg./24 hr. 7 .5 mg./24 hr. 10.8 mg./24 hr.
14 mu./24 hr. 21 mu./24 hr. 17 mu./24 hr.
32% (normal) Normal 24 mg./24 hr. 4.5 Y%
5.2 Y% Negative 46XY
Negative 46XY
Negative 46XY
No spermatogonia or spermatids. Only Sertoli cells lined tubules. Peritubular hyalin slightly increased. Leydig cells slightly decreased
Sparse immature tubules with few germinal cells. Marked decrease in Leydig cells.
Sparse spermatogonia and spermatids. Bertoli cells slightly increased. Leydig cells #nl.
FIG. 1. Case 1, 22-year-old male subject with del Castillo syndrome. Aside from slightly decreased testicular size and reduced facial, axillary and pubic hair, he has normal male appearance or phenotype.
aspermia and, most interestingly, anosmia, all point to the syndrome described by Kallmann in 1944. 3 The association of anosmia and gonadal failure in male wbjects is rare. Apparently this is secondary to dysgenesis of the olfactory lobes and the cause of the hypogonadism was thought to be primary failure of gonadotropin secondary to a hypothalamic defect, the precise nature of which is unknown. The patient in case 3 would appear to have the syndrome reported by Reifenstein in 1948 (figs. 5 and 6). Reifenstein described a group of subjects with a familial form of hypogonadism and gynecomastia which is distinct from Klinefelter's syndrome. The cardinal features of the syndrome are: l) hypospadias, 2) post-puberal testicular atrophy associated with normal or increased urinary gonadotropin excretion, 3) azoospermia and infertility, 4) weak or absent virilization and 5) variable degree of gynecomastia (in our case marked). This patient had each of these features. This would appear to be an X-linked recessive or sex-limited autosomal dominant. The occurrence of gynecomastia in 2 male siblings further supports this contention. 3 Kallmann, F. J., Schoenfeld, W. A. and Barrera, S. E.: The genetic aspects of primary eunuchoidism. Amer. J. Ment. Defic., 48: 203, 1944.
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS
647
Frn. 2. Case 1. Testis biops:y shows only sustentacular or supporting Sertoli cells. No germinal epithelmm (spermatogoma) seen 111 these tubules. Hence, name Sertoli only or de] Castillo syndrome. DISCUSSION
Rimoin and associates recently reviewed hypogonadism in phenotypic men. 4 Their organization of clinical features and laboratory studies is reproduced with their permission in tables 3 and 4. Hypogonadism in chromatin-negative male subjects can occur in 3 basic areas. The first would be those with primary gonadotropin deficiency. The clinical appearances are variable but all patients usually have decreased phallic size, decreased testicular size and decreased secondarv sexual characteristics. :\!Iost patients in this 4 Rimoin, D. L., Borgaonkar, D.S., Asper, S. P., Jr. and Bhzzanl, R. M.: Chromatin-neO'ative hypogonadism in phenotypic men. Amer. J. Med. 44: 225, 1968. '
gonadotropin deficiency area are eunuchoid. Their testicular biopsies classically show decreased Leydig cell formation and infantile seminiferous tubules. The only exception to this is the fertile eunuch who shows active spermatogenesis on biopsy. The cardinal feature in the laboratory study of these patients is a decreased urinary FSH. The normal range usually is from 6 to 60 mouse units per 24 hours. The genetics of this suggest X-linked recessive and male limited autosomal dominant inheritance. Associated abnormalities in this variable group with primary gonadotropin deficiency include anosmia (found in Kallmann's syndrome); retinitis pigmentosa, polydactylia, obesity, mental retardation (found in Laurence-Moon-Biedl syndrome) and occasionally other tropic hormone deficiencies found
648
DONOHUE
in those with isolated gonadotropin deficiency as the cause of their hypogonadism. The second major series in the chromatinnegative male hypogonadism group is that represented by primary testicular deficiency. These include del Castillio syndrome, Reifenstein's syndrome and those with rudimentary testes, bilateral anorchia and acquired testicular lesions following mumps, radiation orchitis, etc. Two of the most interesting are del Castillio and
Reifenstein's syndromes. Del Castillio's syndrome has little in the way of clinical features. The subjects usually appear to be normal male individuals. The testicular biopsy is characteristic. It consists of Sertoli cells only, with complete absence of spermatogonial cells. There is a normal number of Leydig cells. Gonadotropins are usually normal and 17-ketosteroids are generally somewhat depressed. They are azoospermic thought to be X-linked recessive or sex-linked autosomal dominant. The cardinal features of Reifenstein's syndrome have been enumerated in the case presented. The last group in the classification of chromatin-negative male hypogonadism can be caused by adrenal tumor. This rare neoplasm may produce hypogonadism associated with decreased levels of gonadotropin. SUMMARY
FIG. 3. Case 2, 18-year-old male subject with Kallmann's syndrome (having been on oral androgen therapy for 2 years). Penile growth has resulted, both testes remain rudimentary, measuring less than 1 cm. in length. Phenotype otherwise is normal male. Anosmia (inability to smell) is associated physical defect.
