Bilateral Retinal Angiomatous Proliferation in a Variant of Retinitis Pigmentosa.

PURPOSE: To describe the first case of bilateral retinal angiomatous proliferation (RAP) in a patient with a variant of retinitis pigmentosa (RP). CASE REPORT: An 85-year-old man with RP presented with visual acuity decrease and metamorphopsia in the left eye (LE). Fundus examination revealed typical signs of RP in both eyes, associated with intraretinal macular hemorrhage in the LE. Multimodal imaging, using Colour fundus Photography, Fluorescein (FA), and Indocyanine Green Angiography (ICGA) as well as Spectral-Domain Optical Coherence Tomography (SD-OCT) and Optical Coherence Tomography Angiography (OCTA), revealed a type 3 neovascular lesion in the involved eye. Genetic testing (NGS analysis) was performed to search for genetic variants correlated with the disease phenotype displayed by the patient. The patient was treated with intravitreal injections of bevacizumab, according to a fixed protocol of bimonthly injections plus a booster dose at second month. After 9 months, he was referred for visual acuity decrease and metamorphopsia in the fellow eye, where SD-OCT/OCTA showed a type 3 neovascular lesion in the right eye (RE). He was scheduled for intravitreal injections of bevacizumab. In both eyes, treatment with intravitreal bevacizumab was successful.

The microRNA-29a Modulates Serotonin 5-HT7 Receptor Expression and Its Effects on Hippocampal Neuronal Morphology.

miRNAs are master regulators of gene expression in diverse biological processes, including the modulation of neuronal cytoarchitecture. The identification of their physiological target genes remains one of the outstanding challenges. Recently, it has been demonstrated that the activation of serotonin receptor 7 (5-HT7R) plays a key role in regulating the neuronal structure, synaptogenesis, and synaptic plasticity during embryonic and early postnatal development of the central nervous system (CNS). In order to identify putative miRNAs targeting the 3'UTR of 5-HT7R mouse transcript, we used a computational prediction tool and detected the miR-29 family members as the only candidates. Thus, since miR-29a is more expressed than other members in the brain, we investigated its possible involvement in the regulation of neuronal morphology mediated by 5-HT7R. By luciferase assay, we show that miR-29a can act as a post-transcriptional regulator of 5-HT7R mRNA. Indeed, it downregulates 5-HT7R gene expression in cultured hippocampal neurons, while the expression of other serotonin receptors is not affected. From a functional point of view, miR-29a overexpression in hippocampal primary cultures impairs the 5HT7R-dependent neurite elongation and remodeling through the inhibition of the ERK intracellular signaling pathway. In vivo, the upregulation of miR-29a in the developing hippocampus parallels with the downregulation of 5-HT7R expression, supporting the hypothesis that this miRNA is a physiological modulator of 5-HT7R expression in the CNS.

Infantile swallowing: surgical meaning.

AIMS: The aim of this retrospective work on 30 patients affected by dento-skeletal III class and Infantile Swallowing (I.S.), treated between 2006 and 2014, is to analyze the causes of eventual surgical relapses and to underline the consequences of untreated Infantile Swallowing. Infantile Swallowing can be correlated with a relapse in the surgical treatment and therefore requires investigation and treatment beforehand any surgical approach. METHODS: Between the 2006 and 2014 a number of 30 patients affected by III dento-skeletal class and I.S. were treated with a pre-surgery protocol, surgery and a post-surgery protocol. The surgical protocol consisted of: Le Fort I and Bilateral Sagittal Split Osteotomy (BSSO). Out of the 30 patients 3 received previous surgical treatment in another locality without going through pre- and post-surgery protocols for I.S., and they presented themselves about 14 months post-surgery to the first examination having a relapse of the dento-skeletal III class. RESULTS: No skeletal relapse has ever been recorded today in the 30 patients treated with pre and post-surgery protocols and Le Fort I and BSSO osteotomy. CONCLUSIONS: Relapses are commonly attributed to surgical errors or inappropriate surgical program only; in our analysis we observed that the 100% of relapses were due to an untreated or undiagnosed I.S. that caused derangement of bicortical screw and incorrect bony formation and consequently a sort of an improper "distraction osteogenesis".

