Gonadal Disorders in Infancy and Early Childhood

BERNARD GONDOS, M.D.

Sansum Medical Research Foundation, Santa Barbara, CA 93105

ABSTRACT

Disorders of gonadal development can result from chromosomal, genetic, endocrine, or structural abnormalities. The different conditions may have similar clinical features, but behavior and management will vary depending on the particular diagnosis. Disorders that appear in infancy and early childhood are often associated with ambiguous genitalia or abnormal sexual development. Distinction is made on the basis of cyto genetic, hormonal, and, when indicated, histopathologic studies. The cur rent review groups the different abnormalities in the following categories: chromosomal and genetic disorders; structural defects; defective endo crine function; excessive endocrine activity. The principal conditions found in these categories are discussed in terms of pathogenesis and labo ratory procedures required to establish a precise diagnosis.

Introduction reviews on abnormalities of sexual differ entiation, there is need for a practical Evaluation of disorders of gonadal overview to aid in the classification and development involves consideration of differential diagnosis of such disorders at etiologic, clinical and pathophysiologic early stages of development. This review aspects. The complex interaction of mul will concentrate on those gonadal abnor tiple factors in normal and abnormal malities which can be detected in the gonadal differentiation requires a care newborn and early childhood periods. fully integrated conceptual framework in dealing with the developmental disorders. The current review utilizes General Considerations an approach based on correlation of pathologic entities with relevant genetic, The principal manifestation of gonadal chromosomal, biochemical, and clini developmental disorders in the neonatal cal findings encountered in the differ period is the presence of ambigu ent conditions. ous genitalia. Physical examination is The following diagnostic categories therefore key to the detection of such will be considered: chromosomal and abnormalities. Further evaluation will genetic disorders; structural defects; then include cytogenetic, biochemi defective endocrine function; excessive cal, and histopathologic studies, as indi endocrine activity. Although these sub cated, to distinguish among the differ jects have been dealt with in previous ent conditions.

0091-7370/91/0100-0062 $01.20 © Institute for Clinical Science, Inc. GONADAL DISORDERS IN EARLY DEVELOPMENT 63 Karyotypic and genetic abnormalities TABLE I can be detected early in development. Diagnostic findings may include the Disorders of Gonadal Development presence of an abnormal karyotype or a karyotype that is not consistent with the Chromosomal and Genetic Defects Turner's syndrome phenotypic sex. If evaluation indicates Pure gonadal dysgenesis that the chromosomal pattern is consis Mixed gonadal dysgenesis tent with the phenotypic sex, then other True hermaphroditism Kllnefelter's syndrome disorders included in the differential Trisomy X diagnosis need to be considered. Appro XYY syndrome priate hormonal studies will often Y chromosome abnormalities provide the necessary information in Autosomal defects these situations. In some cases, surgical Structural Defects exploration and tissue studies may be Testicular regression syndrome required to establish the diagnosis. Germ cell aplasia Gonadectomy may also be performed Splenogonadal fusion Accessory gonadal tissue to eliminate the risk of neoplasm Cystic dysplasia of testis development. Ectopic adrenal tissue Cryptorchidism Radiation effects Classification Chemotherapy effects Defective Endocrine Function The classification of disorders of Testosterone synthesis disorders gonadal development in table I is based Androgen Insensitivity syndrome Testosterone reduction defect on a separation into pathophysiologic Persistent Mullerian duct syndrome categories. Other classifications may uti Leydig cell hypoplasia lize distinction by gonadal morphology Hypogonadotroplc hypogonadism and phenotypic appearance, i.e., male Excessive Endocrine Activity pseudohermaphroditism, female pseu Gonadotropin-dependent premature dohermaphroditism. For the pathologist, development it seems most useful to group the dis Gonadotropin-independent premature orders according to their underlying eti development ology and pathogenesis. Chromosomal and genetic disorders include a wide variety of abnormalities. The common feature is the gonadal streak (gonadal dysgenesis) or some disorders are recognized in the newborn other abnormality of gonadal differentia period. The two most common disorders tion. The underlying disorders range in this group (Turner’s syndrome, Kline from a missing sex chromosome (Turner’s felter’s syndrome) are not associated syndrome) to supernumerary sex chro with abnormalities of the external geni mosomes (Klinefelter’s syndrome) to sex talia at birth and are generally not diag chromosome abnormalities to autosomal nosed until much later in development abnormalities associated with aberrant or adulthood. gonadal development. In addition, there Structural defects in gonadal develop are some conditions with a normal karyo ment constitute a heterogeneous group. type but with genetic defects resulting in The abnormal differentiation in these abnormal gonadal development. Only conditions is not associated with evident some of the chromosomal and genetic karyotypic abnormalities or with any 64 GONDOS characteristic pattern of endocrine dys activity is independent of gonadotro function. Thus, other etiologic factors pin stimulation can be diagnosed in must be involved, but with the exception early childhood. of those abnormalities resulting from The remainder of this review will be exposure to radiation or chemotherapy devoted to consideration of those condi effects, the cause is generally unknown. tions associated with gonadal abnormali Some of the conditions are of no special ties in infancy and early childhood. In clinical significance and may be recog table II are indicated the major findings nized only at surgical exploration for useful in the differential diagnosis of unrelated reasons or as incidental find these disorders. ings at autopsy. Testicular regression and cryptorchidism are conditions of special

