Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.

BACKGROUND: Genetic and epigenetic alterations in the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP) type Ia/c and Ib, respectively. For these heterogeneous diseases characterized by multiple hormone resistances and Albright's Hereditary Osteodystrophy (AHO) the current classification results inadequate because of the clinical overlap between molecular subtypes and a standard clinical approach is still missing. In the present paper several members of the Study Group Endocrine diseases due to altered function of Gsα protein of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) have reviewed and updated the clinical-molecular data of the largest case series of (epi)/genetically characterized AHO/PHP patients; they then produced a common healthcare pathway for patients with these disorders. METHODS: The molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up were collected using two different cards. RESULTS: In patients with genetic mutations the growth impairment worsen during the time, while obesity prevalence decreases; subcutaneous ossifications seem specific for this group. Brachydactyly has been detected in half of the subjects with epigenetic alterations, in which the disease overts later in life, often with symptomatic hypocalcaemia, and also early TSH and GHRH resistances have been recorded. CONCLUSIONS: A dedicated healthcare pathway addressing all these aspects in a systematic way would improve the clinical management, allowing an earlier recognition of some PHP features, the optimization of their medical treatment and a better clinical-oriented molecular analysis. Furthermore, standardized follow-up data would provide new insight into less known aspects.

Laparoscopic versus open appendectomy in the management of acute appendicitis in children: a multicenter retrospective study.

AIM: Acute appendicitis is one of the most common indications for emergency surgery in children. Open appendectomy (OA) has been the gold standard treatment for over 100 years. In the last three decades, the introduction of minimally invasive techniques, such as laparoscopic appendectomy (LA) and transumbilical laparoscopically assisted appendectomy (TULAA), has changed the approach to the disease. However, there is still no agreement with benefits of these new therapeutic options, especially in children. The aim of this retrospective study is comparing the outcomes of OA, LA and TULAA in the paediatric patient. METHODS: Children suffering from acute appendicitis were treated with LA or TULAA in the Department of Paediatric Surgery and with OA in the Department of General Surgery. Data were abstracted from database of both centers' archives. Operator, operating time, length of hospitalization (LOH), intra- and postoperative complications and histological finding were analyzed. RESULTS: We recruited 196 patients: 46 treated with LA, 62 with TULAA and 88 with OA. Operative time was significantly shorter in OA. The three techniques had the same incidence of intraoperative and postoperative complications. The incidence of wound infection was higher with the TULAA approach. LOH was significantly shorter in the TULAA group. There was no correlation between LOH and histological finding. CONCLUSION: We demonstrated that LA, TULAA and OA are similar in most respects and are equally safe modalities in paediatric patients. Further randomized controlled studies are necessary.

Trichobezoars in children: therapeutic complications.

Trichobezoars are concretions formed by the accumulation of hair or fibers in the gastrointestinal tract, usually associated with underlying psychiatric disorders in females between 13 and 20 years old. Endoscopy, the gold standard for diagnosis, brings some additional advantages: sample taking, size reducing and, rarely, mass removal. This study shows that endoscopy can cause severe complications resulting in a surgical emergency.

Transumbilical laparoscopic treatment of Congenital Infantile Fibrosarcoma of the Ileum.

Congenital-Infantile Fibrosarcoma (CIF) is a malignant mesenchymal tumor representing 10-20% of soft-tissue tumors. Complete surgical resection is generally the treatment of choice. The most recurrent cytogenetic abnormality was identified as the traslocation t(12;15)(p13:q25), which bears the fusion of Tel gene EVT6 with TrkC gene. This study describes a case of infantile fibrosarcoma of the ileum in a female newborn examined for intestinal occlusion and its laparoscopic treatment.

Conservative management of accessory spleen torsion in children.

Accessory spleen torsion is very rare condition especially in children. The aim of this study is to report the conservative treatment option. In April 2009 we observed a 10-year-old child affected by hereditary spherocytosis who reported acute abdominal pain without fever or vomiting. At hospitalization all blood tests were within normal value. Abdominal ultrasounds showed an increase in spleen volume and a solid round-shaped hypoechogenic formation with hyperechogenic areas in the lower pole without vascolarisation on color-Doppler scan. These findings suggested torsion of the accessory spleen. We opted for a conservative approach: analgesics on demand and antibiotics. After a week symptoms resolved spontaneously and patient was discharged in good health conditions. Follow-up ultrasound scans were performed at one week, three-six months and one year after hospitalization and showed a progressive reduction of the dimensions of the solid round-shaped formation. Accessory spleen torsion needs to be added to the differential diagnosis of cases of acute abdomen in children. Ultrasounds with eco-color-Doppler scans seem to be the best option for the diagnosis of such condition in the pediatric age since other diagnostic methods are more invasive and require sedation of patients. Once accessory spleen torsion is correctly diagnosed it is possible to opt for its conservative treatment.

