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Filippo De Luca, Valérie Mitchell, Malgorzata Wasniewska, Teresa Arrigo, Maria Francesca Messina, Mariella Valenzise, Luisa de Sanctis and Najiba Lahlou

Context

McCune–Albright syndrome (MAS) is a disorder caused by a post-zygotic gain-of-function mutation in the gene encoding the Gs-α protein. Sexual precocity, common in girls, has been reported in only 15% of boys, and little is known on the long-term evolution of MAS in males.

Objective

In a boy with MAS, we studied spermatogenesis, testis histology, and immunohistochemistry with the aim to shed light on seminiferous tubule activity.

Design

A boy who presented at the age of 2.9 years with sexual precocity, monolateral macroorchidism, increased testosterone levels, and suppressed gonadotropins was followed up until the age of 18.

Results

Throughout follow-up testicular asymmetry persisted and gonadotropin and testosterone pattern did not change. At the age of 18, inhibin B was undetectable while α-immunoreactive inhibin was within normal range. Anti-Mullerian hormone level was slightly subnormal. Sperm cells were 3 900 000 per ejaculate. Histology of both testes showed spermatogonia, spermatocytes, and, in some tubes, matured spermatozoa. Sertoli cells were markedly stained with anti-inhibin α-subunit antibody in both the testes. There was no immunostaining of Sertoli, Leydig, or germ cells with anti-βA or anti-βB antibody. MAS R201H mutation was identified in both the testes.

Conclusion

The 15-year follow-up in this boy with MAS demonstrated that autonomous testicular activation and gonadotropin suppression persisted over time. This provides an interesting model of active spermatogenesis despite long-term FSH suppression. It also suggests that FSH is needed for the full expression of the inhibin βB-subunit gene, an expression previously reported in the germ and Leydig cells of normal adult subjects.

Restricted access

Domenico Cucinotta, Filippo De Luca, Alfonso Gigante, Teresa Arrigo, Antonino Di Benedetto, Antonino Tedeschi, Fortunato Lombardo, Giacomo Romano and Concetta Sferlazzas

Cucinotta D, De Luca F, Gigante A, Arrigo T, Di Benedetto A, Tedeschi A, Lombardo F, Romano G, Sferlazzas C. No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study. Eur J Endocrinol 1994;130:253–8. ISSN 0804–4643

Plasma glucose and insulin responses to oral glucose and insulin sensitivity by the euglycemic hyperinsulinemic clamp technique were investigated in 30 cystic fibrosis patients with normal fasting blood glucose levels and normal (N = 12), impaired (N = 12) or diabetic (N = 6) glucose tolerance, and in 12 control subjects. In a subgroup of 10 cystic fibrosis patients with non-diabetic glucose tolerance both oral glucose tolerance test and clamp were performed again 48–52 months later. Following oral glucose, glycemic responses were higher in cystic fibrosis patients than in controls, whereas insulin responses were reduced significantly only in the patients with diabetic glucose tolerance. Insulin sensitivity did not differ significantly in the patient subgroups with different degrees of glucose tolerance and in controls. In the 10 patients who underwent a 4-year follow-up, insulin responses to oral glucose decreased significantly, whilst insulin sensitivity did not change substantially. Insulin sensitivity persisted unmodified even in the patients with deteriorating glucose tolerance. No correlations were observed between metabolic data and clinical status of patients. In conclusion, in cystic fibrosis subjects with fasting euglycemia and different degrees of glucose tolerance: (i) insulin sensitivity is not impaired; (ii) eventual changes of glucose tolerance over time are not associated with modifications of insulin sensitivity; (iii) insulin secretion deteriorates over time even in the patients with stable glucose tolerance; (iv) eventual deterioration of both glucose tolerance and insulin secretion is not linked to a worsening of either nutritional or clinical parameters.

