Complex glycerol kinase deficiency leads to psychomotor and body-growth failure

Complex glycerol kinase deficiency usually presents with Duchenne muscular dystrophy, glycerol kinase deficiency and adrenal hypoplasia congenital. We describe a follow-up patient with complex glycerol kinase deficiency who had appropriate intrauterine development, but who at 1 month of age manifested severe growth delay and psychomotor retardation. Targeted therapy did not bring about the regression of symptoms: both bodyweight and height were below the 3rd centile until 8 years of age, and his Griffith's Mental Development scale score was 71 at age 5 years.     

IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities; MIM 300290) is a multisystem disorder with a broad phenotype, which, if unrecognized, may result in major and possibly life-threatening complications. Initial clinical features overlap with those of Russell-Silver syndrome (RSS) and isolated growth hormone (GH) deficiency, conditions from which it must be distinguished. We report an Australian male with adrenal hypoplasia congenita (AHC) in association with IMAGe syndrome. The patient had intrauterine growth restriction (IUGR) and dysmorphic features comprising small, low-set ears, micrognathia, bilateral cryptorchidism, micropenis, and skeletal abnormalities. Signs of adrenal insufficiency occurred at aged 4.6 years. Our patient differs from those previously described by the late onset of adrenal insufficiency and the presence of GH deficiency. IMAGe is a complex syndrome involving dysmorphic features; disorders of growth, gonadal, and adrenal function; and skeletal abnormalities.     

Sonography of congenital adrenal hyperplasia due to partial deficiency of 3β-hydroxysteroid dehydrogenase: a case report

We report the case of a patient with congenital adrenal hyperplasia (CAH) secondary to a partial deficiency of 3β-hydroxysteroid dehydrogenase. This form occurs in less than 1 % of all patients with CAH. Sonographic evaluation of the adrenal glands demonstrated width and length measurements significantly above normal values. The sonographic findings are not diagnostic of the particular enzyme deficiency in CAH, and the exact etiology should be pursued with laboratory investigation. Received: 28 June 1996 Accepted: 15 October 1996     

Postnatal virilization mimicking 21-hydroxylase deficiency in 3 very premature infants

Premature infants are known to have elevated 17-hydroxyprogesterone and adrenal androgen concentrations immediately after birth, but the levels decrease rapidly. Virilization of normal premature female infants as a result of these high androgens has not been described. Three premature female infants born at 24 to 25 weeks' gestation, with birth weights 550 to 880 g and significant neonatal complications were noted to develop clitoromegaly 2 weeks to 3 months after birth. All 3 had elevated 17-hydroxyprogesterone >100 nmol/L and testosterone >3 nmol/L concentrations. All were treated as simple virilizing 21-hydroxylase deficiency, but subsequent genetic analysis revealed no CYP21 mutations. Follow-up after discontinuation of treatment revealed no recurrent virilization and normal adrenal steroid levels. Postnatal virilization in sick premature girls may occur, and investigations may suggest 21-hydroxylase deficiency. Genetic analysis of CYP21 should be performed before the diagnosis is confirmed. Further studies are needed to better document the natural history and possible causes of postnatal adrenal androgen secretion in sick premature infants.     

Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency

In an attempt to prevent in utero virilization of female fetuses with 21-hydroxylase deficiency, six mothers at risk were treated with either hydrocortisone (n = 1) or dexamethasone (n = 5) in early pregnancy. Treatment was continued to term in the two pregnancies in which the diagnosis of an affected female fetus was confirmed. In patient 1 (hydrocortisone treatment) fetal adrenal suppression was only partial but the external genitalia were only slightly abnormal. In patient 2 (dexamethasone treatment) fetal adrenal suppression was achieved and the external genitalia were normal at birth. These encouraging results open a new prospect for treating congenital adrenal hyperplasia in utero.     

