Patrizia Matarazzo

Hypothalamo-hypophysial Dysfunction After Traumatic Brain Injury in Children and Adolescents: A Preliminary Retrospective and Prospective Study

With two study protocols, one retrospective and the other prospective, we evaluated hypothalamo-hypophysial dysfunction (HHD) in paediatric patients treated for traumatic brain injury (TBI) in the neurosurgical or intensive care department at our hospital. The retrospective group comprised 22 patients who had experienced TBI 0.7-7.25 years before the study. The prospective group included 30 patients assessed at TBI (T0), 26 of 30 after 6 months (T6), and 20 of 26 after 12 months (T12). Auxological and hormonal basal parameters of hypothalamo-hypophysial function were evaluated at recall in the retrospective group, and at T0, T6 and T12 in the prospective group. Basal data and standard dynamic tests in selected patients revealed one with precocious puberty, one with total anterior hypopituitarism, one with central hypogonadism, and one with growth hormone (GH) deficiency in the retrospective group; three patients with cerebral salt-wasting syndrome, one with diabetes insipidus and seven with low T3 syndrome at T0 (all transient), one with hypocorticism at T6 confirmed at T12, and one with GH deficiency at T12 in the prospective group. The results of our study show that post-TBI HHD in our paediatric cohort is not uncommon. Of the 48 patients who underwent a complete evaluation (22 retrospective study patients and 26 prospective study patients evaluated at T6) five (10.4%) developed HHD 6 months or more after TBI. HHD was newly diagnosed in one previously normal patient from the prospective group at 12 months after TBI. GH deficiency was the most frequent disorder in our paediatric cohort.

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.

Bisphosphonate treatment of bone fibrous dysplasia in McCune-Albright syndrome.

One of the main features of McCune-Albright syndrome is bone fibrous dysplasia (BFD) often associated with severe clinical outcomes, such as bone pain, bone deformities and pathological fractures. Medical treatment with bisphosphonates started 15 years ago. Recent trials in pediatric patients with BFD have shown encouraging results. We evaluated long-term efficacy and safety of pamidronate treatment of BFD in children and adolescents with MAS. The drug was administered at 4 month-1 year intervals according to alkaline phosphatase levels. The study included 14 patients (10 females and 4 males between the ages of 5.3 and 18.7 years) with moderate or severe BFD. Follow up lasted 1.9-9 years. Bone pain, fractures, deformities, and bone turnover markers were evaluated before every therapeutic course. The study shows the beneficial effects of long-term bisphosponate treatment on BFD lesions leading to reduced fracture rate and bone pain, and radiological evidence of long bone lesion healing.

Clinical presentation of McCune-Albright syndrome in males.

UNLABELLED The aims of this study were: (a) to survey gender prevalence and clinical findings at diagnosis in a series of patients who manifested at the time of this study the classical triad of McCune-Albright syndrome (MAS); (b) to investigate whether clinical presentation of MAS in boys may be different from that in girls; (c) to confirm whether boys with MAS may show a peculiar picture of testicular microlithiasis (TM) by testicular ultrasonography (US). Twenty-six patients (10 boys) with the classical clinical manifestations of MAS were recruited for the present study from the database of the Italian Multicenter Study Group on MAS. Age at diagnosis of MAS was significantly lower in girls than in boys (p < 0.025). Whilst there was no difference in the prevalence of skin and bone fibrous dysplasia for the two groups, a significantly higher prevalence of peripheral precocious puberty (PPP) was found in girls (chi2 = 6.5, p < 0.025). Moreover, PPP onset was earlier in females than in males (2.8 +/- 2.3 vs. 6.9 +/- 2.7 years, p < 0.005). In one boy, aged 2.9 years, the first clinical manifestation of MAS was monolateral testicular enlargement in the context of a picture of classical PPP. US scanning of the testes, at the time of the present study, showed bilateral hyperechogeneic multiple spots, compatible with diagnosis of TM, in 6/10 boys. CONCLUSIONS (a) MAS is slightly more frequent in females. (b) PPP in MAS is significantly more frequent and earlier in girls. (c) PPP in boys with MAS is generally associated with bilateral testicular enlargement, but monolateral macroorchidism may also be seen. (d) TM may be another marker for MAS in males.

Genetics of McCune-Albright syndrome

McCune-Albright syndrome (MAS) is a rare proteiform disease due to postzygotic, somatic mutations at codon R201 of the GNAS1 gene that results in cellular mosaicism. Different methods have been used in the molecular analysis of DNA samples from several tissues of patients with one or more MAS signs, with various mutation detection rates. We review data from the literature to investigate whether patient inclusion criteria for GNAS1 analysis, the molecular methods used to search for R201 mutations, and the type of tissues analysed, can influence the mutation detection rate in MAS. Our study indicates that to overcome the problems related to GNAS1 analysis in MAS, sensitive and specific molecular methods must be used to look for the mutation from all available affected tissues and from easily accessible tissues, and even more so in the presence of atypical and monosymptomatic forms of MAS.

Long-term outcome of male-limited gonadotropin-independent precocious puberty.

