Sexual Developmental Disorders in Pediatrics.

Abstract: Disorders of sex development (DSD) are a heterogeneous group of pathologies that result in an alteration in sex determination or differentiation. DSD are estimated to affect 1: 4,500 newborns and according to the 2006 Chicago Consensus classification, DSD can be divided into three categories: those with a 46 XX karyotype, those with a 46 XY karyotype and those relating to sex chromosomes. It is crucial to correctly identify the pathology already in the first days of life to direct the patient and his family to the best path of care. For this reason, the role of the pediatrician is fundamental in the correct identification of the clinical picture and in supporting the family during the long process that involves the management of these patients. To make a diagnosis, it is necessary to follow a path led by a multidisciplinary team that includes several steps such as the execution of the genetic analysis, the evaluation with diagnostic imaging methods and laboratory evaluations. The therapeutic management, on the other hand, is still very complex even if in recent years we have moved from an attitude of early gender reassignment to an approach of watchful waiting to let the patient choose when she/he is mature enough to do so, which gender she/he feels to belong. It should not be forgotten that throughout this process the pediatrician must be both supportive and clinically active in the management of the child and his family.

From mini-puberty to pre-puberty: early impairment of the hypothalamus-pituitary-gonadal axis with normal testicular function in children with non-mosaic Klinefelter syndrome.

PURPOSE: Klinefelter syndrome (KS) is a genetic disorder caused by the presence of an extra X chromosome in males. The aim of this study was to evaluate the hypothalamic-pituitary-gonadal (HPG) axis and the clinical profile of KS boys from mini-puberty to early childhood. PATIENTS AND METHODS: In this retrospective, cross-sectional, population study, 145 KS boys and 97 controls aged 0-11.9 years were recruited. Serum FSH, LH, testosterone (T), Inhibin B (INHB), sex hormone binding globulin (SHBG) and anti-Müllerian hormone (AMH) were determined. Auxological parameters were assessed. To better represent the hormonal and clinical changes that appear in childhood, the entire population was divided into 3 groups: ≤ 6 months (group 1; mini-puberty); > 6 months and ≤ 8 years (group 2; early childhood); > 8 and ≤ 12 years (group 3; mid childhood). RESULTS: During mini-puberty (group 1), FSH and LH were significantly higher in KS infants than controls (p < 0.05), as were INHB and T (respectively p < 0.0001 and p < 0.005). INHB was also significantly higher in KS than controls in group 2 (p < 0.05). AMH appeared higher in KS than in controls in all groups, but the difference was only statistically significant in group 2 (p < 0.05). No significant differences were found in height, weight, testicular volume, and penile length. CONCLUSIONS: No hormonal signs of tubular or interstitial damage were found in KS infants. The presence of higher levels of gonadotropins, INHB and testosterone during mini-puberty and pre-puberty may be interpreted as an alteration of the HPG axis in KS infants.

Fetal growth patterns in Beckwith-Wiedemann syndrome.

We provide data on fetal growth pattern on the molecular subtypes of Beckwith-Wiedemann syndrome (BWS): IC1 gain of methylation (IC1-GoM), IC2 loss of methylation (IC2-LoM), 11p15.5 paternal uniparental disomy (UPD), and CDKN1C mutation. In this observational study, gestational ages and neonatal growth parameters of 247 BWS patients were compared by calculating gestational age-corrected standard deviation scores (SDS) and proportionality indexes to search for differences among IC1-GoM (n = 21), UPD (n = 87), IC2-LoM (n = 147), and CDKN1C mutation (n = 11) patients. In IC1-GoM subgroup, weight and length are higher than in other subgroups. Body proportionality indexes display the following pattern: highest in IC1-GoM patients, lowest in IC2-LoM/CDKN1C patients, intermediate in UPD ones. Prematurity was significantly more prevalent in the CDKN1C (64%) and IC2-LoM subgroups (37%). Fetal growth patterns are different in the four molecular subtypes of BWS and remarkably consistent with altered gene expression primed by the respective molecular mechanisms. IC1-GoM cases show extreme macrosomia and severe disproportion between weight and length excess. In IC2-LoM/CDKN1C patients, macrosomia is less common and associated with more proportionate weight/length ratios with excess of preterm birth. UPD patients show growth patterns closer to those of IC2-LoM, but manifest a body mass disproportion rather similar to that seen in IC1-GoM cases.

Reference ranges for thyroid hormones in normal Italian children and adolescents and overweight adolescents.

