-
M Wasniewska,
A Balsamo,
M Valenzise,
A Manganaro,
G Fagioli,
S Bombaci,
V Conti,
M Ferri,
T Aversa, A Cicognani,
F De Luca
[show abstract]
[hide abstract]
ABSTRACT: Background: Increased artery intima-media thickness (IMT) was found in adults with classical congenital adrenal hyperplasia (CAH). No data are available in patients with non-classical (NC) CAH. Aims: To evaluate IMT in adolescents with classical and NC CAH and to compare the results with those recorded in a control population. Patients and Methods: 18 adolescents with either classical (Subgroup A1) or NC CAH (Subgroup A2) were compared with 16 controls (Group B). All subjects underwent IMT ultrasonography measurement at different sites; results were correlated with clinical, metabolic and insulin resistance (IR) data. Results: When compared with Group B, both subgroups exhibited higher IMT values at all sites. No differences were found between classical and NC CAH. Univariate analysis of factors impacting on IMT of CAH patients demonstrated that: a) abdominal aorta (AA) IMT was positively correlated with cumulative glucocorticoid doses, triglyceride serum levels and diastolic blood pressure SDS and negatively with androstenendione and ACTH levels; b) common carotid (CC) IMT was positively associated with triglycerides and triglyceride / HDL ratio. At multiple regression analysis the independent positive predictors of AA and CC IMTs were respectively triglyceride levels and triglyceride / HDL ratio. Conclusions: : a) even adolescents with NC CAH and not only those with classical form may be at higher risk of artery alterations; b) this risk is not necessarily associated with either obesity or waist/height ratio or dyslipidemia; c) an important role in the pathogenesis of artery alterations in CAH may be played by intermittent iatrogenic hypercortisolism and secondary IR.
Journal of endocrinological investigation 12/2011; · 1.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Congenital adrenal hyperplasia (CAH) is mainly caused by the deficiency of the 21-hydroxylase enzyme coded by the CYP21A2 gene. However, some alleles in the non-classical form (NC-CAH) remain without identified mutations, suggesting the involvement of regulatory regions.
Our objective was to study an allele carrying the variant *13 G>A in the 3'UTR of the CYP21A2 gene identified in some patients with a mild form of NC-CAH in order to verify the possible implication of this variation with the phenotype observed.
Among all the subjects in whom the CYP21A2 gene was analyzed, 14 patients and 7 relatives heterozygous or homozygous for the *13 G>A substitution in 3'UTR were selected. Sequencing of DNA, genotyping, multiplex ligation-dependent probe amplification (MLPA), in vitro studies and bioinformatic analysis were performed.
The haplotype of the *13 G>A allele was identical in all the subjects with a monomodular structure composed by one C4A gene and one CYP21A2 gene without a second module with the CYP21A1P pseudogene. No other concomitant mutations were found in the region extending from 3 kb in the promoter and encompassing the polyadenylation signal. Both bioinformatic analysis and in vitro studies predicted an alteration of the RNA folding and expression, but no miRNA target sequences were found in this region.
The identification of a substitution in the 3'UTR of the gene associated with a mild form of NC-CAH suggests the importance of analyzing the CYP21A2 untranslated regions to better characterize and treat this subgroup of patients.
Journal of endocrinological investigation 04/2011; 35(3):298-305. · 1.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The inlet patch (IP) is an area of heterotopic gastric mucosa in the cervical esophagus commonly seen during upper endoscopy. Although generally asymptomatic IP has been associated with esophageal and supraesophageal symptoms and, though rare, in adult with malignant transformation. We describe two cases of recurrent episodes of laryngospasm associated with IP. In both cases there was a good response to prolonged acid suppression therapy.