Three cases of hypogonadism in phenotypic male subjects with normal karyotypes have been presented. Their classification and diagnostic requirements have been reviewed. These hypogonadal male subjects were also distinguished from "Klinefelter's syndrome", a term that geneticists feel should be limited to those cases in which buccal smears are chromatin-positive and karyotypes are abnormal. Therefore, if a hypogonadal male subject is found to be chromatinnegative and to have a normal male karyotype, this is not Klinefelter's syndrome and a clinical study including testicular biopsy and hormonal assays should be done to establish precise diagnosis.
FIG. 4. Case 2. Testis biopsy shows sparse immature tubules with few germinal cells. Mostly sustentacular cells seen in this section. Leydig cells also reduced.
649
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS
Fro. 5. Case 3. A, 17-year-old male subject. with Reifenstein's syndrome. Gynecomastia is apparent.. B, hypospadias also apparent., another sign of R.eifenstein's syndrome. TABUJ
3. Chromatin-negative male hypogonaclism Clinical Features
Syndrome Habitus
Gynecomastia
----~ T
Prirnary gonadotropin def-iclency Isolated gona.
E
Testicular Size -----~
+!-
E
+
N
E
+!-
N/1
E
l
f, !.-.Iypoth:::i.Jr:,mic-pitui-
E/N
Nil
N
+!-
E
+
N E N
Infantile; absent spennatog;enesis Infantile Maturation arrest, hyalinization Active spermatogenesis Infantile; absent spcrmatogenesis Infantile
l
N
.Fm-tile eunuch e, LauTence-11oon-Biedl syndrome tuitary lesions II. Pricnary testicular deficiency a. Germinal aplasia/del Castillo syndrome or Sertoli cell only syndrome b. Reifenstein's syndrome Rudimentary testes d. Bilateral anorchia Ore hi tis (m. urnps, radiation) f. Prepubertal castratior,_ IIL Feminizing adrenal tumor
Testicular Biopsy
Secondary LeyPhallic Sexual Seminiferous Tubules dig Size CharacCells teristics - - - - - - - - - - · · - ~ - - - - - - - - - - - - - - ----- - - -
N/1
N
N
Hypospadia,s
l l
N
Absent I,
N
N
E
N
Hyalinization; diminished spermatogenesis Few small tubulm Absent Tubular degeneration and
N
Atrophic and fib:rntic atrophic hyalini2c
NIL
l\[-normal, E-eunuchoid; +·-pl'esent
Sertoli cells only, abseuce of spermatogonial celL':'-
- L,d ucec~ tn absent and
N
N
i -·ele"'l:ated. Christian.
650
DONOHUE
Frn. 6. Case 3. Testis biopsy shows diminished spermatogenesis, few spermatogonia, mostly Sertoli cells, normal Leydig cells. TABLE 4. Chromatin-negative male hypogonadism Laboratory Studies Syndrome
Urinary Urinary Gonado- 17-Ketotropins steroids
Sperm Count
I. Primary gonadotropin deficiency gonadotropin a. Isolated deficiency b. Kallmann's syndrome C,
N
Rosewater's syndrome
d. Fertile eunuch e. Laurence-Moon-Bied syndrome
N
t
t
Nit
Nit t
Genetics
(a) Autosomal recessive (b) X-linked recessive or sex limited dominant X-linked recessive or sex-limited autosomal dominant X-linked recessive or sex-limited autosomal dominant ? Autosomal recessive Autosomal recessive
Nit
f. Hypothalamic-pituitary lesions
Associated Abnormalities
+/-
Other tropic hormone deficiencies
Anosmia
Retinitis pigmentosa, polydactylia, obesity, mental retardation + /- central nervous system involvement;+!- other tro~ pie hormone deficiencies
II. Primary
testicular deficiency a. Germinal aplasia/ del Castillo syndrome Sertoli cell only syndrome b. Reifenstein's syndrome
c. Rudimentary testes d. Bilateral anorchia e. Orchitis (mumps) f. Prepubertal castration III. Feminizing adrenal tumor
N/i
? X-linked recessive or sex-limited autosomal dominant
N/1
N
i i N/i t t
l
t Nit
X-linked recessive or sex-limited autosomal dominant
l l l
N/i
t
N/i
l
N-normal, E-eunuchoid. --+-~nresent. -~ahRent, 1-reduced to absent and i-elevated.
