Age at diagnosis in patients with chronic congenital endocrine conditions: a regional cohort study from a reference center for rare diseases.

BACKGROUND: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as  it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late. OBJECTIVE: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. PATIENTS AND METHODS: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. RESULTS: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. CONCLUSION: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

Arterial Spin Labeling and Central Precocious Puberty.

PURPOSE: To evaluate a non-invasive method to assess the progressivity of idiopathic central precocious puberty (CPP) by quantifying perfusion of the pituitary stalk with arterial spin labeling (ASL) and using the gonadotropin-releasing hormone (GnRH) test as a reference test to define progressive CPP. METHODS: In a single center retrospective study, 52 consecutive patients, observed between October 2015 and April 2017 and referred with early signs of puberty, were evaluated using the GnRH test and cerebral magnetic resonance imaging (MRI). Patients with peripheral or non-idiopathic puberty were excluded. The distribution of perfusion values between patients with progressive and non-progressive CPP was compared using a nonparametric Mann-Whitney U­test. RESULTS: In this study 35 patients were included and 29 had progressive CPP. These patients displayed significantly higher cerebral blood flow (CBF) values than the 6 patients with non-progressive CPP (p = 0.006). The median CBF for patients with non-progressive and progressive CPP was 45.25 ml/min/100 g (interquartile range 36.9-54) vs. 65 ml/min/100 g (interquartile range 55.5-74.5), respectively. To determine if the CPP was progressive, the best CBF threshold was 55.5 ml/min/100 g with a sensitivity of 76%, a specificity of 83% and an accuracy of 77%. There were strong significant correlations between CBF and LH peak (r = 0.67, p < 0.001) and between CBF and LH/FSH peaks ratio [r = 0.71, p < 0.001] during the GnRH test. CONCLUSION: Arterial spin labelling (ASL) offers a novel tool to assess the progressivity of idiopathic CPP.

Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

AIMS: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. METHODS: Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. RESULTS: Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 +/- 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). CONCLUSIONS: Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.

Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties.

Deletions of the long arm of chromosome 20 are rare. Here, we report on two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and post-natal growth retardation, intractable feeding difficulties, abnormal subcutaneous adipose tissue, similar facial dysmorphism, psychomotor retardation and hypotonia. Standard cytogenetic studies were normal, but high-resolution chromosomes analysis showed the presence of a chromosome (20)(q13.2-q13.3) interstitial deletion. Karyotypes of both parents were normal. Molecular studies using FISH and microsatellite polymorphic markers showed that the deletion was of paternal origin and was approximatively 4.5 Mb in size. A review of other reported patients with similar deletions of the long arm of chromosome 20 shows that the observed phenotype might be explained in the light of the GNAS imprinted locus in particular by the absence of the Gnasxl paternally imprinted gene and the TFA2PC gene in the deleted genetic interval.