Paolo Cavarzere

Current and emerging treatments for the management of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is the most common bone genetic disorder and it is characterized by bone brittleness and various degrees of growth disorder. Clinical severity varies widely; nowadays eight types are distinguished and two new forms have been recently described although not yet classified. The approach to such a variable and heterogeneous disease should be global and therefore multidisciplinary. For simplicity, the objectives of treatment can be reduced to three typical situations: the lethal perinatal form (type II), in which the problem is survival at birth; the severe and moderate forms (types III–IX), in which the objective is ‘autonomy’; and the mild form (type I), in which the aim is to reach ‘normal life’. Three types of treatment are available: non-surgical management (physical therapy, rehabilitation, bracing and splinting), surgical management (intramedullary rod positioning, spinal and basilar impression surgery) and medical-pharmacological management (drugs to increase the strength of bone and decrease the number of fractures as bisphosphonates or growth hormone, depending on the type of OI). Suggestions and guidelines for a therapeutic approach are indicated and updated with the most recent findings in OI diagnosis and treatment.

Prevalence of overweight and obesity in 2- to 6-year-old Italian children

Objective: To assess the prevalence of overweight and obesity in 2‐ to 6‐year‐old Italian children and to compare the prevalence between the north and the south of the country.

Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency

Objective  Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin–aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.

Neonatal Screening for Congenital Adrenal Hyperplasia in North-Eastern Italy: A Report Three Years into the Program

Aims: To evaluate the incidence of congenital adrenal hyperplasia (CAH) in the Northern Italian population and the efficiency of the North-Eastern Italy screening program. To adjust cut-off levels for 17-hydroxyprogesterone (17-OHP) in relation to gestational age and birth weight, comparing the benefits in terms of reduction of recall rates with the two approaches and ultimately choosing the better of the two. Subjects and Methods: Since September 2001, blood samples from neonates born in North-Eastern Italy have been screened with a fluoroimmunoassay method for 17-OHP determination (DELFIA). A preliminary cut-off level of ≧30 nmol/l was set both for term and preterm newborns. The values of 17-OHP were analysed usingstatistical methods in relation to gestational age and birth weight in order to modify the cut-off on the basis of our data. Results: After 33 months of screening we screened 128,282 newborns and detected 6 affected babies. During the first 8 months of screening among the recalled babies, 89.6 and 78.1% were preterm and low-birth-weight newborns, respectively, with a recall rate of 2.59% for premature neonates and of 4.94% for babies with birth weights <2,500 g. We chose a new cut-off value of 50 nmol/l for preterm newborns only and, after 4 months, the recall rate was reduced to 0.83% for these infantsand to 1.83% for low-birth-weight infants. Conclusion: After 33 months of screening for CAH in North-Eastern Italy, we report an incidence of 1:21,380. In 5 out of 6 affected babies, the diagnosis was established only after a positive screening test, which prevented a severe salt-wasting crisis in these babies. The cut-off level related to gestational age led to a significant reduction in the number of false-positives among preterm babies.We therefore intend to continue with the screening program for CAH in North-Eastern Italy, keeping a gestational-age-related cut-off in the hope that our data may encourage a national screening program for CAH.

Prepubertal serum inhibin B in cryptorchid infants and in monorchid boys with compensatory testicular hypertrophy

OBJECTIVE To investigate the prepubertal serum inhibin B levels in monorchid boys with compensatory testicular hypertrophy (CTH) and in surgically treated cryptorchid boys with normal testicular volume. DESIGN Prospective study. SETTING Pediatric Division, University of Verona, Italy. PATIENT(S) Thirty-two prepubertal boys: 11 monorchids with CTH and 21 cryptorchids. For comparison we analyzed 15 healthy boys. MAIN OUTCOME MEASURE(S) All patients underwent a GnRH agonist test. Inhibin B measurement was performed at basal time. RESULT(S) There was a significant difference in mean testicular volume between monorchid and cryptorchid or healthy children, with boys with CTH evidencing larger testicle volume. There was no significant difference in inhibin B levels between boys with CTH and cryptorchid, but the levels were significantly lower in both groups than in the control group. Boys with CTH had significantly higher serum levels of basal FSH than children with cryptorchid. The FSH peak response to GnRH agonist stimulation was significantly higher in boys with CTH than in those with cryptorchid. CONCLUSION(S) Monorchid infants with CTH showed low inhibin B and high FSH levels. Our finding may confirm the hypothesis that CTH is unable to prevent testicular insufficiency in adulthood. We suggest an early hormonal evaluation of boys with CTH at puberty, together with early sperm analysis.