BACKGROUND: As thyroid hormones are essential for normal pubertal growth and sexual development, TSH, free T3 (FT3) and free T4 (FT4) levels undergo progressive modification during childhood and puberty. AIM: To establish thyroid hormone reference ranges in pre-pubertal children, pubertal adolescents, and adults and to evaluate any differences in thyroid function between overweight and normalweight pubertal subjects. SUBJECTS AND METHODS: Chemiluminescent microparticle immunoassay was used to analyze TSH, FT3 and FT4 concentrations in serum samples from 508 children and adolescents aged 6 to 18 yr and 100 healthy adults aged 30 to 60 yr, and from 68 overweight pubertal adolescents. As data were not normally distributed, we compared them through non-parametric tests for independent samples and the reference ranges were assumed to lie between the 2.5th and 97.5th percentile. RESULTS: We found a progressive and significant reduction in TSH, FT3, and FT4 levels in the three groups with increasing age. TSH levels were significantly higher in overweight patients than in the normal-weight group, but there were no significant differences for FT3 or FT4. CONCLUSIONS: This study revealed significant differences in levels of thyroid hormone between different age groups and allowed us to establish normal reference ranges for pre-pubertal children between 0.87-5.19 mIU/l for TSH, 4.75-8.59 pmol/l for FT3, and 13.09-20.61 pmol/l for FT4, and for pubertal adolescents between 0.76- 4.51 mIU/l for TSH, 4.26-8.46 pmol/l for FT3 and 10.94-19.09 pmol/l for FT4.

A survey of Italian and Spanish neonatologists and paediatricians regarding awareness of the diagnosis of FAS and FASD and maternal ethanol use during pregnancy.

BACKGROUND: Ethanol is the most widely used drug in the world and a human teratogen whose consumption among women of childbearing age has been steadily increasing. There are no Italian or Spanish statistics on ethanol consumption during pregnancy nor any information regarding prevalence of fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD). There is also a reasonable suspicion that these two diseases are underdiagnosed by professionals from the above-reported countries. The objectives of this study were: 1) to evaluate the experience, knowledge and confidence of Italian and Spanish neonatologists and paediatricians with respect to the diagnosis of FAS and FASD, and 2) to evaluate professionals awareness of maternal drinking patterns during pregnancy. METHODS: A multiple-choice anonymous questionnaire was e-mailed to Italian neonatologists registered in the mailing list of the corresponding Society and administered to Italian and Spanish paediatricians during their National Congress. RESULTS: The response rate was 16% (63/400) for the Italian neonatologists of the National Society while a total of 152 Spanish and 41 Italian paediatricians agreed to complete the questionnaire during National Congress. Over 90% of the surveyed physicians declared that FAS is an identifiable syndrome and over 60% of them identified at least one of the most important features of FAS. Although over 60% Italian responders and around 80% Spanish responders were aware that ethanol use in pregnancy is dangerous, approximately 50% Italian responders and 40% Spanish ones allowed women to drink sometimes a glass of wine or beer during pregnancy.Neonatologists and paediatricians rated confidence in the ability to diagnosis FAS and FASD as low, with over 50% responders feeling they needed more information regarding FAS and FASD identification in newborn and child. CONCLUSIONS: Italian and Spanish neonatologists and paediatricians do not feel confident about diagnosing FAS and FASD. More training is needed in order to accurately diagnose ethanol use during pregnancy and correctly inform pregnant women on the consequences on the newborn.

Precocious puberty in two girls with Chiari I malformation: a contribution to a larger use of brain MRI in the diagnosis of central precocious puberty.

Up to now Chiari malformation has been reported only in four subjects with precocious puberty, with a prevalence among boys. This article describes the case of two female children affected by progressive precocious puberty detected through brain magnetic resonance imaging (MRI). Brain imaging, even without neurological signs, can identify patients at risk of developing subsequently severe neurological symptoms. Our observation supports the usefulness of brain MRI both in males and females, even when no symptoms are present, to identify and detect high risk cases. However, there is no consensus in Literature in performing MRI in all the patients of both sexes with central precocious puberty, due to its high costs.

Posaconazole for treatment of refractory invasive fungal disease.

Invasive fungal infections are usually associated with immunocompromised states About 40-60% of these patients are refractory to standard antifungal therapy We describe the effect of posaconazole in the treatment of a 12 years-old girl with uncontrolled diabetes mellitus with life-threatening cerebral mucor mycosis and a 4 year old girl boy with chronic granulomatous disease presenting with invasive Aspergillus nidulans infection.

Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group.

The main clinical feature of Turner syndrome (TS) is growth failure, with a mean spontaneous adult height ranging between 136 and 147 cm, according to the specific curves of various populations. Though a classical deficiency of GH has not been generally demonstrated, GH has been administered since 1980 in trials, using replacement doses just initially, with a subsequent trend to increase it. We report the outcome of GH therapy given at the fixed dose of 0.33 mg/kg/week in 60 TS girls observed until adult height; 59 untreated TS girls, matched for auxological, karyotypical characteristics and time of observation, born within the same decade served as controls to evaluate GH efficacy. The calculation of the gain in cm over PAH was performed on specific Italian Turner curves, as well as height evaluation as SD score and growth velocity. The same calculations were made using Lyon references and Tanner standards. The mean CA at the beginning of GH treatment was 10.9 +/- 2.76 yr (range 4.5-15.9). Mean adult height of treated group was 151 +/- 6.1 cm with a gain over the PAH calculated at start of therapy (142.9 +/- 5.3 cm) of 8.2 +/- 3.9 cm. Ns change was observed between the PAH at first observation (143.6 +/- 7.0 cm) and adult height (144.3 +/- 5.6 cm) in the control group. Treatment was well tolerated, no relevant side effects were observed, glucose metabolism resulted no more affected than in untreated subjects, IGF-I levels remained within 2 SD. Our results in 60 TS girls, though the dose remained unchanged throughout the treatment, show a good response, characterized by a striking variability in each patient (mean gain in cm over PAH at adult height of 8.17 +/- 3.9, range 3-21 cm), and significant also in comparison with the control group. As the chronological age at start of therapy ranged between 4.5 to 15.9 yr, the results were further evaluated dividing the patients into two groups, according to the age, < or >11 yr. Thirty girls were <11 yr (mean 8.7 +/- 1.76 yr) and 30 were >11 yr (mean 13.2 +/- 1.4 yr). The gain in cm over the PAH in each group was, respectively, 8.1 +/- 3.4 and 8.2 +/- 4.3 cm without any significant difference between the two groups, showing no negative correlation between the CA at the beginning of GH and the response to treatment.

Absence of association between a variant of the mast cell chymase gene and atopic dermatitis in an Italian population.

Atopic dermatitis (AD) is a chronic dermatitis which belongs to the group of atopy-related diseases together with asthma and rhinitis. IgE and mast cell chymase (MCC) play a key role in atopic or allergic inflammation of the skin. An association between AD and a genetic variant of the MCC has been reported in a Japanese population, but failure of confirmation has rendered this association questionable. We have tested for genetic association to an MCC variant in relation to AD in an Italian population. No significant association was found between AD and MCC genotypes. These data suggest that BstXI MCC polymorphism may not be involved in AD.

A major susceptibility locus for atopic dermatitis maps to chromosome 3q21.

Atopic dermatitis (eczema) is a chronic inflammatory skin disease with onset mainly in early childhood It is commonly the initial clinical manifestation of allergic disease, often preceding the onset of respiratory allergies. Along with asthma and allergic rhinitis, atopic dermatitis is an important manifestation of atopy that is characterized by the formation of allergy antibodies (IgE) to environmental allergens. In the developed countries, the prevalence of atopic dermatitis is approximately 15%, with a steady increase over the past decades. Genetic and environmental factors interact to determine disease susceptibility and expression, and twin studies indicate that the genetic contribution is substantial. To identify susceptibility loci for atopic dermatitis, we ascertained 199 families with at least two affected siblings based on established diagnostic criteria. A genome-wide linkage study revealed highly significant evidence for linkage on chromosome 3q21 (Zall=4.31, P= 8.42 10(-6)). Moreover, this locus provided significant evidence for linkage of allergic sensitization under the assumption of paternal imprinting (hlod=3.71,alpha=44%), further supporting the presence of an atopy gene in this region. Our findings indicate that distinct genetic factors contribute to susceptibility to atopic dermatitis and that the study of this disease opens new avenues to dissect the genetics of atopy.

Pregnancy in patients with Turner's syndrome: six new cases and review of literature.

