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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 9 4068-4071
Copyright © 2001 by The Endocrine Society

Special Features

Adrenocorticotropin-Dependent Precocious Puberty of Testicular Origin in a Boy with X-Linked Adrenal Hypoplasia Congenita Due to a Novel Mutation in the DAX1 Gene

Sorahia Domenice, Ana Claudia Latronico, Vinicius Nahime Brito, Ivo Jorge Prado Arnhold, Fernando Kok and Berenice Bilharinho Mendonca

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM 42 da Disciplina de Endocrinologia e Metabologia (S.D., A.C.L., V.N.B., I.J.P.A., B.B.M.), and Departamento de Neurologia, Hospital das Clínicas (F.K.), Universidade de São Paulo, Caixa Postal 3671, Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Berenice B. Mendonca, M.D., Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Caixa Postal 3671, Sao Paulo, Brazil. E-mail: beremen{at}usp.br

Abstract

Primary adrenal insufficiency is a rare condition in pediatric age, and its association with precocious sexual development is very uncommon. We report a 2-yr-old Brazilian boy with DAX1 gene mutation whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. T levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce T levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Testotoxicosis was ruled out after normal sequencing of exon 11 of the LH receptor gene. At age 3 yr he developed clinical and hormonal features of severe primary adrenal insufficiency. The entire coding region of the DAX1 gene was analyzed through direct sequencing. A nucleotide G insertion between nucleotides 430 and 431 in exon 1, resulting in a novel frameshift mutation and a premature stop codon at position 71 of DAX-1, was identified. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and T levels to the prepubertal range. These findings suggest that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.

PRIMARY ADRENAL insufficiency is an uncommon disorder in pediatric age. Genetic disorders, such as congenital lipoid adrenal hyperplasia, adrenal hypoplasia congenita, hereditary isolated glucocorticoid deficiency, triple A syndrome, and adrenoleukodystrophy, have been considered as causes of primary hypoadrenalism during childhood (1, 2, 3, 4, 5).

Adrenal hypoplasia congenita is a rare inherited disease of adrenal cortex that can occur in two distinct forms: the autosomal recessive miniature adult form and the X-linked cytomegalic form (6). In the X-linked cytomegalic form, the adrenal glands lack the permanent zone of the adrenal cortex, whereas abnormally large fetal adrenal cells persist, resulting in a structural disorganization of the adrenal gland (7). Affected boys typically present with adrenal insufficiency in early infancy or childhood (8, 9, 10). Rare cases of delayed-onset primary adrenal failure or progressive deterioration of adrenal function after an asymptomatic period during infancy have been described (8, 9, 10).

The DAX1 gene was mapped to the short arm of the X chromosome (Xp21) and encodes a transcriptional repressor factor that is classified as an atypical orphan nuclear receptor. The sequence of the carboxyl-terminal region of DAX1 has homology to the ligand-binding domain of several nuclear receptors. However, DAX1 lacks the zinc finger DNA-binding domain that is characteristic of other members of the nuclear receptor family. Instead, it possesses an amino- terminal domain that harbors repetitive regions rich in glycine and alanine residues (11, 12). DAX1 is expressed in adrenal cortex, gonads, hypothalamus, and pituitary and plays a key role in the development of the adrenal gland and hypothalamic-pituitary-gonadal axis (13, 14). Mutations in this gene in humans cause X-linked adrenal cytomegalic form of adrenal hypoplasia and hypogonadotropic hypogonadism (15, 16). Recently, a unique case extended the clinical spectrum of the disease, including mild forms of hypogonadotropic hypogonadism, delayed-onset of adrenal insufficiency, and abnormal spermatogenesis (17). The majority of DAX1 mutations reported are frameshift or nonsense mutations (8). These mutations cause truncation of the functionally important carboxyl-terminal region of the protein and impair DAX-1 interaction with other factors and genes (18).

