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Original Studies |
Division of Pediatric Endocrinology, Department of Pediatrics, Christian Albrechts University, Kiel, Germany
Address all correspondence and requests for reprints to: W. G. Sippell, M.D., Division of Pediatric Endocrinology, Department of Pediatrics, Universitäts-Kinderklinik, D-24105 Kiel, Schwanenweg 20, Germany. E-mail: sippell{at}pediatrics.uni-kiel.de
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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The locus for X-linked AHC has been mapped to Xp21.3–21.2 by deletion studies of male patients with a contiguous gene syndrome, including AHC, glycerol kinase deficiency (GKD), and Duchenne muscular dystrophy (DMD) (9). The gene order Xpter-AHC-GKD-DMD-cen was established from the deletion studies (10). The locus for autosomal recessive AHC is not known. Recently, the gene responsible for X-linked AHC has been cloned. This gene, termed DAX-1 (for dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X-chromosome, gene 1), encodes for a new member of the nuclear hormone receptor family (11). Deletions of the DAX-1 gene and different point mutations in the coding region have been found in patients with X-linked AHC; most are frameshift mutations and stop mutations that might be expected to result in a nonfunctional truncated protein (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Mutations in the DAX-1 gene appear to be sufficient to account for both AHC and hypogonadotropic hypogonadism.
We report here on our present series of 18 male AHC patients, diagnosed by our method of multisteroid analysis in a small plasma sample (21). We describe hormonal studies with special regard to steroid determinations during the neonatal period. In addition, we describe five previously unreported point mutations in both exons of the DAX-1 gene.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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During the past 20 yr, a total of 18 boys from 16 families were
diagnosed by our laboratory as suffering from congenital adrenal
insufficiency caused by congenital hypoplasia of the permanent adrenal
cortex. All patients were of Caucasian origin. The clinical data of all
patients are summarized in Table 1
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Fifteen boys presented with salt wasting and failure to thrive in the
first weeks of life (range, 1 week to 2 months of age). One boy (case
15) presented at age 5 months with a hypoglycemic convulsion while
showing laboratory and clinical signs of salt-wasting. His younger
brother (case 16) was prenatally diagnosed, and treatment was initiated
immediately after a diagnostic ACTH test on day 3 of life (22). One boy
(case 8) expressed no signs or symptoms of adrenal insufficiency until
age 3 yr, when his younger brother (case 9) was diagnosed as having
AHC. Patients presenting with salt wasting showed typical laboratory
signs, such as hyponatremia, hyperkalemia, metabolic acidosis, and
elevated PRA. In these boys blood glucose levels were normal at
presentation. Seven boys had unilateral or bilateral cryptorchidism.
Those patients who had already reached postpubertal age suffered from
delayed puberty caused by hypogonadotropic hypogonadism. Patients with
a contiguous gene syndrome also had pseudohypertriglyceridemia,
elevated blood glycerol concentrations, and/or increased serum
creatinine kinase levels. From the total of 18 boys, 12 suffered
exclusively from adrenal insufficiency, 6 had a contiguous gene
syndrome (2 had AHC and GKD, and 4 had AHC, GKD, and DMD). In 8
families, we found a history of unexplained deaths of male infants in
the first months of life or of typical signs or symptoms of primary
adrenal insufficiency such as hyperpigmentation. A primary diagnosis of
congenital adrenal hyperplasia due to 21-hydroxylase or
11ß-hydroxylase deficiency was assumed in 4 boys. Two of the boys
with a contiguous gene syndrome including AHC, GKD, and DMD died in the
first months of life. However, the boys with isolated AHC also had a
poor prognosis, as we observed 1 death in Addisonian crisis and 1 case
of severe brain damage after prolonged convulsions in this series of
patients.
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Materials and Methods |
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Hormone determinations were performed in all patients for diagnostic purposes. The diagnosis of adrenal insufficiency was confirmed by measuring adrenal plasma steroids before and after short term ACTH stimulation. The ACTH stimulation test was performed to confirm cortisol deficiency and to exclude enzymatic defects of adrenal steroid biosynthesis. The ACTH test was performed in the untreated patients or after a short discontinuation of treatment, with an iv bolus injection of 125 µg ACTH-(1–24) (Synacthen, Ciba-Geigy, Wehr, Germany) between 0800–1000 h. Blood samples were taken immediately before and 60 min after ACTH injection, collected in prechilled heparinized tubes, and immediately centrifuged at 4 C. Plasma was stored frozen at -20 C until assayed. Plasma steroids were measured using a previously described method for the simultaneous determination of multiple adrenal steroids in a small plasma volume of 1–2 mL developed in our laboratory (21). For the plasma steroids, intra- and interassay coefficients of variation ranged from 6.9–14.5% and from 11.9–16.3%, respectively. The results are expressed in nanomoles per L; to convert to nanograms per mL, divide by the following factors: aldosterone, 2.774; corticosterone, 2.886; 11-deoxycorticosterone, 3.026; progesterone, 3.18; 17-hydroxyprogesterone, 3.026; 11-deoxycortisol, 2.887; cortisol, 2.759; and cortisone, 2.774. Normal ranges for different pediatric age groups using our method of multisteroid analysis (21) have been reported previously (24).
