Primary Adrenal Insufficiency in Childhood: Data From a Large Nationwide Cohort.

CONTEXT: Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children. OBJECTIVE: To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. PATIENTS AND METHODS: Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. RESULTS: The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was -0.70 ± 1.20 standard deviation score. CONCLUSIONS: We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.

Novel non-classic CYP21A2 variants, including combined alleles, identified in patients with congenital adrenal hyperplasia.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is an inborn error of metabolism and a common disorder of sex development where >90% of all cases are due to 21-hydroxylase deficiency. Novel and rare pathogenic variants account for 5% of all clinical cases. Here, we sought to investigate the functional and structural effects of four novel (p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro) and three combinations of CYP21A2 variants (i.e. one allele containing two variants p.[Ile172Asn;Val358Ile], p.[Val281Leu;Arg369Gln], or p.[Asp377Tyr;Leu461Pro]) identified in patients with CAH. METHODS: All variants were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells and enzyme activities directed toward the two natural substrates (17-hydroxyprogesterone and progesterone) were determined. In parallel, in silico prediction of the pathogenicity of the variants based on the human CYP21 X-ray structure was performed. RESULTS: The novel variants, p.Val358Ile, p.Arg369Gln, p.Asp377Tyr, and p.Leu461Pro exhibited residual enzymatic activities within the range of non-classic (NC) CAH variants (40-82%). An additive effect on the reduction of enzymatic activity (1-17%) was observed when two variants were expressed together, as identified in several patients, resulting in either NC or more severe phenotypes. In silico predictions were in line with the in vitro data except for p.Leu461Pro. CONCLUSIONS: Altogether, the combination of clinical data, in silico prediction, and data from in vitro studies are important for establishing a correct genotype and phenotype correlation in patients with CAH.

Thyroid function in patients with Prader-Willi syndrome: an Italian multicenter study of 339 patients.

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT - high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H - low/normal TSH and low fT4), subclinical hypothyroidism (SH - high TSH and normal fT4), and hyperthyroidism (HyperT - low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.

Subclinical hypothyroidism in paediatric population treated with levothyroxine: a real-world study on 2001-2014 Italian administrative data.

OBJECTIVE: To estimate the prevalence of subclinical hypothyroidism (SH) among children, by using levothyroxine low dosage as disease proxy, and to describe prescription pattern. DESIGN: An historical cohort study was performed through administrative databases of 12 Italian Local Health Units covering 3,079,141 inhabitants. A cohort of children (aged 0-13 years) was selected in the period 2001-2014. A subgroup of new users (aged 0-9 years) was identified and followed up for 5 years. METHODS: The prevalence was provided as mean value of the whole period, as annual trend, by patient gender and age. Demographic details, information on levothyroxine dosage, comorbidities and co-medications were provided. Therapy duration and medication persistence were evaluated among new users. RESULTS: 644 children treated with levothyroxine low dosage was selected, with a mean annual prevalence of 0.20 per 1000 children. The temporal trend of prevalence was stable, with a slight reduction in the 2005-2008. Prevalence by age showed an increase after 10 years. Patients were treated with an average annual dose of 4290 µg/year and 66.9% of children were affected by comorbidities. Among 197 new users, 62.9% received therapy only for one year, whereas out of those treated two or more years, 89.0% resulted persistent to the therapy. CONCLUSIONS: This study provides real-world epidemiology of SH among children, and it depicts the clinical and therapeutic characteristics of these subjects. Its findings showed that the SH treatment of this disorder was widely variable, also due to lack of evidence concerning paediatric population.

Long-term glucocorticoid effect on bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

INTRODUCTION: Patients with 21-hydroxylase deficiency (21OHD) assume a lifelong glucocorticoid (GC) therapy. Excessive GC treatment increases the risk of osteoporosis and bone fractures, even though the role of substitutive therapy is not fully established: we analyzed the effect of GC dose on bone metabolism and bone mineral density (BMD) over time in patients with 21OHD. METHODS: We studied bone metabolism markers and BMD in 38 adult patients with 21OHD (19-47 years, 24 females and 14 males) and 38 matched healthy control. In 15 patients, BMD data were available at both baseline and after a long-term follow-up. RESULTS: BMD was lower in patients than in controls at lumbar spine (0.961±0.1g/cm(2) vs 1.02±0.113g/cm(2), P=0.014) and femur neck (0.736±0.128g/cm(2) vs 0.828±0.103g/cm(2), P=0.02); otherwise, after height correction, only femoral neck BMD was lower in patients (0.458±0.081g/cm(2) vs 0.498±0.063g/cm(2), P=0.028). In those 21OHD subjects with at least 10 years follow-up, we observed an increase in lumbar BMD (P=0.0429) and a decrease in femur neck BMD values (P=0.004). Cumulative GC dose was not related to bone metabolism or BMD. No patient experienced clinical fragility fractures. CONCLUSIONS: BMD values are decreased in patients with 21OHD, which are in part explained by decreased height, but not by the dose of glucocorticoids. Nevertheless, bone status should be carefully monitored in patients with 21OHD.

