Late-onset 21-hydroxylase Deficiency Research Articles

HLA and Hormonal Studies in 5 Patients with Late-Onset 21-Hydroxylase Deficiency Syndrome (210HDS)

SCARONI, C.; ORLANDINI, E.; PASINI, VENTURI C.; GANGEMI, M.; MANTERO, F. Author Information

HLA and Hormonal Studies in 5 Patients with Late-Onset 21-Hydroxylase Deficiency Syndrome (210HDS)

HLA and Hormonal Studies in 5 Patients with Late-Onset 21-Hydroxylase Deficiency Syndrome (210HDS)

Late-onset 21-hydroxylase deficiency: Reliable diagnosis by steroid analysis of random urine collections

The feasibility of performing steroid analysis by capillary gas chromatography on random urine samples for the detection of mild late-onset 21-hydroxylase deficiency was evaluated. Comparisons were made of basal excretions of androgen and 17α-hydroxyprogesterone metabolites with plasma levels (basal and stimulated) of 17α-hydroxyprogesterone and testosterone in six patients with the disorder. The following steroid metabolite excretion ratios were determined for normal controls and affected individuals. 1) 17α-hydroxypregnanolone /tetrahydrocortisone + tetrahydrocortisol + 5α-tetrahydrocortisol (cortisol metabolites) (normal 0.017 − 0.10, affected 0.17 − 0.42); 2) pregnanetriol/cortisol metabolites (normal 0.03 − 0.15, affected 0.17 − 0.99); 3) pregnanetriolone/cortisol metabolites (normal 0.02 − 0.014, affected 0.08 − 0.20); 4) androsterone + etiocholanolone/cortisol metabolites (normal 0.26 − 1.02, affected 0.34 − 1.47). Among the 21-deoxy steroid ratios, there was no overlap between affected and unaffected individuals. Two of six affected individuals had androsterone + etiocholanolone/cortisol metabolite ratios in the normal range. This method provides excellent discrimination between normal and affected individuals, precluding the need for an ACTH-stimulation test. It is anticipated that it will be increasingly used for diagnosis of the condition.

Clinical and biological phenotypes in late-onset 21-hydroxylase deficiency.

We analyzed data from 20 patients with late-onset 21-hydroxylase deficiency (LOHD). Three clinical phenotypes could be distinguished among the 18 women. Seven (39%) presented with clinical features suggesting polycystic ovarian disease (PCOD). However, despite androgen levels similar to those of patients with typical PCOD, high serum LH to FSH ratios were not consistently found. Seven other women (39%) presented with isolated hirsutism, suggesting idiopathic hirsutism. The remaining 4 women (22%) had no manifestations of androgen excess and were considered to have the cryptic form of LOHD. Serum 17-hydroxyprogesterone (17-OHP) and androgen levels were similar in the 3 phenotypes, suggesting that the clinical expression of LOHD in women is modulated by individual factors, such as androgen sensitivity. The 2 men were detected by family study and were clinically normal. Since clinical diagnosis of LOHD is impossible, we concentrated on hormonal data with the aim of providing guidelines for the biological diagnosis of LOHD. Assay of basal serum 17-OHD at 0800 h in both sexes and in the early follicular phase in women was sufficient to establish the diagnosis of LOHD in most patients. If doubtful results are obtained, i.e. serum 17-OHP levels between 2 and 5 ng/ml, an ACTH test must be performed. Post-ACTH serum 17-OHP levels exceeding 10 ng/ml confirm the diagnosis of LOHD. Such results should avoid confusion with heterozygotes for 21-hydroxylase deficiency, whose frequency is high within the general population and may be even higher in patients with idiopathic hirsutism or PCOD.

HLA and hormonal studies in 5 patients with late-onset 21-hydroxylase deficiency syndrome (21OHDS).