A similar method, using extraction, chromatography, and RIA, was used for plasma testosterone and androstenedione measurements (25). Dehydroepiandrosterone sulfate was measured using a commercial RIA (Sorin Biomedica, Milan, Italy). LH and FSH were measured using immunoradiometric assay (Maia Clone, Serono Diagnostics, Freiburg, Germany) or enzyme immunoassay (EIA) (Serozyme, Serono Diagnostics).
Molecular genetic studies
Blood samples for molecular genetic studies were taken after informed consent had been obtained from the patients and their parents. The families were told that the molecular genetic testing was of a research nature, and clinical decisions and genetic counseling should not be based solely on this information.
Nucleotide sequences of exons and exon/intron boundaries
Genomic DNA was extracted from peripheral blood leukocytes, and
the DAX-1 gene was amplified in three fragments containing the two
exons by PCR. The following primers were used for amplification of the
DAX-1 gene: DAX1s, 5'-CAC TGG GCA GAA CTG GGC TAC-3'; DAX1as, 5'-CTG
CAG CAT GCT GGG CTC CG-3'; DAX2s, 5'-CCG CTT GCA GTT CGA GAC TGT G-3';
DAX2as, 5'-CGC CCC TAG ATA GGC ACT GCC-3'; DAX3s, 5'-GCT AGC AAA GGA
CTC TGT GGT G-3'; and DAX3as, 5'-CCC TCA TGG TGA ACT GCA CTA C-3'. PCR
was performed for 35 amplification cycles after an initial denaturation
at 94 C for 3 min (denaturation at 94 C for 1 min, annealing at 68 C
(primers DAX1s and DAX1as) or 65 C (primers DAX2s and DAX2as, primers
DAX3s and DAX3as), and extension at 72 C using DNA polymerase (XL PCR
Kit, Perkin-Elmer, Foster City, CA). The final extension was performed
at 72 C for 5 min. PCR products were run on a 1–2% agarose gel.
Before direct sequencing, PCR products were pretreated using
exonuclease I and shrimp alkaline phosphatase. The nucleotide sequence
of both strands of the PCR products was directly determined by
thermocycle sequencing using the Thermo Sequenase radiolabeled
terminator cycle sequencing kit, following the manufacturer’s
instructions (Amersham Life Science, Cleveland, OH). Primers used for
sequencing reactions are listed in Table 2.
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When amplification of the patients’ DNA with the DAX-1 primers (DAX1s and DAX1as, DAX2s and DAX2as, DAX3s and DAX3as) was unsuccessful, a deletion of the DAX-1 gene was assumed. Additional markers were used to identify the telomeric and centromeric break points (10, 12, 13). Primers for PCR amplification of partial exons of the GKD gene and the DMD gene have been designed according to the published GenBank sequence data (26, 27).
A schematic representation of the genomic organization of the DAX-1
gene and localization of the primers that were used to amplify the
exons and the exon-intron boundaries and to sequence the PCR products
are indicated in Fig. 1.
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Results |
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Plasma steroid levels of the eight determined mineralocorticoids
and glucocorticoids demonstrated complete adrenal cortical
insufficiency in all 18 patients. Repeated multisteroid analyses were
performed in some patients (Table 3).
Basal aldosterone and cortisol plasma levels, repeatedly measured at
different ages, are shown in Figs. 2 and 3, respectively. Aldosterone was at or
below the lower limit of detection of the assay (0.055 nmol/L) in all
patients at first presentation, whereas plasma cortisol determined by
our highly specific method was above the upper normal limit in some
patients at first presentation. At age 6 months, plasma cortisol was
below normal except in one patient (case 9). We measured few
dehydroepiandrosterone sulfate plasma levels; however, they were below
the lower limit of detection of the RIA (<25 nmol/L) in every case,
except of case 8 (105 nmol/L). This particular boy had normal cortisol
plasma levels at age 3 yr.
