Implications of deferred diagnosis of paediatric intracranial germ cell tumours.

AIMS: This study analysed the clinical features of a cohort of children with intracranial germ cell tumours (IC-GCTs). We retrospectively reviewed timelag between symptoms onset, clinic-radiological findings, diagnosis and outcomes. METHODS: Symptoms at diagnosis were divided into four groups: (1) raised intracranial pressure (RICP); (2) visual impairment; (3) endocrinopathies; (4) other. Total diagnostic interval (TDI), defined as the interval between symptom onset (including retrospective recall of symptoms) and definitive diagnosis of IC-GCT, was calculated and compared to survival rates. RESULTS: Our cohort included 55 children with median follow-up of 78.9 months (0.5-249.9). The majority (63.6%) had germinomas and 10.9% were metastatic at diagnosis. IC-GCTs were suprasellar (41.8%), pineal (36.4%), bifocal (12.7%) or in atypical sites (9.1%). The most common presenting symptoms were related to RICP (43.6%); however, by the time of tumour diagnosis, 50.9% of patients had developed endocrine dysfunctions. All pineal GCTs manifested with RICP or visual impairment. All suprasellar GCTs presented with endocrinopathies. TDI ranged between 0.25 and 58.5 months (median 4 months). Pineal GCTs had the shortest TDI (median TDI 1 month versus 24 months in suprasellar GCTs, p < .001). TDI > 6 months was observed in 47.3% of patients and was significantly associated with endocrine presenting symptoms. No statistically significant difference was found in progression-free survival and overall survival between patients with TDI > 6 months and with TDI ≤ 6 months. CONCLUSION: Approximately half of the IC-GCT patients in this cohort had TDI > 6 months. These presented mostly with endocrine deficits. TDI > 6 months was not associated with increased relapse or mortality rates.

A frequent oligogenic involvement in congenital hypothyroidism.

Congenital hypothyroidism (CH), the most frequent form of preventable mental retardation, is predicted to have a relevant genetic origin. However, CH is frequently reported to be sporadic and candidate gene variations were found in <10% of the investigated patients. Here, we characterize the involvement of 11 candidate genes through a systematic Next Generation Sequencing (NGS) analysis. The NGS was performed in 177 unrelated CH patients (94 gland-in-situ; 83 dysgenesis) and in 3,538 control subjects. Non-synonymous or splicing rare variants (MAF < 0.01) were accepted, and their functional impact was predicted by a comprehensive bioinformatic approach and co-segregation studies. The frequency of variations in cases and controls was extended to 18 CH-unrelated genes. At least one rare variant was accepted in 103/177 patients. Monogenic recessive forms of the disease were found in five cases, but oligogenic involvement was detected in 39 patients. The 167 variations were found to affect all genes independently of the CH phenotype. These findings were replicated in an independent cohort of additional 145 CH cases. When compared to 3,538 controls, the CH population was significantly enriched with disrupting variants in the candidate genes (P = 5.5 × 10-7), but not with rare variations in CH-unrelated genes. Co-segregation studies of the hypothyroid phenotype with multiple gene variants in several pedigrees confirmed the potential oligogenic origin of CH. The systematic NGS approach reveals the frequent combination of rare variations in morphogenetic or functional candidate genes in CH patients independently of phenotype. The oligogenic origin represents a suitable explanation for the frequent sporadic CH occurrence.

Mild TSH resistance: Clinical and hormonal features in childhood and adulthood.

OBJECTIVE: Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. DESIGN: Observational, retrospective study. PATIENTS: Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. MEASUREMENTS: The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15 years). RESULTS: Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. CONCLUSIONS: Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.

Vitamin D in childhood and adolescence: an expert position statement.