importance because of problems in dif G o n a d a l D y s g e n e s is ferential diagnosis and the potential for germ cell neoplasia. The different forms of gonadal dysgene Defects in endocrine function gener sis constitute a complex group of dis ally occur in males with a normal 46, XY orders resulting from chromosomal karyotype but with characteristic pheno anomalies that produce defective typic abnormalities. Fetal androgen gonadal development. Abnormalities secretion is essential for normal sex dif may result from chromosome loss or X ferentiation in males, but there is not a chromosome defects, as in Turner’s syn corresponding role for fetal sex hor drome, autosomal recessive gene defects mones in female genital tract develop (46,XX pure gonadal dysgenesis), or X- ment. Consequently, the preponderance linked recessive gene defects (46,XY of disorders in this group occurs in pure gonadal dysgenesis). In these con genetic males. Since androgen produc ditions, diagnosis is most often made at tion normally begins early in fetal devel the time of puberty based on findings opment, conditions of defective endo such as primary amenorrhea, elevated crine function are often evident at the gonadotropins, and characteristic soma time of birth. This is not always the case, tic abnormalities. as in the androgen insensitivity syn The clinical and pathologic features of drome (testicular feminization), in which mixed gonadal dysgenesis enable diag the external genitalia appear to be nor nosis in the newborn period. In this con mal female, and the disorder may not be dition, presence of a streak gonad on one recognized until the time of puberty or side and a dysgenetic testis on the other later. Diagnosis as soon as possible is, is the typical abnormality which can however, extremely important because result in ambiguous genitalia. The eti of the increasing risk for neoplasia. ology of mixed gonadal dysgenesis Excessive endocrine activity asso includes a variety of possible defects ciated with early gonadal development is such as translocation, deletion, or other commonly referred to as precocious abnormality of the Y chromosome.26 Sex puberty. Most of the disorders result chromosome mosaicism is often the from hypothalamic or pituitary abnor result. The most frequent karyotype is malities and the gonadal disorders are 45,X/46,XY, but other variants also secondary to excessive gonadotropin occur. Patients may be phenotypically stimulation. The manifestations charac male or female or have ambiguous geni teristically become evident in mid and talia. The risk for neoplasia in this condi late childhood rather than the newborn tion is greatly increased, and gonadec- period. In contrast, certain primary tomy is recommended. In individuals defects in which the premature gonadal with gonadal dysgenesis, presence of a Y GONADAL DISORDERS IN EARLY DEVELO PM ENT 65 TABLE II Gonadal Disorders In Infancy and Early Childhood Type Etiology Phenotype Karyotype Gonads Mixed gonadal Chromosome Variable 45,X/46,XY a Streak/dysgenetic dygenesfs abnormality testis True hermaphro Chromosome Variable 46,XX a Ovarian and ditism and/or gene testicular tissue abnormality Testicular Unknown Variable 46,XV Absent/streak or regression rudimentary syndrome testes Cryptorchidism Unknown Male 46.XY Testes with pro gressive germ cell depletion Androgen Gene-related Variable 46 .XY Testes with germ synthesis enzyme cell depletion. defects defects Leydig cell hyperplasia Androgen Gene-related Female or 46.XY Testes with germ insensitivity receptor male b cell depletion. syndrome disorders Leydlg cell hyperplasia 5a-reductase Gene-related Female at birth. 46.XY Testes with progres deficiency enzyme defect male at puberty sive germ cell depletion Persistent Gene-related Male 46.XY Testes with minimal Mullerian duct antlmullerian changes hormone defect Leydlg cell Unknown Female 46,XY Testes with absent hyperplasia or sparse Leydlg cells Gonadotropin- Unknown; Male 46 .XY Testes with pre independent familial mature germ cell male sexual and Leydlg cell precocity development a Other karyotypes occur b Depends on type

