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Embryonic testicular regression syndrome: Variable phenotypic expression in siblings
200
August 1980 TheJournalofPEDIATRICS
Embryonic testicular regression syndrome: Variable phenotypic expression in siblings Two 46,XY agonadal siblings with variable degrees of sexual ambiguity are described. The eldest chiM is a phenotypic male with micropenis. The younger patient, a phenotypic female with slight fusion of the genital folds and absent mi~llerian ducts, conforms to the criteria usually accepted for the diagnosis of true agonadism. Coexistence of anorchia and true agonadism in the same sibship supports the hypothesis, suggested by others, that both disorders are related and are due to the regression o f the embryonic testes.
N a t h a l i e J o s s o * and Marie-Louise Briard, Paris, F r a n c e
NORMAL SEX D I F F E R E N T I A T I O N o f the XY m a m m a l ian fetus is mediated by the fetal testis, which sequentially determines mtillerian duct regression, wolffian duct stabilization, closure o f the urogenital sinus and urethral groove, and growth o f the phallus: In experimental animals, castration o f male fetuses results in varying degrees of sexual ambiguity, depending on the developmental stage at which the testes have been removed: early castration produces a normal female phenotype with retention of mtillerian ducts,' whereas the same procedure, performed later in fetal life, results in hypospadias and enlargement of the prostatic utricle, but does not interfere with normal male differentiation of the internal genital tract:. In h u m a n subjects, testicular insufficiency during the second half o f pregnancy leads to micropenis without structural a b n o r m a l i t i e s of the genital tract, 3. ' whereas 46,XY patients with total gonadal aplasia are usually phenotypic females with normal miillerian ducts. 5 However, in rare instances, variable degrees o f virilization have been observed in 46,XY agonadal individuals: some are phenotypic males and others phenotypic females or intersexes lacking milllerian ducts. The term "true agonadism" has been coined to describe the latter situation. 6 It has been suggested that anorchia and true agonadism
From the Unit~ de Recherches de Gbnbtique Mbdicale. Supported by INSERM. *Reprint address: Unite de Recherches de Genetique Medicale, 1NSERM, Hospital des Enfants Malades, 149, rue de Sevres, 75730 Paris Cedex 15, France.
Vol. 97, No. 2, pp. 200-204
10
12
13 14
Fig. 1. Family pedigree of Patients 1 and 2. 9 - Fetal wastage; 11 10 pulmonary tuberculosis, married, no children; III 10 and 13: Normal 46,XX girls; IV 12 and 14 Patients I and 2.
represent related clinical entities due to regression o f the fetal testis at different developmental stages, r. ' The occurrence of both disorders in the same sibship lends support to this hypothesis and, to the best o f our knowledge, has not hitherto been reported. CASE REPORTS Patient 1. This is the third child of a family of five. The family pedigree is shown on Fig. 1. The parents are not related and inquiry revealed no sexual abnormality in either family. The high degree of fetal wastage in the patient's sibship could be related to closely spaced pregnancies in unfavorable socioeconomic conditions. No clinical or cytogenetic abnormalities were found in two sisters and an elder brother. The patient, reared as a boy, was admitted to a surgical ward at age 2 for repair of bilateral inguinal hernias. Bilateral cryptorchidism was noted at that time. At hernioplasty, a vas deferens was found on both sides, extending to the fundus of the hernial sac and then looping back to an incompletely descended epididymis, widely separated from a minuscule "testis-like" structure. Biopsy, performed only on the right side, revealed abundantly
0022-3476/80/080200+05500.50/0 9 1980 The C. V. Mosby Co.
