A non-classical presentation of APECED in a family with heterozygous R203X AIRE gene mutation.

PURPOSE: Biallelic loss-of-function mutations of AIRE cause the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. However, single nucleotide mutations may cause a milder phenotype. In this paper, we describe an unusual and mild phenotype in a mother and her two children (son and daughter) who carry a rare heterozygous mutation of AIRE. METHODS AND RESULTS: The son presented with alopecia and subclinical hypothyroidism due to Hashimoto's Thyroiditis (HT); the daughter had alopecia, vaginal mycosis, stomach pains and subclinical hypothyroidism due to HT; and the mother had alopecia, vaginal mycosis and stomach pains. Organ- and non-organ-specific autoantibodies were evaluated as well as antibodies against interleukin-17A, -17F, -22 (IL-Abs) and interferon -α and -ω (IFN-Abs). The organ- and non-organ-specific autoantibodies screening was negative in the son, while the daughter was positive for liver-kidney microsomal antibodies (LKMAbs) and the mother was positive for glutamic acid decarboxylase antibodies (GADAbs). Daughter and mother were also positive for IFN-Abs. Analysis of the AIRE gene identified a rare heterozygous R203X mutation in all three family members. CONCLUSIONS: We describe for a first time a family with heterozygous R203X AIRE mutation causing an APECED-like condition, as confirmed by presence of IFN-Abs. The unusual mild phenotype should be reassuring for the patients and assist in their clinical management.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

The relationship between hyperthyrotropinemia and metabolic and cardiovascular risk factors in a large group of overweight and obese children and adolescents.

PURPOSE: Mild TSH elevations are frequently observed in obese patients, in the absence of any detectable thyroid disease. Our objective is to evaluate the relationship between the raised TSH levels and the biochemical and clinical consequences of obesity. METHODS: This is a retrospective cross-sectional study of a large population of obese children and adolescents. We evaluated 833 subjects (340 m, 493 f), aged 14.4 ± 2.5 (range 5.2-18.5) years, height SDS 0.27 ± 1.04 (-3.49-4.35), and BMI SDS 2.94 ± 0.59 (1.60-4.68). Body composition, free T4, TSH, anti-TPO antibodies, anti-TG antibodies, inflammation markers (total WBC and the subtypes, ultrasensitive C-reactive protein), and metabolic parameters [AST, ALT, γGT, ALP, glycaemia, insulin, total cholesterol (TC), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C), triglycerides (TG)] were measured, and oral disposition index (ODI) and cardiovascular risk factors (TC/HDL-C and TG/HDL-C) were calculated. After exclusion of the subjects showing anti-thyroid antibodies, the remaining 779 (325 m, 454 f) were then subdivided into two subgroups according to a TSH value below (group A) or above (group B) 4.5 mU/L. RESULTS: Clinical characteristics and hematological markers of patients with and without positive anti-thyroid antibodies were similar, with the exception of higher TSH levels in the latter group. Using analysis of covariance, the subjects of group B had significantly higher values of TC (170.3 ± 28.7 vs 163.3 ± 32.9 mg/dL; p < 0.05), systolic (125.8 ± 13.5 vs 124.5 ± 13.1 mm/Hg), and diastolic blood pressure (79.2 ± 8.0 vs 77.9 ± 8.2 mm/Hg) than subjects of group A. No difference was observed in body composition, ODI, and the cardiovascular risk factors between these two groups. CONCLUSION: TSH elevation in overweight and obese children and adolescents, being associated with a higher TC and blood pressure, might negatively influence the cardiac status. Longitudinal studies are requested, however, to confirm this hypothesis and, therefore, to conclude whether a substitutive treatment with l-thyroxine is really needed in these patients.

Evaluation of function and structure of arterial wall in girls and young women with Turner syndrome.

