Franco Rigon

Pamidronate treatment of bone fibrous dysplasia in nine children with McCune-Albright syndrome

McCune‐Albright syndrome is a rare genetic disorder consisting of skin and bone dysplasia and peripheral endocrinopathies. Little data have been collected regarding bisphosphonate treatment of bone fibrous dysplasia in paediatric patients with this syndrome. The aim of our study was to investigate the therapeutic efficacy of pamidronate in these patients. Nine patients with moderate to severe forms of bone fibrous dysplasia were treated with pamidronate intravenously (0.5‐1 mg/ kg/daily for 2‐3 d) at 0.5‐1‐y intervals. Patients were treated over a time period of 0.5‐3.5 y. During treatment no spontaneous fracture occurred. Bone pain and gait abnormality due to pain disappeared after 2‐3 therapeutic cycles. Cranial asymmetry and limb length discrepancy remained unchanged. Elevated serum alkaline phosphatase and urine hydroxyproline values were reduced by the treatment, demonstrating drug activity at the lesional level. The effectiveness of pamidronate was also seen at the non‐lesional level through an increase in bone density. Radiographic and scintigraphic evidence of lesion healing was not attained. Pamidronate treatment can ameliorate the course of bone fibrous dysplasia in children and adolescents with McCune‐Albright syndrome.

Natural course of subclinical hypothyroidism in Down’s syndrome: Prospective study results and therapeutic considerations

Pathogenesis, natural course and therapeutic management of subclinical hypothyroidism (SH) in Down’s syndrome (DS) remain object of debate in literature. In the present study thyroid function, antithyroid antibody (ATA) prevalence and serum lipid concentrations were investigated in a group of 344 Down patients (DP) and data were compared with those obtained from a control group of 257 age and sex matched healthy subjects. Thyroid function and ATA prevalence were also studied in 120 parents of DP. SH prevalence was clearly higher in DP (32.5% of cases) than in controls (1.1%) and parents (0%). Similarly, ATA prevalence was higher in DP (18% of cases) than in controls (5.8%) and parents (6.6%). In spite of this, no correlation was found in DP between SH and ATA prevalences, since ATA were detected in 18.7% of SH-DP and in 15.8% of euthyroid DP. Thus, circulating ATA were not detected in the majority of SH-DP. No significant differences regarding T4, FT4, T3 and serum lipid levels among SH and euthyroid DP and controls were found. Moreover, TSH levels were only slightly increased, generally less than 10 μU/ml, in most cases of SH-DP. Follow-up was longer than 24 months (range 2–7 years, mean 3.1) in a group of 201 DP: two different patterns of SH course were observed, mainly depending on the presence or the absence of circulating ATA. In particular, 35.7% of ATA-positive SH-DP developed a clinically evident thyroid disease (overt hypothyroidism or hyperthyroidism), while no similar case was recorded among ATA-negative SH-DP. On the contrary, a significant number of these patients (33.9% of cases) showed a spontaneous normalization of TSH levels. The present data suggest that: a) DS per se seems to be a clinical risk condition in developing thyroid autoimmune diseases, b) SH represents a very common conditions in DP and in most cases it appears to be independent of the presence of circulating ATA, c) SH alone, that is in the absence of detectable ATA, does not seem to be predisposing condition to develop a clinically evident thyroid disease, as a spontaneous normalization of TSH levels is often observed. From the therapeutic point of view, it seems unlikely that L-thyroxine substitutive therapy could lead to some improvement in SH-DP in the absence of detectable ATA. A wait and see policy with frequent thyroid function screening could be considered adequate, thus avoiding chronic hormonal therapy at least in DP in whom TSH levels tend to spontaneously normalize. On the contrary, L-thyroxine should not be delayed in ATA-positive SH-DP due to the frequent evolution towards an overt thyroid disease.

