T. Arrigo

Etiology and age incidence of precocious puberty in girls: a multicentric study.

We review the etiology and age incidence of precocious puberty in 438 girls examined between 1988-1998; 428 (97.7%) had central precocious puberty (CPP), the remaining 10 (2.3%) gonadotropin-independent precocious puberty (GIPP) of ovarian origin. The majority of CPP girls (59.6%) were aged between 7-7.9 yr, 22.4% were 6 year olds, and only 18% were under 6 years old. Cranial CT and/or MRI performed in 304/428 girls, showed neurogenic abnormalities in 56/304 (18.4%) CPP girls; 30 (9.9%) were due to previously diagnosed intracranial abnormalities and the remaining 26 (8.5%) were detected at the diagnosis of CPP. The frequency of neurogenic CPP tended to be higher in girls under 4 years of age while the frequency of idiopathic CPP tended to be higher in girls aged between 7-7.9 years, but no statistically significant differences were found. Interestingly, some CNS anomalies either of tumoral or congenital origin were detected at presentation in 7% of the girls aged over 7 years. Other related or coincidental clinical anomalies, mainly due to genetic diseases, were observed in 22/304 (7.2%) patients. History of precocious maternal menarche was found in 12/304 (4%) girls. In conclusion, idiopathic CPP was observed in 74% of the girls in this study. Neurogenic anomalies or other coincidental or related clinical findings were observed in the remaining 26%. The increased frequency of idiopathic CPP in girls aged over 7 years may suggest an early, but otherwise normal onset of puberty in many of these girls as a consequence of the trend towards earlier maturation. Nonetheless, the finding of CNS anomalies also in the older patients, raises the question of whether these patients should undergo a complete diagnostic work-up.

Beta Cell Function, Peripheral Sensitivity to Insulin and Islet Cell Autoimmunity in Cystic Fibrosis Patients with Normal Glucose Tolerance

Beta cell function, peripheral sensitivity to insulin and specific pancreatic autoimmunity were studied in 30 youngsters with cystic fibrosis (CF) accurately selected in order to fulfill the criteria for normal glucose tolerance. With respect to weight-matched controls, patients with CF exhibited a significantly lower glucose tolerance and a globally preserved, although delayed, insulin response to oral glucose tolerance test, while first-phase insulin secretion after i.v. glucose was blunted. Peripheral sensitivity to insulin, assessed in vivo by both the euglycemic clamp technique and the number of insulin receptors, directly measured in circulating monocytes, was superimposable in patients and controls. Serum islet-cell antibodies were not found in any of the patients. In conclusion, disorders of beta cell function may be observed in CF patients even when glucose tolerance is within the normal range. Such abnormalities are not associated with changes in peripheral sensitivity to insulin and do not seem to depend on specific autoimmune events.

Changes in thyroid function tests induced by 2 month carbamazepine treatment in l-thyroxine-substituted hypothyroid children

In five l-thyroxine-substituted hypothyroid children with partial epilepsy serum total thyroxine (T4) and free T4 (FT4) significantly (P<0.01) decreased following 2 months of carbamazepine (CBZ) administration (20 mg/kg per BW per day) from mean (±SD) values of 12.7±1.1 μg/dl and 15.5±1.8 pg/ml to mean values of 7.5±2.3 and 10.1±1.7, respectively. In all but one patient important changes in both serum total and free triiodothyronine (T3, FT3) were not observed; consequently T3∶T4 and FT3∶FT4 ratios significantly (P<0.05) increased in the whole series. Three subjects had post-treatment serum TSH that rose to hypothyroid levels parallel to a T4 decrease. The negligible thyroid hormone secretion and the unmodified T3-uptake (T3U) or T4-binding globulin (TBG) exclude direct effects of CBZ on thyroid gland and on carrier serum proteins, respectively. The findings observed, instead, might be due to accelerated T4 metabolic clearance together with augmented T4 to T3 conversion rate, as previously demonstrated for diphenylydantoin. The sharp reduction in T4 and FT3 concentrations is the peripheral display of this event, which is associated with a decompensation of the metabolic status, as indicated by serum TSH enhancement. In all cases a supplement of l-thyroxine by itself was able to restore euthyroid TSH serum concentrations, suggesting that hypothyroidism in patients with partial epilepsy to whom CBZ had been administered requires a higher l-T4 substitutive regimen.