UNLABELLED: Vitamin D is a key hormone in the regulation of calcium and phosphorus metabolism and plays a pivotal role in bone health, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Great interest has been placed in recent years on vitamin D's extraskeletal actions. However, while recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious and autoimmune diseases, the actual impact of vitamin D status on the global health of children and adolescents, other than bone, remains a subject of debate. In the meantime, pediatricians still need to evaluate the determinants of vitamin D status and consider vitamin D supplementation in children and adolescents at risk of deficiency. This review is the result of an expert meeting that was held during the congress "Update on vitamin D and bone disease in childhood" convened in Pisa, Italy, in May 2013. CONCLUSION: The collaboration of the international group of experts produced this "state of the art" review on vitamin D in childhood and adolescence. After dealing with vitamin D status and its determinants, the review outlines the current debate on vitamin D's health benefits, concluding with a practical approach to vitamin D supplementation during childhood and adolescence. WHAT IS KNOWN: • Vitamin D deficiency is a worldwide health problem. • Vitamin D deficiency affects not only musculoskeletal health but also a potentially wide range of acute and chronic diseases. What is New: • We reviewed the literature focusing on randomized controlled trials of vitamin D supplementation during childhood and adolescence. • This review will help pediatricians to appreciate the clinical relevance of an adequate vitamin D status and it will provide a practical approach to vitamin D supplementation.

Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism.

OBJECTIVE: To determine the evolution of congenital hypothyroidism in preterms and the clinical features of permanent forms. STUDY DESIGN: We retrospectively evaluated 24 preterm children detected by newborn screening for congenital hypothyroidism: first screening with blood-thyroid stimulating hormone cutoff ≥10 mU/L and second screening with blood-thyroid stimulating hormone cutoff ≥5 mU/L. After the age of 2 years, patients with eutopic thyroid had diagnostic reevaluations, including thyroid function testing and thyroid ultrasonography after L-thyroxine therapy withdrawal. RESULTS: The first screening identified 21.7% of patients with thyroid stimulating hormone elevation, and the second screening identified 73.9% of patients. One patient (4.4%) was identified with a third screening test; 21 patients had an eutopic thyroid and 3 patients a thyroid dysgenesis. At reevaluation, 5 patients (23.8%) showed permanent hypothyroidism (serum-thyroid stimulating hormone [s-TSH] >10 mU/L) resulting in the need to reintroduce therapy, 5 patients (23.8%) showed persistent hyperthyrotropinemia (s-TSH 5-10 mU/L), and 11 infants (52.4%) transient hypothyroidism (s-TSH <5 mU/L). The main clinical features of patients affected by permanent hypothyroidism were 1 case of assisted reproduction, 2 twins, 2 small for gestational age, 1 maternal thyroiditis, and 2 patients with malformations/syndromes. CONCLUSIONS: Premature birth is a significant risk for congenital hypothyroidism with eutopic thyroid. In preterm infants, the evolution of congenital hypothyroidism remains difficult to predict. Our data emphasizes the high incidence of transient hypothyroidism in preterm infants, and the importance of diagnostic reevaluation to determine the definitive diagnosis.

Graves disease in children: thyroid-stimulating hormone receptor antibodies as remission markers.

OBJECTIVE: To evaluate clinical and biochemical features of 115 children (98 female, mean age 11.3 ± 3.5 years) with Graves disease to identify possible determinants of remission. STUDY DESIGN: We defined as positive outcome the improvement of clinical features and restoration of euthyroidism or induction of hypothyroidism after antithyroid drug (ATD) therapy and as negative outcome hyperthyroidism persistent over 2 years of ATD therapy or relapsed after ATD withdrawal. RESULTS: Thirty-eight children (33%) had remission after 2 years of ATD therapy. The absence of goiter at diagnosis was correlated with a better outcome. Median thyroid-stimulating hormone receptor antibody (TRAb) values at diagnosis were significantly lower in patients with a positive outcome (P = .031). We found a significant relationship between the time required for TRAb normalization and the patient outcome; TRAb normalization within 1 year from time of Graves disease diagnosis was significantly more common among patients with a positive outcome (P < .0001), and the mean time for TRAb normalization was significantly shorter in patients with a positive outcome (1.3 ± 0.8 years) compared with that observed in patients with a negative outcome (2.5 ± 2.7 years, P = .026). CONCLUSIONS: Although no clinical variable investigated is constantly associated with a definite outcome, the absence of goiter at the diagnosis may be associated with a better outcome. The most relevant predictor of Graves disease outcome was serum level; TRAb at time of Graves disease diagnosis less than 2.5 times the upper reference limit, TRAb normalization during ATD, and TRAb normalization timing each may predict positive outcomes. These results may have a role in the empiric clinical management of pediatric patients with Graves disease.

Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Serum thyrotropin concentration in children with isolated thyroid nodules.

OBJECTIVE: To investigate the correlation between serum thyroid-stimulating hormone (TSH) concentration and nodule nature in pediatric patients with thyroid nodules, with the aim of identifying a marker able to differentiate benign and malignant nodules. STUDY DESIGN: This was a retrospective analysis of serum TSH concentrations in a multicentric case series of 125 pediatric patients with benign and malignant thyroid nodules. RESULTS: Of the 125 patients, 99 had benign thyroid nodules and 26 had differentiated thyroid cancer (24 papillary and 2 follicular). Final diagnosis was based on surgery in 57 cases and on a benign cytology plus clinical follow-up in 68 cases. Serum TSH concentration was significantly higher in patients with thyroid cancer compared with those with benign nodules (3.23 ± 1.59 mU/L vs 1.64 ± 0.99 mU/L; P < .001). Binary logistic regression analysis revealed that serum TSH was the sole predictor of malignancy (P < .001). Dividing the patient cohort into 5 groups based on serum TSH quintiles (TSH cutoffs 0.40, 1.00, 1.50, 1.80, and 2.80 mU/L), we observed that cancer prevalence increased in parallel with serum TSH (P < .001), with respective rates of 0%, 4%, 16%, 32%, and 52% in the 5 quintile groups. CONCLUSION: Because cases with malignant nodules are most likely seen in the upper normal serum TSH range (ie, >2.8 mU/L), serum TSH concentration can serve as a predictor of thyroid cancer in pediatric patients with thyroid nodules and can inform the decision of when to submit patients to further investigation by cytology.

Snyder-Robinson syndrome: a novel nonsense mutation in spermine synthase and expansion of the phenotype.

Snyder-Robinson syndrome is a rare form of X-linked intellectual disability caused by mutations in the spermine synthase (SMS) gene, and characterized by intellectual disability, thin habitus with diminished muscle mass, osteoporosis, kyphoscoliosis, facial dysmorphism (asymmetry, full lower lip), long great toes, and nasal or dysarthric speech. Physical signs seem to evolve from childhood to adulthood. We describe the first Italian patient with Snyder-Robinson syndrome and a novel nonsense mutation in SMS (c.200G>A; p.G67X). Apart from the typical features of the syndrome, the index patient presented with an ectopic right kidney and epilepsy from the first year of age that was characterized by focal motor seizures and negative myoclonus. The clinical and molecular evaluation of this family and the review of the literature expand the phenotype of Snyder-Robinson syndrome to include myoclonic or myoclonic-like seizures (starting even in the first years of life) and renal abnormalities in affected males.

Suprasellar granular cell tumor of the neurohypophysis in a child: unusual presentation in pediatric age of a rare tumor.