PURPOSE: Patients with Turner syndrome (TS) are frequently affected by congenital as well as acquired cardiovascular diseases. The aim of the study was to evaluate the blood pressure, the endothelial function (FMD) and the intima media thickness (IMT) at the level of the common carotid arteries in a group of girls and young women with TS in comparison to healthy controls. METHODS: We evaluated 40 unselected TS patients, with a mean age of 18.6 ± 0.9 years and 103 age matched healthy subjects. MAIN OUTCOME MEASURES: blood pressure, FMD and IMT. RESULTS: No differences were found in systolic and diastolic blood pressure between TS patients and controls. FMD was higher in TS than in controls (14.2 ± 1.4 vs 11.4 ± 0.3%, p = 0.005) whereas IMT was not statistically different in the two study groups (0.54 ± 0.04 vs 0.57 ± 0.01 mm). However, in TS patients an inverse correlation was found between FMD and both age (-0.03 ± 0.01, p = 0.003) and years of estrogen therapy (-0.72 ± 0.31, p < 0.03), whereas a positive correlation was found between IMT and age (R 2 = 0.35, p < 0.0001) and estrogen therapy duration (R 2 = 0.65, p < 0.0001), suggesting a clear tendency toward a premature decrease in FMD and premature increase in IMT compared to controls. CONCLUSIONS: Young TS patients show an arterial wall which is functionally and structurally comparable or better than controls. They show, however, a premature derangement of the arterial function and structure, which seems to be partly influenced by age and duration of oestrogen treatment.

Incidence of congenital hypothyroidism in the Autonomous Province of Bolzano: benefit of increased iodine intake.

PURPOSE: Although a nation-wide salt iodization program on voluntary basis was implemented in 2005, many areas in our country are still characterized by mild iodine deficiency. Differently from the rest of Italy, an efficient program of iodine prophylaxis was implemented in 1981 in the Autonomous Province of Bolzano. The aim of this study was to investigate whether an adequate iodine intake in the population may affect the incidence of permanent congenital hypothyroidism (CH). METHODS: The incidence trends of permanent CH between 1987 and 2006 in Bolzano Province and in the rest of Italy were estimated. RESULTS: Over the years, the CH incidence has remained steadily lower in Bolzano than in the rest of the country. CONCLUSIONS: Primary prevention of permanent CH may be possible by assuring an adequate nutritional iodine intake in the population. However, the time needed to observe a decrease in the incidence of CH is about a decade under conditions of iodine sufficiency.

Prematurity and low birth weight lead to altered bone geometry, strength, and quality in children.

PURPOSE: Prematurity and low birth weight are associated with a decrease in bone mass. Aim of the study was to investigate bone geometry, strength, and quality in children born at term small for gestational age (term SGA), premature appropriate for gestational age (prem AGA), and premature SGA (prem SGA). METHODS: 91 patients (46 f, 45 m), mean age 11.28 years, height SDS 0.03 ± 0.21, and BMI SDS -0.31 ± 0.19. 20 were term SGA, 22 prem SGA, and 49 prem AGA. Bone geometry was assessed on the 2nd metacarpal bone, by evaluating the outer and inner diameter, the cortical area, medullary area, metacarpal index, cross-sectional area, and bone strength. Bone quality was evaluated by ultrasound and expressed as amplitude-dependent speed of sound and bone transmission time (BTT). RESULTS: Term SGA, prem SGA, and prem AGA had values of bone geometry, strength, and quality significantly lower than our reference range (p < 0.05). Findings in the three groups were similar, apart from BTT, which was significantly reduced in prem SGA (p < 0.05). Fat percentage was the main determinant of BTT. CONCLUSIONS: Children born either prematurely or SGA seem to have smaller and weaker bones. Those born both premature and SGA were the most affected.

Clinical case seminar in pediatric thyroid disease.

Pediatric thyroid diseases cover a large spectrum of congenital and acquired forms, ranging from congenital primary or central hypothyroidism, autoimmune thyroid disease, iodine deficiency, rare genetic defects of thyroid hormone action, metabolism and cell membrane transport to benign nodules and malignant tumors. The previous 15 papers of the textbook Paediatric Thyroidology gave a systematic overview of the current knowledge and guidelines on all these diseases. In this final paper, the authors collected a series of patient histories from their clinics illustrating frequently encountered clinical problems and providing key learning points and references to each case. Although not fully comprehensive, it aims at providing relevant clinical knowledge on thyroid diseases of the neonate, the child, and the adolescent.

Gonadal function in males with autoimmune Addison's disease and autoantibodies to steroidogenic enzymes.