chromosome, and lack of testicular T r u e H ermaphroditism descent, the likelihood of tumor devel opment is estimated at 25 to 30 per The presence of both ovarian and tes cent.17 While the risk for neoplasia may ticular tissue in the same or opposite be related to the associated testicular gonads is referred to as true hermaphro maldescent, factors responsible for the ditism. This anomaly may result from sex dysgenetic development may also play a chromosome mosaicism, chimerism, ro le.20 Gonadoblastoma is well recog translocation, or an autosomal mutant nized as the characteristic form of neo gene.23 The diagnosis should be consid plasia. More recently, intratubular germ ered in all patients with ambiguous geni cell neoplasia has been described in talia. Chromosome patterns most often mixed gonadal dysgenesis.16 Both forms encountered are 46,XX and 46,XX/ can lead to invasive germ cell tumors. 46,XY mosaicism. The diagnosis can be 66 GONDOS established only after histologic examina cent of infants. Cryptorchidism, in tion of the gonads. There may be an which the testis is located along the ovary on one side and a testis on the normal route of descent but has not other, bilateral ovotestes, or an ovotestis reached a normal scrotal position, is on one side and an ovary or a testis on the most common situation. This is to the other. Ultrastructural examination be distinguished from the retractile has indicated that the gonadal elements testis which is undescended at birth are immature rather than structurally but undergoes spontaneous descent abnormal.19 during the first few months of life and Patients are at increased risk for functions normally thereafter. Cryptor gonadal neoplasms. The degree of risk chidism must also be distinguished has not been established, but it is evi from the ectopic testis which is located dent that presence of a Y chromosome is outside the normal route of descent. not required for tumor development.14 The etiology and pathogenesis of crypt orchidism are poorly understood. In T e s t ic u l a r R e g r e s s io n S y n d r o m e some cases, endocrine abnormalities seem to be involved whereas in other The testicular regression syndrome instances mechanical and intrinsic (gonadal agenesis, anorchia, embryonic testicular factors appear to be responsi- testicular dysgenesis, vanishing testis syn b l e . 9 No specific chromosomal drome) refers to a heterogeneous group of or genetic abnormalities have been conditions occurring in individuals with a consistently associated with 46, XY karyotype and lack of or rudimen cryptorchidism. tary testicular tissue. These patients may The diagnosis is usually established have female, male, or ambiguous external by physical examination. Since descent genitalia and poorly developed internal into the scrotum may occur during the structures. The gonads are either absent first few months after birth, the diag or small, accounting for the various terms nosis of cryptorchidism cannot be that have been used to describe this established with certainty prior to one anomaly. Since neither genetic nor chro year of age. Lack of descent is much mosomal abnormalities have been identi more frequent in premature than in fied in these patients, the pathogenesis full-term infants. Determination of the most likely relates to developmental most appropriate management of defects occurring during early testicu cryptorchidism is complicated by lack lar differentiation .2,3 of definite information concerning the The pathologic changes in the testicu age at which irreversible damage to the lar regression syndrome are variable. In maldescended testis occurs. some cases a thorough search fails to The risk of germ cell neoplasia is reveal any gonadal tissue, whereas in greatly increased in individuals with other situations streak gonads can be cryptorchidism. Approximately 10 per found. The latter may include primitive cent of patients with testicular tumors testicular cords containing germ cells have a history of cryptorchidism .5 and Sertoli cells, and Leydig cells are The relative risk of cancer in cryptor- occasionally present. Removal of the chid testes has been reported as gonadal tissue is required as a precaution 10 to 40 times that in normally against neoplasia. descended testes.13

