Silvia Einaudi

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.

Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis

OBJECTIVE To investigate the association between juvenile autoimmune thyroiditis (JAT) and thyroid cancer in pediatric patients. DESIGN We conducted a retrospective study among children and adolescents affected by JAT. SETTINGS Data from 6 Italian pediatric endocrinology centers were collected. PARTICIPANTS Three hundred sixty-five children and adolescents affected by JAT diagnosed at 3.6 to 17.0 years of age. INTERVENTIONS All patients underwent clinical examination and thyroid function test every 6 to 12 months and thyroid echography every 12 to 24 months. Fine-needle aspiration biopsy was performed in 39 patients with nodule diameter of 1 cm or larger, as well as in 4 patients with nodule diameter of less than 1 cm and echographic findings suspicious for neoplasm. Twenty-three patients underwent surgery. MAIN OUTCOME MEASURES Thyroid function, echographic pattern, nodule diameter, the presence of lymphadenopathy, and cytologic and histologic diagnoses were considered. RESULTS Thyroid nodules were found in 115 patients; findings in 11 of these were consistent with papillary carcinoma, with 5 exhibiting lymph node metastasis. The prevalence of male sex among patients with cancer was greater than that among patients with JAT (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.44-6.20). The growth of nodules during levothyroxine sodium therapy (OR, 15.60; 95% CI, 1.87-181.90) and the finding of lymphadenopathy (OR, 5.44; 95% CI, 1.05-30.50) were statistically significantly associated with the presence of cancer, while uninodularity and hypoechogenicity were not. CONCLUSIONS The observed prevalences of thyroid nodules and thyroid cancer in our JAT case series were 31.5% and 3.0%, respectively. Papillary carcinoma was the only histotype detected. The finding of lymphadenopathy, a lack of response to levothyroxine therapy, and nodule hypoechogenicity suggested malignancy. Fine-needle aspiration biopsy was reliable in selecting patients for referral to surgery.

Prevalence and Characteristics of Familial Hyperaldosteronism: The PATOGEN Study (Primary Aldosteronism in TOrino-GENetic forms)

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, and patients display an increased prevalence of cardiovascular events compared with essential hypertensives. To date, 3 familial forms of PA have been described and termed familial hyperaldosteronism types I, II, and III (FH-I to -III). The aim of this study was to investigate the prevalence and clinical characteristics of the 3 forms of FH in a large population of PA patients. Three-hundred consecutive PA patients diagnosed in our unit were tested by long-PCR of the CYP11B1/CYP11B2 hybrid gene that causes FH-I, and all of the available relatives of PA patients were screened to confirm or exclude PA and, thus, FH-II. Urinary 18-hydroxycortisol and 18-oxocortisol were measured in all of the familial PA patients. Two patients were diagnosed with FH-I (prevalence: 0.66%), as well as 21 of their relatives, and clinical phenotypes of the 2 affected families varied markedly. After exclusion of families who refused testing and those who were not informative, 199 families were investigated, of which 12 were diagnosed with FH-II (6%) and an additional 15 individuals had confirmed PA; clinical and biochemical phenotypes of FH-II families were not significantly different from sporadic PA patients. None of the families displayed a phenotype compatible with FH-III diagnosis. Our study demonstrates that familial forms of hyperaldosteronism are more frequent than previously expected and reinforces the recommendation of the Endocrine Society Guidelines to screen all first-degree hypertensive relatives of PA patients.

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541.

Steroid Withdrawal Syndrome During Steroid Tapering in Childhood Acute Lymphoblastic Leukemia: A Controlled Study Comparing Prednisone Versus Dexamethasone in Induction Phase

Children with acute lymphoblastic leukemia (ALL) receive as part of induction therapy a 4-week course of high-dose glucocorticoid, which is either abruptly discontinued or shortly tapered. The aim of this study was to evaluate the signs and symptoms of steroid withdrawal syndrome and performance status (according to Lansky scale) during the 9-day tapering period and 1 week after withdrawal of the steroid in 63 children randomly allocated to receive prednisone or dexamethasone as part of induction treatment according the AIEOP ALL 2000 protocol. Twenty of 28 (75%) patients on dexamethasone versus 18 of 35 (51.4%) on prednisone (P < 0.05) developed at least one steroid withdrawal symptom during the study period. Three or more symptoms were observed in 39.3% (11/28) of the dexamethasone group and 8.6% (3/35) of the prednisone group (P < 0.05). Dexamethasone patients developed clinical signs earlier (within 3 days from the steroid tapering) than symptomatic prednisone patients. In the prednisone group, the symptoms were less severe and the performance status was higher (P < 0.05). Steroid withdrawal morbidity in ALL children during induction is a frequent and clinically relevant complaint. A more gradual (for dexamethasone) or a more prolonged (for prednisone) tapering might be suggested.