Responses to GHRH plus arginine test are more concordant with IGF-I circulating levels than responses to arginine and clonidine provocative tests.

BACKGROUND/OBJECTIVE: Although pharmacological GH stimulation tests are still considered the gold standard for GH deficiency (GHD) diagnosis, they are burdened by poor specificity. The majority of children diagnosed as having GHD show normal GH responses when re-tested at the end of growth, thus questioning the initial diagnosis. We evaluated the concordance between IGF-I levels and GH responses to provocative tests. METHODS: We analyzed 105 GHRH plus arginine tests, 79 arginine tests, and 124 clonidine tests performed in 192 short children. IGF-I levels ≤-2SD score (SDS) were considered suggestive for high likelihood of GHD. The percentage of positive and negative results for each test was determined and compared with IGF-I levels, clinical follow-up and response to therapy. RESULTS: In children with IGF-I>-2SDS the arginine test showed a concordance rate of 6.9%, the clonidine test of 28.6%, and GHRH plus arginine test of 70%. In children with IGF-I≤-2SDS the concordance was 96.1%, 85.7%, and 46.4%, respectively. The overall concordance was 66.7% for GHRH plus arginine, 42.7% for clonidine, and 27.8% for arginine tests. CONCLUSION: Our results suggest that GHRH plus arginine test provides the best concordance with the assessment of IGF-I levels thus suggesting that the combination of the two procedures may significantly reduce the need of a second provocative test.

Retinol-binding protein 4 in neonates born small for gestational age.

BACKGROUND: Retinol-binding protein 4 (RBP4) is an adipocyte-derived 'signal' that may contribute to the pathogenesis of insulin resistance and Type 2 diabetes. The relationship of RBP4 with insulin resistance and metabolic risk in human beings has been the subject of several studies. Subjects born small for gestational age (SGA) are at risk of insulin resistance and Type 2 diabetes. Though RBP4 could represent an early marker of insulin resistance, to date, none have determined RBP4 in SGA children. AIM: Our aim was to measure RBP4 concentrations in cord blood of SGA newborns compared with those in children born with a birth weight appropriate for gestational age (AGA) and to determine whether serum RBP4 levels at birth correlate with insulin sensitivity markers. SUBJECTS AND METHODS: Sixty-four newborns, 17 born SGA (mean gestational age: 36.4+/-2.1 weeks), and 47 born AGA (mean gestational age: 37.0+/-3.6 weeks) were studied. The main outcome measures included anthropometry, lipid profile, insulin, homeostasis model assessment, quantitative insulin-sensitivity check index, adiponectin, and RBP4. RESULTS: RBP4 concentrations were significantly reduced in SGA newborns (p<0.002). No relationship was found between RBP4 and insulin sensitivity parameters. Stepwise regression analysis revealed that birth weight was the major predictor of RBP4 serum concentrations (p<0.001). CONCLUSION: RBP4 is reduced in SGA newborns, birth weight representing the major determinant of RBP4 concentrations, and is not related to insulin sensitivity. No significant difference in adiponectin levels and insulin sensitivity markers was found between SGA and AGA neonates.

Catch-up growth in body mass index is associated neither with reduced insulin sensitivity nor with altered lipid profile in children born small for gestational age.

OBJECTIVE: Low birth weight is a risk factor for coronary heart disease. Persons who have coronary events as adults tend to have been small at birth and thin at 2 yr of age, after which they tended to increase their body mass index (BMI). Our aim was to determine whether BMI gain is associated to alterations in insulin sensitivity and/or lipid profile in children born small for gestational age (SGA). DESIGN: Retrospective case-control study. METHODS: We studied 78 children (mean age 7.8+/-2.5 yr): 26 SGA children with catch-up growth in BMI (CGB-SGA) (BMI= 10th to 75th centile), 26 SGA without catch-up growth (NCGB-SGA) (BMI<10th centile), and 26 appropriate for gestational age (AGA) control children (BMI: 10th to 75th centile). For each CGB-SGA child, we selected an NCGB-SGA and an AGA child of the same gender, age (within 1 yr), and pubertal status. SGA children were also subdivided into 2 groups according to post-natal catch-up growth in height (CGH). RESULTS: Glucose was significantly lower in NCGBSGA than AGA group (p=0.02). No significant differences in fasting insulin, fasting glucose/insulin ratio, homeostasis model assessment, quantitative insulin-sensitivity check index, and lipid profile were found among the 3 groups. HDL-cholesterol proved significantly reduced in SGA children with post-natal CGH (p=0.02). CONCLUSIONS: Our findings do not support the hypothesis of early alterations in insulin sensitivity and lipid metabolism in CGB-SGA subjects during childhood provided that BMI remains within the normal range. Finally, the finding of reduced HDL-cholesterol levels in CGH-SGA children suggests detrimental metabolic effects of the height gain.

Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children.

BACKGROUND: Recent studies have linked raised levels of IGF-I and/or reduced levels of its main binding protein, IGF binding protein (IGFBP)-3, with the risk of developing cancer. A GH dose-dependent increase in IGF-I/IGFBP-3 molar ratio has been reported in subjects treated with GH, raising concern about the long-term safety. OBJECTIVE: The aim of this study was to evaluate changes in serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio over the first 12 months of replacement GH therapy in GH deficient (GHD) children. METHODS: The study included 20 GHD children who had not previously received GH treatment, and 40 untreated non-GHD short children closely matched for age, gender, pubertal stage, and body mass index (BMI), as controls. Serum IGF-I, IGFBP-3 levels were measured before and after 12 months of GH treatment. Based on the molecular weight of IGF-I (7500) and IGFBP- 3 (40,000, mean of glycosylated variants), we calculated the molar ratio of IGF-I/IGFBP-3. RESULTS: IGF-I/IGFBP-3 molar ratio significantly increased during GH therapy (p=0.01). No significant difference in IGF-I/IGFBP-3 ratio was found between GHD children and controls at the different time points. In the multiple regression analysis, BMI (beta=0.33) and age (beta=0.33) proved to be the major predictors of the IGF-I/IGFBP-3 molar ratio (adjusted r2=0.53, p<0.0001). CONCLUSIONS: Our results suggest that at a conventional replacement dose GH does not alter the IGF-I/IGFBP-3 molar ratio. Potential fears related to long-term cancer risk are likely to be greatest in patients exposed to high-dose GH therapy and with genetic predisposition to high IGF-I and/or low IGFBP-3 concentrations.

Insulin resistance and insulin-like growth factors in children with intrauterine growth retardation. Is catch-up growth a risk factor?

AIMS: To investigate (a) the prevalence of insulin resistance in children with intrauterine growth retardation (IUGR); (b) whether catch-up growth is associated with a higher risk of insulin resistance; (c) the insulin-like growth factor (IGF) system status. METHODS: 49 children with IUGR aged 9.1 +/- 3.3 years underwent anthropometric measurements, and assessment of insulin resistance and IGF system parameters. A fasting glucose/insulin ratio (G/I) <6 was chosen as suggestive of insulin resistance. RESULTS: 11/49 (22%) children had a G/I <6. Postnatal growth closely correlated with birth size and actual body mass index (BMI). None of the insulin resistance parameters was related to linear growth and BMI. Liver function markers were significantly related to insulin sensitivity status. The IGF system status was normal and did not correlate with insulin resistance indicators. CONCLUSIONS: (a) Children with IUGR have a high prevalence of reduced insulin sensitivity; (b) postnatal catch-up growth is related to intrauterine growth and actual nutritional status; (c) insulin sensitivity status is not related to postnatal growth but to liver function; (d) IGF system is normal and not related to the insulin resistance parameters during childhood.

Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome.

Pallister-Hall syndrome is a disorder of development consisting of hypothalamic hamartoma, pituitary dysfunction, central polydactyly and visceral malformations. This disorder is inherited as an autosomal dominant trait and is caused by mutations of the GLI3 gene encoding a zinc finger transcription factor. We describe a case of Pallister-Hall syndrome with growth hormone neurosecretory dysfunction, successfully treated with growth hormone until attainment of final height. We conclude that children with Pallister-Hall syndrome and short stature be evaluated carefully for spontaneous somatotropic function and, if necessary, treated with growth hormone.

Spontaneous pneumomediastinum with subcutaneous emphysema: unusual presenting feature of a common condition.

Pneumomediastinum refers to the presence of free air in the mediastinum and is frequently associated with subcutaneous emphysema. It is known that a number of medical and surgical conditions may be complicated by pneumomediastinum. However, here we report the case of a young female in whom pneumomediastinum was the presenting feature of a widespread medical condition rather than its complication.