In this report we describe a 2-yr-old boy with X-linked adrenal hypoplasia congenita due to a new frameshift mutation in the DAX-1 whose first clinical manifestation was isosexual gonadotropin-independent precocious puberty. In this patient, steroid replacement therapy resulted in the decrease in testicular size and T levels to the prepubertal range, indicating an ACTH-dependent precocious puberty of testicular origin.

Case Report

A 2-yr-old Brazilian Mulatto boy was referred to the endocrinology unit with suspected precocious puberty. His mother had noticed the presence of pubic hair and enlargement of the penis at 6 months of age. He presented frequent erections and hyperactivity. On the first physical examination his height was 99 cm (+2.28 SD), penile size was 7 x 2 cm, and pubic hair was Tanner stage II. Testes measured 2.8 x 1.2 cm bilaterally (Table 1Go). No mass was palpable in the abdomen or testis. Bone age was 6 yr. Serum hCG, TSH, T4, dehydroepiandrosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, cortisol, and 11-deoxycortisol levels were normal (Table 2Go). T levels were elevated [ranging from 54–138 ng/dl (1.9–4.8 nmol/liter); normal, <30 ng/dl (1.0 nmol/liter)], and basal and GnRH-stimulated LH and FSH levels (Table 1Go) were compatible with the prepubertal pattern determined in our laboratory (19). Testicular ultrasound did not disclose any abnormalities, and magnetic resonance imaging of the central nervous system was normal. At that time, a diagnosis of gonadotropin-dependent precocious puberty with prepubertal LH levels was postulated, and the boy was started on GnRH agonist therapy (leuprolide, 3.75 mg/month). However, GnRH agonist therapy did not reduce T levels. To investigate the presence of testotoxicosis, we sequenced the exon 11 of the LH receptor gene, which disclosed a normal sequence (20).


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  		Table 1. Clinical and hormonal profiles of a boy with X-linked adrenal hypoplasia congenita and ACTH-dependent precocious puberty of testicular origin

 

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  		Table 2. Basal and ACTH-stimulated steroid levels in a boy with X-linked adrenal hypoplasia congenita

 
At age 3 yr, he became increasingly pigmented and was admitted with upper respiratory tract infection, lethargy, vomiting episodes, and abdominal pain. Candidiasis and vitiligo were absent. At this time he presented hyponatremia (sodium, 127 mEq/liter) and hyperkalemia (potassium, 5.9 mEq/liter). Serum basal cortisol and aldosterone levels were very low and did not rise after ACTH stimulation (Cosyntropin, 250 µg, iv; Table 2Go). T levels were 178 ng/dl (6.2 nmol/liter) and did not increase after acute ACTH stimulation. PRA was elevated (7.3 ng/ml·h; normal range, 0.9–1.9 ng/ml·h), and plasma ACTH levels were extremely elevated [5016 pg/ml (1104.5 pmol/liter); normal, <60 pg/ml (13.3 pmol/liter)]. Computed tomography scan of the abdomen did not reveal adrenal masses or calcifications. Serum levels of steroid-21-hydroxylase autoantibodies and plasma concentrations of very long chain fatty acids were normal, ruling out the diagnoses of autoimmune disease and adrenoleukodystrophy, respectively.

After 2 months of cortisone acetate (20 mg/m2·d) and 9{alpha}-fludrocortisone (50 µg/d) replacement therapy, he presented a clear decrease in testicular size, and T levels reached normal prepubertal levels (Table 1Go). A second GnRH stimulation test was again compatible with a prepubertal pattern of LH response (Table 1Go). Interestingly, basal T levels were high once more when the patient had an upper respiratory tract infection; and they returned to normal prepubertal values after increasing steroid supplementation. This boy has been followed for 24 months, and his T levels remained within the prepubertal range. A recent bone age was 7 yr (chronological age, 5 yr), and growth was 8.5 cm in the last year.

The patient had an older brother who had died prematurely from pneumonia at age 7 yr. This boy presented hyperpigmentation, but signs of sexual precocity were absent according to his mother. The patient’s mother and father were not consanguineous, and their heights were 150 and 167 cm, respectively.

