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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1628-1632
Copyright © 1999 by The Endocrine Society

Original Studies

Gonadal Histology with Testicular Carcinoma in Situ in a 15-Year-Old 46,XY Female Patient with a Premature Termination in the Steroidogenic Acute Regulatory Protein Causing Congenital Lipoid Adrenal Hyperplasia

Eckhard Korsch, Michael Peter, Olaf Hiort, Wolfgang G. Sippell, Benno M. Ure, Berthold P. Hauffa and Martin Bergmann

Department of Pediatrics (E.K.), Childrens Hospital of Cologne, D-50735 Cologne; Department of Pediatric Endocrinology (M.P., W.G.S.), University of Kiel; Department of Pediatric Endocrinology (O.H.), University of Lübeck; Department of Pediatric Surgery (B.M.U.), Childrens Hospital of Cologne; Department of Pediatric Hematology/Oncology and Endocrinology (B.P.H.), University of Essen; and Department of Veterinary Anatomy (M.B.), University of Giessen, Germany

Address all correspondence and requests for reprints to: Eckhard Korsch, M.D., Department of Pediatrics, Childrens Hospital of Cologne, Amsterdamerstrasse 59, D-50735 Cologne, Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Mutations in the steroidogenic acute regulatory protein (StAR) gene cause congenital lipoid adrenal hyperplasia, characterized by diminished or absence of adrenal and gonadal steroids, resulting in severe adrenal insufficiency and ambiguous or complete female external genitalia in genetic males.

We report on a 15-yr-old 46,XY phenotypic female, referred because of lack of pubertal development. ACTH and gonadotropin concentrations were elevated; and aldosterone, cortisol and its precursors, and sex steroids before and after stimulation were below the lower limit of detection. In the StAR gene, a homozygous nonsense mutation (TGG -> TAG) in exon 7 (W250X) was identified. Histologic examination after gonadectomy showed seminiferous tubules containing immature Sertoli cells and a few single germ cells with positive placental-like alkaline phosphatase immunoreactivity, indicating carcinoma in situ.

This is the first report on testicular morphology, at a pubertal age, in a female patient with 46,XY karyotype and a mutation in the StAR gene, in whom gonadal neoplasia had developed.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL lipoid adrenal hyperplasia (CLAH) is an autosomal recessive inherited disorder, characterized by a deficiency of adrenal and gonadal steroid hormones (1). Recent studies have shown that mutations in the steroidogenic acute regulatory (StAR) gene cause this most severe genetic disorder in steroid hormone biosynthesis (2, 3, 4, 5).

StAR promotes the transfer of cholesterol to the inner mitochondrial membrane mediating the acute trophic regulation of steroid hormone synthesis (3, 6, 7). Mutations in the StAR gene may lead to a defect of the conversion of cholesterol to pregnenolone with the absence of nearly all steroids and a markedly elevation of the basal concentrations of ACTH and renin. Deficient adrenal steroidogenesis may lead to severe salt loss, cardiovascular collapse, and death if treatment is not initiated appropriately (4, 6). Deficient fetal testicular steroidogenesis most often results in phenotypically normal female genitalia in patients with 46,XY karyotype. In XY individuals with CLAH, testes are located either intraabdominally or in the inguinal canal. There is little information about testicular development in this disorder in older patients (8, 9, 10) and no information about patients in a pubertal age. Removal of nonfunctional undescended testes has been generally recommended because of the risk of malignant progression of testicular tissue, which has not been reported in patients with StAR defects yet (11, 12, 13). This is the first report on testicular morphology at a pubertal age influenced by high endogenous gonadotropin concentrations in a female patient with 46,XY karyotype and a mutation in the StAR gene, in whom gonadal neoplasia had developed.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patient history

This phenotypically normal female child was born spontaneously after 41 weeks of an uneventful gestation. Parents were of Serbian origin and were not related. Birth wt was 3280 g; birth length was 52 cm. At the age of 2 weeks, an inguinal hernia was noted, and a gonad that was thought to represent an ovary could be palpated in the left hernial sack. Parents refused surgery of the suspected herniated ovary.