PURPOSE: Granular cell tumors (GCT) of the neurohypophysis are rare, solitary, nodular-shaped lesions, mostly presenting in the adult age with a female predilection. They rarely grow to a sufficient size to cause mass effect related symptoms and they may be found in most cases incidentally at autopsy of older patients. Few cases of symptomatic GCT of the neurohypophysis have been reported in the literature and only one of these in a pediatric patient in the first decade of life, who presented with central precocious puberty. METHODS: We report the case of a 11-year-old boy with a large suprasellar GCT of the neurohypophysis, complaining severe headache and pituitary insufficiency. Before our referral, the child was operated at another insitution through a pterional approach for tumor biopsy and underwent chemotherapy because of the misleading diagnosis of glioma. RESULTS: The patient was operated on by a fronto-orbito-zygomatic approach with subtotal tumor resection. At last follow-up examination, a partial hypopituitarism was detected. The quality of life with replacement therapy was excellent. Fractionated radiotherapy on tumor remnant was advised. CONCLUSIONS: The reported case is exceptional because the tumor developed in a male pediatric patient, causing clinical symptoms related to intracranial hypertension and unusual endocrinological features. GCT has to be considered in the differential diagnosis of suprasellar masses, to avoid misleading interpretation and consequent wrong therapeutic management.

Different Efficacy of Burosumab on Physical Performance and Serum Phosphate in Adult Patients with X-Linked Hyphophosphatemic Rickets during the First Six-Month of Treatment.

Burosumab is a monoclonal anti-FGF23 antibody used to treat patients with X-linked hypophosphatemic rickets (XLH). Its effect on serum phosphate and physical performance was compared in patients during a 6-month treatment with burosumab. Eight adult patients with XHL were treated with burosumab (1 mg/kg s.c. every 28 days). In the first 6 months of treatment, calcium-phosphate metabolism variables were measured, and muscle performance (tested with chair and walking test) and quality of life (tested with fatigue, BPI-pain and BPI-life questionnaires) were estimated. A significant increase in serum phosphate was observed during the treatment. From the 16th week, serum phosphate became significantly lower than its value in the 4th week. No patients had serum phosphate below the normal range at the 10th week, but seven patients were hypophosphatemic in the 20th and 24th week. All patients improved the execution time of the chair test and walking test, which reached a plateau after the 12th week. BPI-pain and BPI-life scores significantly decreased from baseline to the 24th week. In conclusion, a six-month burosumab treatment may significantly improve the general condition and physical performance of adult patients with XLH; this improvement was more stable and more indicative of treatment efficacy than that of serum phosphate.

Difficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma.

Consumptive hypothyroidism is a rare condition related to massive infantile hemangiomas producing an excess of the thyroid-hormone-inactivating enzyme type 3 iodothyronine deiodinase. We report the first case of consumptive hypothyroidism secondary to a large parotid hemangioma, highlighting the difficulties in selecting an adequate therapeutic strategy. The affected child was initially referred to our center for congenital hypothyroidism with a hypoplastic thyroid gland. L-Thyroxine (L-T4) replacement therapy was started at seven days of life. In the following weeks, the hemangioma rapidly increased in volume and the child developed severe hypothyroidism refractory to high doses of L-T4 therapy. The concentration of reverse triiodothyronine was elevated, suggesting that the underlying cause was an excessive conversion of thyroid hormones by high type 3 iodothyronine deiodinase levels in the tumor. Corticosteroid treatment showed only partial benefit. Introduction of propranolol instead led to normalization of thyroid hormones along with a dramatic involution of the hemangioma.

Surgical management of pediatric Graves' disease: an effective definitive treatment.