Motor phenotype is not associated with vascular dysfunction in symptomatic Huntington's disease transgenic R6/2 (160 CAG) mice.

Whereas Huntington's disease (HD) is unequivocally a neurological disorder, a critical mass of emerging studies highlights the occurrence of peripheral pathology like cardiovascular defects in both animal models and humans. The overt impairment in cardiac function is normally expected to be associated with peripheral vascular dysfunction, however whether this assumption is reasonable or not in HD is still unknown. In this study we functionally characterized the vascular system in R6/2 mouse model (line 160 CAG), which recapitulates several features of human pathology including cardiac disease. Vascular reactivity in different arterial districts was determined by wire myography in symptomatic R6/2 mice and age-matched wild type (WT) littermates. Disease stage was assessed by using well-validated behavioural tests like rotarod and horizontal ladder task. Surprisingly, no signs of vascular dysfunction were detectable in symptomatic mice and no link with motor phenotype was found.

Prediction of response to growth hormone treatment in pre-pubertal children with growth hormone deficiency.

BACKGROUND: GH therapy response varies substantially among patients. Several models were developed to predict the efficacy of GH therapy in children. AIM: To evaluate the accuracy of a growth prediction model using data from an Italian pediatric GH deficiency (GHD) cohort (GeNeSIS, Growth Prediction Sub-study). METHODS: Open-label, multicenter study in 22 Italian pre-pubertal GH treatment- naïve patients with GHD (8 female, 14 male, 0.5 to 12.2 yr), 18 isolated GHD, 4 multiple pituitary hormone deficiency given recombinat human GH therapy (0.025-0.035 mg/kg/day) for 12 months. Growth prediction was performed, after 3 months of treatment, using baseline data [bone age (BA) and IGF-I], a urinary marker of bone turnover [deoxypyridinoline crosslinks (DPD)] at 4 weeks, and height velocity (HV) at 3 months. Results were expressed as 1st-yr HV using the following equation: 1-yr HV (cm) = 3.543 - (2.337 × BA) - (0.010 × IGF-I) + (0.100 × DPD) + (0.299 × 3-month HV). Predictions were compared to the 1st-yr HV and accuracy was calculated as percentage of the difference between mean calculated HV and the real 1st-yr HV. RESULTS: For females predicted HV was 12.98 ± 4.82 cm/yr and actually was 13.05 ± 3.91 cm/yr after the 1st year; for males predicted HV was 13.95 ± 5.39 cm/yr and actually was 12.93 ± 5.02 cm/yr. CONCLUSIONS: In this paediatric Italian cohort with GHD, a growth prediction model seems to be a valid tool to assess 1st-yr response to GH treatment in Italian children.

GH secretion in a cohort of children with pseudohypoparathyroidism type Ia.

Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by Albright's hereditary osteodistrophy (AHO) and resistance to hormones that act via the alpha subunit of the Gs protein (Gsalpha) protein, ie PTH, TSH, FSH/LH, and, as recently described in limited series, GHRH. However, the current lack of data on GHRH secretion, obesity and short stature included in the AHO phenotype hampers interpretation of GH secretory status and its effects on these subjects. We evaluated GH secretion after GHRH plus arginine (Arg) stimulus, IGF-I levels and anthropometric features in an exclusively pediatric population of 10 PHP-Ia subjects. Of our PHP-Ia children, 5 out of 10 (50%) showed impaired GH responsiveness to the provocative test, with a lower prevalence than the 75-100% previously reported. A negative correlation (p=0.024) was found between GH secretion and body mass index (BMI), whereas no correlation emerged between GH and IGF-I values (p=0.948). Height and growth velocity did not significantly differ between GH-deficient and GH-sufficient subjects. In the 5 GH-deficient patients, GHRH resistance could arguably be responsible for hormonal impairment; however, 3 of them were obese, showing normal stature and IGF-I levels: the increased BMI in these subjects could influence GH secretion and its effects. In conclusion, GH deficiency is frequent among PHP-Ia children and its prevalence is variable, two factors indicating that GH secretory testing should be part of the routine management of this patient group. It could be argued that GHRH resistance is the pathogenetic mechanism in most patients, but further studies on GHRH secretion are needed to define which values can be considered as raised. Lastly, because BMI has been indicated as a major determinant of evoked adult GH response to provocative testing, GH levels related to increased BMI also in childhood could be helpful in defining GH assessment in obese or overweight PHP-Ia children.