REFERENCES Bow1m, P., LEE, C. S., MrGEON, C. J., KAPLAN, N. M., WHALLEY, P. J., McKusrcK, V. A. AND REIFENS'l'EIN, E. C., JR.: Hereditary male pseudohermaphroditism with hypo-
gonadism, hypospadias, and gynecomastia: Reifenstein's syndrome. Ann. Int. Med., 62: 252, 1965. FERGUSON-SMITH, M.A. AND JOHNSTON, A. W.: The human chromosomes in disorders of sex
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS
differentiation. Trans. Ass. Amer. Phys., 73: 60, 1960. GRUMBACH, M. M., BLANC, W. A. AND ENGLE, E. T.: Sex chromatin pattern in seminiferous tubule dysgenesis and other testicular disorders: relationship to true hermaphrodism and to Klinefelter's syndrome, with a review of gonadal ontogenesis. J. Clin. Endocrinol., 17: 703, 1957. HELLER, C. G. AND NELSON, W. 0.: Hyalinization of the seminiferous tubules associated with normal or failing Leydig-cell function; discussion of relationship to eunuchoidism, gynecomastia, elevated gonadotrophins, de-
651
pressed 17-ketosteroids and estrogens. J. C!in. Endocrinol., 5: 1, 1945. KLINEFELTER, H. F., JR., REIFENSTEIN, E. C., JR. AND ALBRIGHT, F.: Syndrome characterized by gynecomastia, aspermatogenesis without A-leydigism and increased excretion of folliclestimulating hormone. J. Clin. Endocrinol., 2: 615, 1942. WILKINS, L., BLIZZARD, R. M. AND MIGEON, C. J.: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 3rd edit. Springfield, Illinois: Charles C Thomas, p. 276, 1965.
Vol. 103, May Printed in U.S.A.
Copyright© 1970 by The Williams & Wilkins Co.
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS JOHN P. DONOHUE From the Department of Urology, Indiana University Medical Center, Indianapolis, Indiana
Herein are reported 3 distinct forms of hypogonadism in true chromatin-negative male subjects with normal male karyotypes. These patients are to be distinguished from hypogonadal patients with Klinefelter's syndrome whose buccal smears are chromatin-positive and karyotypes are abnormal. In other words, patients with Klinefelter's syndrome are chromatin-positive and have an extra X chromosome. (A variety of other abnormal chromosomal constitutions, involving at least 2 X chromosomes and 1 Y, have since been found in Klinefelter's syndrome 1). TABLE
1.
normal (fig. 1). Biopsy of the testis revealed considerable peritubular fibrosis. Diagnosis would have been Klinefelter's syndrome if a normal male buccal smear and karyotype had not been found. The testis tubules were lined only with sustentacular cells (Sertoli cells) and no germinal epithelium was seen (fig. 2). This case represents primary testicular deficiency characterized by germinal cell aplasia, in that the testis tubules are lined only by Sertoli cells. This is called del Castillo or the "Sertoli only" syndrome. 2 The clinical and laboratory features of this syndrome
Clinical evaluations
Case 1 Del Castillo's Syndrome Age/Race/Sex Complaint Beard Habitus Breasts Phallus Testes Escutcheon Vasography Ejaculation Sperm count Height Family history Other finding
22, white, male No ejaculation Sparse, much decreased Slim male Normal Normal, 8 cm. Slightly small and soft, 2 cm. Decreased male Normal None 0
5'9" Normal
Case 2 Kallmann's Syndrome
Case 3 Reifenstein's Syndrome
16, white, male Small testes Much decreased Slim male Normal Small, 3 cm. Small, 1 cm.