PURPOSE: The optimal treatment for pediatric Graves' disease (GD) is controversial. Antithyroid drugs are often used initially, but they are associated with a high failure rate. Therefore alternative therapies have become important. In the present study, we analyze our institution's experience regarding the safety and efficacy of thyroid surgery among pediatric patients with GD. METHODS: This is a retrospective chart review of 27 pediatric patients (age ≤ 18 years) with GD who underwent thyroid surgery between 1991 and 2009 at a single academic Institution. We recorded preoperative, intraoperative, and short-term postoperative data. RESULTS: All 27 patients were initially treated with thionamides. The high rate of hyperthyroidism relapse after discontinuation of medical treatment, age < 5 years, adverse reaction to medical therapy, severe ophthalmopathy, and patient preference justified the final decision to proceed with surgery as definitive therapy. All patients underwent total thyroidectomy. We had no mortality; surgical complications were rare: 4 (14.8 %) cases of transient hypocalcemia, 1 (3.7 %) of permanent hypocalcemia, 3 (11.1 %) of transient RLN neuropraxia, and 2 (7 %) of keloid scar. No bleeding, permanent RLN palsy or relapse hyperthyroidism were reported. CONCLUSIONS: Surgical therapy for pediatric GD performed by experienced thyroid surgeons is a safe, definitive and cost-effective treatment.

Endocrine manifestations of paediatric intracranial germ cell tumours: from diagnosis to long-term follow-up.

PURPOSE: We examined endocrine manifestations in a cohort of paediatric patients with IC-GCTs at diagnosis and during follow-up, integrating clinical, radiological, histopathological and laboratory data. METHODS: Diabetes insipidus (DI), growth hormone deficiency (GHD), hypothyroidism, adrenal insufficiency, precocious puberty (PP)/hypogonadism were diagnosed clinically and biochemically. The prevalence of endocrine manifestations was compared to survival rates. RESULTS: Our population included 55 children (37 males, 18 females) diagnosed with IC-GCT with a median follow-up of 78.9 months from diagnosis (range 0.5-249.9). At tumour diagnosis, 50.9% patients displayed endocrinopathies: among them, 85.7% were affected by DI, 57.1% central adrenal insufficiency, 50% central hypothyroidism, 28.5% GHD, 10.7% hypogonadotrophic hypogonadism, 10.7% PP. These patients presented predominantly with suprasellar germinoma. If not diagnosed previously, endocrine disorders arose 15.15 months (1.3-404.2) after end of treatment (EOT) in 16.4% patients. At least one endocrinopathy was identified in 67.3% of subjects at last follow-up visit, especially GHD and adrenal insufficiency. DI, hypothyroidism, and adrenal insufficiency occurred earlier than other abnormalities and frequently preceded tumour diagnosis. Subjects with and without endocrine manifestations who survived beyond 12 months after EOT did not show significant difference in overall survival and progression-free survival (p = 0.28 and p = 0.88, respectively). CONCLUSION: Endocrinopathies were common presenting symptoms in our population. If present at diagnosis, they often persisted hence after. The spectrum of endocrinopathies expanded during follow-up up to 33.7 years after EOT. Although they did not seem to affect survival rate in our cohort, close lifelong surveillance is mandatory to provide the best care for these patients.

Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.

Vitamin D dependent rickets, diagnostic and therapeutic difficulties: two case reports.

There are two types of vitamin D dependent rickets (VDDR) that cause rickets in children. Vitamin D dependent rickets type 1 (VDDR-I) is caused by an inborn error of vitamin D metabolism, which interferes with renal conversion of calcidiol (25OHD) to calcitriol (1,25(OH)2D) by the enzyme 1alpha-hydroxylase. Vitamin D dependent rickets type 2 (VDDR-II) is caused by a defect in the vitamin D receptor (VDR). We report cases of two African children affected by VDDR-I and VDDR-II, respectively. Establishing an early diagnosis of these genetic forms of rickets is challenging, especially in developing countries where nutritional rickets (NR) is the most common variety of the disease. A prompt diagnosis is necessary to initiate adequate treatment, resolve biochemical features and prevent complications, such as severe deformities that may require surgical intervention.

Linear growth and puberty in childhood obesity: what is new?