Apparent Mineralocorticoid Excess by a Novel Mutation and Epigenetic Modulation by HSD11B2 Promoter Methylation

CONTEXT Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disease resulting from mutations within the hydroxysteroid (11β-dehydrogenase2 [HSD11B2]) gene causing a prominent mineralocorticoid receptor activation by cortisol and hypokalemic low renin hypertension as the main clinical feature. OBJECTIVE The objective of the study was to characterize AME for possible novel HSD11B2 mutations and to define the role of HSD11B2 promoter methylation in the phenotypic expression of the disease. SUBJECTS Two proband brothers and 10 relatives participated in the study. METHODS Peripheral blood mononuclear cell DNA was used for HSD11B2 exon sequencing, and a new predicted structure of 11β-hydroxysteroid dehydrogenase type 2 was generated by an in silico three-dimensional modeling. Promoter methylation was determined by bisulfite pyrosequencing. Urinary tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone ratio, a surrogate marker of 11β-hydroxysteroid dehydrogenase type 2 activity, was measured by gas chromatography-mass spectrometry. RESULTS A novel homozygous variant at HSD11B2 exon 3 site (c.C662G) resulting in an alanine-to-glycine change at position 221 was discovered by sequencing the DNA of the probands. A monoallelic mutation was found in the DNA of the parents and other four relatives. In silico three-dimensional modeling showed that the Ala221Gly substitution could perturb a hydrophobic interaction by reducing the enzymatic affinity for the substrate. The HSD11B2 promoter methylation of normotensive heterozygous relatives was similar to that of wild types, whereas the hypertensive heterozygous subjects showed higher methylation than wild types, consistently with a transcriptional repressive effect of promoter hypermethylation. CONCLUSIONS A novel HSD11B2 functional mutation accounting for an Ala221Gly substitution causes AME. The hypertension phenotype is also epigenetically modulated by HSD11B2 methylation in subjects heterozygous for the mutation.

Congenital hypothyroidism with delayed TSH elevation in low-birth-weight infants: incidence, diagnosis and management

OBJECTIVE To evaluate the incidence of congenital hypothyroidism (CH) with delayed TSH elevation among low-birth-weight (LBW) newborns in North-Eastern Italy and to verify if they need a second or third screening. DESIGN Analysis of clinical and biochemical data of newborns affected by CH with delayed TSH elevation identified by neonatal screening. METHODS Data of all newborns with birth weight (BW) <2500 g and evidence of delayed TSH elevation at newborn screening were collected between 2011 and 2014. Confirmatory tests were based on serum TSH and FT4 levels. All their clinical signs at diagnosis were reported. RESULTS 57.5% of LBW newborns with delayed TSH increase at neonatal screening presented a CH with delayed TSH elevation and began a treatment with l-thyroxine. The incidence of this condition in North-Eastern Italy is therefore 1:908. The remaining infants presented a subclinical hypothyroidism (21.25%) or a complete normal serum thyroid function (21.25%). These data could be drawn only from a retesting strategy of neonatal screening. CONCLUSIONS Our report describes the incidence of CH with delayed TSH rise in North-Eastern Italy and differentiates this clinical condition from other thyroid dysfunctions of preterm or LBW newborns. The second-screening strategy for CH in neonates with BW < 2500 g proved useful in detecting newborns who otherwise would not be identified at the first screening.

Sleep-disordered breathing is associated with blood pressure and carotid arterial stiffness in obese children.