Geometry and bone density.

Bone development is a key process in the growing child. It is, therefore, of paramount importance to survey this process, which is characterized by increasing length and size of the bone together with its progressive mineralization. The bone status can be evaluated by different techniques, each of them having its pros and cons. Furthermore, it should be underlined that the results of bone assessment depend not only from the employed technique but also from the auxological characteristics of the subjects. It is, therefore, the aim of this review to examine the characteristics of the various methods of bone evaluation, such as dual energy X-ray absorptiometry (DEXA), peripheral quantitative computed tomography (pQCT), ultrasound and metacarpal index and to explain how changes in bone structure and geometry may influence the results.

[Congenital hypopituitarism in agenesis of the anterior pituitary gland: immediate management and follow-up]. / Ipotuitarismo congenito da agenesia dell'adenoipofisi. Gestione immediata e follow-up.

We report a case of an infant admitted to our division at 50 days of age, who presented acute abdomen, respiratory insufficiency, skeletal abnormalities, craniofacial dismorphism, low gain of weight. Despite negative at neonatal screening for hypothyroidism, laboratory analyses showed marked decrease of all pituitary hormones but ACTH, and low levels of cortisol. Magnetic resonance was indicative of adenohypophysis agenesis with maintained neurohypophysis. Results of substitutive therapy are reported.

Premature thelarche and environmental pollutants.

Premature thelarche is usually considered a benign condition that disappears without influencing statural growth nor the timing of puberty. It is generally held a phenomenon of endogenous origin but exposure to oestrogenic pollutants must also be taken into consideration since environmental and epidemiological studies have shown that humans and some animal species are adversely affected by environmental chemical substances that interfere with the endocrine system and are known as endocrine disrupters. Environmental pollutants acting as endocrine disrupters include oestrogens and oestrogen-like products that are universally present in the form of hormones used in stockbreeding, chemicals employed in industry and agriculture, and substances naturally contained in plants and cereals. So far few studies have examined the influence of exogenous oestrogenic or oestrogen-like substances in premature thelarche, and there have been equally few reports of the occurrence of many cases in a circumscribed environment and a limited period of time. Since many agents are in a position to make a contribution to the biological mechanisms underlying thelarche, there is no easy way of determining the role of a given substance in the onset of the clinical picture. Furthermore, it must not be forgotten that both the metabolic clearance rate and the serum levels of oestradiol in healthy prepubertal children are still uncertain and even very low doses of exogenous steroid hormones might thus have significant biological effects. Aim of the work is to underline the importance of the exposure to oestrogenic environmental pollutants as possible cause of premature thelarche.

Menstrual disorders in adolescence.

Altered frequency of the menstrual cycle accompanied by pain are manifestations of functional anomalies of the female reproductive system. These symptoms require prompt and accurate diagnosis and therapy to prevent a chronic condition that can seriously disturb the adolescent's psychic well being. The most common anomalies of the menstrual cycle and the causes of altered cycle frequency are outlined, as are useful criteria for diagnosing premenstrual syndrome dysmenorrhea and for distinguishing the causes and alterations in frequency and amount of menstrual discharge from other disturbances, including amenorrhea and abnormal uterine bleeding. The treatment of dysmenorrhea and quantitative alterations of the menstrual cycle is the focus of this article.

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.

