46,XX pure gonadal dysgenesis with growth hormone deficiency and impaired 3β-hydroxysteroid dehydrogenase activity

Patients with 46,XX pure gonadal dysgenesis generally are of normal stature and have less than usual amounts of pubic and axillary hair. We report on a patient who presented at age 11.9 years with short stature, absence of breast development, and excessive pubic hair. Her karyotype in leukocytes, fibroblasts, and streak gonad was 46,XX. The patient was diagnosed as having growth hormone deficiency. Elevated ACTH stimulated levels of 17-hydroxypregnenolone and dehydroepiandrosterone and elevated ACTH stimulated ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone suggested inadequate adrenal 3β-hydroxysteroid dehydrogenase activity. Treatment with growth hormone resulted in improvement in growth velocity and replacement with estrogen in feminization. We suggest that the finding of short stature in patients with 46, XX pure gonadal dysgenesis should not be attributed to the syndrome, but rather requires investigation for possible growth hormone deficiency. The poor growth of our patient prior to growth hormone replacement implies that dehydroepiandrosterone, unlike testosterone and estrogen, is ineffective in promoting linear growth in the absence of adequate growth hormone.     

Turner's syndrome with concomitant hypopituitarism: case report

The unique case of a young woman with concomitant pituitary insufficiency and gonadal dysgenesis due to Turner's syndrome is described. At the age of 17 years, when first examined elsewhere, this patient was prepubertal and short and a diagnosis of growth hormone deficiency was made. One year later, while on growth hormone (GH) substitution, thyrotrophin deficiency and hypogonadotrophic hypogonadism were confirmed and thyroxine and sex steroid substitution therapy was initiated. Upon evaluation in our clinic, at the age of 30 years, the low final height achieved with the GH substitution therapy, a number of clinical characteristics and the absence of ovarian tissue on ultrasound led to examination of the patient's karyotype, which revealed concurrent gonadal dysgenesis due to Turner's syndrome. This case illustrates that the co-existence of primary and secondary hypogonadism may obscure and delay the diagnosis of Turner's syndrome, a diagnosis which alters the counselling of the patient from the reproductive perspective.     

Growth hormone deficiency and growth hormone therapy in Ullrich-Turner-Syndrome

Summary In a girl with Ullrich-Turner-Syndrome (gonadal dysgenesis 45, XO) and growth hormone deficiency, 10 U of human growth hormone/m² body surface area/week increased the growth rate from 2.0 to 4.1 cm/year. Doses of up to 36 U/m²/week did not improve the growth rate in 4 girls with Ullrich-Turner-Syndrome who had normal plasma growth hormone concentration and incretion. We conclude that growth hormone therapy is unsuccessful in dwarfism in Ullrich-Turner-Syndrome and should be reserved for patients with proven growth hormone deficiency.Supported by Deutsche Forschungsgemeinschaft, SFB 51/C10     

Comparison of adult height between patients with XX and XY gonadal dysgenesis: support for a Y specific growth gene(s).

Adult height was compared between published cases of patients with XX gonadal dysgenesis (XXGD) and those with XY gonadal dysgenesis (XYGD). The mean adult height of XYGD patients (171.0 cm (SD 7.8), n = 27) was significantly greater than that of XXGD patients (164.4 cm (7.7), n = 27) (p less than 0.01). This finding supports the existence of a Y specific growth gene(s) which promotes statural growth independently of the effects of gonadal sex steroids.     

The X linked recessive form of XY gonadal dysgenesis with a high incidence of gonadal germ cell tumours: clinical and genetic studies.

Five phenotypic females in one family had the genotype 46,XY and all had gonadal germ cell tumours. Studies of the family pedigree suggest that this form of XY gonadal dysgenesis is inherited in an X linked recessive manner. G banding of elongated metaphase chromosomes from two subjects with XY gonadal dysgenesis and a female carrier showed no aberrations of the X chromosome. The titres of H-Y antigen in three girls with XY gonadal dysgenesis were in the male control range. Thus it appears that, in the X linked form, XY gonadal dysgenesis may be caused by a point deletion or mutation of a gene on the X chromosome, which controls the gonad specific receptor for the H-Y antigen. Studies of Xg blood groups were uninformative about linkage of Xg with the X borne gene causing the XY gonadal dysgenesis. Dermatoglyphic studies in the girls with XY gonadal dysgenesis and female carriers revealed high a-b palmar ridge counts and a tendency for the A mainline to terminate in the thenar area. Both of these features have been described in patients with Turner's syndrome.     