Volume 97 Number 2
Embryonic testicular regression syndrome
20 1
Fig. 2. Genitography illustrating the variable degree of virilization of the urogenital sinus in the two siblings. Case 1: The urethra is that of a normal male except that the penile segment is extremely short. The pocket just below the bladder represents an enlarged prostatic utricle, the equivalent of the vagina in the male. Case 2: The bladder is not opacified; instead, a vagina of normal size but lacking a cervical imprint is demonstrated. B: bladder, V: vagina, P: prostatic utricle, U: urethra. vascularized fibrous tissue, with no identifiable testicular tubules. Both these structures were placed in the scrotum. The patient was brought to our attention in 1972 at age 10 years, because genital development was then thought to be abnormal. Clinical examination showed a child of normal stature and bone age, with no other congenital malformations. The phallus was 2.5 cm long, with the urethral orifice at its tip. The scrotum was empty, and urethrography demonstrated an enlarged prostatic utricle (Fig. 2). Karyotype was normal, 46,XY. Urinary gonadotropins were undetectable by bioassay. Plasma testosterone concentration, both before and after prolonged gonadotropin stimulation performed according to Saez et al, ~was 0.5 ng/ml, a value in the normal range for prepubertal children in the hospital laboratory at that time. Normal peripheral responsiveness to exogenous testosterone was documented by nitrogen balance studies on a constant intake of 10 gm/day: testosterone propionate (20 mg/m ~) during three days reduced urinary nitrogen excretion from 31.3 gm over a three-day control period to 19.1 gm during a treatment period of similar length. Testosterone therapy was initiated at age 12, but shortly afterward the patient's family moved and he was lost to follow-up. Patient 2. This is the youngest "sister" of Patient 1. She was considered a normal female at birth and was routinely examined at age 2, because of the abnormalities detected in her 10-year-old brother. Physical examination showed a child of normal stature, with no extragenital malformations. The clitoris was not enlarged and a single perineal orifice was visible. A urogenital sinus with a well-developed vagina was demonstrated radiologically (Fig. 2). Karyotype was 46,XY. Endocrine investigations revealed an increased gonadotropin excretion (3 to 25 MU). Plasma testoste-
rone concentration after hCG stimulation, performed as in Patient 1, was 0.3 ng/ml. At laparotomy (Pr. C. Nihoul-Feketr) the pelvis appeared empty, apart from two pea-sized structures located in an ovarian position, which were excised. Histologic examination revealed fibrous stroma (Fig. 3, A) with coexistence of mt~llerian (Fig. 3, B) and wolllian (Fig. 3, C) structures. Serial sections failed to reveal gonadal tissue. DISCUSSION Both siblings described in this report are genetic males with total absence o f g o n a d a l tissue. A g o n a d i s m was d e m o n s t r a t e d at l a p a r a t o m y a n d was confirmed by biochemical studies since n e i t h e r patient responded to gona d o t r o p i n stimulation, a test which has occasionally detected functional Leydig cells missed at surgery.' ..... Total bioassayable g o n a d o t r o p i n s were slightly elevated in the 2-year-old patient, b u t not in her 10-year-old brother. W i n t e r a n d F a i m a n I'~ a n d Conte et al TM have d o c u m e n t e d elevated serum levels o f g o n a d o t r o p i n s in a g o n a d a l children d u r i n g the first years of life. Contrasting with their identical gonadal status, our patients have m a r k e d p h e n o t y p i c differences. The eldest child, a phenotypic male with a hypoplastic but structurally n o r m a l penis, is an example o f congenital anorchia, a rare condition diagnosed in 0.56% o f cases o f bilateral cryptorchidism, l~ A n o r c h i c patients have complete internal a n d external male sex differentiation, a l t h o u g h persis-
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The Journal of Pediatrics August 1980
Fig. 3. Histologic structure of the rudimentary organ found in ovarian position in Patient 2. A, Fibrous tissue; B, mtillerian remnants; and C, wolffian remnants. (Periodic acid-Schiff; • 200.)
tence of mtillerian ducts has been reported in one instance '~ and reduced penile size in several. 16-19 Our second patient meets the criteria required for the diagnosis of"true agonadism," a syndrome initially described in siblings by Overzier and Linden s and subsequently reported in 16 additional sporadic cases 7. ~. . . . . . . ~l and in another pair of sibs? ~ These 46,XY agonadal patients have female or ambiguous external genitalia, with a blind and often shallow vagina. Congenital malformations, including ocular abnormalities, deafness, and low intelligence, have been described in two cases2 ~ 2~ At laparotomy, internal genital organs are represented by small ovoid structures, located on the lateral pelvic walls and containing rudimentary woltlian or mtillerian structures. "True agonadism" is distinguished from the Swyer syndrome, or "pure gonadal dysgenesis,''~ by the fact that in the latter condition miallerian ducts have differentiated normally into uterus and tubes, and external genital ambiguity is not observed, i.e., no sign of fetal testicular function, whether anti-miillerian or androgenic, can be detected. Pure gonadal dysgenesis is transmitted by either an X-linked recessive or a sex-limited dominant mutant geneS3. 2, which appears to block Y-mediated testicular differentiation. In true agonadlsm, there is evidence for adequate anti-miillerian and usually also for partial androgenic fetal testicular function. The fact that gonadotropin-responsive Leydig cells have been described in this condition H9 ~ lends further support to the hypothesis that testicular tissue must have been present at some time during development in this type of patient.