F De Luca, Istituto di Clinica Pediatrica, Policlinico Universitario, 98100 Messina, Italy

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Domenico Cucinotta, Teresa Arrigo, Filippo De Luca, Antonino Di Benedetto, Fortunato Lombardo, Riccardo Scoglio, Concetta Sferlazzas and Giuseppe Magazzú

Cucinotta D, Arrigo T, De Luca F, Di Benedetto A, Lombardo F, Scoglio R, Sferlazzas C, Magazzú G. Metabolic and clinical events preceding diabetes mellitus onset in cystic fibrosis. Eur J Endocrinol 1996;134:731–6. ISSN 0804–4643

Serial assessments of glucose tolerance, of glucose and insulin areas during an oral glucose tolerance test (OGTT) and of clinical parameters as well were evaluated retrospectively in seven diabetic cystic fibrosis patients (study group) during the 4–6.3 years that preceded diabetes mellitus diagnosis. The same metabolic and clinical parameters were also evaluated in seven age-matched patients who did not develop diabetes during a similar observation period (control group). In the study group, glucose tolerance was impaired in all patients but one since the first OGTT and glucose areas progressively increased over time, whereas in the control group glucose tolerance remained stable during the whole observation period. A significant and progressive blunting of insulin secretion occurred over time in both groups. Insulin secretion, however, was reduced but not exhausted at diabetes diagnosis. Neither modification of glycosylated haemoglobin levels over time nor serum islet cell antibodies at diabetes onset were observed in the study group. The overall clinical course of the disease was not different in either group and remained stable during the observation period. These results indicate that in cystic fibrosis diabetes mellitus onset is preceded by a long-standing deterioration of glucose tolerance, whilst insulin secretion progressively declines over time, irrespectively of glucose tolerance status. The prediabetic worsening of glucose tolerance is not necessarily linked to a worsening of overall clinical status.

Filippo De Luca, Istituto di Clinica Pediatrica, Policlinico Universitario, 98100 Messina, Italy

Free access

Malgorzata Wasniewska, Tommaso Aversa, Mariacarolina Salerno, Andrea Corrias, Maria Francesca Messina, Alessandro Mussa, Donatella Capalbo, Filippo De Luca and Mariella Valenzise

Aim

To follow-up for 5 years thyroid status evolution in 127 girls with mild (TSH 5–10 mU/l) subclinical hypothyroidism (SH) of different etiologies.

Patients

The population was divided into two age-matched groups of 42 and 85 girls with either idiopathic (group A) or Hashimoto's thyroiditis (HT)-related SH (group B). Group B was in turn divided into three subgroups, according to whether SH was either isolated or associated with Turner syndrome (TS) or Down syndrome (DS).

Results

At the end of follow-up the rate of girls who became euthyroid was higher in group A (61.9% vs 10.6%), whereas the rates of patients who remained SH (55.3% vs 26.2%), became overtly hypothyroid (30.6% vs 11.9%) or required levothyroxine (l-T4) therapy (63.5% vs 23.8%) were higher in group B. Among the girls of group B, the risk of remaining SH or developing overt hypothyroidism was higher in the subgroups with TS or DS than in those with isolated HT.

Conclusions

Long-term prognosis of mild and idiopathic SH is frequently benign, even though a l-T4 treatment may be needed throughout follow-up in almost a quarter of cases; long-term prognosis is different in the girls with either idiopathic or HT-related SH; and the association with either TS or DS impairs the outcome of HT-related SH.

Free access

Manuela Cerbone, Donatella Capalbo, Malgorzata Wasniewska, Sara Alfano, Giuseppina Mattace Raso, Ugo Oliviero, Antonio Cittadini, Filippo De Luca and Mariacarolina Salerno

Objective

To investigate the effect of levothyroxine (L-T4) treatment on early markers of atherosclerotic disease in children with mild idiopathic subclinical hypothyroidism (SH).

Design

Two-year, open, case–control prospective study.

