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Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The introduction of life-saving glucocorticoid replacement therapy 70 years ago has changed the perception of CAH from a paediatric disorder into a lifelong, chronic condition affecting patients of all age groups. Alongside health problems that can develop during the time of paediatric care, there is an emerging body of evidence suggesting an increased risk of developing co-morbidities during adult life in patients with CAH. The mechanisms that drive the negative long-term outcomes associated with CAH are complex and involve supraphysiological replacement therapies (glucocorticoids and mineralocorticoids), excess adrenal androgens both in the intrauterine and postnatal life, elevated steroid precursors and adrenocorticotropic hormone levels. Alongside a review of mortality outcome, we discuss issues that need to be addressed when caring for the CAH patient including female and male fertility, cardio-metabolic morbidity, bone health and other important long-term outcomes of CAH., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: This analysis of previously published reports was performed to examine the effects of gonadotropin‐releasing hormone (GnRH) agonist treatment on adult height and the factors associated with adult height outcomes. Context: GnRH agonists are first‐line agents in the treatment of precocious puberty. However, studies regarding the treatment effect on subjects with early puberty have reported inconsistent results. Design: A total of 14 studies identified from a search of electronic databases (AMED, EMBASE, MEDLINE and RISS) were included. Controlled studies with girls who developed puberty before 10 years of age and measurements of the adult heights of the subjects were selected. Studies using only long‐acting GnRH agonists to suppress puberty were included. Adult height, duration of the treatment, age at the start of treatment and bone age advancement were analysed. Results: The mean age of the subjects ranged from 6.3 to 9.0 years. The meta‐analysis showed a pooled mean difference in adult height of 3.2 cm and a 95% confidence interval of 1.3‐5.1 cm. The height difference between the treated subjects and controls was significantly associated with the duration of treatment (P =.005) rather than the age at the start of treatment (P =.084) or the difference between bone age and chronological age (P =.427). Conclusions: Administration of GnRH agonists in girls who develop early puberty and demonstrate advanced bone age may be effective for increasing adult height, especially if a sufficiently long treatment duration can be achieved. [ABSTRACT FROM AUTHOR]

Objectives Estimates of high blood pressure ( BP) incidence in children with congenital adrenal hyperplasia ( CAH) vary widely; risk factors are poorly understood. We estimated incidence of hypertension by CAH subtype and sex, and assessed its association with body mass index, hydrocortisone and fludrocortisone. Design Longitudinal. Patients Chart review of 180 paediatric CAH patients (120 salt wasting; 60 simple virilizing; 93 females) seen from 1970 to 2013. Measurements High BP was diagnosed by diastolic or systolic blood pressure measurement ≥95th percentile for age, sex and height; hypertension was diagnosed with high BP on at least three clinic visits. Results Children with classic CAH who received fludrocortisone had a significantly higher rate of hypertension (55% vs 31%) than those who did not. Hypertension incidence was higher in salt-wasting CAH (58%) than in simple-virilizing CAH (35%). Hypertension first occurred before age 5 years in 91% of salt-wasting males and 50% of cases in salt-wasting females; most simple-virilizing cases occurred during ages 10-18 years. Rates of hypertension were higher in children who had three or more measurements with 17- OHP < 400 ng/dl (12·12 nmol/l), and this difference was significant in salt-wasting males. Children on fludrocortisone who had three or more readings of 17- OHP < 400 ng/dl (12·12 nmol/l) had a significantly higher rate of hypertension than those who did not. Hydrocortisone dose was not associated with hypertension. Conclusion Children with CAH are at higher risk for hypertension than the general paediatric population, and incidence differs by sex and CAH subtype. Hypertension was higher in children on fludrocortisone and who were oversuppressed. [ABSTRACT FROM AUTHOR]

Objective A high prevalence (60%) of central adrenal insufficiency ( CAI) has been reported in Prader-Willi syndrome ( PWS) using the metyrapone test. We have assessed CAI in adults with PWS using the low-dose short synacthen test ( LDSST). Design Basal cortisol and ACTH, and 30-min cortisol after the administration of 1 μg synacthen, were determined in 53 PWS adults (33 females). A peak cortisol value of ≥500 nmol/l was taken as normal. Hormonal profiles were analysed in relation to gender, genotype and phenotype. Deficient patients were retested by high-dose short synachten test ( HDSST) or a repeat LDSST. Results Mean ± SD basal cortisol and ACTH were 336·6 ± 140·7 nmol/l and 4·4 ± 3·7 pmol/l respectively. Cortisol rose to 615·4 ± 135·0 nmol/l after LDSST. Eight (15·1%) patients had a peak cortisol response <500 nmol/l, with a lower mean ± SD (range) basal cortisol of 184·9 ± 32·0 (138·0-231·7) compared with 364·1 ± 136·6 (149·0-744·5) in normal responders ( P < 0·001). Seven of the eight patients underwent retesting, with 4 (7·5%) showing persistent suboptimal responses. Basal and peak cortisol correlated in females ( r = 0·781, P < 0·001). Logistic regression revealed that only female gender and baseline cortisol were predictors of cortisol peaks (adjusted R square 0·505). Conclusions Although CAI can be part of the adult PWS phenotype, it has a lower prevalence (7·5%) than previously reported. Clinicians are advised to test PWS patient for CAI. Our study also shows that basal cortisol is closely correlated with adrenal response to stimulation, indicating that its measurement may be helpful in selecting patients for LDSST. [ABSTRACT FROM AUTHOR]