Incidence and prevalence rate estimation of GH treatment exposure in Piedmont pediatric population in the years 2002-2004: Data from the GH Registry.

OBJECTIVE: The aim of this study is to estimate the annual incidence and prevalence rate of the GH treatment exposure in patients under the age of 18 treated for hypopituitarism or isolated GH deficiency (GHD) in Piedmont, during the period January 1, 2002 to December 31, 2004. METHODS: The selection criteria for recombinant human GH (rhGH) treatment in childhood were approved by the Ministry of Health in Italy in the yr 1998. The present analysis is based on data from the Registry of subjects receiving GH therapy (GH Registry) made up of the 918 pediatric patients (age <18 yr) with a diagnosis of GHD (excluding Prader-Willi and Turner syndromes and other conditions), diagnosed in the period January 1, 2002 - December 31, 2004. The case series has been described as regards the number of cases per year of diagnosis; the prevalence and incidence rates, calculated per 10,000 (per ten thousand) inhabitants, are given for each year of the study period. RESULTS: The prevalence rate increases slightly from 8.62 per thousand in 2002 to 9.44 per thousand in 2004 and the incidence rates estimated were 2.49 per ten thousand, 1.86 per ten thousand and 1.97 per ten thousand in the yr 2002, 2003 and 2004, respectively. CONCLUSION: The Piedmont GH Registry represents the first database available in Italy and could set an example for the other Italian regions as well.

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.

Hyperparathyroidism.

Hyperparathyroidism is a disease characterized by hypercalcemia with hypophosphoremia resulting from increased secretion of parathyroid hormone (PTH). The disease may be divided into 3 forms: a) primary, b) secondary, c) tertiary (secondary refractory form). Primary hyperparathyroidism is rare in children; hyperplasia is more frequent during the early years of life (neonates and infants) and is difficult to distinguish from adenoma in children. The disease may be asymptomatic; elevated calcemia levels (>12 <13.5 mg/dl) are accompanied by anorexia, asthenia and persistent stipsis; severely elevated concentrations (>13.5 mg/dl) are accompanied by nausea, vomiting, polyuria due to osmosis, with dehydration and progressive onset of lethargy, stupor and coma. Osteopenia or osteitis fibrosa cystica may be present due to augmented bone resorption. Height and weight increases are altered due to anorexia and dehydration. Differential diagnosis includes iatrogenic causes of hypercalcemia (excessive vitamin D intake, prolonged immobilization, etc.) and idiopathic familial hypercalcemia. Emergency treatment is required in cases of extremely elevated hypercalcemia (Ca >13.5-14 mg/dl), due to risk of injury to the heart, the central nervous system, the gastrointestinal tract and the kidneys. The 4 cardinal points of treatment are: hydration, calciuresis, inhibition of bone calcium resorption, treatment of the cause underlying hyperparathyroidism. Secondary hyperparathyroidism is found in cases where chronic hypocalcemia is present, particularly in chronic renal failure, untreated deficiency rickets, chronic intestinal malabsorption, hepatobiliary disease, types I and II vitamin D-dependent rickets, tubular acidosis or Fanconi's syndrome. The tertiary form is distinguished by the autonomous nature of the parathyroid glands which have become hypertrophic/hyperplastic due to uncontrollable, chronic severe renal failure. It can also be of iatrogenic origin due to excessive intake of inorganic phosphates in familial hypophosphatemic rickets or chronic vitamin D deficiency.

Characterization of early presentation idiopathic ovarian failure in girls and adolescents.