Subclinical hypothyroidism: The state of the art

Subclinical hypothyroidism (SH) is a common clinical problem, particularly in adulthood and the elderly. Its prevalence is conditioned by several etiological and risk factors. The highest age- and sex-specific rates are in women over 60. SH may be associated with manifestations of mild thyroid failure, which may reverse under levothyroxine (L-T4) therapy. The risk of progression to overt hypothyroidism is distinctly higher in cases with underlying thyroid disease. A population routine screening is not generally recommended, but screening is encouraged in high-risk groups. L-T4 therapy may be indicated in subjects with TSH levels which are repeatedly and consistently elevated (>10 μIU/ml) and may be considered in those with TSH ranging between 4.5–5.5 and 10 μIU/ml, particularly if anti-thyroid antibodies are positive and/or hypothyroid symptoms are present. Treatment should be based, at least initially, on L-T4 low doses.

Longitudinal evaluation of glucose tolerance and insulin secretion in non-diabetic children and adolescents with cystic fibrosis: results of a two-year follow-up

Thirty‐two patients with cystic fibrosis and repeatedly normal fasting blood glucose underwent oral glucose tests and islet‐cell antibody assessments on two occasions approximately two years apart. Fourteen patients underwent two iv glucose tolerance tests also. Although in the group as a whole mean glucose areas in response to the oral test remained substantially unmodified over the two‐year period, the prevalence of glucose tolerance abnormalities increased from 37.5 to 50%. Insulin output in response to both oral and iv tolerance tests decreased over time. Worsening of insulin secretion and/or of glucose tolerance was never accompanied by deteriorating clinical status. Islet‐cell antibodies were detected in no patients, even in those who developed a diabetic glucose tolerance. These results support, on a longitudinal basis, the view of a progressive impairment of B‐cell function in cystic fibrosis, which may precede the onset of metabolic abnormalities and is not triggered by autoimmunity.

Effects of a gluten-free diet on catch-up growth and height prognosis in coeliac children with growth retardation recognized after the age of 5 years

The effects of a gluten-free diet on catch-up growth and predicted height were evaluated in 12 children with coeliac disease diagnosed after the age of 5 years and followed for 2–5.5 years. In the majority of the patients, height and bone age were retarded at the time of diagnosis. Under a gluten-free diet growth velocity, age-related height, predicted height and relative bone age increased, height for bone age slightly decreased. In four patients the predicted height remained below the target height, indicating incomplete catch-up growth.

Testicular microlithiasis heralding mixed germ cell tumor of the testis in a boy

The clinical implications of the association between testicular microlithiasis (TM) and germ cell tumor (GCT) of the testis are still debated since the natural history of incidentally discovered TM has not been defined. Therefore, it is questionable whether TM can be considered as a precursor of malignancy. We are reporting the case of a 9-yr-old boy with a mixed GCT who had presented 3 yr earlier with TM and hydrocele. This evolution suggests that testicular GCT may develop some years later in a boy with pre-existing and incidentally discovered TM. Our case history and other reports of the literature might suggest a strong association between both conditions, thus vindicating the view that individuals with TM should have clinical and ultrasound follow-up. Longitudinal evaluation may be particularly indicated in the patients with additional testicular dysgenetic features, apart from TM.

Congenital adenohypophysis aplasia: clinical features and analysis of the transcriptional factors for embryonic pituitary development.