46,XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred

46,XY gonadal dysgenesis is characterized by abnormal testicular determination. We describe a large kindred in which various disorders of sexual development were observed, ranging from completely female phenotype without ambiguities of the external genitalia (five cases) to men with isolated penile or perineal hypospadias (four cases), including two cases with moderate virilization and one case with ambiguity of the external genitalia. Histologic examination of gonadal tissue was performed on seven subjects. These findings were suggestive of complete gonadal dysgenesis in one patient, partial gonadal dysgenesis in three patients, and mixed gonadal dysgenesis in three patients. Four patients developed gonadal tumors (two gonadoblastoma, two dysgerminoma, and one immature teratoma, i.e., one patient had a dysgerminoma with some areas of gonadoblastoma). All affected subjects had no other congenital anomalies or dysmorphic features. Analysis of families with several affected individuals with 46,XY gonadal dysgenesis implied an X-linked mode of inheritance because of the apparent absence of male-to-male transmission. However, a sex-limited autosomal dominant mode of inheritance affecting only XY individuals could not be ruled out. Analysis of the pedigree we report indicated an autosomal dominant mode of inheritance because of male-to-male transmission. This kindred supports the involvement of at least one autosomal gene in non-syndromic 46,XY gonadal dysgenesis.     

46,XX pure gonadal dysgenesis with growth hormone deficiency and impaired 3 beta-hydroxysteroid dehydrogenase activity.

Patients with 46,XX pure gonadal dysgenesis generally are of normal stature and have less than usual amounts of pubic and axillary hair. We report on a patient who presented at age 11.9 years with short stature, absence of breast development, and excessive pubic hair. Her karyotype in leukocytes, fibroblasts, and streak gonad was 46,XX. The patient was diagnosed as having growth hormone deficiency. Elevated ACTH stimulated levels of 17-hydroxypregnenolone and dehydroepiandrosterone and elevated ACTH stimulated ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone suggested inadequate adrenal 3 beta-hydroxysteroid dehydrogenase activity. Treatment with growth hormone resulted in improvement in growth velocity and replacement with estrogen in feminization. We suggest that the finding of short stature in patients with 46,XX pure gonadal dysgenesis should not be attributed to the syndrome, but rather requires investigation for possible growth hormone deficiency. The poor growth of our patient prior to growth hormone replacement implies that dehydroepiandrosterone, unlike testosterone and estrogen, is ineffective in promoting linear growth in the absence of adequate growth hormone.     

Mapping a gene for 46,XY gonadal dysgenesis by linkage analysis

46,XY gonadal dysgenesis was transmitted as an autosomal-dominant trait in a large family with multiple affected members. Expressivity of the trait was highly variable, ranging from pure to partial gonadal dysgenesis associated with normal female genitalia or sexual ambiguity, to mild hypospadias in otherwise normal males. The phenotypic features of this trait appeared to be confined to the genitourinary system. Multipoint parametric analysis using markers D5S664, D5S633, and D5D2102 yielded an LOD score of 4.47, assuming sex-limited, autosomal-dominant inheritance with a penetrance of 0.6. Because mutation in testis-determining genes leads to gonadal dysgenesis in 46,XY individuals, we postulate that the gene mapped by this study normally plays a role in gonadal differentiation.     