C ryptorchidism A n d r o g e n S y n t h e s is D e f e c t s

Maldescent of the testis is a complex Defects in testosterone synthesis can condition occurring in 0.5 to one per result in incomplete virilization during GONADAL DISORDERS IN EARLY DEVELO PM ENT 67 fetal development in individuals with a The testes of patients with the andro normal 46,XY karyotype. Deficiencies gen insensitivity syndrome are at risk for can occur at any of the five enzymatic germ cell neoplasia. The incidence steps required for the conversion of cho increases with age.12 In addition, nodu lesterol to testosterone. Three of the lar aggregates of seminiferous cords reactions are also involved in glucocorti filled with Sertoli cells may appear in the coid synthesis, so that in certain cases gonads of patients with this condition. both adrenal and gonadal effects can be The nodules are usually small but may present. The disorders are inherited in be confused with neoplastic tissue at the an autosomal recessive or X-linked time of surgical exploration. Most recessive fashion.25 Some individuals are authorities consider them developmental severely affected and have little or no malformations, to be distinguished from evidence of male phenotypic develop Sertoli cell neoplasms which are large ment, whereas other patients have mini and replace the testicular parenchyma.15 mal abnormalities. Depending on the type and severity of the disorder, clinical 5a-REDUCTASE D e f i c i e n c y findings may include hypospadias and ambiguous genitalia with or without an The tissues of patients with 5a-reduc- associated adrenal insufficiency. The tase deficiency cannot reduce testoster gonads are in an abdominal or inguinal one to 5a-dihydrotestosterone, a condi location or in the labioscrotal folds. tion which results in incompletely Pathologic changes in the testis are sec developed male genitalia. The defect is ondary, including prominent sheets transmitted as an autosomal recessive of Leydig cells of fetal type and semi trait and produces a characteristic abnor niferous tubules containing only Sertoli mality of the external genitalia formerly cells.8 called pseudovaginal perineoscrotal hypospadias.24 Although the phenotypic appearance at birth is female or ambigu

A n d r o g e n I nsensitivity S y n d r o m e ous, male sexual maturation becomes evident at puberty.10 The diagnosis can Androgen receptor deficiency in tar be established by demonstrating an ele get tissues may be the basis for abnormal vated testosterone to dihydrotestoster development of phenotypic sex in indi one ratio. viduals with 46,XY karyotype, bilateral The condition is not a primary gonadal testes, and normal testosterone produc disorder, but the defective formation of tion. Complete androgen insensitivity, dihydrotestosterone can result in tes also known as complete testicular femini ticular abnormalities. Lack of descent zation, is an X-linked recessive disorder is commonly present. Other effects in which the external genitalia and sec may include diminution of germ cells ondary sex characteristics are unambigu and abnormal maturation at the time ously female.7 Incomplete androgen of sperm atogenesis.11 insensitivity is much less frequent than the complete form, but because it is P e r s i s t e n t M u l l e r i a n D u c t S y n d r o m e associated with some degree of ambigu ity of the external genitalia is more likely Defects in the regression of the Mul to be detected in the newborn or early lerian ducts in the male fetus can occur childhood period. In contrast to the secondary to abnormalities in the syn complete form, Wolffian duct deriva thesis or action of antimullerian hormone tives are present although not com produced by the Sertoli cells.22 Affected pletely developed. individuals have a 46,XY karyotype, 68 GONDOS male external genitalia, bilateral testes, pituitary system, it is important to distin and Wolffian duct derivatives as well as guish this disorder from gonadotropin- an uterus and uterine tubes. The condi dependent forms of male sexual tion is usually uncovered during repair of precocity. an inguinal hernia and was formerly known as uteri herniae inguinale. Most Sum mary patients have cryptorchid testes and reduced tubular diameters. As in other Disorders of gonadal development forms of testicular maldevelopment, become evident at various stages of mat there is an increased risk of subsequent uration depending on the clinical mani germ cell neoplasms.21 festations. Some of the conditions are diagnosed only at puberty as a result of

