Benefits of rescreening newborns of mothers affected by autoimmune hypothyroidism

Infants of mothers with autoimmune hypothyroidism (AH) are at risk of developing late-onset hypothyroidism, often escaping at newborn screening. This condition might be caused both by the action of maternal antibodies and/or by maternal treatment

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

Circulating ghrelin levels in girls with central precocious puberty are reduced during treatment with LHRH analog.

Decreased levels of ghrelin have been measured in growing children during puberty. No data are available for girls with central precocious puberty (CPP). Aims: To explore ghrelin changes before, during, and after GnRH analog treatment in girls with CPP. Subjects and methods: A sample of 20 Caucasian girls (8.08±0.65 years of age) with CPP was recruited. Height and weight, bone age, LH, FSH, 17β estradiol (E2), and ghrelin were measured before starting treatment with GnRH analog, 18 months after therapy began and again 6 months after therapy discontinuation. Results: LH and E2 serum levels decreased significantly during treatment (2.45±2.03 vs 0.67±0.49 Ul/l, P<0.01 and 28.17±9.7 vs 15 pmol/l, P<0.01 respectively), returning to baseline levels after the discontinuation of therapy (4.75±1.66 UI/l and 29.23±6.99 pmol/l respectively). LH peaked following LHRH stimulation significantly (P<0.01) decreased during treatment (24.45±14.17 vs 1.3±0.18 UI/1) andthen increased after therapy discontinuation (12.58±6.09, P<0.01). Ghrelin decreased significantly (P<0.05) duringtreatment (1849±322 vs 1207±637pg/ml), and increased, though not significantly (P=0.09) after therapy withdrawal (1567±629 pg/ml). Conclusions: Contrary to what is expected in physiologic puberty, where ghrelin is progressively reduced, the prepubertal hormone millieau induced by GnRHa treatment in patients suffering from central precocious puberty (CPP) did not promote an increase in ghrelin circulating levels. Therefore, in CPP, ghrelin secretion seems to be independent from pubertal development per se. Concomitant estrogen suppression during treatment may play a potential role in the regulation of ghrelin secretion in these girls

Genotype in the diagnosis of 21-hydroxylase deficiency: who should undergo CYP21A2 analysis?

AMS: to confirm the diagnosis of 21-hydroxylase deficiency (21-OHD) by the analysis of CYP21A2 gene in infants with clinical and/or biochemical features of 21-OHD in order to clarify which patients to submit to genetic analysis; to analyze the genotype-phenotype concordance in these infants. SUBJECTS AND METHODS: We studied 25 children with clinical and/or biochemical features of 21-OHD. All of them and their parents were submitted to genetic analysis of CYP21A2. Patients were classified in 3 groups according to mutations' severity: severe (group A), moderate (group B) or mild (group C). RESULTS: CYP21A2 gene mutations were found in 17 children. Whereas all infants of groups A and B presented a classical form of 21- OHD, children of group C had a non-classical form of 21-OHD. Four infants resulted heterozygotes and 4 children were wildtype. A girl clinically presenting a non-classical form of 21-OHD resulted compound heterozygote with one of the mutations not described in literature (R25W) and whose residual enzymatic activity is not already known. All affected children presented a 17-OHP level after ACTH stimulation greater than 100 nmol/l. We found an optimal concordance between 17-OHP levels after ACTH test and genotype. CONCLUSIONS: CYP21A2 analysis permitted to confirm the diagnosis of 21-OHD in 68% of our children. To improve this percentage we suggest to perform the CYP21A2 analysis only when 17-OHP after ACTH test is greater than 100 nmol/l. Moreover, we found an optimal genotype-phenotype concordance in the 21-OHD patient

Growth Hormone Deficiency and Lysinuric Protein Intolerance: Case Report and Review of the Literature

Background: Lysinuric protein intolerance (LPI; MIM# 222700) is a rare metabolic disorder caused by a defective cationic amino acids (CAA) membrane transport leading to decreased circulating plasma CAA levels and resulting in dysfunction of the urea cycle. Short stature is commonly observed in children with LPI and has been associated with protein malnutrition. A correlation between LPI and growth hormone deficiency (GHD) has also been postulated because of the known interaction between the AA arginine, ornithine, and lysine and growth hormone (GH) secretion. Our report describes a case of GHD in an LPI patient, who has not presented a significant increase in growth velocity with recombinant-human GH (rhGH) therapy, suggesting some possible pathogenic mechanisms of growth failure. Case Presentation: The proband was a 6-year-old boy, diagnosed as suffering from LPI, erythrophagocytosis (HP) in bone marrow, and short stature. Two GH provocative tests revealed GHD. The patient started rhGH therapy and a controlled-protein diet initially with supplementation of oral arginine and then of citrulline. At 3-year follow-up, no significant increase in growth velocity and in insulin-like growth factor-1 (IGF-1) levels was observed. Inadequate nutrition and low plasmatic levels of arginine, ornithine, lysine, and HP may have contributed to his poor growth. Conclusion: Our case suggests that growth failure in patients with GHD and LPI treated with rhGH could have a complex and multifactorial pathogenesis. Persistently low plasmatic levels of lysine, arginine, and ornithine, associated with dietary protein and caloric restriction and systemic inflammation, could determine a defect in coupling GH to IGF-1 production explaining why GH replacement therapy is not able to significantly improve growth impairment. We hypothesize that a better understanding of growth failure pathophysiology in these patients could lead to the development of more rational strategies to treat short stature in patients with LPI