The influence of prenatal dexamethasone treatment on urinary excretion of adrenocortical steroids in newborns

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency suspected in 14 newborns (5 F, 9 M), was treated prenatally with dexamethasone from weeks 7–9 of gestation. The 24 h urinary excretion of selected adrenocortical steroids derived from fetal and definitive adrenal zones was evaluated in these newborns at the age of 3–9 days. Among 11 babies born healthy, in one of six treated until confirmation of male karyotype in gestational weeks 12–17 and in four of five treated until delivery, suppression of fetal adrenal zone steroids was observed, accompanied additionally in three by a diminished excretion of tetrahydrocortisone. In three babies born affected (2 male, 1 female), excretion of 17α-hydroxyprogesterone and 21-deoxycortisol metabolites did not differ from 12 affected, age-matched controls, not treated prenatally. However, some influence on suppression of the fetal adrenal zone metabolite 16α-hydroxypregnenolone was observed in two newborns treated until delivery. Conclusions Heterogeneity in the fetal adrenal response to maternal dexamethasone treatment was confirmed. Suppression of fetal adrenals, especially within the fetal adrenal zone, can be observed in some babies born healthy until at least 1 week after birth. Received: 19 August 1997 / Accepted in revised form: 9 January 1998     

Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by a defect in cortisol and often aldosterone secretion, and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenocortical androgen secretion. Anti-androgen therapy with flutamide is an option that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid. METHODS: We examined the pharmacokinetic parameters of hydrocortisone administered i.v. as a bolus at a dose of 15 mg/m2 in a 17.3 year-old female patient with classic CAH before and four weeks after institution of flutamide treatment by determining serum cortisol concentrations at 10 min intervals for 6 h following the i.v. bolus of hydrocortisone. RESULTS: Treatment with flutamide resulted in a decrease in cortisol clearance from 420 ml/l to 305 ml/l (27% reduction), and a decrease in volume of distribution from 51.61 to 451 (12.9% reduction). The half-life of cortisol increased from 85.3 min to 102.1 min. CONCLUSIONS: Flutamide treatment decreases cortisol clearance, thereby prolonging its half-life. These findings indicate that a reduction in the daily dose of glucocorticoid replacement may need to be considered when flutamide is added to the treatment regimen of patients receiving hydrocortisone.     

Effect of hydrocortisone dose schedule on adrenal steroid secretion in congenital adrenal hyperplasia

To explore the potential effect of dose schedule on the adrenal suppressive action of hydrocortisone in congenital adrenal hyperplasia, eight patients (six with 21-hydroxylase deficiency and two with 11-hydroxylase deficiency) were given five different dose schedules. Two of the schedules used single daily doses (morning or evening), two twice daily doses (two-thirds dose in the morning or evening), one and three equal doses at morning, noon, and night. Each dose schedule used the same total daily hydrocortisone dose (12.5 mg/m2/day), which is within the normal range of hydrocortisone production rate. Each schedule was given for 4 to 6 weeks. The different dose schedules caused the predicted alterations in the temporal pattern of adrenal steroid levels, with the greatest apparent suppression during the 2 to 4 hours after each dose. None of the schedules, however, caused significant differences in the mean 24-hour plasma concentration of 17-hydroxyprogesterone (21-hydroxylase deficiency) or 11-deoxycortisol (11-hydroxylase deficiency) or in the 24-hour urine pregnanetriol or 17-ketosteroid concentrations, either in the six patients undertreated at the dose of 12.5 mg/m2/day or in the two patients adequately treated. Nocturnal administration of all or a part of the daily dose did not improve adrenal suppression. These observations suggest that treatment of congenital adrenal hyperplasia with a once-a-day hydrocortisone dose schedule may be as effective as conventional multiple-dose schedules. Until this hypothesis has been tested by more extended clinical studies, however, we do not recommend a once-a-day schedule. Regardless of the dose schedule, the total daily hydrocortisone dose must be adjusted to achieve a normal rate of growth and bone age advancement.     