[Dyggve-Melchior-Clausen syndrome: description of 2 further cases]. / La sindrome di Dyggve-Melchior-Clausen: descrizione di due nuovi casi clinici.

In this paper we describe the clinical and radiographic features of a spondylo-epi-methaphyseal dysplasia. Dyggve-Melchior-Clausen syndrome. In these two new cases, without severe mental retardation, we have highlighted the clinical and radiological findings, progression of the skeletal changes that have allowed us to make a diagnosis.

Growth hormone and dysmorphic syndromes.

In order to study the pathogenesis of short stature in some of the best known and most frequent dysmorphic syndromes, we have reviewed the most significant studies conducted on somatrotropin secretion and on response to replacement treatment with human growth hormone in pediatric patients. In particular, the study examines the results presented in the literature, and in a few of our cases, those obtained with regard to Noonan, Silver-Russell and Prader-Willi syndrome patients, to achondroplasia and hypochondroplasia patients, and to Down syndrome patients. Finally, we shall present a review of a few, less frequent dysmorphic syndromes with short stature, in which a growth hormone deficiency has been diagnosed and replacement treatment attempted.

Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions.

We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The phenotypic manifestations of the observed patients were consistent with velo-cardio-facial syndrome (VCFS). A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome. The presence of certain traits of DGS/VCFS should lead to investigations of the parathyroid function and molecular analysis of the 22q11 region hybridization studies.

Short stature as the primary manifestation of monosymptomatic celiac disease.

It is generally accepted that celiac disease (CD) must always be taken into consideration when dealing with children manifesting growth failure. It is therefore important to have laboratory tests capable of detecting patients who should undergo intestinal biopsy. Auxological and endocrine parameters, bone age, some nutritional indices (hemoglobin, serum iron, calcium, total protein, and albumin), and anti-gliadin antibodies (AGA) IgA and IgG and 1-h blood xylose levels were evaluated in 49 children of short stature. On the basis of the intestinal biopsy, 29 (59.1%) patients affected by CD were found. When patients with atrophic and normal intestinal mucosa were compared, significant differences in the frequency of pathological values of hemoglobinemia, serum iron, AGA, and 1-h blood xylose levels were found, whereas no difference was observed in the levels of serum calcium, total protein, and albumin. Bone age was delayed in 81% of the celiac patients and in 47% of the controls. In particular, AGAs were found in 27 of 29 celiac patients and in three control subjects who showed a low level of one of the two antibodies. The results of our study demonstrate that AGA (IgA and IgG), together with 1-h blood xylose, hemoglobinemia, serum iron, and family history of CD determination, are extremely useful for screening patients of short stature. This type of screening cannot, however, replace the intestinal biopsy because such tests cannot be completely sensitive and specific.

Enzyme polymorphism and clinical variability of diseases: study of acid phosphatase locus 1 (ACP1) in obese subjects.

The ACP1*A allele of erythrocyte acid phosphatase (ACP1) has a lower enzymatic activity when compared to other ACP1 alleles and is associated with maximal rate of body growth during intrauterine life. In three different samples of obese subjects (total number = 218). ACP1*A was associated with extreme body mass deviations. No difference in ACP1 allele distribution was observed between obese and nonobese subjects. These data suggest that a genetically determined variability of ACP1 influences the degree of obesity, but only when obesity itself has been triggered by some other factors.

[Treatment of somatotropic deficiency with biosynthetic growth hormone]. / Trattamento dell'insufficienza somatotropinica con ormone della crescita biosintetico.

A total of 21 patients with somatotropic deficiency have been enrolled in a clinical trial of biosynthetic growth hormone (bio-GH) and pituitary growth hormone (pit-GH). Five of them not previously treated (naïve) and 7 previously treated with pit-GH, received bio-GH; 9 received only pit-GH. Biosynthetic-GH was given 12 UI/m2/week. Height velocities during treatment rose, for naïve patients, from 3.6 +/- 0.3 cm/year (before treatment) to 8.7 +/- 1.3 cm/year (after 12 months treatment). For previously treated patients, after a period at least 6 months without any GH therapy, the increase in height was from 2.5 +/- 0.9 cm/year to 6.8 cm/year; and for the patients who received only pit-GH was from 3.4 +/- 1.2 cm/year to 8.0 +/- 1.1 cm/year. No significant difference was observed between the growth velocities obtained with the two preparations. No specific side-effects were noted.