Untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) is an inherited metabolic disease caused by the deficiency of one of the enzymes necessary for cortisol synthesis. With carefully supervised medical treatment, CAH patients have the capacity for normal puberty and fertility. We report on a 12.4-year-old female who, because of the early interruption of treatment, developed progressive virilization with reduced final height and altered psycho-social orientation to male. One of the reasons for interrupting replacement therapy in our case was the difficult social and economic status of the family, who lived for many years without basic medical care.     

Pregnancy outcomes in women with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE: Despite earlier detection, treatment, and surgical advances, fertility prognosis in women with classical 21-hydroxylase deficiency (21-OHD) is still low, especially in the salt-wasting (SW) form. PATIENTS AND METHODS: We analysed the course and outcome of four pregnancies in two simple virilizing (SV) and one SW patient. RESULTS: The evaluation of carrier status indicated that all three fathers had two normal CYP21 genes. During the pregnancy, the dose of prednisolone was increased in one of the SV patients and the SW patient. In the SW patient who developed pre-eclampsia, the dose of fludrocortisone was also increased. Three patients gave birth to a total of four healthy girls who were heterozygotes for 21-OHD with normal genitalia (one by vaginal delivery and three by Caesarean section). Family studies revealed that the mother of the SW patient has nonclassical 21-OHD. CONCLUSION: Improving a low birth rate in females with SW 21-OHD remains a problem and new approaches are required. If the mother has 21-OHD (even nonclassical 21-OHD), pre-conception counselling and paternal genotyping are advisable and prenatal dexamethasone therapy should be considered.     

Blood pressure in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

BACKGROUND: In patients with congenital adrenal hyperplasia (CAH) recording of blood pressure (BP) must be included in monitoring treatment to detect hypertension. AIM: To investigate the BP patterns in patients with CAH. METHODS: Twenty-three children and adolescents (age 6-17 years) and 11 adult patients (age 18-26 years) were studied (21 females, 13 males; 28 salt-wasting patients). In the whole group BP in the outpatient clinic was compared with BP under hospitalisation and in 11 of the children and adolescents also with 24-hour ambulatory blood pressure monitoring (ABPM). RESULTS: BP in the ward in children and adolescents but not in adults was significantly higher than BP in the outpatient clinic, where BP was in the upper normal range. There was also a significant difference between BP in the outpatient clinic and the lower ABPM in the 11 patients tested. Atrial natriuretic peptide (ANP) in blood serum showed normal values. CONCLUSIONS: BP measured in outpatients in a relaxed and calm atmosphere meets the requirements for monitoring of treatment. Measurement of BP on the ward leads to falsely high results. ABPM is not necessary. Estimation of ANP provides no additional information.     

Nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency

Nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder distinguished from classic 21-OHD by clinical and hormonal criteria. It is most often described as a disorder of adrenal steroidogenesis with onset of virilization in late childhood, peripubertally or postpubertally. An overview of adrenal steroidogenesis is presented elsewhere in this publication. It is the aim of this article to focus on the clinical and hormonal manifestations of the disorder, with discussion of the current methods of diagnosis and management. Recent advances in classic and molecular genetics will follow.     

Successful prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

A mother carrying a fetus affected with 21-hydroxylase deficiency received prenatal treatment with dexamethasone (0.5 mg, tid, p.o.) started from the very beginning of the 8th week of gestation. Prenatal diagnosis had to rely on amniocentesis with karyotyping and steroid hormone determination, because HLA and DNA data from the deceased index case or direct molecular genetic techniques were not available. The pre- and postnatal diagnosis of 21-hydroxylase deficiency was based on mass spectrometric determination of 17-hydroxyprogesterone. Dexamethasone was discontinued for 5 days prior to amniocentesis. Monitoring of cortisol, dehydroepiandrosterone-sulphate and oestriol in maternal plasma revealed suppressed maternal and fetal adrenal glands throughout pregnancy. Plasma dexamethasone levels confirmed excellent maternal compliance. At term, an eutrophic girl with normal female genitalia was delivered. The diagnosis of 21-hydroxylase deficiency and salt loss was confirmed postnatally. Regarding the side-effects of dexamethasone, the benefit/risk ratio was in favour of prenatal dexamethasone therapy.     

Adrenocortical tumor in a patient with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

An adrenal cortical tissue tumor developed in a patient with poorly controlled salt-losing congenital adrenal hyperplasia. A 16-year-old girl became progressively virilized from 13 to 16 years of age. Base line serum progesterone, 17-hydroxyprogesterone, and testosterone levels were high and there was a diurnal pattern of the hormones. Initially elevated urinary 17-ketosteroid and serum steroid levels were decreased by high dose dexamethasone therapy, and at laparotomy an adenoma was found in the cortex of the hyperplastic left adrenal gland. It is inferred that persistent adrenocorticotrophic hormone stimulation may result in neoplastic transformation of hyperplastic adrenal cortical tissue in patients with congenital adrenal hyperplasia.     