11beta-hydroxylase deficiency masked by alternative medicines

A 3.5-year-old Vietnamese boy presented with precocious pseudopuberty, hypertension and a skin rash that was treated with Vietnamese medications for 6 weeks, with resolution. Serum androgen levels were prepubertal, adrenal ultrasound was normal but a large unknown abnormal peak was detected in the urine steroid profile. Cessation of medications disclosed elevation of plasma androgen and 11-deoxycortisol levels. The unidentified urine steroid profile peak disappeared and a tetrahydro-11-deoxycortisol peak was detected. This patient represents a difficult and challenging diagnosis of 11beta-hydroxylase deficiency. Careful evaluation of history and physical finding in the presence of apparent biochemistry discrepancy resulted in a correct diagnosis.     

Pituitary-Adrenal Axis During Human Development

Investigation of early human fetal tissue has helped us elucidate the onset of the activation of the pituitary-adrenal axis during human development. Adrenal steroidogenesis and ACTH secretion from the pituitary starts at 7–8 weeks postconception, providing the rationale for prenatal treatment using dexamethasone offered to fetuses at risk of 21-hydroxylase deficiency (21-OHD). Fluctuation of 3beta-hydroxysteroid dehydrogenase (HSD3B2) in human fetal adrenal has several significant meanings. Its activity during early gestation is essential for inhibiting androgen production in the adrenal and safeguarding normal female sexual development. The enzyme may be reduced during mid-gestation in order to maintain pregnancy and to prevent preterm labor. Its reappearance in late gestation is also crucial for fetal maturation and parturition at term. Late-onset circulation failure observed in extremely low birth weight newborns may be associated with the paucity of HSD3B2 in their adrenals. In fetuses with 21-OHD, a proportion of increased 17alpha-hydroxyprogesterone may be converted to dihydrotestosterone through the backdoor pathway and contribute to the virilization of female fetuses.     

Progressive high frequency hearing loss: An additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency

In an earlier report, we found that X-linked congenital adrenal hypoplasia may be associated with gonadotrophin deficiency. This combination has since been confirmed by many others. At the last examination, our patients were 22.4, 19.9 and 17.5 years old. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone, but in all of them, a progressive hearing loss had appeared, starting at high freqencies at about 14 years of age. The loss progressed with age to lower frequencies, and the oldest patient had some remaining hearing capacity at 125–500 Hz only with a perceptive hearing loss of –95 dB at frequencies above 500 Hz. It is concluded that patients with this syndrome should be examined for hearing loss. X-linked adrenal hypoplasia may also be associated with glycerol kinase deficiency and myopathy. A molecular XP-deletion has suggested a locus for hypogonadotrophic hypogonadism distal to the glycerol kinase and adrenal hypoplasia loci. The observations in our patients suggest that the locus for at least this type of X-linked deafness may be in the same area.     

Diagnosis of 21-hydroxylase deficiency in newborn infants by GC-MS of urinary steroids

In a study using gas chromatography-mass spectrometry (GC-MS) on urine specimens from 16 normal infants and 16 infants with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (aged 1 day to 4 weeks), the major steroids recognized in all infants were: 16 alpha-hydroxy-dehydroepiandrosterone, 16 beta-hydroxy-dehydroepiandrosterone, 16-oxo-androstenediol, androstenetriol, 15 beta,17 alpha-dihydroxy-pregnenolone and 16 alpha-hydroxy-pregnenolone. Pregnanetriol was detectable in three normal infants (aged 3, 6 and 15 days) but the levels seen in 15 CAH patients were in a higher range. Pregnanetriolone, 5 beta-17-hydroxy-pregnanolone and 15 beta,17 alpha-dihydroxy-pregnanolone were present in the urine of 15 CAH patients, but were not detectable in any of the normal infants. The older the patient, the higher the level was of each of these four steroids. The results indicate that, even on day 1, patients with CAH due to 21-hydroxylase deficiency may be positively identified using GC-MS of urine specimens. This does not preclude the possibility that a minority of patients with CAH, most likely those with mild 21-hydroxylase deficiency, may not exhibit the characteristic GC-MS findings on day 1, as seen in one of the 16 CAH patients.     