Late-onset 21-hydroxylase deficiency (21OHD) presents biochemical evidence of 21OHD and virilization in peri-or postpubertal age; it has been demonstrated that late-onset 21OHD is linked to HLA system. We present the HLA typing, the baseline and the ACTH-stimulated hormonal levels in 5 patients with late-onset 21OHD and in their family members. We identified 3 HLA identical male sibs within their respective families, 2 sibs sharing one haplotype with the affected member and 2 homozygous normal sibs. We observed elevated baseline (greater than 4 ng/ml) and ACTH-stimulated 17-hydroxyprogesterone levels, increased baseline Androstenedione levels, slightly elevated or normal DHEA-S and Testosterone values and subnormal response of Cortisol levels to ACTH in patients and in the HLA-identical sibs, reduced SHBG levels in patients but not in their identical sibs. The heterozygous family members presented hyperresponsiveness of 17-hydroxyprogesterone but not of androgens after ACTH. We confirm that late-onset of 21OHD is an autosomal recessive disease linked to HLA-B; there is in fact biochemical evidence of mild 21OHD in patients and in their HLA identical sibs and 17-hydroxyprogesterone levels in the range of heterozygotes for classical 21OHD in parents and sibs predicted by HLA to be carriers. Thus HLA typing and hormonal data, particularly 17-hydroxyprogesterone, are useful, also in this form of congenital hyperplasia, in detecting heterozygotes.

HLA associations in late-onset 21-hydroxylase deficiency in Israel.

HLA associations in late-onset 21-hydroxylase deficiency in Israel.

Pre-Pubertal Gynaecomastia as the Presenting Feature of Late-Onset 21-Hydroxylase Deficiency

We describe an 8-year-old boy with pre-pubertal gynaecomastia as the presenting feature of late-onset 21-hydroxylase deficiency, an association not previously reported. Although absolute oestrogen levels were not higher than previously described in 21-hydroxylase deficiency, the gynaecomastia may have arisen through a relative disproportion of the C18 to C19 steroids.

Late onset 21-hydroxylase deficiency presenting as pre-pubertal gynaecomastia

Pre-pubertal gynaecomastia has been described in 11β- but not in 21-hydoxylase deficiency. An 8-yr old boy presented with bilateral 5 cm breast buds: P2 G2 Testes 2/2 ml; height 138.5 cm bone age (TW2) 12.5 yrs. Serum hormone levels basally and post-ACTH are shown below. Prolactin was 254 μU/1, DOC 91 pmol/l supine PRA 3.0 ng/ml/hr, SHBG 155 nmol/l. GnRH stimulation at O' and 20': LH 2.6 and 4.2, FSH 5.4 and 6.3 iu/1. El 450 pmol/l. Capillary GLC of urine showed typical pattern of 21-OHase defect.Comparison of DHEAS/E1+E2 and A/E1+E2 gave values comparable to transient pubertal gynaecomastia range for bone age as reported by Moore et al (JCEM 1984 58: 492) and in which peripheral conversion of adrenal androgen to E1 and E2 is suggested as the cause of the condition. It remains unexplained why pre-pubertal gynaecomastia is rare in 21-OHase but not 11β-OHase deficiency.

The endocrine pattern of late onset adrenal hyperplasia (21-hydroxylase deficiency).

We describe 5 adult women with severe hirsutism due to late onset 21-hydroxylase deficiency. Diagnosis was performed on the finding of high serum 17-hydroxyprogesterone (17OHP) levels with a marked hyperresponse to an ACTH test. The endocrine study showed in most patients a gonadotropin behavior similar to that observed in classical polycystic ovary (PCO) syndrome. Prolactin levels were slightly increased in basal conditions and presented an exaggerated response to TRH stimulation.