The past 12 years have witnessed an explosion in our understanding of the development of the anterior pituitary gland, and of mechanisms that underlie the diagnosis of growth hormone deficiency (GHD) and combined pituitary hormone deficiency (CPHD). The anterior pituitary is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors that leads to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of GHD/CPHD. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2 and SOX3. Depending upon the expression patterns of these molecules, the phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. The phenotype and the mode of inheritance can be highly variable. Novel mutations within the GH-1 and GHRHR genes have also shed light on the phenotype and pathogenesis of isolated GHD (IGHD). To date, genetic mutations have been identified in a modest proportion of patients with IGHD/CPHD and associated syndromes such as SOD. It is, however, clear that many genes remain to be identified, and characterization of these will further elucidate the pathogenesis of these complex conditions. [ABSTRACT FROM AUTHOR]

Following a successful clinical trial in 1996, the long-acting GnRH analogue goserelin (Zoladex LA 10·8 mg; Astra Zeneca) has been our preferred treatment for central early (CEP) or precocious puberty (CPP). However, some female patients have expressed concern about perceived weight gain during therapy and delay in the onset or resumption of menses on completion of therapy. The primary aim of this study was to investigate these concerns by determining the auxological parameters and timing of menarche or re-menarche in all girls with CEP/CPP who have completed a course of Zoladex LA treatment. The secondary aim was to assess auxological outcome in girls who have attained final height.Case records of all girls with idiopathic CEP/CPP or CEP/CPP secondary to CNS pathology treated with Zoladex LA since 1996 were reviewed. A total of 46 girls who have completed therapy were identified, of whom 11 had reached final height.Height, weight and bone age (RUS (TW2) method) were measured before treatment, when Zoladex LA was stopped and at final height. Body mass index (BMI) was calculated as a clinical measure of body fatness. Pubertal status was assessed pre- and post-treatment by Tanner staging and pelvic ultrasonography. Timing of menarche or re-menarche following cessation of treatment was recorded.The mean (range) age of starting GnRH analogue therapy was 8·3 (1·8–10·5) years and the duration of treatment was 2·9 (0·7–8·9) years. Pre-treatment height was above average at 0·72 SD but had declined to 0·28 SD by the end of therapy. The 46 girls were heavier than average before treatment (Wt SDS 1·04) with no change in weight status on completion of therapy. Mean BMI SDS increased significantly from 0·93 to 1·2 during treatment, indicating that the girls became relatively fatter. Using recommended BMI cut-off values for defining overweight and obesity in children of the 85th and 95th centiles, 41% of the cohort were overweight and 28% were obese before treatment, rising to 59% and 39%, respectively, at the end of therapy. The average time interval to onset or resumption of menses after stopping treatment was 1·46 years (median 1·5, range 0·8–2·0 years). None of the following variables was found to be predictive of the time interval to menarche after completion of therapy: duration of treatment; chronological age; bone age; Tanner breast stage or uterine maturation at the end of treatment; the frequency of injections required to suppress puberty; or treatment with alternative GnRH analogue prior to Zoladex LA. Mean final height in 11 girls was 159·7 cm (−0·63 SD), close to the mean parental target height of 160·9 cm (−0·48 SD). Nine of the 11 girls (82%) attained final heights within or above their target range. In keeping with the whole cohort this subset of girls became fatter during treatment, although this difference was not statistically significant. However, they returned to their pretreatment size at final height (mean BMI SDS 1·18, 1·41 and 1·16 before, at the end of treatment and at final height, respectively).Our cohort of 46 girls treated with long-acting goserelin was already considerably overweight at the start of therapy and became fatter during treatment. However, adiposity appeared to return to pretreatment levels in the 11 girls followed up to final height. Most of the girls who have attained final height are within or above their expected target range. The relatively long time interval to menarche of 1·5 years after stopping treatment is unexplained but may reflect a residual suppressive effect on the hypothalamo–pituitary axis of this long-acting GnRH analogue. Anticipation of the timing of menarche has proved to be of value in planning when to stop therapy in girls in whom treatment is mainly for practical and/or psychological reasons. [ABSTRACT FROM AUTHOR]