One week later, the child was readmitted to the hospital because of vomiting. At that time, the girl had developed a deeply brownish complexion. Shortly after admission, the girl went into cardiac arrest, with a serum K+ of 9.6 mmol/L, serum Na+ of 131 mmol/L, and severe metabolic acidosis (pH 7.19; pC02, 26 mm Hg; base excess, -17 mmol/L).

Documented endocrinological investigations showed that steroids and their metabolites in the urine (17-ketosteroids, 0.2 mg/24 h; 17-hydroxycorticosteroids, 0.3 mg/24 h; free cortisol, <10 µg/24 h) and in the serum (17-hydroxyprogesterone, <0.5 ng/mL; testosterone, <10 ng/dL; aldosterone, 1.8 pg/mL) were low, and adrenal hypoplasia was suspected. A therapy with hydrocortisone and 9{alpha}-fluorcortisol was instituted and later replaced by 9{alpha}-fluorcortisol alone.

This was followed by severe electrolyte disturbances at ages 6 months, 8 months, and 11 months. At that time, hydrocortisone was again added to the therapeutic regimen. From the age of 2.2 yr, the girl had no follow-up visits until she was presented to our department, the first time, at the age of 15.3 yr, with lack of pubertal development. She had somehow survived on and off hydrocortisone and 9{alpha}-fluorcortisol, with doses at the will of the mother, ranging from 0–15 mg/day (0–9.6 mg/m2·day) for hydrocortisone and 0–0.05 mg/day for 9{alpha}-fluorcortisol.

Informed consent was obtained from her parents for molecular genetic analysis.

Clinical findings

On admission, the 15.35-yr-old female was in good general health, with normal vital signs (blood pressure: 90/50 mm Hg) but with psychomental retardation. Her height was 164.5 cm [18 percentile (-0.9 SDS) for a male, 59 percentile (+0.2 SDS) for a female reference population (14)] and weight was 53.6 kg. The patient’s target height, as a female, calculated from parental height, was 161 cm [27 percentile (-0.6 SDS)]. She showed general hyperpigmentation of the skin and especially the mucous membranes. The external genitalia were that of a normal prepubertal female, with no signs of virilization (Tanner stage 1 breast and pubic hair development). Only in the left inguinal region, a gonad with an estimated vol of about 6 mL could be palpated. There were no other abnormalities with regard to the physical examination.

At laparoscopy, a small prepubertal testis, 2.5 x 1.5 x 1.5 cm, proximal to the right internal inguinal ring, was removed. The left testis was found distal the external inguinal ring and had a size twice that of the contralateral intraabdominal gonad (4.0 x 2.0 x 2.0 cm).

Radiological examinations

X-ray of the left hand and wrist revealed a bone age of 13.5 yr, compared with the male standards; and 12 yr, compared with the female standards (15). Ultrasonographic examination of the abdomen showed small-sized adrenal glands without hyperplasia, complete lack of Müllerian structures, and the presence of a homogenous structure in the left inguinal area. Magnetic resonance imaging confirmed the presence of small adrenal glands. Imaging of the hypothalamic-hypophyseal region showed a normal hypothalamic region, a normal pituitary stalk, a normal posterior bright spot, and a ball-shaped anterior pituitary gland with a height of 8 mm.

Hormone determinations

The ACTH test was performed after a 2-day discontinuation of treatment, with an iv bolus injection of 250 µg 1–24ACTH (Synacten, Ciba-Geigy, Wehr, Germany) between 0800 h and 1000 h. Blood samples were taken immediately before and 30 min after ACTH injection. Plasma steroids were measured using a previously described method for the simultaneous determination of multiple adrenal steroids in a small plasma vol of 1–2 mL (16). Intraassay and interassay coefficients of variation ranged from 6.9–14.5% and from 11.9–16.3%, respectively. Normal ranges have been reported previously (16, 17).