Thyroid diseases in patients treated during pre-puberty for medulloblastoma with different radiotherapic protocols

We evaluated thyroid disease in 32 patients treated, during pre-puberty, for medulloblastoma, followed for at least 4 years and without relapse during observation. After surgery the patients underwent chemotherapy (CT) and radiotherapy (RT). The protocols were as follows: 20 patients (group A) SNC 76 and SNC 85 protocols which included conventional fractionated RT (36–40 Gy to the craniospinal axis and a 14–18 Gy boost to the posterior fossa, administered as 1.5–1.8 Gy per fraction per day) and a junction between the cranial and the spinal fields at C2–C3 level; 12 patients (group B) SNC 91 protocol which included hyperfractionated RT (36 Gy to the craniospinal axis and a 30 Gy boost to the posterior fossa; this was administred as 1 Gy per fraction twice per day) and a junction at levels C5–C6 or C6–C7 level. The mean age at diagnosis was 7.4±3.2 years for group A and 8.4±2.6 years for group B. Thyroid function was evaluated yearly and ultrasonographic characteristics every 2 years. The patients were followed for a mean of 10.8±3.8 for group A and 6±1.4 years for group B. Primary hypothyroidism was diagnosed in 16 group A patients and 4 group B patients, and central hypothyroidism was diagnosed in 2 group A patients (difference in risk of developing hypothyroidism evaluated with a Wilcoxon-test: p=0.048). Ultrasonography showed reduced thyroid volume in 7 group A cases, and structural changes in 21 patients (17 group A, 4 group B); 9 L-thyroxine-treated patients were confirmed hypothyroid after having stopped therapy. A thyroid nodule was detected in two cases (one from each group). In conclusion, our data indicate that thyroid injury may be diminished by the use of hyperfractionation and low-junction radiotherapy in the treatment of medulloblastoma.

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.

Central Precocious Puberty: Treatment with Triptorelin 11.25 mg

Background. Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). Aim. To assess the efficacy of triptorelin 11.25 mg in children with CPP. Patients. 17 patients (16 females) with CPP (7.9 ± 0.9 years) were treated with triptorelin 11.25 mg/90 days. Methods. Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7 ± 16.5 IU/L at baseline to 0.9 ± 0.5 IU/L at M3 (P < 0.0001); they did not significantly changed at M6 and M12. Conclusions. Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Phenotypic Variation of SF1 Gene Mutations

Knockout of the steroidogenic factor 1 (Sf1) gene in 46,XY mice causes complete adrenal failure associated with gonadal dysgenesis, undervirilization, and persistence of mullerian ducts [1]. SF1 (NR5A1, SF1/Ad4BP/FTZF1) is a member of the nuclear receptor superfamily, and it plays a crucial role in the fetal development of the adrenal gland [2] and testes [3]. Sf1 is considered to be the master regulator of the reproductive system because it regulates the expression of a wide array of genes required for testis and adrenal development and hormone synthesis [4].

GROWTH HORMONE TREATMENT IN IRRADIATED CHILDREN WITH BRAIN TUMORS

We assessed the efficacy of GH treatment in 25 GH deficient patients irradiated for brain tumors (eight with glioma cranio-irradiated, eleven with medulloblastoma and six with ependymoma craniospinal-irradiated). We administered GH at doses of 0.6-0.9 IU/kg/week for one to three years at least two years after diagnosis of the tumor. We assessed the efficacy of the treatment each year by comparing the values of height velocity over bone age and change in the ratios progression of chronological age/progression of bone age and progression of statural age/progression of bone age. The treatment promoted satisfactory growth; better results were obtained in patients with glioma, who received cranial irradiation only, than in those with medulloblastoma or ependymoma, who received spinal irradiation as well. Moreover, the growth prognosis improved, especially in the cranio-irradiated patients. In our series of patients four presented tumor recurrence; these results did not differ significantly from those in irradiated patients with cerebral tumors who were not treated with GH.