Brief historical note: The concept of “gonadal dysgenesis”

The history of gonadal dysgenesis cautions against overinterpretation of data: The streak gonads are neither the result of dysgenesis nor of embryonic origin but represent late fetal/neonatal degeneration; the X-chromatin-negative character of the buccal smear and the frequency of color vision defects did not indicate male sex in the Ullrich-Turner syndrome but rather an XO constitution; severity of dysgenesis did not correlate with risk of gonadal neoplasia but with genotype; the gonadal lesion in the Ullrich-Turner syndrome was not due to a pituitary defect but a primary ovarian lesion; patients with the Noonan syndrome do not have the Turner phenotype. The concept of gonadal dysgenesis, introduced by Kermauner in 1912, has outlived its usefulness. Improved methods of phenotype analysis, family studies, and endocrine and cytogenetic methods have shown it to be causally and pathogenetically heterogeneous and have contributed to a better identification and delineation of the several different genetic entities which it formerly comprised.     

Brief historical note: the concept of "gonadal dysgenesis".

The history of gonadal by dysgenesis cautions against overinterpretation of data: The streak gonads are neither the result of dysgenesis nor of embryonic origin but represent late fetal/neonatal degeneration; the X-chromatin-negative character of the buccal smear and the frequency of color vision defects did not indicate male sex in the Ullrich-Turner syndrome but rather an XO constitution; severity of dysgenesis did not correlate with risk of gonadal neoplasia but with genotype; the gonadal lesion in the Ullrich-Turner syndrome was not due to a pituitary defect but a primary ovarian lesion; patients with the Noonan syndrome do not have the Turner phenotype. The concept of gonadal dysgenesis, introduced to Kermauner in 1912, has outlived its usefulness. Improved methods of phenotype analysis, family studies, and endocrine and cytogenetic methods have showen it to be causally and pathogenetically heterogeneous and have contributed to a better identification and delineation of the several different genetic entities which it formerly comprised.     

Gonadoblastoma in a patient with an isodicentric X chromosome

Although gonadoblastoma is known to be associated with the presence of a Y chromosome, this case report of a 15-year-old patient with gonadal dysgenesis, gonadoblastoma, and an idic(Xq-) chromosome provides evidence for the occurrence of gonadoblastoma even in the absence of a Y chromosome. A review of previous cases reported to have gonadoblastoma in the absence of a Y chromosome revealed that the presence of some breast development was the common denominator among those patients. Therefore, a patient who presents with gonadal dysgenesis with some breast development, but lacks a Y chromosome may observe as close scrutiny as the patient with gonadal dysgenesis in the presence of a Y chromosome.     

46,XX gonadal dysgenesis with epibulbar dermoid

Pure gonadal dysgenesis with 46,XX genotype is a rare abnormality with unknown etiology. Although sensorineural deafness has been described with 46,XX gonadal dysgenesis, the majority of reported cases of 46,XX gonadal dysgenesis have no associated physical abnormalities. We report a patient with 46,XX gonadal dysgenesis associated with epibulbar dermoids and preauricular skin tags, the classic ocular and skin manifestations of Goldenhar sequence (oculoauricular vertebral dysplasia). We propose that our patient may represent a new and previously unreported syndrome.     

XY gonadal dysgenesis associated with a multiple pterygium syndrome phenotype

Most phenotypic females with an XY male karyotype do not have significant extra-genital anomalies; however, some patients with additional abnormalities have been described. We report on an individual with XY gonadal dysgenesis, mental retardation, microcephaly, growth retardation, and multiple pterygia. Although not previously reported, the possible relationship between these findings is discussed in the context of evident heterogeneity of XY gonadal dysgenesis. Am. J. Med Genet. 68:7–11, 1997 © 1997 Wiley-Liss, Inc.     

性腺发育不全患者荧光原位杂交和BAC-FISH的诊断

目的 探讨荧光原位杂交(fluorescence in situ hybridization,FISH)和BAC-FISH(bacterial artificial Chromosonle-FISH)在性腺发育不全患者临床医学遗传学诊断中的应用.方法 对5例临床检查诊断为性腺发育不全患者进行染色体荧光Q显带、G显带核型分析、FISH和BAC-FISH等分子-细胞遗传学检查诊断.结果 5例性腺发育不全患者中2例为46,XY核型的单纯性性腺发育不全,另外3例分别为45,X/47,XXX;45,X/46,XY或45,X/46,X,der(Y)嵌合体核型的混合性性腺发育不全.结论 性染色体的异常是导致患者性腺发育不全的原因,结合应用FISH和BAC-FISH等分子-细胞检测技术可为性腺发育不全患者的临床诊断和治疗提供准确的医学遗传学依据.     