Osteogenesis Imperfecta: clinical, biochemical and molecular findings

Mutations in COL1A1 and COL1A2 genes, encoding the 1 and 2 chain of type I collagen, respectively, are responsible for the vast majority of cases of Osteogenesis Imperfecta (95% of patients with a definite clinical diagnosis). We have investigated twenty two OI patients, representing an heterogeneous phenotypic range, at the biochemical and molecular level. A causal mutation in either type I collagen gene was identified in twenty of them: no recurrent mutation was found in unrelated subjects; fifteen out of twenty mutations had not been reported previously. In two patients we could not find any causative mutation in either type I collagen gene, after extensive genomic DNA sequencing. Failure of COL1A1/COL1A2 mutation screening may be due, in a few cases, to further clinical heterogeneity, i.e. additional non collagenous disease loci are presumably involved in OI types beyond the traditional Sillence’s classification

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-birthweight (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) &lt;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 &lt; 2500 g proved useful in detecting newborns who otherwise would not be identified at the first screening

20 {YEARS} {OF} {NEONATAL} {SCREENING} {FOR} {CONGENITAL} {ADRENAL} {HYPERPLASIA} {IN} {NORTH}-{EASTERN} {ITALY}: {ROLE} {OF} {LC}-{MS}/{MS} {AS} A {SECOND} {TIER} {TEST}

Background: Newborn screening for congenital adrenal hyperplasia (CAH) based on 17-OHP concentration in dried blood spots has been taking place in North Eastern Italy since 2001. Since 2017, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been introduced, for the first time in Italy, as a second tier test. Aims: Our study aims to evaluate, on the one hand, the effectiveness of the newborn screening for CAH after 20 years of testing and, on the other, the impact that the introduction of the second tier test had on the diagnostic accuracy of the screening program. Method and materials: Since 2001 dried blood spots taken from newborns have been screened with a time-resolved fluoroimmunoassay for 17-OHP determination. Over the years, the cut-off levels of 17-OHP were adjusted according to gestational age (GA). Since 2017, a second tier test in LC/MSMS was introduced for samples displaying fluoroimmunoassay 17-OHP exceeding the cut-off. Results: 862.521 newborns have been screened over a period of twenty years. The total incidence of 21-hydroxylase deficiency (21-OHD) was 1:25.368, moreover a case of 11-β-hydroxylase deficiency was identified. All these diagnosis were genetically confirmed. Sensitivity and specificity of the screening program were 97% and 99.4%, respectively. The use of LC-MS/MS as second tier test significantly reduced the recall rate and increased the positive predictive value. Conclusions: Screening for CAH is useful in the neonatal diagnosis of classic form of 21-OHD, allowing a precocious treatment of affected children. The introduction of a LC-MS/MS second tier reduced the recall rate, avoiding unnecessary blood withdraws and medical evaluations and preventing stress to families. Furthermore, it helped identify rarer forms of CAH

Children with premature pubarche: is an alterated neonatal 17-Ohp screening test a predictive factor?

Abstract Background Neonatal screening for 21 hydroxylase deficiency is designed to detect classical form of congenital adrenal hyperplasia (CAH). It is still unclear whether newborns who result false positives at neonatal screening might later develop signs of androgen excess. The aim of this study is to verify whether a slightly elevated 17-OHP at newborn screening is a predictive factor for premature pubarche. Methods We evaluated all infants born between 2001 and 2014 with premature pubarche. In case of increased bone age, they were submitted to functional tests to find out the cause of their symptoms. Their 17-OHP values at newborn screening for CAH were reconsidered. Results We identified 330 patients (269 females, 61 males) with premature pubarche. All these children had a normal 17-OHP at newborn screening with the exception of a child, born preterm and not affected by CAH. Conclusions An elevated 17-OHP at newborn screening is not a predictive factor for premature pubarche. A likely cause of increased 17-OHP level at screening is an immaturity of adrenal gland or a neonatal stress. Therefore a strict follow up of these neonates during childhood is not necessary