Molecular studies

This study was approved by the ethics committee of Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (São Paulo, Brazil). After obtaining informed consent from the parents, blood samples were taken from the patient and his mother, and DNA was extracted from leukocytes (21). The entire coding region and exon-intron boundaries of the DAX1 gene were amplified by PCR using specific primer pairs as described previously (22). The protocol of PCR amplification was performed as follows. All samples were denatured for 10 min at 94 C and amplified for 30 cycles of 60 sec at 94 C, 90 sec at 62 C, and 2 min at 72 C. The PCR products were pretreated with an enzymatic combination of shrimp alkaline phosphatase and exonuclease I (United States Biochemical Corp., Cleveland, OH) and directly sequenced using the BigDye terminator cycle sequencing ready reaction kit (PE Applied Biosystems, Foster City, CA) in an ABI PRISM 310 automatic sequencer.

Results

Direct sequencing revealed a G base insertion between nucleotides 430 and 431in exon 1 of DAX1 gene (430–431insG), which resulted in a novel frameshift, and a premature stop codon at position 71 in the boy with adrenal insufficiency. His mother was heterozygous for this same mutation, indicating an X-linked inheritance. A known silent polymorphism in codon Cys38 (TGC->TGT) of the DAX1 gene was also identified in the boy and his mother.

Discussion

Primary adrenal insufficiency can occur at any time during life, including the neonatal period, infancy, and childhood. Children usually present with failure to thrive or poor feeding, hypoglycemia, vomiting, diarrhea, dehydration, shock, and generalized pigmentation. The development of signs of puberty due to adrenal insufficiency is very unusual. We report here a rare case of primary adrenal insufficiency in a boy who presented precocious puberty at first evaluation. He had an isosexual gonadotropin-independent precocious puberty that was reversed after treatment of the primary adrenal insufficiency with glucocorticoids and mineralocorticoids. The best known cause of isosexual gonadotropin-independent precocious puberty reversible with glucocorticoid replacement is the occurrence of testicular nodules in patients with untreated virilizing congenital adrenal hyperplasia (23, 24). Gonadal ectopic adrenal tissue, which has the same embryological origin and function of the topic tissue, may also become hyperplastic under excessive ACTH production and present as a testicular mass. In our patient no mass or testicular nodules were identified. Considering the diagnosis of X-linked adrenal hypoplasia congenita in this boy we excluded the possibility of functional ectopic adrenal tissue in testis.

A genetic adrenal disorder was strongly suspected in this patient based on the information of his brother’s death. Molecular analysis revealed a G insertion between nucleotides 430–431 within exon 1 of the DAX1 gene in this boy. This novel frameshift mutation caused a premature stop codon at position 71 that impaired protein function, indicating the etiological diagnosis of the primary adrenal insufficiency as X-linked adrenal hypoplasia congenita. Interestingly, all mutations associated with adrenal hypoplasia congenita reported to date alter the structure of the carboxyl-terminal region of DAX-1 protein, and the majority of them are frameshift or nonsense mutations.