H-Y antigen generating and receptor systems in abnormal sexual development

This paper reports data from one case of XY gonadal dysgenesis and one case of XY mixed gonadal dysgenesis. Their H-Y antigen expression was determined on peripheral blood leukocytes and on gonad-derived fibroblasts. The former case was found to be H-Y negative while the latter was H-Y positive. The origin of these disorders is discussed in terms of mutations affecting the H-Y antigen generating and receptor systems.     

Peritoneal mesothelioma in a male pseudohermaphrodite with asymmetrical gonadal differentiation

A diffuse peritoneal mesothelioma occurring in a patient with male pseudohermaphroditism and asymmetrical gonadal differentiation (mixed gonadal dysgenesis) is described. Malignancies of mesodermal origin, usually derivatives of the urogenital ridge, appear to occur with increased frequency in male pseudohermaphrodites. This appears to be the first reported instance of a mesothelioma in a male pseudohermaphrodite with mixed gonadal dysgenesis. The clinical and pathologic features of this tumor, including the electron microscopic findings, are presented.     

The occurrence of gonadal dysgenesis in association with monozygotic twinning.

A case is presented of a monozygotic twin pair, discordant for phenotypic sex, in which the female member showed gonadal dysgenesis and chromosomal mosaicism. Review of the pertinent literature reveals that in monozygotic twin pairs, phenotypic and karyotypic concordance is the usual occurrence for Down's and Klinefelter's syndromes, whereas discordance often accompanies gonadal dysgenesis. Mosaicism is a frequent concomitant of gonadal dysgenesis in monozygotic twins. Our case strengthens the probability of a real association between mosaicism and monozygotic twinning in gonadal dysgenesis.     

Gonadal dysgenesis in del(18p) syndrome

We report on a girl with syndromal gonadal dysgenesis and a de novo del(18p). Genetic factors controlling gonadal development are located not only on the X chromosome, but also on autosomes. The present case suggests that one of these genes is situated on 18p. We conclude that patients with del(18p) syndrome should be evaluated for gonadal dysgenesis. © 1995 Wiley-Liss, Inc.     

The Perrault syndrome: clinical report and review

We report on two Japanese sisters with Perrault syndrome, i.e., autosomal recessive ovarian dysgenesis associated with sensorineural deafness. They also had ataxic gait, pes equinovarus, nystagmus, limited extraocular movements, and short stature. One older affected sister had partial growth hormone deficiency. Our review included 21 patients from 8 families, including our patients; 16 are women with ovarian dysgenesis and deafness, 3 deaf males without gonadal defect, one a woman with ovarian dysgenesis without deafness, and one a girl with deafness in whom ovarian function was not evaluated. Perrault syndrome may not be uncommon; some cases may have gone unrecognized, especially when a single child in a family is affected.     

Association of deletion 9p, 46,XY gonadal dysgenesis and autistic spectrum disorder

Deletions of distal chromosome 9p24 are often associated with 46,XY gonadal dysgenesis and, depending on the extent of the deletion, the monosomy 9p syndrome. We have previously noted that some cases of 46,XY gonadal dysgenesis carry a 9p deletion and exhibit behavioural problems consistent with autistic spectrum disorder. These cases had a small terminal deletion of 9p with limited or no somatic anomalies that are characteristic of the monosomy 9p syndrome. Here, we present a new case of 46,XY partial gonadal dysgenesis and autistic spectrum disorder associated with a de novo deletion of 9p24 that was detected by ultra-high resolution oligo microarray comparative genomic hybridization. The deletion included the candidate sex-determining genes in the region DMRT1 and DMRT3. These data suggest that a gene responsible for autistic spectrum disorder is located within 9p24. It remains to be determined if the gonadal dysgenesis and autistic spectrum disorder are caused by a single gene or if they are caused by distinct genetic entities at 9p24.