Delayed myelination is not a constant feature of Allan-Herndon-Dudley syndrome: report of a new case and review of the literature.

INTRODUCTION: Allan-Herndon-Dudley syndrome is an X-linked condition caused by mutations of the monocarboxylate transporter 8 gene. This syndrome is characterized by axial hypotonia, severe mental retardation, dysarthria, athetoid movements, spastic paraplegia, and a typical thyroid hormone profile. In most of the cases reported so far, brain magnetic resonance imaging showed delayed myelination of the central white matter and this finding greatly affects the diagnosis of the syndrome. CASE REPORT: We present a new case studied with magnetic resonance imaging and spectroscopy and we reviewed all the articles published between 2004 and 2012 containing information on brain neuroimaging in this syndrome. An Italian boy, showing a classical phenotype of the syndrome, was diagnosed at 17months of age. Genetic analysis revealed a new frameshift mutation of the monocarboxylate transporter 8 gene. His brain magnetic resonance imaging and spectroscopy, performed at the age of 14months, were normal. DISCUSSION: Among the 33 cases reported in the literature, 3 cases had normal neuroimaging and in 7 of 14 cases, having a longitudinal follow-up, the initial finding of delayed myelination gradually improved. Our case and the review of the pertinent literature suggest that Allan-Herndon-Dudley syndrome should be suspected in males with the typical neurological and thyroid profile, even in cases with normal brain myelination.

Brain involvement in Alström syndrome.

BACKGROUND: Alström Syndrome (AS) is a rare ciliopathy characterized by cone-rod retinal dystrophy, sensorineural hearing loss, obesity, type 2 diabetes mellitus and cardiomyopathy. Most patients do not present with neurological issues and demonstrate normal intelligence, although delayed psychomotor development and psychiatric disorders have been reported. To date, brain Magnetic Resonance Imaging (MRI) abnormalities in AS have not been explored. METHODS: We investigated structural brain changes in 12 genetically proven AS patients (mean-age 22 years; range: 6-45, 6 females) and 19 matched healthy and positive controls (mean-age 23 years; range: 6-43; 12 females) using conventional MRI, Voxel-Based Morphometry (VBM) and Diffusion Tensor Imaging (DTI). RESULTS: 6/12 AS patients presented with brain abnormalities such as ventricular enlargement (4/12), periventricular white matter abnormalities (3/12) and lacune-like lesions (1/12); all patients older than 30 years had vascular-like lesions. VBM detected grey and white matter volume reduction in AS patients, especially in the posterior regions. DTI revealed significant fractional anisotropy decrease and radial diffusivity increase in the supratentorial white matter, also diffusely involving those regions that appeared normal on conventional imaging. On the contrary, axial and mean diffusivity did not differ from controls except in the fornix. CONCLUSIONS: Brain involvement in Alström syndrome is not uncommon. Early vascular-like lesions, gray and white matter atrophy, mostly involving the posterior regions, and diffuse supratentorial white matter derangement suggest a role of cilia in endothelial cell and oligodendrocyte function.

Impact of metabolic control on bone quality in phenylketonuria and mild hyperphenylalaninemia.

OBJECTIVES: A reduction of bone mineral density of unknown etiology has been reported in phenylketonuria (PKU) by radiological techniques, whereas no data on bone density in mild hyperphenylalaninemia (HPA) are available. We aimed to assess bone condition in PKU and HPA by quantitative ultrasound (QUS), taking into account patients' clinical and biochemical features. PATIENTS AND METHODS: Phalangeal QUS has been used for bone assessment in 78 patients affected by PKU (n = 42) or mild HPA (n = 36). For each patient, blood phenylalanine concentrations in the 2 years before the study have been recorded and related to bone assessment. RESULTS: Overall normal bone quality has been observed in the whole study group (AD-SoS standard deviation score [SDS] 0.25 ± 1.29; BTT SDS -0.13 ± 1.08). PKU adolescents (age older than 15 years, AD-SoS SDS -0.54 ± 1.33; BTT SDS -0.85 ± 1.21) and patients with poor compliance with treatment (blood phenylalanine >10 mg/dL, AD-SoS SDS -0.47 ± 1.39; BTT SDS -0.97 ± 1.14) showed lower BTT SDS with respect to normal population (P = 0.003 and P < 0.001, respectively). Patients with PKU with good compliance with treatment (blood phenylalanine < 10 mg/dL, AD-SoS SDS 0.65 ± 1.33; BTT SDS 0.15 ± 0.94) and patients with mild HPA (AD-SoS SDS 0.44 ± 1.06 and BTT SDS 0.19 ± 0.85) showed normal bone mineral density and cortical thickness. CONCLUSIONS: Good compliance with treatment in PKU during adolescence and adulthood is desirable because diet discontinuation is associated with bone loss. Mild HPA seems not to be complicated by bone damage.