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). We do not
have longitudinal data. Basal plasma LH and FSH levels were also
measured in three boys, indicating an active
hypothalamic-pituitary-gonadal axis at that time (Table 4).
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Because the three patients had previously died we had no material
for DNA studies for cases 2, 6, and 7. The point mutation identified in
case 1 has been previously reported (11). Five novel point mutations
were identified in five patients. Case 3 had a nonsense mutation (C to
A at nucleotide 390) that resulted in a stop codon at position 130
(Y130X; Fig. 4). Case 5 had a single base
deletion (T) at nucleotide 1326 (Fig. 5).
This mutation resulted in a frame shift and a premature stop codon at
position 461. Case 10 had a nonsense mutation (C to T at nucleotide
1258) that resulted in a stop codon at position 420 (Q420X). Case 11
had a single base deletion (T) and insertion of two nucleotides (CC) at
nucleotide 585. This mutation resulted in a frame shift and a premature
stop codon at position 204 (Fig. 6). Case
12 had a single base deletion (G) at nucleotide 544. This mutation
resulted in a frame shift and a premature stop codon at position 263.
Amplification of the genomic DNA with the three primer pairs for the
DAX-1 gene in cases 4, 8, 9, 14, 17, and 18 failed to produce PCR
products. The deletion of these markers confirmed that all were
affected with AHC. Additional markers indicated that two patients had a
deletion of the entire DAX-1 gene: cases 17 (
350 kb; Fig. 7) and 18 (60 kb). Cases 4 and 14 had
deletions of approximately 1 Mb, including the entire AHC-GKD-DMD gene
locus, whereas two siblings (cases 8 and 9) had deletions of
approximately 650 kb, including the AHC-GKD gene locus (Table 5). The two brothers (cases 15 and 16)
with primary adrenal insufficiency and a medical history that strongly
suggested AHC had no mutation in the DAX-1 gene.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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Clinical presentation
Clinical signs and symptoms in infants with AHC include poor feeding, failure to thrive, frequent vomiting, dehydration, and hyperpigmentation. Hyponatremia, hyperkalemia, metabolic acidosis, and hypoglycemia are common biochemical findings characteristic of combined glucocorticoid and mineralocorticoid deficiencies (2, 3, 5, 8). In our present series of patients, 16 presented with a salt-losing crisis within the first weeks of life; only 1 boy (case 15) presented with hypoglycemic convulsion as the first symptom of adrenal insufficiency, although biochemical signs of mineralocorticoid deficiency were present in this boy. He first presented with signs and symptoms of adrenal insufficiency as one of the oldest in our series. His younger brother was prenatally diagnosed (22), and treatment was initiated before any signs or symptoms of adrenal insufficiency developed. One boy did not express any signs of glucocorticoid or mineralocorticoid deficiency before 3 yr of age, when his younger brother was diagnosed as having AHC during the neonatal period. Such delayed onset of symptoms of AHC has also been reported by others (8, 14, 28, 29, 30, 31). Intrafamilial variability has also been described by several researchers (8, 12, 14, 16, 28, 29, 30). Abnormalities in adrenal development seem to be variable, and less severe forms of this disorder could result in subclinical adrenal insufficiency.
The above-mentioned signs and symptoms are indistinguishable from those observed in the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. A relatively common symptom occurring in boys with AHC that we observed in seven patients is unilateral or bilateral cryptorchidism (5). In general, a high rate of undescended testes is observed in patients with hypogonadotropic hypogonadism, which is a common feature of AHC patients (7, 28, 29, 32). It is now believed that all boys with AHC who reach postpubertal age will have delayed puberty caused by hypogonadotropic hypogonadism. There is a clear phenotypic heterogeneity of hypogonadotropic hypogonadism in AHC patients reported in the literature with regard to localization of the defect in the hypothalamus or the pituitary. A primary pituitary defect was suggested by several studies (8, 33, 34, 35) in which patients showed little or no response to prolonged treatment with pulsatile GnRH. However, studies in two of our patients who responded to pulsatile GnRH (cases 12 and 17) suggested a primary defect in the hypothalamus (36, 37). Newer data from the literature suggest that DAX-1 mutations impair gonadotropin production by acting at both the hypothalamic and the pituitary level (16, 38).