Detection of Late-Onset 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia in Adolescents

Because severe hirsutism is difficult to reverse, the evaluation of the adolescent girl with progressive hirsutism should aim at the pathophysiology of androgen excess in order to select appropriate therapies. A prospective study was undertaken to determine the occurrence of late-onset 21-hydroxylase deficiency among adolescents with androgen excess. Twenty-two young women (mean age 17.3 +/- 2.6 years) with androgen excess had serum 17-hydroxyprogesterone measured before and after bolus intravenous infusion of synthetic ACTH (Cortrosyn), 0.25 mg. Two patients, aged 13 and 19 years old, had elevated base line 17-hydroxyprogesterone and 30- and 60-minute responses to Cortrosyn consistent with 21-hydroxylase deficiency. Chromosome 6p haplotypes provided supportive evidence of 21-hydroxylase deficiency. The base line androgen levels, clinical presentation, and a four-day dexamethasone test did not distinguish patients with 21-hydroxylase deficiency from other hirsute adolescents. The Cortrosyn test identifies a population of adolescents who need long-term corticosteroid therapy. The use of major histocompatibility complex haplotypes could be of help in identifying affected siblings prior to the development of significant hirsutism.

Late-Onset Steroid 21-Hydroxylase Deficiency

Hormonal studies and human leukocyte antigen (HLA) genotyping were performed in 5 males and 13 females who were demonstrated to have 21-hydroxylase deficiency. The enzymatic deficiency of steroidogenesis was detected by family studies of 10 females who presented with varying symptoms of androgen excess. The 10 index cases had normal genitalia at birth, but virilized to varying degrees postnatally. The additional 8 affected family members had not sought medical care, but some were found to have signs of virilization on physical exam- ination, while others were normal. Thus both late-onset (symp- tomatic) and cryptic (asymptomatic) 21-hydroxylase deficiency occurred in the same pedigree. The hormonal and genetic linkage studies indicate that the late-onset (symptomatic) form of 21- hydroxylase deficiency, like the cryptic (asymptomatic) and classical forms of 21-hydroxylase deficiency, is transmitted by an autosomal recessive gene which is linked to HLA-B. Further- more, the classical form of 21-hydroxylase deficiency associated with prenatal virilization is transmitted by an allelic variant for steroid 21-hydroxylase different from that of the nonclassical forms, late-onset (symptomatic) and cryptic (asymptomatic) 21- hydroxylase deficiency. Although these latter 2 disorders have different clinical manifestations, they demonstrate a similar de- gree of steroid 21-hydroxylase deficiency that is less severe than that observed in classical 21-hydroxylase deficiency. The hor- monal and genetic linkage data indicate that cryptic (asympto- matic) and late-onset (symptomatic) 21-hydroxylase deficiency result from the same allelic variant at the steroid 21-hydroxylase locus. A glossary of terms is presented to describe the various allelic forms of 21-hydroxylase deficiency with consistency. (J Clin Endocrinol Metab 55: 817, 1982)

Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia.

Hormonal studies and human leukocyte antigen (HLA) genotyping were performed in 5 males and 13 females who were demonstrated to have 21-hydroxylase deficiency. The enzymatic deficiency of steroidogenesis was detected by family studies of 10 females who presented with varying symptoms of androgen excess. The 10 index cases had normal genitalia at birth, but virilized to varying degrees postnatally. The additional 8 affected family members had not sought medical care, but some were found to have signs of virilization on physical examination, while others were normal. Thus both late-onset (symptomatic) and cryptic asymptomatic) 21-hydroxylase deficiency occurred in the same pedigree. The hormonal and genetic linkage studies indicate that the late-onset (symptomatic) form of 21-hydroxylase deficiency, like the cryptic (asymptomatic) and classical forms of 21-hydroxylase deficiency, is transmitted by an autosomal recessive gene which is linked to HLA-B. Furthermore, the classical form of 21-hydroxylase deficiency associated with prenatal virilization is transmitted by an allelic variant for steroid 21-hydroxylase different from that of the nonclassical forms, late-onset (symptomatic) and cryptic (asymptomatic) 21-hydroxylase deficiency. Although these latter 2 disorders have different clinical manifestations, they demonstrate a similar degree of steroid 21-hydroxylase deficiency that is less severe than that observed in classical 21-hydroxylase deficiency. The hormonal and genetic linkage data indicate that cryptic (asymptomatic) and late-onset (symptomatic) 21-hydroxylase deficiency result from the same allelic variant at the steroid 21-hydroxylase locus. A glossary of terms is presented to describe the various allelic forms of 21-hydroxylase deficiency with consistency.

Late-onset 21-hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease.