Few cases of latent adrenal disease associated with precocious puberty were described in the literature (25, 26, 27). Petersen et al. (26) reported a family of adrenocortical hypoplasia in which one affected boy presented signs of precocious puberty. This boy survived until the age of 18 months treated with sodium chloride and deoxycorticosterone without glucocorticoids. At autopsy, the pathological study revealed the absence of topic adrenal glands and the presence of fetal adrenal cortex tissue in fat tissue from the upper renal poles, suggesting the diagnosis of adrenal hypoplasia congenita. Microscopic analysis of the testicular tissue showed an advanced stage of maturity characterized by precursors of interstitial Leydig cells and few cells with more mature nuclei, seminiferous tubules, and a lumen and germinal epithelium containing normal numbers of spermatogonias and some spermatocytes of first order (26). Subsequently, Wittenberg (28) described a family with X-linked adrenal hypoplasia congenita with several affected members in four consecutive generations. Four of the affected boys showed variable degrees of sexual precocity. These patients showed considerable variation regarding symptom onset age and rate of progression of the adrenal insufficiency as well as the precocious puberty. The hormonal profile was performed in only two cases and disclosed elevated T levels along with prepubertal LH levels. These cases were reported before the identification and molecular characterization of the DAX1 gene, and therefore, the molecular etiology of adrenal insufficiency was not established. More recently, Katsumata et al. (29) briefly reported a Japanese boy who developed adrenal insufficiency during the neonatal period associated with signs of precocious puberty at 15 months of age. This boy was evaluated 30 yr ago, and the origin of the precocious puberty was not well established at that time (Katsumata, N., personal communication). He was treated with medroxyprogesterone and/or cyproterone acetate until 13 yr of age. After treatment cessation, normal secondary sexual characteristics failed to develop, suggesting a diagnosis of hypogonadotropic hypogonadism. Molecular analysis of the DAX1 gene in this boy identified a complex frameshift mutation with an AC insertion at position 1007 and duplication of the following 11 nucleotides, resulting in a premature stop codon at amino acid 302 (29). These remarkable cases, including the case described here, raise the possibility that the phenotype associated with DAX-1 mutation may include boys with gonadotropin-independent precocious puberty associated with adrenal insufficiency.

The human melanocortin 1 receptor (MC1R) was detected by immunohistochemical analysis in human Leydig cells (30). Human MCR1 binds mainly to MSH, but also to ACTH, which might indicate a potential action of these hormones on Leydig cell steroidogenesis (31). In our case, the clear regression of testicular size as well as T levels to the prepubertal range determined by the steroid replacement followed by partial decrease in ACTH levels strongly suggests the role of ACTH in the stimulation of T synthesis and secretion by Leydig cells.

Transient expression studies have shown that DAX-1 inhibits the transcriptional activity of SF-1, a key regulator of steroidogenic enzyme genes (18, 32). In addition, DAX-1 binds to DNA hairpin secondary structures and blocks steroidogenesis by inhibiting the expression of the steroidogenic acute regulatory protein (18). Therefore, the loss of DAX-1 transcriptional repression may lead to the overexpression of these two important steroidogenesis activators. We hypothesized that the association of a severe reduction of DAX-1 repression activity and extremely elevated ACTH levels may explain gonadotropin-independent T production by Leydig cells in this boy.

A normal postnatal transient activation of the hypothalamic-pituitary-gonadal axis during the first months after birth has been reported in boys with mutations in the DAX1 gene (33). The patient described here had a gonadotropin response to GnRH at 3.6 yr of age that was compatible with a normal prepubertal pattern, indicating integrity of the hypothalamic-pituitary-gonadal axis at this age. In contrast, failure in the development of normal puberty in boy with adrenal hypoplasia congenita due to mutations in DAX1 is well established (8, 9, 10, 13). Furthermore, hCG stimulation increases T levels in most patients with hypogonadotropic hypogonadism due to DAX1 mutations, indicating the preservation of Leydig cell function in these patients (8). Seminara et al. (34) recently described a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism who was submitted to a prolonged therapy with gonadotropins without spermatogenesis induction. Testicular biopsy of this patient revealed rare spermatogonia and Leydig cell hyperplasia. These findings suggest that some patients with DAX1 mutation can harbor an intrinsic gonadal defect. In the same way, the absence of spermatogenesis has been reported in knockout mice for Ahch (the mouse DAX1 homologs) associated with Leydig cell hyperplasia of unknown origin (35). Therefore, DAX1 mutations might confer autonomous growth and function to Leydig cells.

We conclude that DAX1 mutations in humans can promote a dual effect on Leydig cell function characterized by hyperactivity during infancy and childhood causing gonadotropin-independent precocious puberty in boys, followed by hypofunction in adulthood. Further studies will help elucidate the mechanisms of this unusual pattern of Leydig cell function in patients with DAX1 mutations.

Acknowledgments

Footnotes

This work was supported in part by grants from FAPESP (00/01737-7, to S.D.) and CNPq (300151/96-9, to A.C.L.; 301246/95-5, to B.B.M.).

Received December 8, 2000.

Accepted May 7, 2001.

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