McCune-Albright syndrome: A longitudinal clinical study of 32 patients

We report the diagnostic clinical features and their long term evolution in 32 patients with McCune-Albright syndrome. Patient data are made up of two periods: the first, classified as personal history, is from birth until the time when the diagnosis of McCune-Albright syndrome was made; the second, classified as clinical observation, is from the first observation until the end of follow up. The total duration of these two periods was 9.6+/-2.9 yr; mean age at first observation was 5.7 yr (range 0.7-11 yr). The probability of manifesting main clinical signs according to age was calculated: almost all had skin dysplasia at birth, 50% probability of peripheral precocious puberty in females at 4 years and 50% of bone dysplasia at 8 years of age were found. Other clinical signs had diagnostic relevance when preceding the main signs leading to diagnosis of McCune-Albright syndrome even without specific genetic investigation. The most important clinical manifestations have different evolutions: skin lesions increase in dimensions according to body growth; precocious puberty in females evolves rapidly but periods of regression can be seen in some patients; bone dysplasia in most patients evolves with an increase both in the number of affected bones and in the severity of lesions.

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsα protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsα protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsα activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.

Turner's syndrome in Italy: familial characteristics, neonatal data, standards for birth weight and for height and weight from infancy to adulthood.

In 1990, the Italian Study Group for Turners Syndrome (ISGTS) undertook a nationwide survey, involving the retrospective collection of cross‐sectional data and longitudinal growth profiles of 772 girls with Turners syndrome born between 1950 and 1990. The study was carried out in 29 pediatric endocrinological centers. In this first report, the familial characteristics and neonatal data of Turner girls are described, compared to those of the general population, and related to postnatal somatic development. Furthermore, charts for birth weight and growth standards for height and weight from infancy to adulthood are presented (these are the first charts based on a large sample from the Mediterranean area). The main findings were: (1) incidence of Turner births increases with parental age or parity; (2) most of the neonates are small for dates; (3) girls with normal birth weight tend to be both taller and heavier than girls with low birth weight during the whole growth period; and (4) a 10‐cm difference in midparental height leads to a 6.5‐cm difference in adult stature.

Comparison of clinical-radiological and molecular findings in hypochondroplasia

Hypochondroplasia is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature. A mutation (N540K) in the fibroblast growth factor receptor 3 (FGFR3) gene was described in some patients with this condition. The aims of the study were to identify the frequency of the FGFR3 gene mutation, to define the salient clinical and radiological abnormalities of the affected subjects, and to verify the contribution of molecular findings to the clinical and radiological definition of hypochondroplasia. Based on the most common radiological criteria, we selected 18 patients with a phenotype compatible with hypochondroplasia. Height, sitting height, and cranial circumference were measured in all patients. Radiographs of the lumbar spine, left leg, pelvis, and left hand were also obtained. The presence of the N540K mutation was verified by restriction enzyme digestions. Half of our patients carried the N540K mutation. Although similar in phenotype to the patients without the mutation, they showed in addition relative macrocephaly. The association of the unchanged/narrow interpedicular distance with the fibula longer than the tibia was more common in patients with gene mutation. Although we did not find a firm correlation between genotype and phenotype, in our study the N540K mutation was most often associated with disproportionate short stature, macrocephaly, and with radiological findings of unchanged/narrow interpedicular distance and fibula longer than tibia.

Menstrual pattern and menstrual disorders among adolescents: an update of the Italian data

BackgroundThe most striking event in the whole process of female puberty is the onset of menstruation. To our knowledge, no large population-based studies have been performed on the topic of menstrual health among Italian adolescents in recent years.The aims of this study were to produce up-to-date information on the menstrual pattern of Italian girls attending secondary school, and to estimate the prevalence of menstrual cycle abnormalities in this population.MethodsThis was a cross-sectional study on a population-based sample of Italian adolescents aged 13–21 years attending secondary school. Only girls who had already started menstruating were requested to participate. Information was collected by means of a questionnaire that included items on the girls’ demographic details, anthropometrics, smoking and drinking habits, use of contraceptive pills, and socioeconomic status. The questions on the girls’ menstrual pattern concerned their age at menarche, duration of the most recent menstruation intervals (<21, 21–35, >35 days, variable), average days of bleeding (<4, 4–6, >6 days), and any menstrual problems and their frequency.ResultsA total of 6,924 questionnaires were administered and 4,992 (71%) were returned. One hundred girls failed to report their date of birth, so 4,892 subjects were analyzed. The girls’ mean age was 17.1 years (SD ±1.4); their mean age at menarche was 12.4 (±1.3) years, median 12.4 years (95%CI 12.3–12.5).In our sample population, 3.0% (95%CI 2.5%-3.4%) of the girls had menstruation intervals of less than 21 days, while it was more than 35 days in 3.4% (95%CI 2.9%-3.9%). About 9% of the girls (95%CI 7.7%-9.4%) said the length of their menstruation interval was currently irregular. Short bleeding periods (<4 days) were reported in 3.2% of the sample population (95%CI 2.7%-3.7%), long periods (>6 days) in 19% (95%CI 17.9%-20.1%). Menstruation-related abdominal pain was reported by about 56% of our sample. About 6.2% of the girls (95%CI 5.4%-7.0%) were suffering from dysmenorrhea.ConclusionsIn conclusion, to the best of our knowledge, this is one of the largest studies on menstrual patterns and menstrual disorders among Italian adolescent girls. Adolescent girls referring persistent oligomenorrhoea, in first two years from menarche, had a higher risk for developing a persistent menstrual irregularity. They had longer bleeding periods (>6 days) and this has practical implications because it makes these adolescents potentially more susceptible to iron deficiency anemia. Clinicians need to identify menstrual abnormalities as early as possible in order to minimize their possible consequences and sequelae, and to promote proper health information.We recommend that adolescents should be encouraged to chart their menstrual frequency and regularity prospectively from the menarche onwards.