Steroidogenic enzyme autoantibodies (SEAbs) are frequently present and are markers of autoimmune premature ovarian failure (POF) in females with autoimmune Addison's disease (AAD). The prevalence and significance of SEAbs in males with AAD have not yet been defined. We studied the prevalence of SEAbs in a large cohort of males with AAD and assessed the relationship between SEAbs positivity and testicular function. A total of 154 males with AAD (mean age 34 years) were studied. SEAbs included autoantibodies to steroid-producing cells (StCA), detected by immunofluorescence, and steroid 17α-hydroxylase (17α-OHAbs) and side chain cleavage enzyme (SCCAbs) measured by immunoprecipitation assays. Gonadal function was evaluated by measuring follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), sex hormone-binding globulin (SHGB), anti-müllerian hormone (AMH) and inhibin-B (I-B). Twenty-six males, 10 SEAbs((+)) and 16 SEAbs((-)), were followed-up for a mean period of 7·6 years to assess the behaviour of SEAbs and testicular function. SEAbs were found in 24·7% of males with AAD, with the highest frequency in patients with autoimmune polyendocrine syndrome type 1 (APS-1). The levels of reproductive hormones in 30 SEAbs((+)) males were in the normal range according to age and were not significantly different compared to 55 SEAbs((-)) males (P > 0·05). During follow-up, both SEAbs((+)) and SEAbs((-)) patients maintained normal testicular function. SEAbs were found with high frequency in males with AAD; however, they were not associated with testicular failure. This study suggests that the diagnostic value of SEAbs in males with AAD differs compared to females, and this may be related to the immunoprivileged status of the testis.

The IGSF1 deficiency syndrome: characteristics of male and female patients.

CONTEXT: Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. OBJECTIVE: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. METHODS: All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. RESULTS: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. CONCLUSION: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Tryptophan hydroxylase autoantibodies as markers of a distinct autoimmune gastrointestinal component of autoimmune polyendocrine syndrome type 1.

BACKGROUND: Autoantibodies to tryptophan hydroxylase (TPHAbs) directed against serotonin-producing enterochromaffin cells (EC) have been reported in autoimmune-polyendocrine-syndrome type 1 (APS-1) patients with gastrointestinal dysfunction (GID). Serotonin plays a critical role in enteric function and its peripheral blood levels reflect serotonin release from the gastrointestinal tract. AIMS: We test the hypothesis that TPHAbs mark a distinct autoimmune component of APS-1 characterized by an autoimmune attack toward EC, which results in clinical GID. METHODS: TPHAbs were measured in 64 APS-1 patients. Endoscopy with gastric (antrum/body) and duodenal biopsy was carried in 16 TPHAbs+ patients (8 with and 8 without GID) and in 2 TPHAbs- patients (without GID). Immunohistochemistry of biopsy specimens was carried out using antibodies to serotonin, chromogranin-A, CD3, CD4, CD8, and CD20. Serotonin serum levels were measured in TPHAbs+ and TPHAbs- patients who had endoscopy. RESULTS: Thirty-seven of 64 patients were TPHAbs+ (11/12 with GID and 26/52 without GID; P < .001). Gastric and duodenal biopsies in all 8 TPHAb+ patients with GID showed lymphocytic infiltration with increased CD3+CD8+ intraepithelial lymphocytes and absence of EC. Furthermore, mean serotonin serum levels were below the normal range in TPHAb+ patients with GID (P < .01). In 8 TPHAb+ patients without GID gastric and duodenal biopsies showed different grades of inflammatory infiltration and reduced number of EC. Mean serotonin serum levels were near the lower limit of the normal range. In all TPHAbs+ patients the biopsies showed a reduced number of chromogranin-A positive cells consistent with enteroendocrine cells depletion. TPHAbs- patients without GID showed normal gastrointestinal mucosa and serotonin serum levels. CONCLUSIONS: TPHAbs appear to be markers of a distinct autoimmune component of APS-1. Progressive involvement of the gastrointestinal EC leads to the transition from preclinical to clinical disease, characterized by GID and reduced serotonin serum levels.

The natural history of the hyperthyrotropinemia of children born prematurely.