Pediatric Pulmonology 04/2011; 46(9):934-8. · 2.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations in genes encoding the enzymes involved in one of the 5 steps of adrenal steroid synthesis or the electron donor P450 oxidoreductase (POR) enzyme. Steroid 21-hydroxylase deficiency (21-OHD), the principal focus of this review, accounts for about 90-95% of all CAH cases, and its biochemical and clinical severity depends on the underlying CYP21A2 gene disruption. Molecular genetic advancements have been achieved in recent years, and the aim of this review is to attempt to highlight its contribution to the comprehension and management of the disease. When possible, we will try to achieve this goal also by providing some results from our personal experience regarding: some aspects of CYP21A2 gene analysis, with basic genotype/phenotype relationships; its crucial role in both genetic counselling and in prenatal diagnosis and treatment in families at risk for 21-OHD; its help in the comprehension of the severity of the disease in patients diagnosed by neonatal screening and possibly treated before an evident salt-loss crisis or before performing adequate blood sampling; its usefulness in the definition of post ACTH 17-hydroxyprogesterone values, discriminating between non-classic, heterozygote and normal subjects; and finally the contribution of genes other than CYP21A2 whose function or dysfunction could influence 21-hydroxylase activity and modify the presentation or management of the disease.
Sexual Development 09/2010; 4(4-5):233-48. · 2.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Anthropometry is the technique of expressing body shape in quantitative terms. The measurements are compared with the standard growth curves for the general population and expressed as a SD score or percentiles. The comparison of the different parameters with normal standards requires: standardized landmarks on the body, standardized methods of taking measurements, and standard equipment. Skeletal dysplasias generally present with disproportionate short stature, that may be caused primarily by a short trunk or short limbs. If short limbs are observed, the reduction may affect the proximal (rhizomelic), the middle (mesomelic) or distal (acromelic) segments. Anthropometric measurements should include all the segments of the arms and the legs with a comparison with the normal standards for height age. Short stature homeobox- containing (SHOX) gene defects determine a highly variable phenotype, that includes an osteochondrodysplasia with mesomelic short stature and Madelung deformity, but also presentations without evident malformations. Anthropometric indicators of SHOX deficiency are: disproportionate short stature, reduction of lower limb, reduction of the ratio between arm span and forearm length with respect to height, increase in the sitting/ height stature ratio, increase in limb circumference (arm, forearm, thigh, and leg) with respect to height and increased body mass index. In some forms of skeletal dysplasias and in particular in SHOX gene anomalies that have many characteristics superimposable to idiopathic short stature, only an accurate auxo-anthropometric and dysmorphologic evaluation enable us to propose, fairly accurately, the subjects for the gene study.
Journal of endocrinological investigation 06/2010; 33(6 Suppl):19-25. · 1.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Short stature homeobox-containing (SHOX) gene mutations causing haploinsufficiency have been reported in idiopathic short stature, but the real prevalence of this defect in the population with growth failure is debated. Based on current data, the prevalence of SHOXdefect (SHOX-D) has been calculated to have occurred in at least 1 in 2,000 children. This occurrence rate is higher than that of classic GH deficiency or Turner syndrome. In all probability, the real prevalence of SHOX-D will increase in the future with the improvement of the genetic analysis with investigations for point mutations in the enhancer sequences or for deletions in other parts of this region. A selection criterion to individuate the most appropriate candidates eligible for the SHOX region analysis has been suggested based on the evaluation of a disproportional short stature. The efficacy of GH treatment in these patients has recently been demonstrated with results that are similar to those observed in Turner syndrome.
Journal of endocrinological investigation 06/2010; 33(6 Suppl):15-8. · 1.57 Impact Factor
-
S Bertelloni,
A Balsamo,
L Giordani,
R Fischetto,
G Russo,
M Delvecchio,
M Gennari,
A Nicoletti,
M C Maggio,
D Concolino,
L Cavallo, A Cicognani,
G Chiumello,
O Hiort,
G I Baroncelli,
M F Faienza
[show abstract]
[hide abstract]
ABSTRACT: Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17beta-hydroxysteroid-dehydrogenase type 3 (17beta-HSD3) deficiency in Italy.
Pediatric Endocrine Departments, University Hospitals.
The cases of 5 Italian subjects affected by 17beta-HSD3 deficiency are presented in this study.
Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient).
Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/ Delta4-androstenedione ratio) were informative. Two girls were homozygous for 17beta-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject.
17betaHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/Delta4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCGstimulation is mandatory in pre-puberty. Molecular analysis of 17beta-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity.
Journal of endocrinological investigation 05/2009; 32(8):666-70. · 1.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this article was to evaluate otological diseases in 173 patients (pts) with Turner syndrome (TS). STUDY DESIGN: One hundred and seventy-three pts, mean chronological age (CA) 12+/-6.2 yr. Patients were submitted to different therapies: GH, estrogen therapy (EE), no therapy (no tx). Seventy-nine pts (CA 11 yr) had no otological diseases. Conductive hearing loss (CHL) occurred in 38.7% (CA 11 yr) and otoscopy was: persistent secretory otitis media in 55.2%, chronic otitis media in 10.4%, pars flaccida retraction pocket in 19.4%, mostly bilateral. Cholesteatoma was present in 15%. Sensorineurinal hearing loss (SNHL) occurred in 15.6% (CA 16 yr), 11 of whom were affected by high tone loss, and 15 by loss in midfrequencies (dip between 0.5-3 kHz), bilateral in 93%. Degree of hearing loss (HL) was mild [20-40 decibel hearing level (dBHL)] in 15%, moderate (45-60 dBHL) in 31%, severe (65-80 dBHL) in 8%, profound (dBHL>85) in 2%. We found a significant association between CHL and karyotype 45, X (p<0.025), congenital cranio-facial abnormalities, prevalently with low-set ears (p<0.04), narrow and/or high arched palate (p<0.018), and micrognathia (p<0.004). Our study confirms that the high prevalence of middle ear infections and CHL in TS are probably due to growth disturbances of the structures from the first and second branchial arches. We did not find any association between EE, GH, and HL. We recommend a regular audiological follow-up, especially during childhood, to prevent important middle ear anatomic sequele and to identify HL at an early stage, as the impact on social functioning may be significant.
Journal of endocrinological investigation 09/2008; 31(9):779-83. · 1.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The development of a testis requires the proper spatiotemporal expression of the SRY gene and other genes that act in a dosage-sensitive manner. Mutations in the SRY gene account for only 10-15% of patients with 46,XY gonadal disorder of sex development (DSD). To enable the diagnostics of deletions and duplications of genes known to be involved in different forms of DSD, we developed a synthetic probe set for multiplex ligation-dependent probe amplification (MLPA) analysis. Here, we report the results from the analysis of 22 patients with 46,XY gonadal DSD. The analysis with the DSD probe set has led to the identification of two copy number variations, an 800-kb NR0B1 (DAX1) locus duplication on Xp21 in a patient with isolated partial gonadal dysgenesis and a duplication of the SRD5A2 gene that represents a rare normal variant. The described MLPA kit represents an optimal complement to DNA sequence analysis in patients with DSD, enabling screening for deletions and duplications of several genes simultaneously. Furthermore, the second identification of an NR0B1 locus duplication in a patient with isolated gonadal dysgenesis, without dysmorphic features and/or mental retardation, highlights the importance of evaluating NR0B1 duplication in patients with gonadal dysgenesis.