The interesting observation of an active hypothalamic-pituitary-gonadal axis in an AHC infant within the first 4 months of life has been made by Takahashi and co-workers (19). Our data from four affected boys support this observation. All four boys had testosterone plasma levels within the midpubertal range. We did not perform GnRH testing in these boys; however, basal LH and FSH were in the normal range for boys below age 3 months, indicating an active hypothalamic-pituitary-gonadal axis at this age. We propose the hypothesis that there might be a difference between the central regulation of hypothalamic-pituitary-gonadal activity in infant boys and that in pubertal boys.
A third of the AHC patients reported in our series have a contiguous gene syndrome. The phenotype that includes AHC, GKD, and DMD is relatively frequent, and these boys have a poor prognosis. GKD and DMD should be excluded in every AHC boy by measuring plasma concentrations of triglycerides, glycerol, and creatinine kinase.
Frequency of X-linked AHC
Our data give no indication of the frequency of AHC in the German population. The overall incidence of idiopathic adrenal hypoplasia has been estimated at 1 in 12,500 births or approximately 0.2–0.26% in a large series of consecutive perinatal autopsies (5, 39). When comparing the frequency of congenital adrenal hyperplasia due to 21-hydroxylase deficiency with that of AHC on the basis of the number of steroid analyses performed in our laboratory over the past decade, it can be stated that the diagnosis of AHC is much more rare. The frequency of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the German population is approximately 1 in 13,000 births (40). Thus, the frequency of AHC must be significantly less than 1 in 12,500 births.
Biochemical findings and diagnostic recommendations
We performed one or more plasma multisteroid analyses (21) in the 18 patients described here. We used a highly specific method for steroid determination, using extraction and automated high performance liquid chromatography before RIA to avoid cross-reactions with other abundant fetocortical steroids. With the exception of one boy, all had minimal or undetectably low plasma levels of all adrenal steroids. In the neonates, aldosterone deficiency preceded cortisol deficiency in all cases. When we determined plasma aldosterone in the salt-wasting infants between the first week of life and age 2 months, the plasma aldosterone level was very low, with little or no increase after ACTH stimulation. At the same time, plasma cortisol levels were elevated or in the normal range in most patients, reflecting the still active steroid production in the fetocortex. However, adrenal function subsequently declined, and at age 6 months all of the infants who presented with salt-wasting as neonates were cortisol deficient also. However, some children (such as case 8 in our series) showed a prolonged phase of glucocorticoid sufficiency (31). Thus, in the first weeks of life an ACTH test is often necessary to prove cortisol deficiency. The diagnosis of adrenal insufficiency can also be made with a 24-h urine sample, which is, however, difficult to collect in this very young age group.
Some of the patients were misdiagnosed as having congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The correct diagnosis depends on specific methods for the determination of steroids. We did not observe elevated 17-hydroxyprogesterone plasma levels in any of our patients. However, we detected elevated plasma levels of 11-deoxycortisol and 11-deoxycorticosterone in the first weeks of life, suggesting 11ß-hydroxylase deficiency. This phenomenon was observed in 7 of our 18 patients (cases 2, 4, 5, 6, 8, 10, and 14), and in 1 patient (case 6) it disappeared even after age 6 months. We hypothesize that this might be caused by disturbed steroid production in the persisting fetocortex.
We suggest the following diagnostic recommendations for AHC. Specific measurement of plasma cortisol and aldosterone (and precursor steroids) should be performed before and after ACTH stimulation. Direct RIA procedures without prior purification often give falsely elevated results for aldosterone, cortisol, and their precursors in young infants. During infancy, serial measurements of plasma steroids before and after ACTH administration may also be necessary for a correct diagnosis. The urinary steroid secretion pattern (gas chromatography) is also an important tool for establishing the diagnosis of adrenal insufficiency. In addition, plasma ACTH and PRA should be determined. At the time of normal onset of puberty, secretion of gonadotropins and sex steroids should be examined (e.g. GnRH test and spontaneous nocturnal LH and FSH).
Imaging techniques are not very important in the diagnosis of adrenal hypoplasia; however, they may be helpful to distinguish between adrenal hypoplasia and bilateral adrenal hemorrhage causing adrenal insufficiency.