DNA analysis

Genomic DNA was extracted from peripheral leukocytes by standard procedures. Exons 1–7 of the StAR gene were individually amplified by PCR using primers adapted from published sequences (18, 19). Amplification was performed on a programmable thermocycler (MJ Research, Inc., Watertown, MA) using 100 ng DNA in a 50-µL mixture of 20 pmol of each primer, 20–200 µmol (deoxy-ATP, deoxy-GTP, thymidine 5'-triphosphate, deoxycycidine triphosphate), 50 µg/mL BSA, 20 mmol Tris (pH 8.4–8.6), and 1.0–2.5 mmol MgCl2. After initial denaturation at 94 C for 300 sec, 34 cycles of annealing between 50–64 C for 90 sec, extension at 72 C for 120 sec, and denaturing at 94 C for 75 sec were employed, followed by a final extension at 72 C for 300 sec. Specificity of amplification products was confirmed by direct sequencing of each exon of a normal control DNA sample. For sequencing, y-33P-ATP end-labeled primers were used in conjunction with the Sequenase sequencing kit, according to the specifications provided by the manufacturer (Amersham Buchler, Braunschweig, Germany). For mutation detection, a nonisotopic single-strand conformation analysis (SSCA) was employed as previously described (20, 21). Briefly, PCR products were denatured for 5 min at 95 C and rapidly chilled on ice afterwards. They were diluted 1:2 in (95% formamide, 89 mmol Tris, 20 mmol EDTA, 89 mmol boric acid, 0.05% bromophenol blue, 0.05% xylene cyanol) and loaded onto 0.8-mm thick 5–8% polyacrylamide gels containing 5–10% glycerol. Electrophoresis was performed at 10–30 W for 12–14 h at room temperature. Electrophoretic band shifts were visualized by silver staining, as described before (20, 21). The exon in which the patient sample showed an aberrant migration pattern was sequenced as described above. Restriction analysis of the exon 7 mutation was performed by digesting the appropriate patient PCR sample with the enzyme AluI at 37 C overnight, according to the specifications of the manufacturer (New England Biolabs, Inc., Schwalbach, Germany), and samples were electrophoresed on a polyacrylamide gel for size determination at 30–40 W for 3–4 h. For all molecular genetic studies, a normal control DNA sample was included for comparative analysis. The parents of the patient were investigated for carrier status, employing restriction fragment analysis.

Histological examination

Gonadal tissue was fixed in Bouin’s solution and embedded in paraffin, according to routine techniques, and cut at 4–7 µm. Sections were deparaffinized and stained with hematoxylin and eosin.

Consecutive sections were additionally immunostained using a polyclonal antibody against human placental-like alkaline phosphatase (PLAP) (DAKO Corp., Hamburg, Germany), with the PAP technique. Briefly, after treatment with 3% H2O2/methanol for 30 min to block endogenous peroxidase, and with normal swine serum for 30 min to block unspecific binding sites, sections were incubated with the anti-PLAP primary antibody (1:100) overnight, followed by swine antirabbit IgG (1:50) (DAKO Corp.) for 30 min and rabbit PAP (1:100) for 30 min. Color was developed with diaminobenzidine/H2O2 for 8 min. Sections were thoroughly washed with TRIS buffer after each incubation. Controls were incubated with normal rabbit serum, instead of primary antibody.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Laboratory results

Chromosomal analysis of peripheral lymphocytes revealed a 46,XY karyotype.

Basal adrenal plasma steroids were undetectably low, with no stimulation after ACTH (Table 1Go). Renin and ACTH were found to be extremely elevated. DHEAS, androstenedione, and testosterone were decreased, with no increase stimulated by human CG (hCG); samples were taken before and 72 h after 5000 IU/m2 hCG im (Primogonyl, Schering AG, Berlin, Germany) (Table 2Go).