L e y d ig C e l l H y p o p l a s ia impaired sexual development or in adulthood during evaluation for infer Failure of normal fetal Leydig cell tility. Those disorders that appear in development results in testosterone infancy and early childhood may present deficiency and lack of virilization .1 special problems in differential diag Patients have female external genitalia nosis. The finding of ambiguous genitalia associated with undescended testes and in the newborn period or premature no Mullerian structures. In contrast to sexual development in early childhood gene-related disorders of testosterone can be produced by a variety of causes. synthesis, there is normal Wolffian duct Arriving at a proper diagnosis depends development indicated by the presence on careful evaluation of cytogenetic, of epididymides and vasa deferentia.4 hormonal, and morphologic data. These This implies that the defect in Leydig findings, in correlation with clinical cell function is secondary. Pathogenesis presentation and family history, should is unclear but may be related to either indicate the particular abnormality and effects on Leydig cell differentiation or the risk for neoplasia. Understanding of unresponsiveness of fetal Leydig cells to the pathogenesis and classification of the gonadotropins. different disorders is critical in deter mining the need for gonadectomy and

G onadotropin -I n d e p e n d e n t further management. S e x u a l P r e c o c it y References A recently described form of male sexual precocity involves excessive tes 1. B r o w n , D . M ., M a r k l a n d , C ., and D e h n e r , L. P.: Leydig cell hypoplasia: A cause of male tosterone production in the absence of pseudohermaphroditism. J. Clin. Endocrinol. pituitary stimulation.18 This condition Metab. 46:1-7, 1978. differs from true or central precocious 2. C o u l a m , C . B.: Testicular regression syndrome. puberty in that premature Leydig cell Obstet. Gynecol. 53:44-49, 1979. 3. E d m a n , C. D ., W in t e r s, A. J., P o r te r , J. C., activation and initiation of spermato W il s o n , J., and M a c D o n a l d , P. C .: E m bry genesis are not gonadotropin-depen onic testicular regression: A clinical spectrum of XY agonadal individuals. Obstet. Gynecol. dent. Findings of premature sexual 49:208-217, 1977. development typically appear early in 4. E i l , C ., A u s t i n , R. M ., S e s t e r h e n n , I ., childhood. The disorder exhibits a male- D u n n , J. F ., C u t l e r , G. B., and Jo h n s o n - b a u g h , R. E .: Leydig cell hypoplasia causing limited autosomal-dominant inheritance male pseudohermaphroditism: Diagnosis 13 pattern, and the evidence supports a pri years after prepubertal castration. J. Clin. Endo mary testicular defect.6 In view of the crinol. Metab. 58:441-448, 1984. 5. G il b e r t , J. B. and H a m il t o n , J. B.: Studies in familial nature of the condition and its malignant testis tumors. Surg. Gynecol. Obstet. lack of dependence on the hypothalamic- 71:731-743, 1940. GONADAL DISORDERS IN EARLY DEVELOPMENT 69