Anterior pituitary agenesis (APA) has very rarely been reported. Therefore, its phenotypical and genotypical features are not well known. The aim of this study was to ascertain whether the clinical picture in 4 subjects with APA and multiple pituitary hormone deficiencies (MPHD) was different compared to the one observed in a selected control group consisting of 7 MPHD individuals with hypoplastic (and not aplastic) adenohypophysis and pituitary stalk interruption syndrome. Another goal was to investigate genetic basis of APA by analyzing for the first time in this condition many of the transcriptional factors which are required for both structural development and cellular differentiation of hypophysis. Age at diagnosis was significantly lower in APA children than in controls (1.5±2.3 vs 11.1 ±7.6 yr, p<0.0005). Microphallus and neonatal cholestasis were observed only in APA subjects (chi-squared=4.3, p<0.05) and also neonatal hypoglycemia was more frequent in APA patients than in controls (X2=4.05, p<0.05). Molecular analyses of the genes of the transcriptional factors POU1F1, PROP1, LHX3, LHX4, ISL1 and HESX1 detected no mutations in APA patients. Conclusions: a) if compared with a selected cohort of MPHD patients with both adenohypophysis hypoplasia and pituitary stalk interruption syndrome, the ones with APA show an earlier and more severe picture of hypopituitarism; b) mutations in several transcription factors that are known to be essential for the development of Rathke’s pouch are not necessarily found in humans with APA. (J. Endocrinol. Invest. 29: 208–213, 2006)

TTF-2/FOXE1 gene polymorphisms in Sicilian patients with permanent primary congenital hypothyroidism.

Thyroid transcription factor-2 (TTF-2/FOXE1) is a polyalanine domain protein that regulates thyroid embryogenesis, but very few patients with permanent primary congenital hypothyroidism (pCH) harbor germline mutations of this or other transcription factors that are involved in thyroid development that might explain the etiology of pCH. Variations within the polyalanine tract are found in a variety of genes and are often reported in association with malformation syndromes; pCH is frequently associated with thyroid malformations and extra-thyroidal malformations. Therefore, in this study we investigated whether alanine (Ala) length polymorphisms and non-polymorphic mutations of the TTF-2 gene in pCH patients might be involved in the pathogenesis of pCH. The entire coding region of the TTF-2 gene was analyzed in 57 Sicilian patients and 142 healthy controls. We found that the homozygous Ala14 polymorphism (Ala14/14) was less frequent in the pCH group than in the controls. In contrast, significantly more pCH patients than controls harbored the Ala16 polymorphism (Ala16/16 and Ala14/16). However, neither the Ala14/14 nor the Ala16 polymorphism was related to extra-thyroidal malformations. Two of the 57 patients carried Ala11/14 and Ala12/14, and one Ala14/14 patient also had the silent polymorphism 387 C/T (Leu129Leu). Other than known polymorphic variants we found no mutation in the TTF-2 gene. Therefore, this study demonstrates that mutations in the TTF-2 gene are rare in pCH patients and suggests that variations in the length of the Ala-tract could at least partially explain the etiology of pCH but not that of extra-thyroidal malformations.

Three-year prospective evaluation of glucose tolerance, β-cell function and peripheral insulin sensitivity in non-diabetic patients with thalassemia major

The aim of this prospective study was to evaluate the evolution of glucose tolerance (GT), insulin secretion and peripheral insulin sensitivity during a 3-yr follow-up in a homogenous population consisting of fourteen non-diabetic adults with thalassemia major (TM). All the patients underwent 2 OGTTs with a 3-yr interval and random mea-surements of fasting glycemia during the entire follow-up. At the time of both OGTTs, peripheral insulin sensitivity was assessed by both homeostatic model assessment (HOMA) index and a novel index derived from the OGTT. At the second OGTT patients exhibited both significantly higher fasting glucose concentrations and enhanced glycemic responses, with greater average glucose areas. GT deterioration over time was accompanied by a reduction of insulin sensitivity, with no concomitant change of insulin secretion. No patient developed diabetes mellitus (DM) during follow-up. To conclude, the natural history of glycometabolic status in TM adults seems to be characterized by a GT deterioration over time, which may probably reflect an increase of insulin resistance. GT deterioration is more evident in patients with the highest responses to the 1st OGTT and particularly in those with pre-existing impaired GT.