In the human male fetus, miillerian ducts begin to degenerate at the 30 mm stage (eight weeks after the mother's last menstrual period) and are completely regressed at 50 mm (10 weeks)? 5 However, we have shown in vitro that human miillerian ducts are no longer sensitive to testicular anti-mfillerian hormone after eight weeks? 6 This finding strongly suggests that m~llerian regression is induced by the fetal testis before that date and that degeneration is then irreversible and no longer requires the presence of fetal testicular tissue. Findings to that effect have been reported in the rat fetus by Donahoe et al. a7 Wolffian ducts, the excretory ducts of the mesonephros, do not initially require testosterone for their development but become androgen-dependent when renal function is taken over by the definitive kidney? ~ Exposure to testosterone then results in "stabilization" of wolffian ducts, i.e.,. wolffian ducts do not disappear if testosterone is subsequently withdrawn. The date at which human Wolflian ducts become stabilized is not known but is probably close to the 50 mm stage since female wolffian ducts degenerate at that time? 5 Masculinization of the external genitalia begins in fetuses 40 mm in crown-rump length (65 to 70 days) and is completed when the fetus reaches 70 mm (14 weeks). However, after fusion of the genital folds and formation of the penile urethra, the penis is only 3.5 mm long, approximately equal in size to the clitoris of the female embryo of the same age. Penile growth is mediated through pituitary-dependent testicular secretion between 16 weeks and term? 9
Volume 97 Number 2
In our elder patient, testicular failure occurred after miallerian regression, wolffian stabilization, and penile organogenesis, bui before the period of penile growth, probably during the fourth month of pregnancy. In the younger agonadic sibling, the testis triggered miillerian regression, achieved partial fusion of the genital folds, but did not stabilize the wolffian duct nor stimulate growth of the phallus; testicular failure probably occurred between the 40 and 50 m m stage, i.e., at the beginning o f the third month of pregnancy. The cause o f testicular degeneration during fetal life is not clear. In the present instance, testicular demise appears genetically determined, but available information does not allow us to distinguish between an autosomic recessive, sex-linked recessive, or sex-limited dominant mode of inheritance. Review of the literature shows that genetic factors, which play a prominent role in pure gonadal dysgenesis, 33. 3, are not paramount in all cases o f the embryonic testis regreSsion syndrome. Heritable tendencies toward anorchia do exist, but monozygotic twins are not always concordant for anorchia. "~ True agonadism has been described in siblings only twice ~. 32 if one excludes from the diagnosis the brothers described by Bergada et al, 7 in w h o m an infantile uterus was demonstrated and who are difficult to classify. Coexistence o f anorchia and true agonadism in the same family, reported here for the first time, confirms that both conditions are related and facilitated by a genetically determined predisposition, but sheds no light on the pathogenesis o f embryonic testicular degeneration. REFERENCES
1. Jost A: Recherches sur la diffrrenciation sexuelle de l'embryon de lapin. III. Rrle des gonades foetales dans la diffrrenciation sexuelle somatique, Arch Anat Microsc Morphol Exp 36:271, 1947. 2. Wells IJ, Cavanaugh MM, and Maxwell EL: Genital abnormalities in castrated fetal rats and their prevention by means of testosterone propionate, Anat Rec 118:109, 1954. 3. Lovinger RD, Kaplan SL, and Grumbach MM: Congenital hypopituitarism associated with neonatal hypoglycemia and microphallus: four cases secondary to hypothalamic hormone deficiencies, J PEDIATR87:1171, 1975. 4. Walsh PC, Wilson JD, Allen TD, et al: Clinical and endocrinological evaluation of patients with congenital microphallus, J Urol 120:90, 1978. 5. Sohval AR: The syndrome of pure gonadal dysgenesis, Am J Med 38:615, 1965. 6. Overzier C, and Linden H: Echter Agonadismus (Anorchismus) bei Geschwistern, Gynaecologia 142:215, 1956. 7. Bergada C, Cleveland WW, Jones HW Jr, and Wilkins L: Variants of embryonic testicular dysgenesis: bilateral anorchia and the syndrome of rudimentary testes, Acta Endocrinol (Kbh) 40:521, 1962. 8. Edman CD, Winter AJ, Porter JC, Wilson J, and MacDon-
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25. 26.