A DIFFICULTY IN CONFIRMING 21 HYDROXYLASE DEFICIENCY IN A NEONATE WITH CONGENITAL ADRENAL HYPERPLASIA

The pattern of steroid excretion of a female infant with congenital adrenal hyperplasia was examined on the fifth day of life. The absence of pregnanetriol and the pattern of steroid excretion indicated a 3β-ol-de-hydrogenase deficiency; DHA and other androgens were excreted as sulphate (solvolysable) conjugates. On the other hand, the presence of 11-oxygenated steroids in the urine did not support this diagnosis. The detection of significant quantities of reducing steroids excreted as sulphate conjugates, suggested that either the corticosterone or cortisol pathway was partially open. An ACTH stimulation test at 3 1/2 months of age while the patient was receiving dexamethasone, revealed significant quantities of pregnanetriol in the urine, and a decrease of those steroids excreted in the neonatal period. It is suggested that the ACTH test is a valuable aid in the post neonatal period in the diagnosis of difficult cases of congenital adrenal hyperplasia.     

Impaired adrenal function after glucocorticoid therapy in children with acute lymphoblastic leukemia

BACKGROUND: Glucocorticoids are commonly used in the treatment of childhood acute lymphoblastic leukemia (ALL). The purpose of this study was to assess the incidence of adrenal insufficiency and the time for children with ALL to recover after treatment with the glucorticoids prednisolone or dexamethasone. PROCEDURE: Seventeen children, 2-15 years, with ALL were studied after receiving prednisolone (60 mg/m(2)/day, n = 10) for 5 weeks during remission induction therapy or dexamethasone (10 mg/m(2)/day, n = 7) for 3 weeks during reinduction therapy. Both drugs were tapered over 9 days. The adrenal function was assessed by an ACTH stimulation test within 2 weeks after discontinuing glucocorticoid therapy. In case of adrenal insufficiency, the ACTH test was repeated at 3-5 weeks interval, and patients were put on hydrocortisone substitution therapy. RESULTS: Three out of ten patients had a normal adrenal function within the first 2 weeks after prednisolone therapy. Another three patients recovered within 7 weeks, whereas the remaining four patients still showed adrenal insufficiency at the end of follow-up after 2.5-4 months. For dexamethasone, two out of seven patients showed a normal adrenal function within the first 2 weeks. Of the remaining patients, two recovered within 7 weeks, whereas three patients still had a demonstrated adrenal insufficiency at the end of follow-up after 4-8 months. CONCLUSIONS: Adrenal insufficiency occurs and may persist for several months in children with ALL after treatment with high doses of prednisolone or dexamethasone.     

Donor splice mutation in the 11beta-hydroxylase (CypllB1) gene resulting in sex reversal: a case report and review of the literature

BACKGROUND: Mutations in the gene encoding 110-hydroxylase (CYPI]BJ) are the second most common cause of congenital adrenal hyperplasia (CAH), a disorder characterized by adrenal insufficiency and virilization of female external genitalia. OBJECTIVE: We describe a new case of 1113-hydroxylase CAH caused by donor splice site mutation in the CYPllB1 gene. PATIENT: A 46,XX patient of Pakistani descent was identified with severe virilization soon after birth. The karyotype was negative for SRY. Pelvic ultrasound showed normal uterus and cervix. Periniogram revealed a 3-cm long urogenital sinus, ACTH stimulation test showed normal 17-hydroxyprogesterone, low cortisol, elevated 11-deoxycortisol and deoxycorticosterone (DOC) levels, consistent with 11beta-hydroxylase deficiency. Glucocorticoid treatment was started on the basis of a low baseline cortisol and severely virilized external genitalia. The patient did not develop salt wasting and/or hypertension. RESULTS: Analysis of the CYPllBlgene revealed homozygosity for a codon 318+1G--C substitution at the 5'-splice donor site of intron 5 resulting in a missense mutation. The parents of the patients are consanguineous and are heterozygous for the same mutation. CONCLUSIONS: In a previous reported case a donor splice mutation was identified for the first time at the same position codon 318 of the CYPIIB1 gene. We present this case in detail along with a literature review of 11beta-hydroxylase deficiency CAH.     