17, colored, male Breast enlargement Much decreased (absent) Eunuchoid o+ Markedly enlarged Small, 3 to 4 cm. Normal size
o+
o+
Yes 0 5'10½" 2 sisters, irregular menses, cleft lip Anosmia
Yes 1,000,000
The purpose of this paper is to distinguish from Klinefelter's syndrome with its specific defect of aneuploidy, those hypogonadal male subjects with normal karyotypes (euploidy).
2 brothers with gynecomastia Congenital hypospadias
as previously described, were present. The only variant was low gonadotropin (FSH) urinary excretion whereas usually this syndrome has gonadotropins normal to slightly elevated. This is thought to be an X-linked recessive or sex limited autosomal dominant inheritance. The patient in case 2 would appear to have Kallmann's syndrome (figs. 3 and 4). The marked decrease in testicular and phallic size, secondary sexual characteristics, infantile and dysgenetic seminiferous tubules, decreased to absent Leydig cells, decreased ketosteroids,
CASE REPORTS
The essential clinical and laboratory findings of the 3 cases are summarized in tables 1 and 2. The patient in case 1 became aware of the absence of nocturnal emission and ejaculate when he was a college student. The patient's growth, development and family history were otherwise Accepted for publication June 21, 1969. Read at North Central Section, American Urological Association, Rochester, Minnesota, September 18-21, 1968. 1 Jacobs, P. A. and Strong, J. A.: A case of human intersexuality having a possible XXY sexdetermining mechanism. Nature, 183: 302,.19,,59.
5'8½"
'Del Castillo, E. B., Trabucco, A. and de la Baize, F. A.: Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells. J. Clin. Endocrinol., 7: 493, 1947. 645
646
DONOHUE
TABLE
2. Laboratory studies
Case 1 Del Castillo's Syndrome 17 OH-urinary (normal range 5-15 mg./24 hr.) 17 ketosteroids-urinary (normal range 5-25 mg./24 hr.) Pregnanetriol-urinary (normal range 0-4 mg./24 hr.) Follicle stimulating hormone-urinary (normal range 6-60 mu./24 hr.) T3 resin sponge uptake Growth hormone assay Estrogen-urinary (normal range 4-25 mg./24 hr.) Protein bound iodine (normal range 3.5-9.6 Y%) Buccal smear Chromosome map (normal range 46XY) Testis biopsy
7.7 mg./24 5.8 mg./24 3.2 mg./24 3.4 mg./24 1. 7 mg./24
hr. hr. hr. hr. hr.
Case 2 Kallmann's Syndrome Normal 2.5 mg./24 hr. 3.6 mg./24 hr. Normal 6-16 mu./24 hr.
6 mu./24 hr.
Case 3 Reifenstein1 s Syndrome 14.3 mg./24 hr. 15.7 mg./24 hr. 7 .5 mg./24 hr. 10.8 mg./24 hr.
14 mu./24 hr. 21 mu./24 hr. 17 mu./24 hr.
32% (normal) Normal 24 mg./24 hr. 4.5 Y%
5.2 Y% Negative 46XY
Negative 46XY
Negative 46XY
No spermatogonia or spermatids. Only Sertoli cells lined tubules. Peritubular hyalin slightly increased. Leydig cells slightly decreased
Sparse immature tubules with few germinal cells. Marked decrease in Leydig cells.
Sparse spermatogonia and spermatids. Bertoli cells slightly increased. Leydig cells #nl.
FIG. 1. Case 1, 22-year-old male subject with del Castillo syndrome. Aside from slightly decreased testicular size and reduced facial, axillary and pubic hair, he has normal male appearance or phenotype.
aspermia and, most interestingly, anosmia, all point to the syndrome described by Kallmann in 1944. 3 The association of anosmia and gonadal failure in male wbjects is rare. Apparently this is secondary to dysgenesis of the olfactory lobes and the cause of the hypogonadism was thought to be primary failure of gonadotropin secondary to a hypothalamic defect, the precise nature of which is unknown. The patient in case 3 would appear to have the syndrome reported by Reifenstein in 1948 (figs. 5 and 6). Reifenstein described a group of subjects with a familial form of hypogonadism and gynecomastia which is distinct from Klinefelter's syndrome. The cardinal features of the syndrome are: l) hypospadias, 2) post-puberal testicular atrophy associated with normal or increased urinary gonadotropin excretion, 3) azoospermia and infertility, 4) weak or absent virilization and 5) variable degree of gynecomastia (in our case marked). This patient had each of these features. This would appear to be an X-linked recessive or sex-limited autosomal dominant. The occurrence of gynecomastia in 2 male siblings further supports this contention. 3 Kallmann, F. J., Schoenfeld, W. A. and Barrera, S. E.: The genetic aspects of primary eunuchoidism. Amer. J. Ment. Defic., 48: 203, 1944.