Summary objectives To optimize the indications for treating girls with idiopathic central precocious puberty with GnRH analogues, since outcomes may vary. design Comparison of adult heights with the data at initial evaluation and the target heights. patients Group 1 patients (n = 43) were treated with GnRH analogue from 7·9 ± 0·2 years to 10·8 ± 0·1 years (bone age: 10·3 ± 0·2 years to 12·2 ± 0·1 years) and group 2 patients (n = 29) were monitored without treatment because their predicted adult heights were > 155 cm. The criteria for treatment were a predicted height < 155 cm and/or a LH/FSH peaks ratio of > 0·6. results At initial evaluation, group 1 patients had greater breast development (P = 0·001) and bone age advances (2·0 ± 0·2 years) than those of group 2 (1·3 ± 0·2 years, P < 0·03), and higher plasma oestradiol concentrations (139 ± 11 pmol/l vs. 62 ± 7 pmol/l, P = 0·0001), LH peak (12·2 ± 1·8 IU/l vs. 5·8 ± 2·2 IU/l, P = 0·0001) and LH/FSH peaks ratio (1·3 ± 0·2 vs. 0·5 ± 0·1, P = 0·0001). The predicted height for group 1 at the onset of treatment (156 ± 1·2 cm) was lower than the adult height (159·5 ± 0·8 cm, P = 0·002), but the two were similar (164·1 ± 1·2 cm vs. 162·7 ± 0·9 cm) for group 2. In group 1, the difference between these heights (mean 3·4 cm) was positively correlated with the bone age advance (r = 0·51, P = 0·001), but not with chronological or bone ages, oestradiol, LH peak, LH/FSH peaks ratio before treatment or its duration. It was 5·3 ± 1·2 cm in the 28 patients with a bone age advance of > 2 years and 0 ± 1·3 cm in the other 15 (P < 0·02). It was 6·1 ± 1·3 cm in the 24 patients with predicted height < 155 cm, and... [ABSTRACT FROM AUTHOR]

Examines the incidence of central precocious puberty. Importance of making immediate correct diagnosis; Definition of precocious puberty; Etiology and clinical course of precocious puberty; Forms of central precocious puberty.

BACKGROUND Early onset of puberty is frequently observed in adopted children. During treatment with a gonadotrophin releasing hormone agonist (GnRHa), a decrease in height velocity (HV) precludes height gain. OBJECTIVE AND DESIGN We studied the effect of the addition of GH to GnRHa treatment in a 3-year prospective randomized trial in 30 adopted children with early puberty. PATIENTS Mean age (SD) at start of treatment was 9·6 (0·9) years in girls and predicted adult height (PAH) using a segmented bone age (BA) assessment method was 148·0 (5·3) cm. RESULTS HV decreased gradually in both groups with a higher HV in the group with GH addition (group B). No significant difference between the rates of bone maturation [change in bone age (ΔBA)/change in chronological age (ΔCA)] of both treatment groups was observed. After 3 years of treatment, PAH increase was 5·7 (3·8) cm in group A (GnRHa alone) and 10·1 (3·8) cm in group B (P < 0·01). IGF-I levels were higher in group B. HV decreased slowly in both groups during treatment, unlike stabilization of IGF-I levels. CONCLUSION We conclude that, after 3 years of treatment, the addition of GH to GnRHa results in higher HV and a significant increase in PAH compared to GnRHa alone. [ABSTRACT FROM AUTHOR]

OBJECTIVE Pendred's syndrome is an autosomal recessive disorder characterized by goitre, sensorineural deafness and iodide organification defect. It is one of the most frequent causes of congenital deafness, accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, a 21 exon gene located on chromosome 7. The aim of this study was to examine an Italian family affected with Pendred's syndrome at the molecular level. PATIENTS Thirteen subjects belonging to a family from Southern Italy were evaluated for the clinical and genetic features of Pendred's syndrome. MEASUREMENTS Exons 2–21 of the PDS gene were amplified from peripheral leucocytes by the polymerase chain reaction; mutation analysis was performed by single strand conformation polymorphism, direct sequencing and restriction analysis. RESULTS The index patient had the classical triad of the syndrome and harboured two mutations in the PDS gene in the form of compound heterozygosity. He was found to be heterozygous for a cytosine to adenosine mutation at nucleotide 1523 in exon 13 and for a IVS 1001 + 1G → A mutation. The former is a novel mutation which results in a change of 508 threonine to asparagine in the putative eleventh transmembrane domain. The latter mutation in the donor splice site has already been described in other patients and is thought to lead to aberrant splicing and premature protein truncation. Three subjects who were heterozygous for one mutation had normal phenotypes. Two subjects had sensorineural deafness and were heterozygous for a single mutation. Goitre was found only in patients with Pendred's syndrome and was absent in all other individuals, albeit residing in an iodine-deficient area. CONCLUSIONS We have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects... [ABSTRACT FROM AUTHOR]