The importance of late-onset congenital adrenal hyperplasia as a cause of hirsutism is controversial. Two of 35 women with a chief complaint of hirsutism met the criteria of 21-hydroxylase deficiency. In one, who presented with hirsutism, oligomenorrhea, obesity, infertility, and enlarged cystic ovaries, the initial diagnosis was polycystic ovarian syndrome. Family data showed that her disorder was autosomal recessive and linked to the histocompatibility leukocyte antigens (HLA), as in the classic form of congenital adrenal hyperplasia. Carriers were thus detectable by HLA typing. Thus late-onset congenital adrenal hyperplasia appears to be an allelic variant of congenital virilizing adrenal hyperplasia with a milder enzymatic defect. The diagnosis cannot be made clinically because the disease has the same presentation as idiopathic hirsutism or polycystic ovarian disease. Basal plasma 17-hydroxyprogesterone levels, unlike in classic congenital adrenal hyperplasia, can be normal, and an ACTH stimulation test or sequential measurements of plasma 17-hydroxyprogesterone throughout the day may be needed to show the abnormality. The incidence among hirsute women is estimated to be 6% to 12%, and the calculated gene frequency for the allele coding for attenuated expression of 21-hydroxylase deficiency is 0.015 to 0.057.

Late-Onset 21-Hydroxylase Deficiency Is an Allelic Variant of Congenital Adrenal Hyperplasia Characterized by Attenuated Clinical Expression and Different HLA Haplotype Associations

Three families with late-onset 21-hydroxylase deficiency were studied. Homozygous females presented with symptoms of mild hyperandrogenism such as acne, hirsutism, oligomenorrhea and menometrorrhagia. A homozygous male was asymptomatic and had reached normal adult height. The diagnosis of 21-hydroxylase deficiency was based upon markedly elevated responses of plasma 17-hydroxyprogesterone during a short (30-min) ACTH infusion test. The propositi of two of the families were diagnosed despite long-standing glucocorticoid therapy and adrenal suppression by using a prolonged (48-hour) ACTH infusion. Heterozygotes of late-onset 21-hydroxylase deficiency had mildly elevated 17-hydroxy-progesterone responses to ACTH. Late-onset 21-hydroxylase deficiency was inherited as an autosomal recessive trait with close linkage to the histocompatibility leukocyte antigens. The B14 haplotype was present in all affected members. One affected female had a daughter with classic, salt-losing 21-hydroxylase deficiency. Mixed heterozygosity of this patient for a classic and a late-onset 21-hydroxylase deficiency allele may have caused the classic phenotype in her daughter (homozygote for 2 classic alleles).

Genotyping for 21-hydroxylase deficiency: one or two genes?

We have devised nomograms relating the baseline and ACTH stimulable levels of 17-OHP, Δ 4-androstenedione and testosterone for genotyping 21-hydroxylase deficiency. The nomograms provide a method for classifying the patient with congenital, late onset or cryptic 21-hydroxylase deficiency as well as classifying the heterozygotes for each of these disorders. In addition, the subject predicted by HLA genotyping to be genetically unaffected can also be classified by these nomograms. Further the nomograms permit us to obtain evidence for genetic recombination between HLA and the 21-hydroxylase locus. For example a patient predicted by initial HLA genotyping to be unaffected was classified by the nomogram to be a heterozygote. When HLA-DR typing was performed an informative maternal HLA A:DR recombination was discovered. This recombination explained the heterozygote response of this subject. In another family a maternal DR:GLO recombination was found in an asymptomatic sister who was HLA identical to the patient with late onset 21-hydroxylase deficiency. Although most recombinants have mapped the gene for 21-hydroxylase between B and DR, this DR:GLO recombination presents evidence that there may also be a 21-hydroxylase locus between the DR-GLO loci. The nomograms thus provide a powerful tool to determine the 21-hydroxylase genotype by hormonal testing and assist in mapping the gene for 21-hydroxylase deficiency.

