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.

GH therapy in transition age: state of the art and future perspectives.

Growth hormone (GH) has been recently approved by the Italian Health Authorities for use in transition patients with childhood onset-growth hormone deficiency (CO-GHD). GH in addition to promote linear growth influences several key metabolic processes. In particular, in the transition period, from late adolescent to early adulthood, GH plays an important role in the achievement of a complete somatic development including body composition, muscle mass maturation, full skeletal mineralization and reproductive maturation, as well as in the prevention of metabolic and cardiovascular risk. Therefore, GH replacement should be restarted if a GH stimulation test at the re-evaluation fulfills established criteria. Endocrinologists experienced in the care of GHD adolescent patients held a workshop in Rome, Italy in July 2012 to review in detail the literature data and compare experiences of five Italian endocrinological centers on the negative consequences of interrupting GH treatment and the positive effects of continued GH replacement on intermediary metabolism, heart, muscle, pubertal development, and bone. The aim of the meeting was to delineate the state of the art on GH therapy in transition age and provide suggestions to pediatric and adult endocrinologists for a smooth transition care.

Laparoscopy or retroperitoneoscopy for pediatric patients with adrenal masses?

Minimally invasive approach to the adrenal gland was first reported in 1992. Since then, the experience with the laparoscopic technique for adrenal disease in children has been limited. We report our experience with minimally invasive adrenal surgery in children. Two young girls (2 and 4 years old) with a left adrenal mass were operated using minimally invasive surgery (MIS) in our Unit. Ultrasonography and MRI showed in the oldest a 2 x 3 cm adrenal mass, while in the youngest a 5.5 x 5 cm adrenal tumor was found. According to the pre-existing literature, we approached the smallest lesion via retroperitoneoscopy, and the largest one laparoscopically. The operating time was 110 minutes for retroperitoneoscopy and 75 minutes for laparoscopy. No major intra or postoperative complications occurred. There were no conversions to open surgery. Postoperative hospital stay was 5 days for both patients. In both cases, the anatomo-pathological result was an adenoma. Minimally invasive adrenalectomy is a safe and feasible procedure in children with good results. For lesions smaller than 3-4 cm retroperitonescopy is feasible, while for tumors larger than 5 cm, due to malignancy risk, the laparoscopic approach is indicated. To keep oncologic criteria it is important to avoid tumor rupture and to extract the specimen in an endobag.

Betamethasone therapy in ataxia telangiectasia: unraveling the rationale of this serendipitous observation on the basis of the pathogenesis.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive neurological dysfunction. To date, only supportive care aimed to halt the progressive neurodegeneration is available for the treatment. Recently, an improvement of neurological signs during short-term treatment with betamethasone has been reported. To date, the molecular and biochemical mechanisms by which the steroid produces such effects have not yet been elucidated. Therefore, a review of the literature was carried out to define the potential molecular and functional targets of the steroid effects in A-T. Glucocorticoids (GCs) are capable of diffusing into the CNS by crossing the blood-brain barrier (BBB) where they exert effects on the suppression of inflammation or as antioxidant. GCs have been shown to protect post-mitotic neurons from apoptosis. Eventually, GCs may also modulate synaptic plasticity. A better understanding of the mechanisms of action of GCs in the brain is needed, because in A-T during the initial phase of cell loss the neurological impairment may be rescued by interfering in the biochemical pathways. This would open a new window of intervention in this so far incurable disease.

The Italian screening program for primary congenital hypothyroidism: actions to improve screening, diagnosis, follow-up, and surveillance.

The Italian screening program for primary congenital hypothyroidism (CH) is an integrated system including neonatal screening, diagnosis, treatment, follow-up, and nationwide surveillance of the disease. The aim of the Italian screening program for CH is to identify not only babies with severe permanent CH (core target), but also babies with mild persistent and transient forms of CH who could have a benefit from an early replacement therapy (secondary target). In the last years, despite the important results obtained in terms of standardization of screening and follow-up procedures, it has become clear the need of optimizing the program in order to harmonize the screening strategy and the screening procedures among Regions, and to improve the diagnostic and therapeutic approach in all affected infants. On the basis of available guidelines, the experience of the Italian screening and clinical reference centers, and the knowledge derived from the nation-wide surveillance activity performed by the Italian National Registry of Infants with CH, the Italian Society for Pediatric Endocrinology and Diabetology together with the Italian Society for the Study of Metabolic Diseases and Neonatal Screening and the Italian National Institute of Health promoted actions aimed at improving diagnosis, treatment, follow-up and surveillance of CH in our country. In this paper the most important actions to improve the Italian screening program for CH are described.