OBJECTIVE: Non-autoimmune hyperthyrotropinemia has been previously reported among children born prematurely. The aim of this study was to follow up their thyroid function, volume, and structure and to investigate the relationship with growth, IGF-I, lipid profile, and insulin sensitivity. METHODS: Seventy-two children born prematurely (33.2±2.2 weeks), 26 appropriate (AGA) and 46 small for gestational age (SGA), were evaluated at the age of 7.6±2.3 yr (time 1) and at the age of 11.4±2.3 yr (time 2). We also measured TSH, free T(3) (fT(3)), free T(4) (fT(4)), thyroperoxidase antibodies (TPO-Ab), thyroglobulin antibodies (TG-Ab), thyroid ultrasound, auxological parameters, lipid profile, glucose, and insulin level. RESULTS: In the AGA group TSH was similar in both times (2.7±1.0 vs 3.0±0.9 mU/l) and above the upper normal limit in 4 (15.4%) subjects at time 1 and in 6 (23.7%) subjects at time 2 (ns). In the SGA group, TSH was similar in both times (2.8±1.2 vs 2.5±1.0 mU/l) and above the upper normal limit in 11 (23.9%) subjects at time 1 and 5 (10.8%) subjects at time 2 (ns). fT(4) and fT(3) were always normal and TPO- and TG-Ab absent. Thyroid volume increased progressively, but significantly only in the AGA group (p=0.0005). The thyroid structure was always normal and there was no influence on the growth and the biochemical profile. CONCLUSIONS: Some ex-premature babies show a mild and variable thyroid dysfunction, which does not seem to evolve toward an overt thyroid dysfunction.

Changes in lifestyle improve body composition, thyroid function, and structure in obese children.

BACKGROUND: Alterations in thyroid function and structure have been reported in obesity. Function reverses to normal after weight loss, but nothing is known about structure. AIM: To evaluate the effect of weight loss on thyroid function and structure in obese children. SUBJECTS AND METHODS: The study was conducted in 72 overweight and obese children. Measurement of free T(3) (fT(3)), free T4 (fT(4)), TSH, antithyroid- antibodies and a thyroid ultrasound was performed at the beginning (phase 1) and after a period of 1.8±1.0 yr of lifestyle intervention (phase 2). RESULTS: Height SD score (SDS), body mass index SDS, total fat mass did not change from phase 1 to phase 2. Percentage of fat free mass decreased significantly (p<0.05). Waist/height ratio decreased (0.6±0.1 vs 0.5±0.1; p<0.05) as well as waist/hip ratio (0.9±0.1 vs 0.8±0.1; p<0.05). In phase 1, TSH was 2.8±1.7 mU/l; in phase 2, it was 2.2±0.9 mU/l (p<0.05); 17.2% of children showed a TSH level above the normal range (3.6 mU/l) in phase 1, and 6.2% in phase 2 (p<0.05). fT(4) was 10.8±2.2 pg/ml in phase 1 and 10.7±1.9 pg/ml in phase 2. fT(3) was 4.4±1.3 pg/ml (phase 1) and 3.9±1.1 pg/ml (phase 2) (p<0.05). Thyroid volume was -0.5±0.8 SDS (phase 1) and -0.5±1 SDS (phase 2). A non-significant improvement in thyroid structure was observed. CONCLUSIONS: In conclusion, healthier lifestyle improves body composition, thyroid function, and structure.

A national study of iodine status in Albania.

OBJECTIVE: The aim of the study was to determine the iodine status in Albania following 11 yr of iodine prophylaxis and to evaluate factors influencing the outcome. DESIGN: Eight hundred and forty children, aged 6-13 yr, living in 4 different regions and 365 pregnant women living in the same areas, were enrolled for the study. The prevalence of goiter was assessed by palpation and ultrasound imaging and the urinary iodine and the iodine concentration in the salt of different commercial brands were evaluated. Presence of goiter in the family and their eating habits were also investigated as well as the use of iodized salt in the household. MAIN OUTCOME: In children, the prevalence of goiter was 57.6% by palpation and 24.4% by ultrasound imaging. Median urinary iodine was 86.2 microg/l, with pronounced geographical variations (range 3.52-1079 microg/l). In particular, 29.1% of the children had urinary iodine <50 microg/l and 57.1% <100 microg/l. In pregnant women, the median urinary iodine was 85 microg/l. Median iodine concentration in household iodized salt was 21.2 mg/kg, with 60.3% of the brands being adequately and 39.7% non-adequately iodized. Almost all families (99.6%) claimed to use iodized salt. CONCLUSION: Despite the introduction of iodine prophylaxis, there is still a mild iodine deficiency in Albania, particularly in the inner mountainous areas.

Acute ghrelin response to intravenous dexamethasone administration in idiopathic short stature or isolated idiopathic growth hormone-deficient children.