Pitfall of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency

We report on a newborn with a severe salt-wasting crisis due to congenital adrenal hyperplasia (CAH) with 21-hydroxylase deficiency, in spite of prenatal diagnosis of CAH and awareness of this diagnosis by the parents and the gynecologic and pediatric practitioners. Due to the diagnosis of CAH in the older sister, prenatal treatment with dexamethasone (Dexa) was initiated. Prenatal diagnosis showed an affected male fetus and the prenatal treatment was stopped. The parents and the involved physicians were informed about the diagnosis, treatment, follow-up, and possible complications. Amniotic infection led to preterm delivery in another hospital. Due to perinatal asphyxia, the male newborn received Dexa during mechanical ventilation. Neonatal CAH screening was unsuspicious. An acute salt-wasting crisis with metabolic acidosis at the age of 3 weeks finally led to the correct diagnosis. This experience emphasizes the need to obtain a careful medical history. Furthermore, this case illustrates that neonatal screening for CAH is falsely negative in the event of neonatal Dexa treatment.     

Growth and pubertal characteristics in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

This retrospective study examined the pubertal characteristics and growth in patients with 21-hydroxylase deficiency (21-OHD). There were 18 males and 31 females with salt wasting (SW), simple virilizing (SV), or non-classical (NC) 21-OHD. Mean ages at onset of puberty (AOP) in SW, SV, and NC males were 9.2 +/- 1.9, 10.3 +/- 1.1, and 10.7 +/- 0.8 years, respectively; while mean AOP in SW, SV, and NC females were 9.3 +/- 1.7, 8.6 +/- 1.6, and 8.5 +/- 1.3 years, respectively. Mean final height (FH) in SW males (159.6 +/- 7.8 cm) was less than in SV (166.8 +/- 7.5 cm, p = 0.06) and NC (173.4 +/- 6.4 cm, p = 0.005) males. Mean FH in SW females (157.1 +/- 5.5 cm) was similar to SV (156.0 +/- 8.4 cm) but less than NC (161.3 +/- 5.4 cm, p = 0.01) females. In conclusion, while the patients as a group entered puberty earlier than the general population, SW males entered puberty the earliest and had the most compromised FH outcome.     

先天性肾上腺皮质增生症21-羟化酶缺陷的产前诊断一例

目的　探讨先天性肾上腺皮质增生症 2 1 羟化酶缺陷的产前诊断方法。方法　运用Southern杂交、单链构象多态性分析和人工酶切位点分析的方法检测突变 ,对先天性肾上腺皮质增生症 2 1 羟化酶缺陷先证者 (男 ,3岁 )及其父母进行DNA诊断 ,并于其母亲第 5次妊娠 16周时抽取其羊水进行羊水细胞诊断。结果　先证者存在缺失突变与内含子 2第 6 5 6剪切突变 ,父母各携带其一。羊水细胞未检出两种突变 ,判断胎儿正常。胎儿娩出后发育良好 ,实验室检查正常 ,证实了产前诊断结果。结论　羊水细胞DNA分析是先天性肾上腺皮质增生症 2 1 羟化酶缺陷的产前诊断的可靠方法。     

Indicators of adult height outcome in classical 21-hydroxylase deficiency congenital adrenal hyperplasia

OBJECTIVE: To obtain objective information on the relationship between adult height (AH), glucocorticoid (GC) dose, and degree of hormonal suppression in a population of patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21-OHD CAH) to optimize treatment regimes. STUDY DESIGN: Multicenter retrospective chart review of patients with salt wasting 21-OHD CAH diagnosed in the first 6 months of life, and who had reached AH (n = 54). The data were compiled into a single database. RESULTS: Mean adult height standard deviation score - midparental height standard deviation score was -1.1 for both sexes. Growth velocity was normal during childhood but compromised during infancy and puberty. Onset and tempo of puberty were normal-to-delayed. Bone age was closely correlated with chronologic age (r = 0.93). AH was negatively correlated with androstenedione in infancy (r -0.68; P =.03) and childhood (-0.66; P <.01) and with testosterone in childhood (r -0.44; P =.01), but not with dehydroepiandrosterone or 17-hydroxyprogesterone. GC dose was not associated with AH. CONCLUSIONS: Mean AH was in the lower range of genetic potential in this group of persons with 21-OHD CAH. Androgen levels should be used in conjunction with growth velocity measurements to optimize GC dosing in persons with 21-OHD CAH.     