Clinical Genetics 06/2008; 73(5):453-64. · 3.13 Impact Factor
-
E. Cacciari,
S. Salardi,
U. Volta,
G. Biasco,
S. Partesotti,
W. Mantovani, A. Cicognani,
S. Tonioli,
P. Tassoni,
P. Pirazzoli,
F. B. Bianchi,
F. Barboni,
E. Pisi
Acta Paediatrica 01/2008; 76(4):671 - 672. · 2.07 Impact Factor
-
E. CACCIARI,
A. BALSAMO,
A. CASSIO,
S. PIAZZI,
F. BERNARDI,
S. SALARDI, A. CICOGNANI,
P. PIRAZZOLI,
F. ZAPPULLA,
M. CAPELLI,
M. PAOLINI,
C.I. CORDARO
Annals of the New York Academy of Sciences 12/2006; 458(1):85 - 89. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Congenital adrenal hyperplasia (CAH) is most commonly due to 21-hydroxylase deficiency and presents with a wide spectrum of clinical manifestations, from prenatal virilization and salt-wasting in the neonatal period to precocious pubarche and late-onset hyperandrogenic symptoms during adulthood. A limited number of mutations account for the majority of all mutated alleles, but a growing number of rare mutations are responsible for the disease in some patients. By sequence analysis of the CYP21A2 gene, we identified two novel (I171N and L446P) and two rare (R341P and R426H) mutations in seven Italian patients with CAH. One of the patients was diagnosed with mild non-classical CAH and was found to be a compound heterozygote (I171N/V281L), while all other patients showed severe phenotypes with latent or manifest salt-wasting. The residual activities measured after expression of the four mutant enzymes in COS-1 cells were all below 1% towards both natural substrates (17-OH-progesterone and progesterone) compared with the wild-type protein. All four mutations are, thus, associated with severe enzyme deficiency and are predicted to cause classic CAH if found in trans with other mutations causing severe enzyme deficiency.
Journal of Molecular Medicine 07/2006; 84(6):521-8. · 4.67 Impact Factor
-
G Plazzi,
A Parmeggiani,
E Mignot,
L Lin,
M C Scano,
A Posar,
F Bernardi,
R Lodi,
C Tonon,
B Barbiroli,
P Montagna, A Cicognani
[show abstract]
[hide abstract]
ABSTRACT: In children, narcolepsy may be the symptom of a brain lesion or genetic disease. The authors report two cases with severe narcolepsy-cataplexy emerging in childhood in close temporal association with obesity and precocious puberty.
Neurology 06/2006; 66(10):1577-9. · 8.31 Impact Factor
-
A Cassio,
A Corrias,
S Gualandi,
L Tato,
G Cesaretti,
C Volta,
G Weber,
G Bona,
M Cappa,
M Bal,
J Bellone, A Cicognani
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the influence of sex as well as pubertal stage at diagnosis on the growth outcome of childhood thyrotoxicosis.
Retrospective, collaborative study.
Longitudinal auxological evaluation in 101 patients (M/F 23/78) for 4.7 +/- 3.1 years subdivided according to pubertal stage at diagnosis into prepubertal (group I) and pubertal (group II).
At diagnosis height and bone age (BA) standard deviation score (SDS) were positive both in girls and boys of groups I and II. In boys of group II, height SDS was significantly higher than in girls of the same group (P = 0.007) and in boys of group I (P = 0.026). During the follow-up, in group I, height SDS remained positive without significant differences between boys and girls, and in group II, height SDS remained significantly lower in girls than in boys. The age at onset of puberty and the age at menarche were within the normal range. Final height (FH) was within target height (TH) range in all groups The FH SDS and the height gain (FH-TH) were similar in girls and in boys in group I and significantly higher in boys than in girls (P < 0.05) in group II. The boys of group II showed a mean height gain significantly greater than that found in all the other groups.
Despite the advancement of BA at presentation, there were no adverse effects on subsequent growth and FH; the growth outcome seems to be better in boys than in girls in group II.
Clinical Endocrinology 01/2006; 64(1):53-7. · 3.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Congenital adrenal hyperplasia (CAH) is most commonly due to 21-hydroxylase deficiency and presents a wide spectrum of clinical manifestations from a severe classical form to a milder late-onset form with a variable severity of hyperandrogenic symptoms. A limited number of mutations account for the majority of the mutated alleles, but additional rare mutations are responsible for the symptoms in some patients. By CYP21 gene analysis, we identified a chimeric CYP21P/CYP21 gene with the fusion breakpoint downstream of the common P30L mutation as well as a GCC to ACC change at codon 15 (A15T) in two subjects with classical CAH and a CCC to TCC change at codon 482 (P482S) in seven subjects referred for nonclassical CAH, precocious pubarche, menstrual irregularities, or hypertrichosis. The two amino acid substitutions were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells, and enzyme activity toward the two natural substrates (17-hydroxyprogesterone and progesterone) was determined. The A15T mutant exhibited no significant difference in activity compared with the wild-type protein, whereas the P482S mutation reduced enzyme activity to 70% of normal. This impairment of activity was confirmed in vivo by detection of heterozygote carriers by the ACTH test.