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aid PC: Embryonic testicular regression, a clinical spectrum of XY agonadal individuals, Obstet Gynecol 49:208, 1977. Saez JM, Frederich A, and Bertrand J: Endocrine and metabolic studies in children with male pseudo hermaphroditism, J Clin Endocrinol Metab 32:61 l, 1971. Kirschner MA, Jacobs JB, and Fraley EE: Bilateral anorchia with persistent testosterone production, New Engl J Med 282:240, 1970. Parks GA, Dumars KW, Limbeck GA, Quinlivan WL, and New MI: "True agonadism": a misnomer? J PEDIATR 84:375, 1974. Aynsley-Green A, Zachmann M, Illig R, Rampini S, and Prader A: Congenital bilateral anorchia in childhood: a clinical endocrine and therapeutic evaluation of twenty-one cases, Clin Endocrinol 5:381, 1976. Winter JSD, and Faiman C: Serum gonadotropin concentrations in agonadal children and adults, J Clin Endocrinol Metab 35:561, 1972. Conte FA, Grumbach MM, and Kaplan SL: A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis, J Clin Endocrinol Metab 40:670, 1975. P~rez-Palacios G, Faz R, Benavides S, Manrique JJ, and Larrea F: Anorchia and persistent mtillerian duct; a variant of the embryonic testicutar regression syndrome. J Clin Endocrinol Metab 47:812, 1978. Chaptal J, Jean R, and Pages P: Sur un cas de dysgrnrsie gonadique avec manifestations androgrniques, Arch Fr Pediatr 15:613, 1958. Lev-ran A: "True agonadism" and its relation to other forms of sex reversal in males, Isr J Med Sci 11:914, 1975. Grant DB, and Dillon M J: Micropenis associated with testicular agenesis, Arch Dis Child 50:247, 1975. Vanelli M, Chaussain JL, Vassal J, and Job JC: L'insuffisance du d~veloppement de la verge (micropenis). Donnres 6tiologiques dans une srrie de 25 cas, Arch Fr Prdiatr 36:471, 1979. Schoen EJ, King AL, Lamont Baritell A, and Knigge WF: Pseudohermaphroditis with multiple congenital anomalies, Pediatrics 16:363, 1955. Philipp E: Die Fehlbildungen der Keimdruese, Dtsch Med Wochenschr 81:1298, 1956. Dewhurst C J, Paine CG, and Blank CE: An XY female with absent gonads and vestigial pelvic organs, J Obstet Gynaecol 70:675, 1963. Emson HE, and Buckwold AE: Agonadism, Can Med Assoc J 93:1080, 1965. Rath F, Scheibenreiter S, and Thalhammer O: Agonadismus (Anorchismus) bei einem sechs Jahre alten Kind, Dtsch Med Wochenschr 93:633, 1968. Sarto GE, and Optiz JM: The XY gonadal agenesis syndrome, J Med Genet 10:288, 1973. Rios EP, Herrera J, Bermudez JA, et al: Endocrine and metabolic studies in an XY patient with gonadal agenesis, J Clin Endocrinol Metab 39:540, 1974. Levinson G, Guzm~in-Toledano R, Jimrnez M, Canales ES, and Z~irate A: Sindrome de agonadismo o ageneseia gonadal en un paciente con pseudohermafroditismo y cariotipo 46,XY, Rev Invest Clin (Mex) 27:231, 1975. Kofman-Alfaro S, Saavedra DO, Ochoa S, Scaglia H, and Perez-Palacios G: Pseudo-hermaphroditism due to XY gonadal absence syndrome, J Med Genet 3:242, 1976.
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29. Wu RH, Boyar RM, Knight R, Hellman L, and Finkelstein JW; Endocrine studies in a phenotypic girl with XY gonadal agenesis, J Clin Endocrinol Metab 43:506, 1976. 30. Penney LL, and Betz G: Agonadism, case report and review, Am J Obstet Gynecol 127:299, 1977. 31. Cleary RE, Caras J, Rosenfield RL, and Young PCM: Endocrine and metabolic studies in a patient with male pseudohermaphroditism and true agonadism, Am J Obstet Gynecol 128:862, 1977. 32. Park IJ, and Jones HW: Familial male hermaphroditism with ambiguous external genitalia, Am J Obstet Gynecol 108:1197, 1970. 33. Sternberg WH, Barclay DL, and Kloepfer HW: Familial XY gonadal dysgenesis, N Engl J Med 278:695, 1968. 34. German J, Simpson JL, Chaganti RSK, Summitt RL, Reid LB, and Merkatz IR: Genetically determined sex-reversal in 46,XY humans, Science 202:53, 1978.