Screening for mutations in the ISL1 gene in patients with thyroid dysgenesis.

CONTEXT: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000- 4000 newborns. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland, all conditions indicated as "thyroid dysgenesis" (TD). A higher prevalence of congenital heart diseases has been documented in children with CH compared to the general population. This association suggests a possible pathogenic role of genes involved in both heart and thyroid development. Among these, it can be included Isl1, a transcription factor containing a LIM homeodomain that is expressed in both thyroid and heart during morphogenesis. OBJECTIVE: In the present study, we investigate the role of ISL1 in the pathogenesis of TD. SETTINGS AND PATIENTS: By single stranded conformational polymorphism, we screened for mutations the entire ISL1 coding sequence in 96 patients with TD and in 96 normal controls. RESULTS: No mutations have been found in patients and controls. CONCLUSION: Our data indicate that, despite the relevant role of ISL1 in thyroid and heart morphogenesis, mutations in its coding region are not associated with TD in our group of patients.

[Turner syndrome and insulin-dependent diabetes mellitus]. / Syndrome de Turner et diabète insulinodépendant.

BACKGROUND: Cases of diabetes mellitus associated with Turner syndrome are noninsulin-dependent. We report a case of insulin-dependent diabetes mellitus (IDDM) with Turner syndrome. CASE REPORT: An 11 year-old girl with Turner syndrome was investigated for glucose tolerance that was normal with glycosylated hemoglobin at 5.1%. The patient was then given growth hormone plus oxandrolone until the age of 15 yr 3 mo; estrogen replacement was initiated at 15 yr 9 mo and progesterone 6 months later. At the age of 16.5 yrs, the patient developed manifestations of diabetes mellitus with polyuria, polydipsia, weight loss. Blood glucose concentration was 415 mg/dl with ketoacidosis. She was given insulin; at that time, blood insulin level was 7 mU/ml, C-peptide 0.8 ng/ml and glycosylated hemoglobin Alc 8.2%. Islet cell auto-antibodies were positive (1/80) and histocompatibility antigens were A1, A2, B14, B18, CW7, DR7, DR11, DQ7. After 6 months of treatment, blood insulin and C-peptide after IV glucagon were nil. There was no familial case of IDDM. CONCLUSIONS: This case of IDDM seems to be the first reported in Turner syndrome. This IDDM could be a manifestation of autoimmunity.

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.

[Height in Turner's syndrome: correlation with parents' height]. / La taille dans le syndrome de Turner: corrélations avec la taille des parents.

In 64 cases of Turner's syndrome (34 XO, 21 with mosaicism and 9 with partial deletion of one X chromosome) there was a closer correlation with mother's height (r = 0.607, p less than 0.001) than with father's height (r = 0.28, p less than 0.05) suggesting that Turner's syndrome could result from deletion of one paternal gonosome more than of one maternal gonosome. Moreover, 6.4% of Turner patients have a mother whose adult height is below -2 DS, contrasting with 3% in other people.

Atypical X-linked SCID phenotype associated with growth hormone hyporesponsiveness.

Severe combined immunodeficiency (SCID) is a heterogeneous group of disorders characterized by defect of T- and B-cell immunity. In many cases of autosomal recessive SCID, thus far described, the molecular alteration involves genes encoding for molecules that participate in the signal transduction. We report on a patient affected by a combined immunodeficiency, characterized by severe T-cell functional impairment, in spite of a close to normal number of circulating mature type T and B cells. NK cells were absent. Associated with the immunodeficiency, this patient also showed short stature characterized by very low growth velocity, delayed bone age and absence of increase of the plasma levels of Insulin growth factor-I (IGF-I) after growth hormone (GH) in vivo stimulation indicating peripheral hyporesponsiveness to GH. Evaluation of the protein tyrosine phosphorylation events occurring following either T-cell receptor (TCR) or GH receptor (GHR) triggering revealed striking abnormalities. No molecular alteration of GHR gene was found, thus suggesting the presence of postreceptorial blockage. Mutational screening and expression analysis failed to reveal any molecular alteration of JAK2 and STAT 5 A/B genes thus ruling out the involvement of these genes in the pathogenesis of this form of SCID. Mutational analysis of IL2Rgamma chain gene revealed the presence of a L183S missense mutation, thus indicating an atypical and a more complex clinical presentation of this X-linked form of SCID. At our knowledge, this is the first report on the GH hyporesponsiveness in this disease.