Methods

A total of 39 children, aged 9.18±3.56 years, with SH and 39 healthy controls were enrolled in the study. Waist-to-height ratio (WHtR), blood pressure, triglycerides, total cholesterol (total-C), HDL-C, LDL-C, non-HDL-C, triglycerides/HDL-C, atherogenic index (AI), homocysteine (Hcy), asymmetric dimethylarginine (ADMA), flow-mediated dilation (FMD) and intima–media thickness (IMT) were evaluated at baseline and after 2 years of L-T4 treatment in SH children and after 2 years of follow-up in controls.

Results

At study entry WHtR was higher in SH subjects compared with controls (0.56±0.08 vs 0.49±0.07, P=0.04) and significantly decreased after 2 years of treatment (0.50±0.06, P<0.0001). Mean HDL-C levels (50.47±11.43 vs 61.06±13.83mg/dL, P=0.002) were lower, while triglycerides/HDL-C (1.63±1.07 vs 1.19±0.69, P=0.05), AI (3.32±0.90 vs 2.78±0.68, P=0.005), and Hcy (9.35±2.61 vs 7.71±1.94μmol/L, P=0.01) were higher in SH subjects compared with controls and improved after 2 years of treatment (HDL-C 56.26±13.76mg/dL, P<0.0001; triglycerides/HDL-C 1.23±0.78, P=0.006; AI 2.82±0.68, P<0.0001; and Hcy 8.25±2.09μmol/L, P=0.06). ADMA concentrations at baseline were higher in SH subjects compared with controls (0.77±0.21 vs 0.60±0.16μmol/L, P=0.001) and decreased after therapy (0.58±0.13μmol/L, P<0.0001). FMD, IMT and other metabolic parameters were not different among SH subjects and controls at baseline and after 2 years.

Conclusions

Children with SH may have subtle pro-atherogenic abnormalities. Although L-T4 treatment exerts some beneficial effects, the long-term impact of therapy on metabolic outcomes in SH children still remains unclear.

Free access

Malgorzata Wasniewska, Mariacarolina Salerno, Alessandra Cassio, Andrea Corrias, Tommaso Aversa, Giuseppina Zirilli, Donatella Capalbo, Milva Bal, Alessandro Mussa and Filippo De Luca

Objective

To prospectively evaluate the course of subclinical hypothyroidism (SH) in children and adolescents with no underlying diseases and no risk factors, which might interfere with the progression of SH.

Design

Clinical status, thyroid function, and autoimmunity were prospectively evaluated at entry and after 6, 12, and 24 months in 92 young patients (mean age 8.1±3.0 years) with idiopathic SH.

Results

During the study, mean TSH levels showed a trend toward a progressive decrease while FT4 levels remained unchanged. Overall, 38 patients normalized their TSH (group A): 16 patients between 6 and 12 months, and 22 patients between 12 and 24 months. Among the remaining 54 patients, the majority maintained TSH within the baseline values (group B), whereas 11 exhibited a further increase in TSH above 10 mU/l (group C). Baseline TSH and FT4 levels were similar in the patients who normalized TSH, compared with those with persistent hyperthyrotropinemia. Even in the patients of group C, both TSH and FT4 at entry were not different with respect to those of groups A and B. No patients showed any symptoms of hypothyroidism during follow-up and no changes in both height and body mass index were observed throughout the observation period.

Conclusions

(a) The natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; (b) the majority of patients (88%) normalized or maintained unchanged their TSH; and (c) TSH changes were not associated with either FT4 values or clinical status or auxological parameters.

Free access

Filippo De Luca, Andrea Corrias, Mariacarolina Salerno, Malgorzata Wasniewska, Roberto Gastaldi, Alessandra Cassio, Alessandro Mussa, Tommaso Aversa, Giorgio Radetti and Teresa Arrigo

Objective

To compare the presentation and clinical course of Graves' disease (GD) in two pediatric populations consisting of 28 patients with Down's syndrome (DS) and 109 controls without DS respectively.