6. G o n d o s , B ., E g l i, C . A ., Ro s e n t h a l , S. M ., with 45,X/46,XY gonadal dysgenesis. J. Pediat. and G r u m b a c h , M. M.: Testicular changes in 106:431-436, 1985. gonadotropin-independent familial male sexual 17. Robboy, S. J., M il l e r , T., D o n a h o e , P. K ., et precocity: Familial testotoxicosis. Arch. Pathol. al.: Dysgenesis of testicular and streak gonads in Lab. Med. 109:990-995, 1985. the syndrome of mixed gonadal dysgenesis. 7. G r if f in , J. E. and W il s o n , J. D .:D isorders of Hum. Pathol. 13:700- 716, 1982. androgen receptor function. Ann. N.Y. Acad. 18. Ro s e n t h a l , S. M ., G r u m b a c h , M. M., and Sei. 438:61-71, 1984. K a p l a n , S. L.: Gonadotropin-independent 8. G r u m b a c h , M . M . and C o n t e , F. A.:Disorders familial sexual precocity with premature Leydig of sexual differentiation. In: Wilson, J. D. and and germinal cell maturation (“familial testotoxi Foster, D. W., eds. Textbook of Endocrinology, cosis”): Effects of a potent luteinizing hormone- 7th ed. Philadelphia, W.B. Saunders, 1985, pp. releasing factor agonist and medroxyprogester 312-401. one acetate therapy in four cases. J. Clin. 9. H adzISELIMOVIC, F.: Cryptorchidism: Manage Endocrinol. Metab. 57:571-579, 1983. ment and Implications. Berlin, Springer-Verlag, 19. R o t h , L. M ., C l e a r y , R . E ., an d H o k u m , 1983. W. L.: Ultrastructure of an ovotestis in a case of 10. Im pe r a t o -M c G in l e y , J., P e t e r s o n , R. E., and true hermaphroditism. Obstet. Gynecol. G a u t ie r , T.: Primary and secondary 5a-reduc- 48:619—624, 1976. tase deficiency. In: Serio, M., Motta, M., Zanisi, 20. S c h e l l h a s , H. F.: Malignant potential of the M., and Martini, L., eds. Sexual Differentiation: dysgenetic gonad. Obstet. Gynecol. 44:398- Basic and Clinical Aspects, New York, Raven 399, 1974. Press, 1984, pp. 233-245. 21. S im p s o n , J. L. and P h o t o p u l o s, G.: the rela 11. Jo h n s o n , L., G e o r g e , F. W., N e a v e s, W. B., tionship of neoplasia to disorders of abnormal et al.: Characterization of the testicular abnor sexual differentiation. Birth Defects 22(1):15- mality in 5a-reductase deficiency. J. Clin. Endo 50, 1976. crinol. Metab. 63:1091-1099, 1986. 22. S l o a n , W. R. and W a l s h , P. C.: Familial per 12. M a n u e l , M ., K a t a y a m a , K . P., and Jo n e s , sistent müllerian duct syndrome. J. Urol. H. W., Jr.: The age of occurrence of gonadal 215:459-461, 1976. tumors in intersex patients with a Y chromo 23. v a n N ie k e r k , W. A.: True hermaphroditism: An some. Am. J. Obstet. Gynecol. 224:293-300, analytic review with a report of 3 new cases. Am. 1976. J. Obstet. Gynecol. 126:890-905, 1976. 13. M a r t in , D. C.: Malignancy and the unde 24. W a l s h , P. C ., M a d d e n , J. D ., H a r r o d , M . J., scended testis. In: Fonkalsrud, E. W. and Men- G o l d s t e i n , J. L ., M a c D o n a l d , P. C ., an d gel, W., eds. The Undescended Testis. Chicago, W il s o n , J. D .: Familial incomplete male pseu Year Book Medical Publishers, 1981, pp. dohermaphroditism, type 2: Decreased dihydro 144-156. testosterone formation in pseudovaginal peri 14. M c D o n o u g h , P. G ., B y r d , J. R ., T h o , P. T., neoscrotal hypospadias. New Engl. J. Med. and O t k e n , L.: Gonadoblastoma in a true her 291:944-949, 1974. maphrodite with a 46,XX karyotype. Obstet. 25. W il s o n , J. D ., and G o l d s t e in , J. L .: Classifica Gynecol. 47:355-358, 1976. tion of hereditary disorders of sexual develop 15. M o s t o f i, F. K. and P r ic e , E . B .: Tumors of the ment. Birth Defects 22(4):l-6, 1975. Male Genital System. Washington, Armed 26. ZÄH, W ., Ka l d e r o n , R. E ., and T u cci, J. R.: Forces Institute of Pathology, 1973. Mixed gonadal dysgenesis: A case report and 16. M ü l l e r , J., S k a k k e b a e k , N . E ., Rit z e n , M ., e t review of the world literature. Acta Endocrinol. al.: Carcinoma in situ of the testis in children 79(Suppl. 197):3-39, 1975.