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Case Report |
From the * Department of Medicine, ASL Cesena,
Ospedale M. Bufalini, Cesena, Italy, the
Integrated Department of Medicine,
Endocrinology, Metabolism, and Geriatrics, NOCSAE of Baggiovara, Chair of
Endocrinology, University of Modena and Reggio Emilia, Modena, Italy; and the
Section of Pathology, Azienda Policlinico di
Modena, Modena, Italy.
| Correspondence to: Professor Cesare Carani, Integrated Department of Medicine, Endocrinology, Metabolism, and Geriatrics, Chair of Endocrinology, University of Modena and Reggio Emilia, Via Giardini 1355, 41100 Modena, Italy (e-mail: carani.cesare{at}unimore.it). |
| Received for publication November 29, 2007; accepted for publication July 3, 2008. |
Congenital adrenal hyperplasia (CAH) is a frequent genetic endocrine disorder, characterized by an impairment of an enzyme involved in the synthesis of cortisol, resulting in increased adrenocorticotropic hormone (ACTH) and adrenal androgen production. More than 90% of CAH is caused by 21-hydroxylase deficiency (21OHD). The phenotype can vary from a mild (nonclassical) to a classical severe (salt-wasting) form, the latter involving also aldosterone deficiency; the classical simple-virilizing form of the disease can lead to male pseudoprecocious puberty with reduction of final height (New, 2006). The overall incidence of the classical 21OHD is of 1:10 000 to 1:15 000 live births in the worldwide population (Pang and Clark, 1990; New, 2006), with a markedly increased frequency in some ethnic groups, in which the nonclassical form of the disease occurs as commonly as 1 in 50–100 individuals (Wilson et al, 2007).
Here, we describe the case of an adult man affected by both KS and CAH because of 21OHD—the first causing androgen deficiency, the latter leading to androgen excess.
Case Report
A 51-year-old man came to our attention because of bilateral mastodynia. At
presentation, bilateral soft gynecomastia was detected and reported to be
present for 5 years. Gynecomastia was confirmed by breast ultrasonography and
mammography. The patient had given little importance to that sign and did not
consult his medical doctor until the occurrence of mastodynia. The patient's
medical history was uneventful and revealed neither problems at birth nor
impaired growth during childhood. Pubertal onset and development were reported
to be normal. He was married since the age of 28 and in a stable relationship
with his wife, although he never had children, consistent with azoospermia
documented at the age of 31 years, when the diagnosis of "idiopathic
infertility" was made. The family history was negative for endocrine
diseases, although data for the patient's mother were incomplete because she
had just died at the time of the patient's first visit. A hormonal evaluation
performed 3 months before the first endocrinological consultation revealed a
hypergonadotropic hypogonadism on the basis of serum total testosterone of 7.6
nmol/L ([2.2 ng/mL], reference range 10–35 nmol/L), FSH of 47 IU/L
(reference range, 1.2–10 IU/L), and luteinizing hormone (LH) of 23 IU/L
(reference range, 0.8–8.3 IU/L). An altered adrenal function was
documented by elevated serum ACTH (38 pmol/L [173 pg/mL], reference range,
2–11 pmol/L) and 17-OH progesterone (57.5 nmol/L [19 µg/L], reference
range, 1.8–9 nmol/L) in the presence of normal urinary cortisol levels
(162 nmol/24 h [59 µg/24 h], reference range, 55–276 nmol/24 h).
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At the first physical examination, bilateral gynecomastia was present (Figure 1), he was 174.5 cm tall with a genetic target height of 176 ± 8.5 cm (Marshall and Tanner, 1970) and an arm span of 180 cm. He weighted 86 kg with a BMI of 28.2. There were no signs of androgen deficiency, and virilization and muscular masses were normal for an adult man (Figure 1). Both testes were small (4 mL) with firm consistency.
On the basis of the data collected, KS and CAH were suspected, and the patient underwent detailed endocrine and genetic evaluations.
Methods
Endocrinological Study—
Blood samples were obtained at 0800 hours after an overnight fast and were
stored at –80°C until assayed. Basal serum cortisol, ACTH, 24-hour
urinary cortisol, dehydroepiandrosterone sulfate (DHEA-S), androstenedione,
17-OH progesterone, total testosterone, estradiol, renin, and aldosterone were
assayed with the use of commercially available kits. Cortisol and 17-OH
progesterone were also tested by ACTH stimulation test (Cortrosyn, Organon,
West Orange, New Jersey, 250 µg bolus IV)
(Nieman, 2003).
Genetic Study—Karyotype analysis. A standard karyotype was performed on peripheral blood cells by the GTG method according to standard procedures with an estimated resolution of 320 bands.