Late onset 21-hydroxylase deficiency is a genetic variant of the classic form of congenital adrenal hyperplasia (CAH)

Three young adult women with the diagnosis of idiopathic hirsutism had markedly abnormal elevations of serum 17-hydroxyprogesterone (17HP) in response to an ACTH stimulation test, indicating a mild degree of 21-hydroxylase deficiency. All three had oligoamenorrhea, exhibited no virilization and had reached a normal adult height. One had pubarche at 6 yrs. An ACTH stimulation test and HLA typing was performed on all available family members. Five of the 6 parents had elevations of 17HP comparable to those found in carriers of classic CAH. Two of the 3 propositi had HLA identical adult male siblings of normal height and masculinization with an identical abnormality in 17HP response to ACTH. One of the affected males developed intratesticular adrenal rest tumors that were reduced in size after dexamethasone therapy. Three HLA nonidentical sisters to the propositi were not affected. One patient married a CAH heterozygote and had two biochemically affected children (female 7 yrs and male 3 yrs) with normal heights, bone ages, and no signs of virilization, except for mildly increased terminal hair on the face and extremities of the daughter. We conclude that late onset congenital adrenal hyperplasia is a genetic variant of CAH with a milder enzymatic block and attenuated clinical expression. The affected gene is linked to the HLA locus. The presentation in females is that of mild masculinization. Males are asymptomatic but adrenal rest tumors in the testes may occur.

The biochemical basis for genotyping 21-hydroxylase deficiency.

We describe three different forms of 21-hydroxylase deficiency-classical congenital adrenal hyperplasia (CAH), late-onset 21-hydroxylase deficiency, and cryptic 21-hydroxylase deficiency-and we present hormonal standards by which to assign the appropriate 21-hydroxylase deficiency genotype for these disorders. The late-onset and cryptic forms of 21-hydroxylase deficiency are biochemically indistinguishable, although patients with the late-onset disorder present with marked clinical symptoms (e.g. virilization) whereas patients with cryptic 21-hydroxylase deficiency are clinically asymptomatic. Our latest studies suggest that late-onset 21-hydroxylase deficiency, like the classical and cryptic 21-hydroxylase deficiencies, is also genetically linked to HLA, the major histocompatibility complex of man. Our biochemical findings provide evidence that a spectrum of 21-hydroxylase deficiencies exist in the population.

Late onset 21-hydroxylase deficiency and HLA in the Ashkenazi population: A new Allele at the 21-hydroxylase locus

The congenital form of 21-hydroxylase deficiency (21-OH-def), which results in virilization at birth from intrauterine exposure to testosterone, results from the inheritance of an HLA-linked recessive disease allele from each parent a t the 21-OH locus (the 21-OH 0 allele). In this study we establish a relationship between intermediate and late onset 21-OH-def and HLA. In studies of five Ashkenazi families, we concluded that these syndromes can be caused by either of two combinations of genes at the 21-OH locus: They can occur in individuals who carry the 21-OH 0 allele on one baplotype and who in addition inherit a “susceptibility” 21-OH-def gene (21-OH 8) from their other parent (genotype = 21-OH 0/21-OH 3; or they can occur in individuals who are homozygous for the “susceptibility” 21-OH-def allele (21-OH 8/21-OH 3). The biochemical abnormality in late onset 21-OH-deficiency is characterized by elevated basline levels of plasma 17-hydroxyprogesterone (17-OH-P) and urinary pregnanetriol and/or relatively high 17-OH-P following ACTH stimulation. Although clinical symptoms are not always present in all family members with this biochemical abnormality, the abnormality appears to behave as a simple autosomal recessive trait that is linked to HLA. Among the five probands studied, eight of the eight haplotypes from five nonconsaguinous families assumed to carry the 21-OH 3 allele had the HLA antigens B14 and DRwl and also had the factor B (Bf) S (Slow) variant. The two remaining disease haplotypes were assumed from biochemical data to carry 21-OH 0 alleles. The results suggest that the biochemical abnormality in these syndromes is linked to HLA and that the 21-OH 3 allele has nonrandom association with the particular HLA haplotype B14, DRwl, BfS in the Ashkenazi population.