Design and methods

The evolution over time of GD was determined in both groups according to the clinical changes and the variations in TSH, free thyroxine, and TSH receptor autoantibodies serum levels during the entire follow-up.

Results

Female prevalence (50 vs 81.6%; χ 2=12.0, P<0.0005) and average age at GD presentation (9.9±4.4 vs 11.5±3.5 years, P<0.05) were significantly lower in DS group than in controls. Clinical responsiveness to methimazole therapy was significantly better in DS patients, as demonstrated by both the lower relapse rates after the first cycle withdrawal (7.1 vs 31.2%; χ 2=7.4, P<0.005) and the higher persistent remission rates after definitive therapy withdrawal (46.4 vs 26.7%; χ 2=4.1, P<0.05). Moreover, in DS group, no patients needed surgery or radioiodine ablation, whereas non-pharmacological treatment was necessary in 11% of controls (χ 2=3.8, P<0.05). Antecedents of Hashimoto's thyroiditis (HT) were documented in 21.4% of DS patients and in 3.7% of controls (χ 2=10.4, P<0.005). Association with other autoimmune diseases was detected in 32.1% of DS cases and in 12.8% of controls (χ 2=5.94, P<0.025).

Conclusions

GD in DS children and adolescents is characterized by several peculiarities: i) earlier presentation; ii) no gender predominance; iii) less severe clinical course; iv) higher frequency of documented HT antecedents; v) more frequent association with other autoimmune diseases.

Free access

Malgorzata Wasniewska, Tommaso Aversa, Laura Mazzanti, Maria Pia Guarneri, Patrizia Matarazzo, Filippo De Luca, Fortunato Lombardo, Maria Francesca Messina and Mariella Valenzise

Objective

To evaluate adult height (AH) in 25 girls with Turner syndrome (TS) who were treated from before 6 years of age for 10.0±1.7 years with a fixed GH dose of 0.33 mg/kg per week.

Patients and design

After a 6-month pretreatment assessment all patients were measured 6-monthly under therapy to assess height SDS (H-SDS) and height velocity (HV) until AH achievement.

Results

Following initial acceleration, HV declined after the first 4 years of therapy. At the end of the sixth year of therapy, H-SDS gain was 1.9±1.1. Thereafter, H-SDS gain from baseline decreased, becoming 0.9±0.9 SDS at AH achievement. Bone maturation velocity did not significantly change throughout the prepubertal period. According to Lyon standards for TS, mean AH SDS was significantly higher than pretreatment H-SDS (P<0.0001), with a mean H-SDS change of 0.9±0.9. However, the prevalence of patients with AH <−2 SDS (according to Sempé standards) was close to those recorded at the start of therapy (16/25 vs 18/25). No significant differences in terms of AH were found between patients with either X monosomy or X-chromosomal abnormalities and between girls with either spontaneous or induced puberty.

Conclusions

We infer that the therapeutic regimen adopted in this prospective study is sufficient to induce a significant growth acceleration during the first year, but the response waned after 6 years of treatment.

Free access

Manuela Cerbone, Carmela Bravaccio, Donatella Capalbo, Miriam Polizzi, Malgorazata Wasniewska, Daniela Cioffi, Nicola Improda, Mariella Valenzise, Dario Bruzzese, Filippo De Luca and Mariacarolina Salerno

Objective

The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine.

Design and methods

Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7±0.6 (range 4–18.0) years. Children had been followed longitudinally for 3.3±0.3 (range 2.0–9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls.

Results

At study entry, height (−0.8±0.2 SDS), bone age/chronological age (BA/CA ratio 0.92±0.6), and body mass index (BMI −0.1±0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (−0.7±0.2 SDS), BA/CA (0.97±0.03), and BMI (−0.1±0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up.

Verbal (99.1±2.2), performance (100.4±1.9), and full-scale (99.7±1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH.

Conclusions

Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.