Pediatric obesity is a growing and alarming global health problem and represents an important determinant of morbidity. Since nutrition plays an important role in regulating growth and development, the excess weight gain related to overnutrition can affect growth patterns, bone maturation and pubertal development. The purpose of this review was to summarize the current knowledge about the effect of primary obesity on linear growth and pubertal development in children and adolescents. Evidence about regulatory hormones and adipokines that may be involved in the physiology of childhood growth in the context of obesity were also discussed. The most recent literature confirms previous studies indicating that linear growth is accelerated (mainly due to longer trunks rather than longer legs) and bone age is advanced in prepubertal children with obesity, while there is a reduction of pubertal height gain and attainment of normal adult height. Conflicting results are reported on the timing of puberty, specifically in boys. Indeed, previous studies suggested earlier onset of puberty in obese girls and overweight boys, and a delayed puberty in obese boys. Conversely, the most recent studies show more consistently an earlier onset and completion of pubertal development also in boys with obesity. Considering the false belief of health associated with transient taller stature in children and the adverse outcomes related to early puberty, interventions on diet and physical activity are urgently needed to tackle the epidemics of childhood obesity in public health and clinical setting.

Pseudohypoparathyroidism: application of the Italian common healthcare-pathway for a homogeneous clinical approach and a shared follow up.

BACKGROUND: Pseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies. METHODS: Through a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice. RESULTS: In addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism. CONCLUSIONS: The presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.

Newborn Screening for Congenital Hypothyroidism: the Benefit of Using Differential TSH Cutoffs in a 2-Screen Program.

CONTEXT: Analysis of a 2-screen program for congenital hypothyroidism (CH) was performed using differential dried-blood spot thyrotropin (bTSH) cutoffs of 10 mU/L at first screening (all infants) and 5 mU/L at second screening (selected infants). OBJECTIVES: This work aimed to characterize CH infants identified by the second screening and compare infants with bTSH of 5.0 to 9.9 and 10 mU/L or greater on second screening. DESIGN AND PATIENTS: Maternal and neonatal clinical features were retrospectively analyzed for 119 CH babies detected on the second screen in the Lombardy region of Italy, 2007 to 2014. RESULTS: Fifty-two (43.7%) of the 119 CH neonates showed bTSH values ranging from 5.0 to 9.9 mU/L at the second screening (low bTSH group) and 67 (56.3%) bTSH of 10.0 mU/L or greater (high bTSH group). The frequency of thyroid dysgenesis and eutopic gland was similar in both groups, as was the frequency of permanent and transient CH. Moreover, a high frequency of extrathyroidal malformations was found in both groups. The percentage of preterm infants (57.7% vs 23.9%, P < .001) and infants admitted to the neonatal intensive care unit (50.0% vs 17.9%, P < .001) was significantly higher in the low vs the high bTSH group. In addition, maternal treatment with glucocorticoids in pregnancy was significantly more frequent in the low bTSH group than in the high bTSH group (11.5% vs 1.5%, P = .042), as well as maternal hypothyroidism and/or goiter (26.9% vs 10.4%, P = .036). CONCLUSIONS: This study has demonstrated that a lower TSH cutoff at the second screening can detect additional cases of CH and that a second bTSH cutoff of 5.0 mU/L is appropriate for identifying preterm newborns and babies with associated risk factors.

Treatment of congenital hypothyroidism: comparison between L-thyroxine oral solution and tablet formulations up to 3 years of age.

OBJECTIVE: Oral solution and tablet formulations of levothyroxine (L-T4) are both used in the treatment of congenital hypothyroidism (CH). However, few studies and with a limited follow-up period have been published comparing these two formulations in children. DESIGN: The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age. METHODS: Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (group D) or tablets (group T). Auxological parameters, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The developmental quotient (DQ) at 1 and 3 years of age was evaluated using Griffiths' Scale. RESULTS: In this study, 254 children were enrolled among which 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (P = 0.002) and 1 month (P = 0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (P = 0.03). No statistical difference was detected between the median DQ; however, group D showed lower values in the language subscale at 12 months and in eye-hand coordination at 36 months. CONCLUSIONS: Both therapeutic strategies are effective in the treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects on cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.