CYP21 gene analysis— The CYP21 gene was analyzed by polymerase chain reaction (PCR) and direct sequencing, after genomic DNA extraction, as previously reported (Barbaro et al, 2004).
Determination of CAGn and GGCn length— Genomic DNA was obtained from peripheral lymphocytes with the QiAmp DNA Blood Mini Kit (Qiagen, Hilden, Germany). The CAG and GGC repeat regions were amplified by PCR and the PCR-amplified product was subjected to direct sequencing with the use of primers employed in the original PCR, the BigDyeTM Terminator Cycle Sequencing Kit (Applied Biosystems, Foster City, California), and the ABI 3100 Sequencer Analyzer (Applied Biosystems).
Sexological Evaluation
Erectile function was evaluated by a validated self-administered
questionnaire: the International Index of Erectile Function (IIEF;
Rosen et al, 2002).
Histological Analysis
Breast and testis histology was performed according to standard
procedures.
Ethics
The patient gave written informed consent for the biochemical and genetic
evaluations and for the publication of the data and pictures.
Results
KS and CAH resulting from 21OHD were diagnosed; in particular, karyotype
analysis showed a 47,XXY polysomy, and the biopsy of the testis revealed
atrophied seminiferous tubules with large interstitial cell clusters of Leydig
cell hyperplasia (Figure 2).
The CYP21 gene analysis from the patient's DNA revealed a homozygous
point mutation in intron 2 (I2; nucleotide 656 A to G), accounting for a
nonclassical 21OHD, the patient's father being heterozygous for the same point
mutation. The analysis of CAG and GGC lengths revealed 24/25 CAG repeats and
17 GGC repeats.
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Endocrine Findings and Treatments— Biochemical evaluation confirmed a condition of hypergonadotropic hypogonadism with serum testosterone slightly below the reference range and androstenedione, 17-OH progesterone, and ACTH serum levels all above the reference range (Table). The ACTH stimulation test showed a slight impairment of cortisol response, as well as an exaggerated peak of serum 17-OH progesterone, consistent with the diagnosis of nonclassical 21OHD. Serum renin and aldosterone were both within the reference range (data not shown).
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A combined treatment with androgen and corticosteroid was proposed as replacement therapy for hypogonadism and partial adrenal insufficiency, respectively. However, initially the patient refused testosterone treatment while accepted to start the cortisone acetate (25 mg daily) treatment, thus manifesting a poor compliance to physician's advice.
After 6 months of corticosteroid treatment, reduction of serum androstenedione, 17-OH progesterone, and ACTH was achieved, whereas DHEA-S serum levels decreased below the lowest end of the reference range. In the same period the patient reported a progressive reduction of sexual desire and of frequency of sexual intercourse, together with an impairment of erectile function. Consistently, the worsening of hypogonadism and the onset of these sexual symptoms were coupled with a marked decrease of the IIEF scores from the baseline (Table). At this point, androgen supplementation therapy with testosterone enanthate (250 mg IM every 21 days) was proposed again and accepted by the patient. This new schedule of combined treatment resulted in improvement of subjective sexual functions, and normalization of both serum testosterone levels and all IIEF score domains (Table). The outcomes before and after both hormonal treatments are summarized in the Table.
In addition, the patient underwent mammary plastic surgery. The breast histology was characterized by hyperplasia of the mammary gland with fibrosis and normal ductular structure.
During the following periodical visits no symptoms were reported.
Discussion
The simultaneous occurrence of KS and CAH is extremely rare. The first
description of a case with concomitant CAH because of 21OHD and KS in a
10-year-old boy affected by sexual precocity and short stature dates back to
1994 (Yamaguchi et al, 1994).
Recently, a second case of a male newborn affected by KS and CAH together with
uniparental isodisomy of chromosome 6 and X, probably a consequence of
multiple episodes of nondisjunction, has been documented
(Parker et al, 2006). In the
past years, Mantovani et al
(2002) reported a high
frequency of simultaneous occurrence of KS and steroidogenic defects in the
analysis of 47,XXY fetuses (3 of 15). Yamaguchi et al
(1994) pointed out the
prevalence of the signs of androgen excess, such as precocious puberty with
severe hyalinization of the seminiferous tubules and marked hyperplasia of
Leydig cells, whereas in the child described by Parker et al
(2006), the genetic and
phenotypic outcomes were highlighted early because intrauterine growth
retardation and a complicated neonatal course made genetic screening
mandatory. If the frequency of both 21OHD and KS are considered, the
association between these 2 diseases should be expected to be greater than
documented.