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35. - Jirasek JE: Development of the genital system and male pseudo-hermaphroditism, Baltimore, 1971, Johns Hopkins University Press. 36. Josso N: Fetal sexual differentiation in mammals, Pediatr Ann 3:67, 1974. 37. Donahoe PK, Ito Y, and Hendren WH III: A graded organ culture assay for the detection of mtiUerian-inhibiting substance, J Surg Res 23:141, 1977. 38. Price D, Zaaijer JJP, Ortiz E, and Brinkmann AO: Current views on embryonic sex/lifferentiation in reptiles, birds and mammals, Am Zool 15(Suppl 1):173, 1975. 39. Feldman KW, and Smith DW: Fetal phallic growth and penile standards for newborn male infants, J PEDIATR 86:395, 1975. 40. Simpson JL: Disorders of sexual differentiation, etiology and clinical delineation, New York, 1976, Academic Press, Inc., p 219.
August 1980 TheJournalofPEDIATRICS
Embryonic testicular regression syndrome: Variable phenotypic expression in siblings Two 46,XY agonadal siblings with variable degrees of sexual ambiguity are described. The eldest chiM is a phenotypic male with micropenis. The younger patient, a phenotypic female with slight fusion of the genital folds and absent mi~llerian ducts, conforms to the criteria usually accepted for the diagnosis of true agonadism. Coexistence of anorchia and true agonadism in the same sibship supports the hypothesis, suggested by others, that both disorders are related and are due to the regression o f the embryonic testes.
N a t h a l i e J o s s o * and Marie-Louise Briard, Paris, F r a n c e
NORMAL SEX D I F F E R E N T I A T I O N o f the XY m a m m a l ian fetus is mediated by the fetal testis, which sequentially determines mtillerian duct regression, wolffian duct stabilization, closure o f the urogenital sinus and urethral groove, and growth o f the phallus: In experimental animals, castration o f male fetuses results in varying degrees of sexual ambiguity, depending on the developmental stage at which the testes have been removed: early castration produces a normal female phenotype with retention of mtillerian ducts,' whereas the same procedure, performed later in fetal life, results in hypospadias and enlargement of the prostatic utricle, but does not interfere with normal male differentiation of the internal genital tract:. In h u m a n subjects, testicular insufficiency during the second half o f pregnancy leads to micropenis without structural a b n o r m a l i t i e s of the genital tract, 3. ' whereas 46,XY patients with total gonadal aplasia are usually phenotypic females with normal miillerian ducts. 5 However, in rare instances, variable degrees o f virilization have been observed in 46,XY agonadal individuals: some are phenotypic males and others phenotypic females or intersexes lacking milllerian ducts. The term "true agonadism" has been coined to describe the latter situation. 6 It has been suggested that anorchia and true agonadism
From the Unit~ de Recherches de Gbnbtique Mbdicale. Supported by INSERM. *Reprint address: Unite de Recherches de Genetique Medicale, 1NSERM, Hospital des Enfants Malades, 149, rue de Sevres, 75730 Paris Cedex 15, France.
Vol. 97, No. 2, pp. 200-204
10
12
13 14
Fig. 1. Family pedigree of Patients 1 and 2. 9 - Fetal wastage; 11 10 pulmonary tuberculosis, married, no children; III 10 and 13: Normal 46,XX girls; IV 12 and 14 Patients I and 2.
represent related clinical entities due to regression o f the fetal testis at different developmental stages, r. ' The occurrence of both disorders in the same sibship lends support to this hypothesis and, to the best o f our knowledge, has not hitherto been reported. CASE REPORTS Patient 1. This is the third child of a family of five. The family pedigree is shown on Fig. 1. The parents are not related and inquiry revealed no sexual abnormality in either family. The high degree of fetal wastage in the patient's sibship could be related to closely spaced pregnancies in unfavorable socioeconomic conditions. No clinical or cytogenetic abnormalities were found in two sisters and an elder brother. The patient, reared as a boy, was admitted to a surgical ward at age 2 for repair of bilateral inguinal hernias. Bilateral cryptorchidism was noted at that time. At hernioplasty, a vas deferens was found on both sides, extending to the fundus of the hernial sac and then looping back to an incompletely descended epididymis, widely separated from a minuscule "testis-like" structure. Biopsy, performed only on the right side, revealed abundantly
0022-3476/80/080200+05500.50/0 9 1980 The C. V. Mosby Co.