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS
647
Frn. 2. Case 1. Testis biops:y shows only sustentacular or supporting Sertoli cells. No germinal epithelmm (spermatogoma) seen 111 these tubules. Hence, name Sertoli only or de] Castillo syndrome. DISCUSSION
Rimoin and associates recently reviewed hypogonadism in phenotypic men. 4 Their organization of clinical features and laboratory studies is reproduced with their permission in tables 3 and 4. Hypogonadism in chromatin-negative male subjects can occur in 3 basic areas. The first would be those with primary gonadotropin deficiency. The clinical appearances are variable but all patients usually have decreased phallic size, decreased testicular size and decreased secondarv sexual characteristics. :\!Iost patients in this 4 Rimoin, D. L., Borgaonkar, D.S., Asper, S. P., Jr. and Bhzzanl, R. M.: Chromatin-neO'ative hypogonadism in phenotypic men. Amer. J. Med. 44: 225, 1968. '
gonadotropin deficiency area are eunuchoid. Their testicular biopsies classically show decreased Leydig cell formation and infantile seminiferous tubules. The only exception to this is the fertile eunuch who shows active spermatogenesis on biopsy. The cardinal feature in the laboratory study of these patients is a decreased urinary FSH. The normal range usually is from 6 to 60 mouse units per 24 hours. The genetics of this suggest X-linked recessive and male limited autosomal dominant inheritance. Associated abnormalities in this variable group with primary gonadotropin deficiency include anosmia (found in Kallmann's syndrome); retinitis pigmentosa, polydactylia, obesity, mental retardation (found in Laurence-Moon-Biedl syndrome) and occasionally other tropic hormone deficiencies found
648
DONOHUE
in those with isolated gonadotropin deficiency as the cause of their hypogonadism. The second major series in the chromatinnegative male hypogonadism group is that represented by primary testicular deficiency. These include del Castillio syndrome, Reifenstein's syndrome and those with rudimentary testes, bilateral anorchia and acquired testicular lesions following mumps, radiation orchitis, etc. Two of the most interesting are del Castillio and
Reifenstein's syndromes. Del Castillio's syndrome has little in the way of clinical features. The subjects usually appear to be normal male individuals. The testicular biopsy is characteristic. It consists of Sertoli cells only, with complete absence of spermatogonial cells. There is a normal number of Leydig cells. Gonadotropins are usually normal and 17-ketosteroids are generally somewhat depressed. They are azoospermic thought to be X-linked recessive or sex-linked autosomal dominant. The cardinal features of Reifenstein's syndrome have been enumerated in the case presented. The last group in the classification of chromatin-negative male hypogonadism can be caused by adrenal tumor. This rare neoplasm may produce hypogonadism associated with decreased levels of gonadotropin. SUMMARY
FIG. 3. Case 2, 18-year-old male subject with Kallmann's syndrome (having been on oral androgen therapy for 2 years). Penile growth has resulted, both testes remain rudimentary, measuring less than 1 cm. in length. Phenotype otherwise is normal male. Anosmia (inability to smell) is associated physical defect.
Three cases of hypogonadism in phenotypic male subjects with normal karyotypes have been presented. Their classification and diagnostic requirements have been reviewed. These hypogonadal male subjects were also distinguished from "Klinefelter's syndrome", a term that geneticists feel should be limited to those cases in which buccal smears are chromatin-positive and karyotypes are abnormal. Therefore, if a hypogonadal male subject is found to be chromatinnegative and to have a normal male karyotype, this is not Klinefelter's syndrome and a clinical study including testicular biopsy and hormonal assays should be done to establish precise diagnosis.
FIG. 4. Case 2. Testis biopsy shows sparse immature tubules with few germinal cells. Mostly sustentacular cells seen in this section. Leydig cells also reduced.
