Gonadal Disorders in Infancy and Early Childhood

ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 21, No. 1 Copyright © 1991, Institute for Clinical Science, Inc. 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

Load more