Volume 97 Number 2
Embryonic testicular regression syndrome
20 1
Fig. 2. Genitography illustrating the variable degree of virilization of the urogenital sinus in the two siblings. Case 1: The urethra is that of a normal male except that the penile segment is extremely short. The pocket just below the bladder represents an enlarged prostatic utricle, the equivalent of the vagina in the male. Case 2: The bladder is not opacified; instead, a vagina of normal size but lacking a cervical imprint is demonstrated. B: bladder, V: vagina, P: prostatic utricle, U: urethra. vascularized fibrous tissue, with no identifiable testicular tubules. Both these structures were placed in the scrotum. The patient was brought to our attention in 1972 at age 10 years, because genital development was then thought to be abnormal. Clinical examination showed a child of normal stature and bone age, with no other congenital malformations. The phallus was 2.5 cm long, with the urethral orifice at its tip. The scrotum was empty, and urethrography demonstrated an enlarged prostatic utricle (Fig. 2). Karyotype was normal, 46,XY. Urinary gonadotropins were undetectable by bioassay. Plasma testosterone concentration, both before and after prolonged gonadotropin stimulation performed according to Saez et al, ~was 0.5 ng/ml, a value in the normal range for prepubertal children in the hospital laboratory at that time. Normal peripheral responsiveness to exogenous testosterone was documented by nitrogen balance studies on a constant intake of 10 gm/day: testosterone propionate (20 mg/m ~) during three days reduced urinary nitrogen excretion from 31.3 gm over a three-day control period to 19.1 gm during a treatment period of similar length. Testosterone therapy was initiated at age 12, but shortly afterward the patient's family moved and he was lost to follow-up. Patient 2. This is the youngest "sister" of Patient 1. She was considered a normal female at birth and was routinely examined at age 2, because of the abnormalities detected in her 10-year-old brother. Physical examination showed a child of normal stature, with no extragenital malformations. The clitoris was not enlarged and a single perineal orifice was visible. A urogenital sinus with a well-developed vagina was demonstrated radiologically (Fig. 2). Karyotype was 46,XY. Endocrine investigations revealed an increased gonadotropin excretion (3 to 25 MU). Plasma testoste-
rone concentration after hCG stimulation, performed as in Patient 1, was 0.3 ng/ml. At laparotomy (Pr. C. Nihoul-Feketr) the pelvis appeared empty, apart from two pea-sized structures located in an ovarian position, which were excised. Histologic examination revealed fibrous stroma (Fig. 3, A) with coexistence of mt~llerian (Fig. 3, B) and wolllian (Fig. 3, C) structures. Serial sections failed to reveal gonadal tissue. DISCUSSION Both siblings described in this report are genetic males with total absence o f g o n a d a l tissue. A g o n a d i s m was d e m o n s t r a t e d at l a p a r a t o m y a n d was confirmed by biochemical studies since n e i t h e r patient responded to gona d o t r o p i n stimulation, a test which has occasionally detected functional Leydig cells missed at surgery.' ..... Total bioassayable g o n a d o t r o p i n s were slightly elevated in the 2-year-old patient, b u t not in her 10-year-old brother. W i n t e r a n d F a i m a n I'~ a n d Conte et al TM have d o c u m e n t e d elevated serum levels o f g o n a d o t r o p i n s in a g o n a d a l children d u r i n g the first years of life. Contrasting with their identical gonadal status, our patients have m a r k e d p h e n o t y p i c differences. The eldest child, a phenotypic male with a hypoplastic but structurally n o r m a l penis, is an example o f congenital anorchia, a rare condition diagnosed in 0.56% o f cases o f bilateral cryptorchidism, l~ A n o r c h i c patients have complete internal a n d external male sex differentiation, a l t h o u g h persis-
202
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The Journal of Pediatrics August 1980
Fig. 3. Histologic structure of the rudimentary organ found in ovarian position in Patient 2. A, Fibrous tissue; B, mtillerian remnants; and C, wolffian remnants. (Periodic acid-Schiff; • 200.)