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  		Table 1. Plasma adrenal steroidal responses to 30-min ACTH test

 

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  		Table 2. Hormones, basal and responses to hCG1 - and GnRH2 -stimulation

 
With GnRH [samples taken before and 30 min after 100 µg/m2 GnRH iv (Relefact LH-RH, Hoechst AG, Frankfurt, Germany)], LH and FSH rose to a range indicating hypergonadotrophic hypogonadism (Table 2Go).

Detection of a homozygous StAR stop mutation

The whole coding region of the StAR gene was successfully amplified by PCR. Specificity of the amplified regions was confirmed by direct sequencing of all exons. Employing SSCA, a variation was seen in the exon 7 amplification product, compared with a normal control (Fig. 1AGo).



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  		Figure 1. Single-strand conformation (SSC)-analysis (A), direct sequencing (B), and restriction analysis (C) of PCR amplification products from the patient’s DNA of exon 7 of StAR gene. Panel A reveals an abnormal migration pattern on SSCA (arrow), suggestive of a homozygous variation. Panel B demonstrates the homogenous guanine to adenine substitution in the patient’s DNA, predictively altering the normally encoded tryptophane in codon position 250 of StAR by a premature termination codon. In panel C, the electrophoresis of the patient’s and the parents’ PCR products, before (u) and after digestion (c = cut) with the restriction enzyme AluI, are demonstrated. In the control DNA, only two fragments appear after restriction. Because of the mutation, in the patient, an additional digestion of the larger fragment (arrow in the Control) occurs, leading to extra bands of 130 bp (arrow) and 60 bp (not shown). Both parents are heterozygous carriers of the mutation, depicting both normal and variant bands.

 
Sequencing revealed a homozygous point mutation affecting the second codon of this exon, with a substitution of guanine by adenine (Fig. 1BGo).

The normally encoded amino acid tryptophane (TGG) in position 250 of the StAR is substituted by a premature termination codon (TAG).

The mutation was confirmed by restriction analysis of exon 7 PCR amplification products. Digestion with AluI revealed induction of an additional restriction site, on electrophoresis. Complete digestion of the patient’s PCR sample proved homozygosity for the mutation; whereas in both parents DNA, a heterozygous carrier state was detected (Fig. 1CGo).

Gonadal histology

The right testis consisted of seminiferous tubules without lumina, containing immature Sertoli cells of Sa and Sb type, according to Hadziselimovic (24), and a few single germ cells. Some of these germ cells showed positive PLAP immunoreactivity, indicating carcinoma in situ (CIS) (Fig. 2Go). In addition, we found areas of hypoplastic seminiferous cords containing only immature Sertoli cells.



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  		Figure 2. Seminiferous tubules, showing normal spermatogonia (arrow) and tumor cells (arrowheads). Tumor cells are characterized by their large and irregular nuclei with several nucleoli (A; paraffin section, stained with hematoxylin and eosin; magnification, x400) and express PLAP (B; paraffin section, immunostained against PLAP; magnification, x400).

 
The interstitial space consisted of mesenchymal connective tissue and a few scattered Leydig cells. The left testis showed the same histological characteristics but without CIS. No hint for the accumulation of lipid droplets could be found in both testes (Fig. 3Go).



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  		Figure 3. Interstitial tissue, consisting of mesenchymal cells (arrowhead) and Leydig cells (arrows), showing no lipid droplets. x, Intratubular tumor cell (paraffin section, stained with hematoxylin and eosin; magnification, x350).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Several mutations have been described in the StAR gene, causing CLAH (4, 5, 25). In the patient presented here, molecular genetic analysis revealed a homozygous nonsense mutation in codon position 250, W250X, which has not been reported previously; and the child affected is the first reported patient of Serbian descent. The mutation, confirmed by restriction fragment analysis, leads to a truncation of the normal encoding 285-amino acid StAR by 35 amino acids. Although coexpression analysis was not performed, it can be deduced from earlier reports (2, 5), that this truncated StAR is inactive and thus causes CLAH.