Long-term outcome of five new cases of male-limited precocious puberty (MPP) is reported. Three patients had positive family history. One patient was untreated; 2 boys received cyproterone acetate (2.0-3.6 mg/kg/daily) without clinical effects. Two patients were treated with ketoconazole (600 mg/daily); in 1, GnRH analogue therapy (Buserelin, 1,600 microg/day) was added after 6 months of effective ketoconazole treatment for development of central precocious puberty. The other patient did not develop central puberty under ketoconazole treatment and improved his predicted adult height from 172.4 to 181.1 cm. Four patients reached final height [B.A. (therapy cyproterone acetate): age 22.0 years, -2.0 SDS; B.G. (untreated): age 15.5 years, -1.7 SDS; M.M. (therapy cyproterone acetate): age 19.5 years, -1.6 SDS; M.F. (therapy ketoconazole plus GnRH analogue): age 21.3 years, -2.2 SDS]; three had reduced testicular volume (B.A.: -1.6/-1.6 SDS; B.G.: -2.1/-2.1 SDS; M.F.: -2.4/-1.9 SDS); one (M.F.) showed oligospermia. We concluded that in MPP cyproterone acetate treatment did not improve final height; ketoconazole was effective in reducing testosterone secretion, but its real effect on final height cannot be determined; the timing of central puberty may be precocious, suggesting that an adjunctive GnRH analogue treatment may be needed. In some patients, testicular impairment may be present in young adulthood.

Thyroid abnormalities in children and adolescents with mccune-albright syndrome

Background: To date, there is no agreement about the frequency or the features of thyroid abnormalities in McCune-Albright syndrome (MAS). The aim of our study was to detect thyroid abnormalities in a cohort of MAS children and adolescents and to give indications for their treatment and follow-up. Methods: In 36 patients, 22 females and 14 males, thyroid function and sonographic features of thyroid were evaluated every 6–12 months. Results: Three males and 1 female had hyperthyroidism: 2 with nodular, 2 with diffuse goiters. They were treated with methimazole (0.2–0.5 mg/kg/day) with good clinical and biochemical responses. The remaining 32 patients were euthyroid, even if 7 displayed sonographic alterations, of whom 5 had nodular goiter with nodules >1 cm, and 2 micronodular goiter. Fine-needle aspiration biopsy was performed in 2 patients with nodules >1 cm, 1 showing hemorrhagic nodule and 1 colloid cystic nodule. Conclusions: Prevalence of thyroid alterations in the studied MAS series was 31%. 64% of 11 patients with thyroid alterations had nodular goiters, with nodules >1 cm. As the onset of thyroid disease ranged from 1 to 20 years, a strict monitoring of thyroid function is recommended every 6 months. Satisfactory treatment can be obtained and maintained with antithyroid drugs.

Levothyroxine treatment in pediatric benign thyroid nodules.

Aim: To evaluate the effectiveness of levothyroxine therapy in benign thyroid nodules in pediatrics. Methods: Data from 78 euthyroid children and adolescents with benign thyroid nodules were retrospectively collected. Subjects were divided into 2 groups: levothyroxine treated (n = 36) and nontreated (n = 42), and the clinical, laboratory and sonographic features of the 2 groups were compared. Nodules were considered benign according to histology, fine-needle aspiration biopsy or by features suggestive for benignity. The groups were followed up for 2.4 ± 1.3 years, and treated patients received a mean dose of levothyroxine of 1.69 ± 0.66 µg/kg/day. Results: Patients in the treated and nontreated groups were comparable for age, sex and follow-up. A reduction in nodule diameter from 2.24 ± 0.94 to 1.86 ± 1.17 cm (p = 0.039) was observed in treated patients, whereas the nodule diameter increased from 1.66 ± 0.86 to 1.78 ± 0.91 cm in nontreated patients (p = 0.024). In the treatment group, 11 patients (30.6%) had a reduction greater than 50% and significantly decreased palpable nodules (p < 0.001). A nonsignificant reduction in reported symptoms was observed, too. The change in nodule size was directly correlated with thyroid-stimulating hormone levels (r = 0.640, p < 0.001) and inversely with levothyroxine dose (r = –0.389, p = 0.009). In nontreated subjects, both palpable nodules and symptoms increased. Conclusion: This study supports levothyroxine treatment effectiveness in shrinking benign nodules.

McCune-Albright syndrome: persistence of autonomous ovarian hyperfunction during adolescence and early adult age.

Gonadal hyperfunction is the most frequent endocrine dysfunction in females with McCune-Albright syndrome (MAS). Peripheral precocious puberty is usually the first MAS manifestation in children, characterized by episodes of hypersecretion of estrogens with a consequent reduction in gonadotropin secretion. Little is known about the course of this endocrine disease in adolescence and during young adult life. The aim of this study was to evaluate ovarian function in 10 females with MAS (age 11.4-20.1 years) to detect the persistence of autonomous ovarian hyperfunction throughout and following adolescence, after at least 1 year wash out of any treatment for precocious puberty. LH, FSH, estradiol, prolactin, androgen secretion, ovarian and breast sonography in luteal and follicular phases of some menstrual cycles were evaluated. We demonstrated the persistence of some ovarian autonomy, documented by hyperestrogenism and/or low or absent gonadotropin secretion and/or ovarian cysts.

Endocrine Function and Water Metabolism in Children and Adolescents with Surgically Treated Intra/Parasellar Tumors

Hydroelectrolytic disorders often complicate surgery of intra/parasellar tumors in children and adolescents. Eighteen patients undergoing microneurosurgical procedures for intra-supra-sellar craniopharyngioma (10 patients), hypothalamic germinomas (3 patients), hypothalamic-chiasmatic astrocytomas (3 patients), pituitary adenomas (2 patients) were studied. The hydroelectrolytic balance was assessed from 8 hours before surgery to 1 week after with a specific protocol in which water metabolism alterations were treated with standard procedure. Diabetes insipidus (DI) was observed in 10/18 patients before surgery and in 15/18 patients after surgery; during surgery it was effectively treated with synthetic desmopressin (DDAVP) and hydroelectrolytic solutions. Hyponatremia, isolated or associated (with diuresis contraction or polyuria), seen during surgery and in the following 24 hours, was treated with variation of the infusion rate. We show that close monitoring and treatment of hydroelectrolytic disorders in patients submitted to neurosurgery for intra/ parasellar tumors may significantly reduce their morbidity and mortality rate.