Acylated ghrelin has been originally described for its potent GH-releasing activity mediated by the activation of the GH secretagogue receptor type 1a. More recently, ghrelin has been reported to exert several other GH-independent biological actions, among which in the modulation of metabolic functions. Glucocorticoids are well known to exert important metabolic functions but also to modulate GH secretion, although through mechanisms that have not been fully clarified so far. Interestingly, the existence of a feedback link between glucocorticoids and ghrelin system has already been reported. The aim of our study was to evaluate the acute GH and ghrelin responses to dexamethasone (DEX) administration in children with idiopathic short stature (ISS) or isolated idiopathic GH deficiency (GHD). Eight children with ISS (age: 9.5+/-1.2 yr) and 7 with GHD (12.1+/-1.4 yr) underwent iv DEX administration (0.3 mg/body surface area at 0 min). IGF-I, GH, and ghrelin levels were assayed at baseline and every 30 min from 120 up to 240 min after DEX. Compared to baseline levels DEX decreased ghrelin in ISS at 120 min and 240 min (p<0.04). On the other hand DEX did not modify ghrelin levels in GHD. After DEX, ghrelin was reduced in ISS compared to GHD (p<0.02). DEX increased GH in ISS but not in GHD (peak: 11.1+/-1.2 vs 7.6+/-0.9 microg/l). Basal, as well as after-DEX ghrelin levels negatively correlated with IGF-I in GHD (p<0.03) and with height SD score (HSDS) in ISS (p<0.02). Acute DEX administration is able to decrease ghrelin in ISS, but not in GHD children. Both basal and after-DEX ghrelin levels negatively correlate with IGF-I and HSDS. All these data suggest the existence of a feedback link among ghrelin, glucocorticoids and the GH/IGF-I axis.

Variations in biological and immunological activity of growth hormone during the neonatal period.

BACKGROUND/AIMS: It was postulated that a high growth hormone (GH) bioactivity might explain the rapid growth rate of neonates. The aim of this study is to verify changes in serum GH biological potency (Bio-/Immuno-GH ratio) and their effects on serum growth factors during the first month of life in term and preterm babies. METHODS: Blood samples were collected from 10 small-for-gestational-age preterm (SGAPT), 17 appropriate for gestational age preterm (AGAPT) and 26 AGA term (T) neonates on days 4, 15 and 30 of life to evaluate serum GH values measured by IFMA (IFMA-GH) and bioassay (Bio-GH), serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3). RESULTS: High serum Bio-GH values on the first few days of life correspond to high IFMA-GH values, suggesting full biological potency of circulating GH. Furthermore, IGF-I/IGFBP-3 molar ratio values in preterm babies were higher than in full-term infants. CONCLUSIONS: These data confirmed the hypothesis that the higher growth velocity in the first month of life of preterm neonates is due to an increased bioavailability of IGF-I. A progressive maturation of the hypothalamic-pituitary-IGF-I axis without any alteration in the GH biological potency seems to underpin the increase of the growth factors early in life.

Geometry and bone density.

Bone development is a key process in the growing child. It is, therefore, of paramount importance to survey this process, which is characterized by increasing length and size of the bone together with its progressive mineralization. The bone status can be evaluated by different techniques, each of them having its pros and cons. Furthermore, it should be underlined that the results of bone assessment depend not only from the employed technique but also from the auxological characteristics of the subjects. It is, therefore, the aim of this review to examine the characteristics of the various methods of bone evaluation, such as dual energy X-ray absorptiometry (DEXA), peripheral quantitative computed tomography (pQCT), ultrasound and metacarpal index and to explain how changes in bone structure and geometry may influence the results.

Menstrual disorders in adolescence.

Altered frequency of the menstrual cycle accompanied by pain are manifestations of functional anomalies of the female reproductive system. These symptoms require prompt and accurate diagnosis and therapy to prevent a chronic condition that can seriously disturb the adolescent's psychic well being. The most common anomalies of the menstrual cycle and the causes of altered cycle frequency are outlined, as are useful criteria for diagnosing premenstrual syndrome dysmenorrhea and for distinguishing the causes and alterations in frequency and amount of menstrual discharge from other disturbances, including amenorrhea and abnormal uterine bleeding. The treatment of dysmenorrhea and quantitative alterations of the menstrual cycle is the focus of this article.