Does Graves’ Disease during Puberty Influence Adult Bone Mineral Density?

Aim: To evaluate the bone mineral density at lumbar spine and at femoral neck in a group of young adults in whom Graves’ disease developed during childhood and adolescence. Patients and Methods: We examined 28 patients (5 male, 23 female, age 20.9 ± 3.3 years) who were 11.8 ± 2.9 years old at the onset of Graves’ disease. They were treated either with methimazole (14 patients) or with methimazole plus l-thyroxine (14 patients). At the time of the investigation, 13 patients were considered cured following antithyroid treatment, 2 were still on antithyroid drugs, 3 were on replacement therapy with l-thyroxine because of hypothyroidism, and 10, treated either surgically or with 131I, were on replacement therapy. The bone mineral density was measured at the lumbar spine (L2–L4) and at the femoral neck, using dual-energy X-ray absorptiometry. Results: The spinal bone mineral density SD score was –0.28 ± 1.02, the femoral neck bone mineral density SD score was 0.36 ± 1.02, and both were not different from zero (NS). We did not find any correlation between the bone mineral density of the femoral neck and that of the lumbar spine and the clinical parameters. Conclusion: Graves’ disease, beginning in childhood and adolescence, when appropriately treated, does not affect attainment of peak bone mass.

Cardiac Performance in Turner’s Syndrome Patients on Growth Hormone Therapy

Objectives: To investigate possible cardiac morphofunctional alterations observed in 26 Turner’s syndrome (TS) patients on prolonged high-dose growth hormone (GH) therapy. Study Design: We examined 26 TS subjects treated with rhGH (1 U/kg/week) for a mean period of 4.9 years (range 1–7.8) and 37 age-, weight- and height-matched healthy girls. Left ventricular volume, mass, systolic function, cardiac index, systemic vascular resistance and diastolic function were evaluated by two-dimensional and Doppler echocardiography. Results: Heart rate and systolic blood pressure (BP) were higher in TS patients than in controls, while diastolic BP was lower. Left ventricular volumes, ejection fraction, mass index, M/V ratio and cardiac index did not differ significantly; systemic vascular resistance was slightly decreased. Left ventricular fractional shortening and mean velocity of circumferential shortening were slightly increased while end-systolic meridional stress was decreased in TS. Contractile state was normal in TS. Diastolic function assessment showed a shortening of isovolumetric relaxation and diastolic filling times with an increased atrial contribution and a normal pulmonary venous flow. Conclusion: Cardiac morphology in TS patients on GH therapy is similar to controls. The observed changes in left ventricular systolic and diastolic function should be interpreted as an adaptation to the higher heart rate and reduced peripheral vascular resistance induced by GH therapy.

Bilateral cerebral occipital calcifications and migraine‐like headache

Computed tomography scanning in two young patients with recurrent, pulsating, migraine-like headache showed parieto-occipital calcifications. One patient presented with an atypical form of the Sturge-Weber syndrome, and the other with celiac disease and folic acid deficiency. The clinical features were analyzed and compared with those in other cases reported in the recent literature which have shown bioccipital calcifications but no cutaneous angiomas, sometimes associated with visual and/or intelligence deficit and epilepsy. Finally, the possible connection between cerebral calcifications and headache is discussed.