This study focused retrospectively on a selected cohort of 20 adolescents with early onset premature ovarian failure (POF) and no apparent underlying cause, in order to characterize the idiopathic ovarian failure at pediatric age. This characterization was based on medical history, pedigree analysis, phenotypical and audiological evaluation, final and target heights, pelvic ultrasonography, endocrine assessment, routine hematochemical analyses and complete autoimmune screening. We found that: a) idiopathic POF presented either before or after puberty onset and also with secondary amenorrhea; b) final height prognosis was impaired only in patients with prepubertal presentation of POF; c) ovarian pattern at ultrasonography and endocrine picture were similar those previously reported in patients with adult onset POF; d) clinical history and pedigree analysis, phenotypical and audiological examination and complete autoimmune screening failed to highlight the existence of any possible cause for POF in 15/20 patients; e) no alterations of total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol serum levels were detected in any patient. On the basis of these results we concluded that: a) final height of the adolescents with POF may be impaired only in patients in whom POF presents as a pubertal delay; b) other parameters do not generally differ from those described by previous reports on young adults with POF, except for serum lipid levels which were normal in the present cohort.

Final height in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the Italian experience.

OBJECTIVE: To investigate the influence of target height (TH), gender, phenotype, glucocorticoid formulation and age at onset of treatment on final height (FH) in patients with 21-hydroxylase deficiency (21OHD). PATIENTS: Clinical data of 93 patients--46 simple virilizing (SV), 35 salt-wasting (SW) and 12 late onset (LO)--were collected in six pediatric endocrinology units in Italy. RESULTS: FH and TH were always below the mean height of the general population (mean FH, SDS: SW patients -1.3 +/- 1.2, SV patients -1.8 +/- 0.9, LO patients -1.7 +/- 1.1; mean TH, SDS: SW patients -0.6 +/- 0.8, SV patients -0.7 +/- 0.9, LO patients -1.4 +/- 1.3). FH was significantly below TH in patients with classic form (SW and SV, p <0.001), but not in LO patients. In classic form, TH seems to be related to FH, followed by age at onset of therapy and by steroid formulation, these variables explaining 30% of FH variance. CONCLUSIONS: In the classic form, substitutive therapy started before 21 months of age improved the long-term outcome. Lower TH in LO patients could be due to undiagnosed non-classic 21OHD in some of their parents. FH in LO patients seems not to benefit from corticosteroid therapy, even if late diagnosis may partly account for this result.

Pubertal development in patients with McCune-Albright syndrome or pseudohypoparathyroidism.

Gain or loss of function mutations of the GNAS1 gene lead to McCune-Albright syndrome (MAS) or pseudohypoparathyroidism Ia (PHP-Ia), respectively. Patients with MAS, caused by a post-zygotic missense mutation leading to constitutive activation of Gs alpha, suffer from gonadotropin-independent precocious puberty, and delayed or incomplete sexual development and reproductive dysfunction is found in women with PHP-Ia, an inherited disorder caused by deficient expression or function of the Gs alpha protein. In females with MAS, 50% developed precocious puberty by the age of 4 years, the remaining between 4 and 8 years. Peripheral precocious puberty is often atypical and characterized by alternate periods of rapid progression and regression of pubertal development; menstrual bleeding may occur before breast development. Ovarian cyst growth and regression is often described as a sign of ovarian follicle hyperactivation. Notwithstanding this clinical heterogeneity, a subset of patients with MAS develop relentlessly progressive precocious puberty ultimately resulting in premature epiphyseal fusion and reduced adult stature. Long-term information on reproductive function has been obtained in females: some patients had regular menses without ovarian cysts on pelvic US scan, whereas others were oligomenorrheic and showed recurrent ovarian cysts. In males with MAS, precocious puberty occurred in three patients between 4 and 9 years of age. In one patient, long-term follow-up demonstrated normal plasma testosterone and gonadotropin values at the age of 17 years. On testicular sonography, multiple hyperechogeneic spots were found in both testicles (snow-storm appearance). Female patients with PHP-Ia were oligomenorrheic or amenorrheic; more than half had delayed or incomplete sexual development, They were mildly hypoestrogenic with normal to slightly elevated serum gonadotropin levels. These clinical and biochemical findings indicate partial resistance of the theca and granulosa cells of the ovary to gonadotropins due to deficient Gs alpha activity. Responsiveness might be sufficient to promote some degree of follicular development and steroid secretion, but insufficient to induce ovulation