Diagnosis of 21-hydroxylase deficiency in newborn infants by GC-MS of urinary steroids

Abstract In a study using gas chromatography-mass spectrometry (GC-MS) on urine specimens from 16 normal infants and 16 infants with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (aged 1 day to 4 weeks), the major steroids recognized in all infants were: 16α-hydroxy-dehydroepiandrosterone, 16β-hydroxy-dehydroepiandrosterone, 16-oxo-androstenediol, androstenetriol, 15β, 17α-dihydroxy-pregnenolone and 16α-hydroxy-pregnenolone.
Pregnanetriol was detectable in three normal infants (aged 3, 6 and 15 days) but the levels seen in 15 CAH patients were in a higher range. Pregnanetriolone, 5β-17-hydroxy-pregnanolone and 15β, 17α-dihydroxy-pregnanolone were present in the urine of 15 CAH patients, but were not detectable in any of the normal infants. The older the patient, the higher the level was of each of these four steroids.
The results indicate that, even on day 1, patients with CAH due to 21-hydroxylase deficiency may be positively identified using GC-MS of urine specimens. This does not preclude the possibility that a minority of patients with CAH, most likely those with mild 21-hydroxylase deficiency, may not exhibit the characteristic GC-MS findings on day 1, as seen in one of the 18 CAH patients.     

CUSHING'S SYNDROME IN A THREE MONTH OLD GIRL

This paper describes the rare occurrence of Cushing's syndrome in a female infant aged eleven weeks. An adrenal adenoma was found to be the cause, and its removal was followed by a return to a normal appearance. This patient is the first with this condition seen in this age group at the Royal Children's Hospital since 1948. The Hospital's experience with adrenal tumours since that time is also presented, together with a review of the recent literature.     

Deletion of the long arm of the Y chromosome in an adolescent with short stature and hypogonadism

We describe a patient with short stature more than that expected for non-treated congenital adrenal hyperplasia due to nonclassic 21-hydroxylase deficiency with deletions in the long arm of the Y chromosome including the CGY gene and the AZF subregions.     

Triple-A syndrome--the first Chinese patient with novel mutations in the AAAS gene

We report on the first Chinese patient with triple-A syndrome, who presented at 22 months with status epilepticus secondary to hyponatraemia and hypoglycaemia. Subsequent endocrine investigations confirmed primary adrenal insufficiency and aldosterone deficiency. In the presence of achalasia and alacrima, this patient satisfies the diagnostic criteria of triple-A syndrome. Further molecular testing detected compound heterozygous mutations in the AAAS gene: a c.580C --> T transition in exon 7 and a c.771delG single nucleotide deletion in exon 8. Testing of parents and brother confirmed their heterozygous carrier status.     

Effects of Fetal Androgen on Childhood Behavior

The effects of fetal androgen excess or deficiency on postnatal behavior were examined in 7 males and 14 females with congenital adrenal hyperplasia or hypoplasia aged 3 to 21 years. The subjects were divided into 3 groups: those with androgen excess (A+) comprised a group of 13 patients with classical 21-hydroxylase deficiency and one with ll-β-hydroxylase deficiency; a normal or reduced androgen (a) group was represented by one patient with late-onset 21-hydroxylase deficiency and one with congenital adrenal hypoplasia; and a group with absent androgen (A) consisted of 5 patients with a cholesterol side-chain cleaving-enzyme deficiency. Behavior was evaluated as male (M) or female (F) according to the pattern of play, classification of which was based on data of prevalent play in 1,275 preschool and 400 school boys and girls. Play prevalent in both sexes was classified as neutral (N). The mothers of the patients were requested to check the preferred play during childhood from a randomized play list. The androgen excess group showed M or bisexual (M/F) type, whereas all of the androgen deficient group revealed F type irrespective of gender. In preschool children, coincidence of M or F play type with genetic sex, social sex and androgen exposure was 38%, 53% and 90%, respectively, indicating androgen-dependency of playing patterns. This persisted into school age, although the coincidence rate was slightly changed by environmental effects. These results suggest that fetal androgen plays a role in the sexual differentiation of the central nervous system .