先天性肾上腺皮质增生症早期治疗回顾分析

目的探讨先天性肾上腺皮质增生症(CAH,21-羟化酶缺乏)早期治疗的疗效。方法回顾性分析1997年至2011年出生,在6月龄内诊断并开始治疗的69例CAH患儿病史资料,了解早期治疗对患儿生长发育的影响,探讨治疗随访的评估指标。结果 69例患儿于生后4~180 d开始接受治疗,平均中位年龄47 d;平均生长速率为(7.4±1.1)cm/年;末次随访中位年龄3.4岁(0.67~9.92岁),身高均位于正常儿童生长水平的第25~50百分位;76%患儿的骨龄接近实际年龄;预测男女患儿终身高分别为(168.9±8.5)cm和(155.4±8.0)cm,71%位于遗传靶身高范围内,优于以往报道的诊断和治疗年龄>1岁患儿的终身高[(151.0±7.0)cm];真性性早熟发生率为5.79%(4/69),低于以往报道≤3岁及>3岁治疗者性早熟发生率(分别为14%及50%);治疗期间电解质、促肾上腺皮质激素(ACTH)、睾酮水平控制正常比例占86%~93%,17-羟孕酮波动较大;促肾上腺皮质激素、17-羟孕酮、睾酮呈正相关。结论早期治疗能改善CAH患儿的生长,降低性早熟发生率,提高终身高。     

Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

The need for a reliable screening test for classical congenital adrenal hyperplasia prompted development of newborn screening programs. Worldwide incidence of classical congenital adrenal hyperplasia in this report was taken from newborn screening programs in France, Italy, Japan, New Zealand, Scotland, and the United States. Two populations in which the occurrence of congenital adrenal hyperplasia among live births has been reported with greater than usual frequency are the Yupik Eskimos of southwestern Alaska (1:282) and the people of La Reunion, France (1:2,141). Aside from these populations, 1,093,310 newborns were screened between 1980 and 1988, of whom 77 had congenital adrenal hyperplasia. Thus, worldwide incidence of this disorder was estimated at 1:14,199 live births for homozygous patients, 1:60 for heterozygous subjects, with a gene frequency of 0.0083. Incidence of congenital adrenal hyperplasia among whites was estimated to be 1:11,909 (41:488,279) for homozygous patients, 1:55 for heterozygous subjects with a gene frequency of 0.0091. Incidence for the salt-wasting form of congenital adrenal hyperplasia was 1:18,850 (58:1,093,310) compared with 1:57,543 (19:1,093,310) for congenital adrenal hyperplasia in the simple virilizing form. Thus, salt-wasting congenital adrenal hyperplasia was three times more common than simple virilizing congenital adrenal hyperplasia. Estimated incidence of congenital adrenal hyperplasia in white populations in Italy and France (1:10,866) was higher than in Scotland (1:17,098), New Zealand (1:14,500). The incidence in an Asian population (Japan) (1:15,800) did not differ significantly from that of the white population. In four of five populations, overall incidence was higher than previously reported, as was the frequency of the salt-wasting form (75% v 50% to 66%), suggesting improved case detection by newborn screening.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular characterization of mutations in Indian children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) is the commonest cause of female pseudohermaphroditism. It is most often due to steroid 21-hydroxylase deficiency resulting from mutations in the CYP21 gene. This study was conducted to characterize mutations in the CYP21 gene, determine their frequency and correlate genotype with phenotype in Indian children with CAH. Twenty-eight patients with salt-wasting (SW) or simple-virilizing (SV) forms of the disease as well as parents and siblings were studied. Allele specific PCR was carried out and rapid characterization of six mutations was achieved in 23 patients. Twelve patients were homozygous for the mutations and 11 were heterozygous, of whom eight were compound heterozygotes and three were hemizygotes; no mutation was found in five patients. The homozygosity of the mutations was found to be high in our population. The most common mutation was Ile173Asn (31.8%), followed by intron2 splice (27.2%), Gln319stop (22.7%), gene deletion (15.9%) and Pro31Leu (2.2%). Genotype-phenotype correlations showed that the most frequent mutations in the SW group were intron2 splice and Gln319stop mutations (33.3% each) and Ile173Asn (71.4%) in the SV group.     

Late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency presenting as isolated premature thelarche

A 19 month-old female presented with isolated premature thelarche and significantly advanced bone age. The underlying cause of this clinical presentation was found to be late-onset congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. To the author's knowledge this is the first reported case of late-onset CAH presenting as isolated premature thelarche.