649
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS
Fro. 5. Case 3. A, 17-year-old male subject. with Reifenstein's syndrome. Gynecomastia is apparent.. B, hypospadias also apparent., another sign of R.eifenstein's syndrome. TABUJ
3. Chromatin-negative male hypogonaclism Clinical Features
Syndrome Habitus
Gynecomastia
----~ T
Prirnary gonadotropin def-iclency Isolated gona.
E
Testicular Size -----~
+!-
E
+
N
E
+!-
N/1
E
l
f, !.-.Iypoth:::i.Jr:,mic-pitui-
E/N
Nil
N
+!-
E
+
N E N
Infantile; absent spennatog;enesis Infantile Maturation arrest, hyalinization Active spermatogenesis Infantile; absent spcrmatogenesis Infantile
l
N
.Fm-tile eunuch e, LauTence-11oon-Biedl syndrome tuitary lesions II. Pricnary testicular deficiency a. Germinal aplasia/del Castillo syndrome or Sertoli cell only syndrome b. Reifenstein's syndrome Rudimentary testes d. Bilateral anorchia Ore hi tis (m. urnps, radiation) f. Prepubertal castratior,_ IIL Feminizing adrenal tumor
Testicular Biopsy
Secondary LeyPhallic Sexual Seminiferous Tubules dig Size CharacCells teristics - - - - - - - - - - · · - ~ - - - - - - - - - - - - - - ----- - - -
N/1
N
N
Hypospadia,s
l l
N
Absent I,
N
N
E
N
Hyalinization; diminished spermatogenesis Few small tubulm Absent Tubular degeneration and
N
Atrophic and fib:rntic atrophic hyalini2c
NIL
l\[-normal, E-eunuchoid; +·-pl'esent
Sertoli cells only, abseuce of spermatogonial celL':'-
- L,d ucec~ tn absent and
N
N
i -·ele"'l:ated. Christian.
650
DONOHUE
Frn. 6. Case 3. Testis biopsy shows diminished spermatogenesis, few spermatogonia, mostly Sertoli cells, normal Leydig cells. TABLE 4. Chromatin-negative male hypogonadism Laboratory Studies Syndrome
Urinary Urinary Gonado- 17-Ketotropins steroids
Sperm Count
I. Primary gonadotropin deficiency gonadotropin a. Isolated deficiency b. Kallmann's syndrome C,
N
Rosewater's syndrome
d. Fertile eunuch e. Laurence-Moon-Bied syndrome
N
t
t
Nit
Nit t
Genetics
(a) Autosomal recessive (b) X-linked recessive or sex limited dominant X-linked recessive or sex-limited autosomal dominant X-linked recessive or sex-limited autosomal dominant ? Autosomal recessive Autosomal recessive
Nit
f. Hypothalamic-pituitary lesions
Associated Abnormalities
+/-
Other tropic hormone deficiencies
Anosmia
Retinitis pigmentosa, polydactylia, obesity, mental retardation + /- central nervous system involvement;+!- other tro~ pie hormone deficiencies
II. Primary
testicular deficiency a. Germinal aplasia/ del Castillo syndrome Sertoli cell only syndrome b. Reifenstein's syndrome
c. Rudimentary testes d. Bilateral anorchia e. Orchitis (mumps) f. Prepubertal castration III. Feminizing adrenal tumor
N/i
? X-linked recessive or sex-limited autosomal dominant
N/1
N
i i N/i t t
l
t Nit
X-linked recessive or sex-limited autosomal dominant
l l l
N/i
t
N/i
l
N-normal, E-eunuchoid. --+-~nresent. -~ahRent, 1-reduced to absent and i-elevated.
REFERENCES Bow1m, P., LEE, C. S., MrGEON, C. J., KAPLAN, N. M., WHALLEY, P. J., McKusrcK, V. A. AND REIFENS'l'EIN, E. C., JR.: Hereditary male pseudohermaphroditism with hypo-
gonadism, hypospadias, and gynecomastia: Reifenstein's syndrome. Ann. Int. Med., 62: 252, 1965. FERGUSON-SMITH, M.A. AND JOHNSTON, A. W.: The human chromosomes in disorders of sex
HYPOGONADISM IN CHROMATIN-NEGATIVE PHENOTYPIC MALE SUBJECTS
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