Molecular genetics
The DAX-1 gene encodes a protein that is very similar to members of the orphan nuclear receptor superfamily (11). The DAX-1 gene is composed of two exons split by one 3.4-kb intron and codes for a 470-amino acid protein. Putative DNA-binding and ligand-binding domains have been identified (15). Little is known about the function of the DAX-1 gene product and its ligand. It has been suggested that DAX-1 together with the transcription factor steroidogenic factor 1 (SF-1) are part of a signal cascade required for the normal development of steroidogenic tissues (41). The remarkable phenotype of the SF-1 knockout mouse, which is similar to that observed in patients with DAX-1 gene mutations, demonstrates that SF-1 is a key mediator in the development of the adrenal glands, gonads, and ventromedial hypothalamic nucleus (42). Recently, the mouse DAX-1 gene has been isolated (43, 44). The murine DAX-1 gene encodes for a 472-amino acid protein, with 75% overall nucleotide sequence homology to the human DAX-1 gene. The mouse model system of altered DAX-1 gene expression will give more insight into the role of DAX-1 protein in tissue- and development-specific gene regulation.
In several studies it has been proven that DAX-1 gene deletions or mutations are responsible for AHC (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). It is now commonly agreed that DAX-1 gene mutations are also responsible for the frequent occurrence of hypogonadotropic hypogonadism in AHC patients. Most of the reported point mutations are frameshift or stop mutations, which produce a truncated nonfunctioning protein. There are three exceptions: two amino acid substitutions, R267P (12) and N440I (18), and one deletion of a single amino acid V269 (12). These three mutations are located in the putative ligand-binding domain of the DAX-1 gene product.
DAX-1 binds to DNA hairpin structures. Binding of DAX-1 to the promoter
of the gene encoding steroidogenic acute regulatory protein (StAR)
results in the transcriptional repression of StAR expression and the
blockade of steroidogenesis (45). Transcriptional repression by DAX-1
is exerted by a bipartite silencing domain present in the putative
ligand-binding domain of DAX-1. It has been shown that the point
mutations R267P and 
V269 impair silencing (46).
In the present study, we demonstrated that those patients in our series with a contiguous gene syndrome have deletions in the AHC-GKD-DMD gene locus, whereas most of the patients with isolated AHC (with hypogonadotropic hypogonadism) had point mutations in the DAX-1 gene. Two patients with AHC and hypogonadotropic hypogonadism had complete deletion of the DAX-1 gene. The point mutations reported here are all frameshift or stop mutations that produce a truncated nonfunctioning protein. The stop codons are distributed over the entire gene. In agreement with Nakae (17), we found that mutations even in the C-terminus of the DAX-1 protein cause AHC. The terminal 11 amino acids are particularly important for normal adrenal cortical embryogenesis.
Some male patients presenting with primary adrenal insufficiency in the first months of life have no DAX-1 gene deletion/mutation. The diagnosis of primary adrenal insufficiency caused by AHC is also made in girls. It must be assumed that the human genome contains other unknown genes that are necessary for normal adrenal cortex development.
As more and more monogenetic disorders are explained on a molecular level, an important question raised is the correlation of genotype to phenotype. As shown in this and others studies, a wide phenotypic variability has been observed among AHC patients (8, 12, 14, 16, 28, 29, 30, 31). The structural differences in the presumptive DAX-1 gene product, as expected from the different point mutations within the gene, do not seem to explain different phenotypes with regard to age at onset of symptoms, severity of symptoms, or occurrence of hypogonadotropic hypogonadism. For example, case 8, with complete deletion of the DAX-1 gene, had a low normal cortisol plasma level with a blunted response to ACTH at age 3 yr, whereas case 5, expressing a presumptive DAX-1 gene product only 10 bp shorter than normal, presented with a decreased cortisol plasma level at age 3 months. These facts suggest that other epigenetic or nongenetic factors may influence the clinical course of AHC.
The pathophysiology of AHC is not well understood. Studying the interplay among SF-1, DAX-1, and their downstream genes (for example StAR) will provide us with a more detailed understanding of the regulatory mechanisms functioning in the process of adrenal cortex differentiation.
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Acknowledgments |
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Received December 1, 1997.
Revised April 22, 1998.
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TopAbstractIntroductionSubjects and MethodsMaterials and MethodsResultsDiscussionReferences |
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P. Caron, S. Imbeaud, A. Bennet, M. Plantavid, G. Camerino, and P. Rochiccioli Combined Hypothalamic-Pituitary-Gonadal Defect in a Hypogonadic Man with a Novel Mutation in the DAX-1 Gene J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3563 - 3569. [Abstract] [Full Text] [PDF]
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A. T. Reutens, J. C. Achermann, M. Ito, M. Ito, W.-X. Gu, R. L. Habiby, P. A. Donohoue, S. Pang, P. C. Hindmarsh, and J. L. Jameson Clinical and Functional Effects of Mutations in the DAX-1 Gene in Patients with Adrenal Hypoplasia Congenita J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 504 - 511. [Abstract] [Full Text]
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