In our patient, we found neither enlarged adrenal glands (by imaging technics) nor lipoid deposits in the testicular tissue. Only Dhom (26) and Ogata et al. (27) reported an accumulation of lipid in the Leydig cells, and Hauffa et al. (9) described seminiferous tubules containing minute lipid droplets in patients up to 4 yr and 10 months. All other published patients (1, 6, 10, 28, 29) did not show any lipids in the testicular tissue. Bose and colleagues (4) hypothesized a two-stage model of the pathogenesis of CLAH: first, the mutant StAR prevents the acute steroidogenic response, in the steroidogenic tissue, to trophic stimulation, but permits basal seroidogenesis independent of the StAR; second, the accumulation of cholesterol esters and sterol auto-oxidation products damages the affected cells and disrupts the basal steroidogenesis that is independent of StAR. Little is known about the timing of this process and the appearance of affected tissue in the course of the disease. Takaya and colleagues (30) reported the disappearance of the adrenal enlargement, by serial abdominal ultrasonography, up to the age of 2 yr and 4 months. The second lipid-accumulating step in Bose’s hypothesis requires a trophic stimulation by corticotropin and gonadotropins. Because the ovary is not stimulated until postnatal life, accumulation of cholesterol esters is not assumed to start before the onset of puberty. In contrast, the fetal testes, stimulated by chorionic gonadotropin in early gestation, are severely affected. Pollack and colleagues (31) found an intense staining with specific StAR immunostaining in fetal testes and a moderate-to-intense staining in the fetal zones, whereas the neocortex of the fetal adrenal glands showed only minimal staining. Consistent with this are the observations of Saenger and colleagues (6, 28). They found normal testes without lipid accumulation, but some accumulation of lipoid droplets in the fetal adrenal cortex, on histological examination of a 46,XY fetus at 18 weeks gestation. According to this, Caron and colleagues (32) described florid lipid deposits in the adrenal cortex, lesser deposits in the testes, and none in the ovaries in StAR knockout mice. It seems that the early stage of CLAH is characterized by the classical feature of noticeably enlarged steroidogenic compartments, whereas the late stage disease appears to be associated with small glands, where no (or only little) lipid deposition can be found.

There are only few reports on testicular histology in 46,XY patients with CLAH mentioning patients up to the age of 8 yr. Authors generally report normal age-related seminiferous tubules and occasional Leydig cells (1, 6, 9, 10, 26, 27, 28, 29). Kirkland and colleagues (8) described the disappearance of germ cells, resulting in Sertoli cell-only syndrome together with a hyalinization of the tubular wall in the testes of an 8-yr-old patient. In our 15-yr-old patient, testicular histology did show tubules with and without germ cells. Data indicate that rather normal testicular development can take place even in the absence of normal steroid hormone production (10), although germ cell degeneration may occur with increasing age.

We also detected germ cells expressing PLAP, indicating a preinvasive lesion (CIS) (33). CIS progresses into invasive germ cell tumor in about half of untreated patients (34, 35). Prevalence of CIS in the general male population is less than 1% (36), whereas men with a history of cryptorchism have a risk of up to 10% (37), rising to about 40% if the maldescendent testis is also atrophic (38). Furthermore, CIS of the testis has been described in patients with complete or incomplete androgen insensitivity syndrome (39, 40, 41) and is found in 15–20% of patients showing 45,X/46,XY gonadal dysgenesis (11). Gonads in testosterone biosynthetic defects should not be prone to neoplasia (12). In our case, it is remarkable that an intraabdominal, but nondysgenetic, testis developed CIS in the absence of all sex steroids. Whether increased gonadotropin stimulation without steroid response or abnormal intraabdominal positioning were further critical oncogenic factors remains speculative. In conclusion, we recommend early gonadectomy in all 46,XY individuals with CLAH, because of the risk of malignant transformation.

Received September 23, 1998.

Revised February 3, 1999.

Accepted February 9, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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