tence of mtillerian ducts has been reported in one instance '~ and reduced penile size in several. 16-19 Our second patient meets the criteria required for the diagnosis of"true agonadism," a syndrome initially described in siblings by Overzier and Linden s and subsequently reported in 16 additional sporadic cases 7. ~. . . . . . . ~l and in another pair of sibs? ~ These 46,XY agonadal patients have female or ambiguous external genitalia, with a blind and often shallow vagina. Congenital malformations, including ocular abnormalities, deafness, and low intelligence, have been described in two cases2 ~ 2~ At laparotomy, internal genital organs are represented by small ovoid structures, located on the lateral pelvic walls and containing rudimentary woltlian or mtillerian structures. "True agonadism" is distinguished from the Swyer syndrome, or "pure gonadal dysgenesis,''~ by the fact that in the latter condition miallerian ducts have differentiated normally into uterus and tubes, and external genital ambiguity is not observed, i.e., no sign of fetal testicular function, whether anti-miillerian or androgenic, can be detected. Pure gonadal dysgenesis is transmitted by either an X-linked recessive or a sex-limited dominant mutant geneS3. 2, which appears to block Y-mediated testicular differentiation. In true agonadlsm, there is evidence for adequate anti-miillerian and usually also for partial androgenic fetal testicular function. The fact that gonadotropin-responsive Leydig cells have been described in this condition H9 ~ lends further support to the hypothesis that testicular tissue must have been present at some time during development in this type of patient.
In the human male fetus, miillerian ducts begin to degenerate at the 30 mm stage (eight weeks after the mother's last menstrual period) and are completely regressed at 50 mm (10 weeks)? 5 However, we have shown in vitro that human miillerian ducts are no longer sensitive to testicular anti-mfillerian hormone after eight weeks? 6 This finding strongly suggests that m~llerian regression is induced by the fetal testis before that date and that degeneration is then irreversible and no longer requires the presence of fetal testicular tissue. Findings to that effect have been reported in the rat fetus by Donahoe et al. a7 Wolffian ducts, the excretory ducts of the mesonephros, do not initially require testosterone for their development but become androgen-dependent when renal function is taken over by the definitive kidney? ~ Exposure to testosterone then results in "stabilization" of wolffian ducts, i.e.,. wolffian ducts do not disappear if testosterone is subsequently withdrawn. The date at which human Wolflian ducts become stabilized is not known but is probably close to the 50 mm stage since female wolffian ducts degenerate at that time? 5 Masculinization of the external genitalia begins in fetuses 40 mm in crown-rump length (65 to 70 days) and is completed when the fetus reaches 70 mm (14 weeks). However, after fusion of the genital folds and formation of the penile urethra, the penis is only 3.5 mm long, approximately equal in size to the clitoris of the female embryo of the same age. Penile growth is mediated through pituitary-dependent testicular secretion between 16 weeks and term? 9
Volume 97 Number 2
In our elder patient, testicular failure occurred after miallerian regression, wolffian stabilization, and penile organogenesis, bui before the period of penile growth, probably during the fourth month of pregnancy. In the younger agonadic sibling, the testis triggered miillerian regression, achieved partial fusion of the genital folds, but did not stabilize the wolffian duct nor stimulate growth of the phallus; testicular failure probably occurred between the 40 and 50 m m stage, i.e., at the beginning o f the third month of pregnancy. The cause o f testicular degeneration during fetal life is not clear. In the present instance, testicular demise appears genetically determined, but available information does not allow us to distinguish between an autosomic recessive, sex-linked recessive, or sex-limited dominant mode of inheritance. Review of the literature shows that genetic factors, which play a prominent role in pure gonadal dysgenesis, 33. 3, are not paramount in all cases o f the embryonic testis regreSsion syndrome. Heritable tendencies toward anorchia do exist, but monozygotic twins are not always concordant for anorchia. "~ True agonadism has been described in siblings only twice ~. 32 if one excludes from the diagnosis the brothers described by Bergada et al, 7 in w h o m an infantile uterus was demonstrated and who are difficult to classify. Coexistence o f anorchia and true agonadism in the same family, reported here for the first time, confirms that both conditions are related and facilitated by a genetically determined predisposition, but sheds no light on the pathogenesis o f embryonic testicular degeneration. REFERENCES
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