The interest in describing this case report lies in the uniqueness of the simultaneous occurrence of KS and CAH because of 21OHD in an adult man. This provides clinical evidence of the coexistence of 2 diseases, the first of which causes androgen deficiency and the second androgen excess. In the cases of association between KS and CAH previously reported in the literature, early diagnosis did not allow investigation of the adult phenotype and the pathophysiological correlates (Yamaguchi et al, 1994; Parker et al, 2006). The clinical phenotype of our patient was characterized by very mild clinical features of the 2 syndromes that became evident only in adulthood. The signs of KS (Leydig cell hyperplasia, infertility, gynecomastia) were predominant despite the severe homozygous mutation in I2 of the CYP21 gene, which generally impairs the enzyme activity to only 1%–2% in vitro (Chin et al, 1998; Speiser and White, 2003) and is characterized by a lack of strict correlation between genotypes and phenotypes (Wilson et al, 1995). In this case, neither pubertal delay nor precocious puberty were documented, and the stature of the patient was consistent with his genetic target, being neither reduced by the action of high levels of circulating adrenal hormones (New, 2006) nor increased as expected in KS (2). We speculate that the high levels of adrenal androgens because of CAH were responsible for normal sexual behavior, normal virilization, and muscular tropism in adulthood, thus counterbalancing the partial deficiency of androgens of testicular origin because of KS. The hypothesis that adrenal androgen excess masked the KS-related hypogonadism is supported by the quick and progressive deterioration of sexual health with the lowering of serum testosterone levels when corticosteroid therapy was started. Moreover, cortisone acetate treatment disclosed a clinically relevant pre-existent hypogonadism in the relatively short time of 6 months, thus suggesting that the reduction in adrenal steroids impaired the balance in the androgen status previously created by the 2 syndromes. In fact, a reduction of testosterone levels was documented earlier in the subject described by Yamaguchi et al (1994) during desamethasone treatment.
Some recent studies (Zitzmann et al, 2004; Zinn et al, 2005) showed an association among the length of androgen receptor CAGn repeats, different phenotypes, and social characteristics in men with KS. In particular, androgen receptor activity appears inversely related to the length of the CAGn repeats (Zinn et al, 2005), a relationship that is clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as is the case in KS (Zitzmann et al, 2004). Furthermore, in KS the failure of androgen therapy in suppressing serum LH and the occurrence of gynecomastia seem to be directly related to the CAGn length (Zitzmann et al, 2004).
The role of the length of androgen receptor GGC repeat is less clear. Some authors suggest a possible association among specific CAG/GGC combinations, bilateral cryptorchidism (Ferlin et al, 2005), and the ability of a short GGC repeat to enhance the androgen action (Ding et al, 2005). However, because the CAG repeat length is only intermediate in our patient, it is very difficult to find a strict association between some of the clinical features and the CAG length, so this specific finding did not contribute to the understanding of his KS phenotype. We may however assume that the patient's androgen receptor had defective activity because of the presence of gynecomastia and the lack of LH changes during androgen replacement treatment (Zitzmann et al, 2004). Consistently, the patient's growth and pubertal onset did not accelerate despite the high levels of circulating androgen because of steroid 21OHD, thus supporting the concept of defective androgen receptor activity also in infancy and puberty. This hypothesis is further reinforced by the consideration that pubertal development in adolescents with KS seems to occur at the appropriate time (Christiansen et al, 2003), except for the cases of androgen excess in 47,XXY boys also affected by androgen-producing tumors (Kurzrock et al, 2002), and in the case described by Yamagouchi (Yamaguchi et al, 1994).
In the case described here, it seems that KS has had a phenotypic advantage (absence of precocious puberty, presence of gynecomastia, infertility, and firm testes) over CAH. We can speculate that low testicular androgen production, typical of KS, had a greater relevance than the high adrenal androgen secretion (Yamaguchi et al, 1994; Kurzrock et al, 2002), thus delaying the stimulation of pubertal onset usually induced by CAH. On the other hand, in adulthood, the high androgen levels of adrenal origin played a major role in hormonal balance, allowing normal virilization and sexual behavior.
The medical history of this case of an adult man affected by both KS and CAH suggests that these 2 syndromes, the first inducing low levels and the second accounting for high levels of circulating androgens, balanced out in determining the patient's phenotype.
Acknowledgments
We thank Dr Francesca Magnani (Integrated Department of Medicine, Endocrinology, Metabolism, and Geriatrics, NOCSAE of Baggiovara; Chair of Endocrinology, University of Modena and Reggio Emilia, Modena, Italy) for her technical support in the analysis of CAG and GGC repeat sequences and Dr Lilia Baldazzi and Antonio Balsamo (Department of Pediatrics, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy) for their helpful work in the CYP21 gene analysis. We are indebted to Giuseppina Rossi, MD, for her help in editing the article. We thank Dr Yael Ukmar for proofreading the manuscript.
Footnotes
This work was supported by Ministero dell'Università e della Ricerca (MIUR, ex-40%-2005).
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