Pregnancy in women with Turner's syndrome (TS) is an exceptional event, but is possible in 2% of cases. It can occur in patients with structural anomalies of the X chromosomes in which the Xq13-q26 region, containing the genes that are thought to control ovarian function, is spared; or in patients with a mosaic karyotype containing an 46,XX cell line, which preserves ovarian function. In our Centre we observed six cases of women with Turner's syndrome conceiving. Out of 13 pregnancies, there were six abortions and eight live-births; among the latter, four babies exhibited malformations. Reviewing the literature shows that out of 160 pregnancies which occurred in 74 women with TS, 29% ended in spontaneous abortion, 7% led to the perinatal death of the fetus, 20% gave birth to malformed babies (TS, Down's syndrome, etc.) and only in 38% of cases were healthy children born. This study suggests that the rare TS patients who are able to procreate should undergo prenatal diagnosis techniques. In sterile TS patients the use of artificial fertilization techniques is a possible solution.

"Sex passport" obligation for female athletes. Consideration and criticisms on 364 subjects.

In Ancient Greece determination of sex was made by direct observation of the all-male athletes participating in the Olympic Games. In 1966 the International Olympic Committee (I.O.C.) established that female athletes must submit to a complete physical examination before each international competition. In 1968 they further established that each female participant be granted a "Sex Passport" based upon the findings of a medical and gynaecological examination as well as chromosomal sex determination. The authors, whose department has been responsible for granting Sex Passports for more than 20 years, examined 364 female athletes aged 16 to 29 years using I.O.C. criteria. They found three chromatic-negative cases (0.8%). The present work indicates several scientific shortcomings of the current I.O.C. examination criteria, illustrates three chromatin-negative cases, their consequences and proposed a return to original criteria for examination except in doubtful cases.

Trisomy 9 mosaicism syndrome. A case report and review of the literature.

The authors report on a case of trisomy 9 mosaicism syndrome, a rare chromosome abnormality. The common features of this syndrome are growth and mental retardation, low-set malformed ears, wide sutures and fontanelles, bulbous nose, short palpebral fissures, micrognathia, microphthalmia and enophthalmos, abnormal hands and feet, hip dislocation, joint limitation, cardiovascular defects and urogenital abnormalities. Our patient presented some unusual characteristics, such as 13 pairs of ribs, a vertebral malformation, a hemivertebra and a Dandy-Walker syndrome. They compare their clinical findings with the few cases previously described and they try to contribute to the further clinical definition of the syndrome. It is possible that there is a correlation between the variability of the phenotype and the percentage of trisomic cells in the patient.

[The usefulness of the skeleton in the diagnosis of malformation]. / Utilità dello scheletro nella diagnosi di malformazione.

Most malformation syndromes (70%) show evidence of skeletal anomalies, mainly in the vertebral bodies and in the bony segments of the limbs. This explains the importance of studying the skeleton when faced with any multi-malformation syndrome, using techniques like CT, MRI, echography and densitometry as well as standard radiology. To increase the quantity of information available for diagnostic purposes it would be profitable to create a data bank containing all the possible radiological findings encountered in the numerous multi-malformation syndromes.

The hepatic malignant mesenchymoma: a case report.

We report a case of hepatic mesenchymoma in an 8-year-old girl who presented with abdominal pain and ultrasonographic diagnosis of hepatic echinococcosis. Due to the good general condition of the patient and the diagnostic confirmation of liver hydatid disease by the CT scan, antiparasitic therapy with albendazole was started. After 1 month of therapy the girl's general condition worsened as did the ultrasonographic picture. On laparatomy a large cystic mass was observed within the right hepatic lobe and was removed. Pathological examination of the mass excluded an echinococcal cyst and demonstrated a malignant hepatic mesenchymoma.

[A clinical and cytogenetic study of 50 women with Turner's syndrome. Considerations of the problem of pregnancies in these patients. Part 2]. / Studio clinico e citogenetico di 50 donne con sindrome di Turner. Considerazioni sul problema delle gravidanze in queste pazienti. Seconda comunicazione.

The results of a study on 50 patients with Turner syndrome, all of them older than 14 years and never treated, are reported. In order to correlate karyotypes and clinical manifestations of the syndrome, we performed a complete physical examination and ultra sonographic tests of the heart, kidneys, uterus and ovaries. We found a better spontaneous growth and sexual maturation in mosaic 45.X/46.XX patients than in patients with 45.X and X structural anomalies. No differences were found in heart and kidney congenital anomalies between groups of patients with different karyotypes. We conclude that the presence of an XX-line has an ameliorating effect on height and gonadal function of patients with Turner syndrome.