Introduction: Both sleep-disordered breathing (SDB) and high blood pressure (BP) occur more frequently among obese children than among normal weight children, and this may be due to endothelial dysfunction and worsened arterial stiffness. The aim of this study was to evaluate the possible association between SDB and BP, and the possible role of endothelial function and local and systemic arterial stiffness in a sample of obese children asymptomatic for sleep disturbances. Materials and methods: Thirty-nine obese children were included in the study. Children underwent overnight limited channel polysomnography, and the vascular measurements included the following: office and 24-h ambulatory BP; brachial flow-mediated dilatation, carotid intima–media thickness and carotid distensibility measured using ultrasound; and systemic arterial stiffness index measured using digital volume pulse analysis. Results: Significant correlations between different BP measurements (both office and ambulatory BP monitoring and estimated by Z score) and SDB were found, including correlations involving the respiratory disturbance index, the apnea–hypopnea index (AHI), the number of desaturations per hour and the mean peripheral saturation (r ranging between 0.330 and 0.474). Carotid distensibility was correlated with the AHI (r = −0.367; P = 0.030) and with the mean oxygen saturation (r = 0.401; P = 0.017). In contrast, there was no relationship among flow-mediated dilatation, stiffness index, carotid intima–media thickness and all the tested respiratory markers. In the multivariate analysis, the supine Z SBP remained independently associated with the number of desaturations per hour and the AHI, even after correction for carotid distensibility and BMI. Conclusion: Our data suggest that in obese children asymptomatic for sleep respiratory problems, SDB might worsen BP, in part, through an increase in arterial stiffness.

Serum inhibin B levels before and after varicocelectomy in early adolescence

Background: Whereas no clear relationship has been observed between varicocelectomy and serum inhibin B levels in men, in adolescents comparison between inhibin B levels before and after varicocelectomy is lacking. Aim: To evaluate the effect of varicocele surgical treatment on inhibin B levels in adolescents at the beginning of puberty compared to a group of healthy adolescents. Subjects and methods: We studied 28 adolescents in Tanner 2 pubertal stage with a grade III left-sided varicocele (patients) compared to 13 age- and pubertal stage-matched healthy adolescents (controls). All patients underwent blood tests to determine serum inhibin B levels before and 6 months after varicocelectomy by Palomo procedure. For comparison we investigated inhibin B levels in controls and repeated this test 6 months later. Testicular ultrasound was performed for patients only. Results: Baseline inhibin B concentrations of patients and controls were 109.90±40.26 and 109.33±38.34 pg/ml, respectively. No significant changes were observed in patients’ inhibin B concentrations after varicocelectomy (116.00±42.65 pg/ml), or in controls during the 6 months’ follow-up (99.12±30.09 pg/ml). Doppler examination after treatment shows a complete resolution of varicocele in all the patients without alterations in testicular parenchyma. Conclusions: Varicocelectomy performed on adolescents at T2 pubertal stage might be useful to avoid alteration in inhibin B production and consequently in testicular function. Further studies are necessary to confirm the prognostic value of inhibin B levels and the benefit of early varicocelectomy in preserving the fertility of these adolescents.

Sleep disordered breathing in children with achondroplasia

BackgroundChildren with achondroplasia often have breathing problems, especially during sleep. The most important treatments are adenotonsillectomy (for treating upper obstruction) and/or neurosurgery (for resolving cervicomedullar junction stenosis).Data sourcesWe reviewed the scientific literature on polysomnographic investigations which assessed the severity of respiratory disorders during sleep.ResultsRecent findings have highlighted the importance of clinical investigations in patients with achondroplasia, differentiating between those that look for neurological patterns and those that look for respiratory problems during sleep. In particular, magnetic resonance imaging (MRI) and somatosensory evoked potentials are the main tools to evaluate necessary neurosurgery and over myelopathy, respectively.ConclusionsThe use of polysomnography enables clinicians to identify children with upper airway obstruction and to quantify disease severity; it is not suitable for MRI and/or neurosurgery considerations.