Journal of Clinical Endocrinology & Metabolism 06/2004; 89(5):2402-7. · 6.50 Impact Factor
-
Clinical Genetics 10/2003; 64(3):258-60. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: As survival rates for childhood cancer have improved, the importance of assessing gonadal dysfunction caused by alkylating agents and radiotherapy in children treated for cancer has increased. Infertility is the major long-term side effect of chemotherapy (CT) in males, whereas Leydig cell function is less affected. Our studies confirm that prepuberty does not protect the male gonad from the late effects of CT and that protocols less gonadal-lesive (such as ABVD regimens) should be preferred. Ovaries are less affected, but early depletion of follicles and premature menopause may occur. High-dose busulfan conditioning regimens cause ovarian failure in young females. The role of gonadal irradiation is discussed: high dosages (>2000 cGy) provoke sterility, impaired testosterone secretion in males and estradiol release in females. High dosage hypothalamic-pituitary irradiation causes delayed puberty and hypogonadism in males and females, whereas lower dosages may be associated with early puberty, particularly in females.
Journal of pediatric endocrinology & metabolism: JPEM 03/2003; 16 Suppl 2:321-6. · 0.88 Impact Factor
-
M Bozzola,
A Albanese,
G E Butler,
V Cherubini, A Cicognani,
M Caruso-Nicoletti,
E Crowne,
V De Sanctis,
E Di Battista,
A C Hokken-Koelega,
F Severi,
B Wonke,
L Cavallo
[show abstract]
[hide abstract]
ABSTRACT: Specialised clinics for the long-term follow-up of survivors from childhood cancer have developed over recent years. The problems encountered among patients who received multiple chemotherapy and radiotherapy can be challenging and require high expertise and close collaboration among different professionals (e.g. oncologists, endocrinologists, radiotherapists, psychologists). Endocrine disorders are often seen, particularly among those who received cranial radiotherapy or gonadotoxic chemotherapy; puberty can be affected and the spectrum of disorders may range from precocious or accelerated puberty to delayed, arrested or even absent pubertal development. Growth impairment can be multifactorial and growth hormone deficiency is an important but probably not the only factor involved. Many questions remain about the optimal management of this group of young patients. In the consensus guidelines that follow the overview an attempt is made to help optimise patients' growth and puberty by suggesting practical clinical approaches to some of the most challenging issues.
Journal of pediatric endocrinology & metabolism: JPEM 08/2001; 14 Suppl 2:997-1002. · 0.88 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Turner syndrome (TS) is the most common sex-chromosome abnormality in females. Short stature and hypogonadism are the classical clinical findings. The spontaneous final height (FH) ranges between 139 and 147 cm, representing a growth deficit of about 20 cm with respect to the unaffected population. GH therapy improves FH and should be started during childhood at a high dose of about 1 IU/kg/week (range 0.6-2 IU/kg/week). Some authors advocate combined therapy with an anabolic steroid at various doses (e.g. oxandrolone 0.05-0.1 mg/kg/day). This treatment results in a significantly increased FH, a large proportion of treated girls reaching a FH of more than 150 cm. Gonadal function is compromised during adolescence in about 80% of girls with TS, whilst in about 20% pubertal development occurs spontaneously. Oestrogen therapy should be started at the age of 13-14 years in hypogonadic patients; early onset of treatment (before 12 years) seems to compromise FH. Other concerns in these patients are fertility and osteopenia.
Journal of pediatric endocrinology & metabolism: JPEM 08/2001; 14 Suppl 2:959-65. · 0.88 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To compare final height in two groups of low birth weight children examined for short stature: the first group untreated because of normal growth hormone (GH) secretion, the second treated with human growth hormone (hGH) because of abnormal secretion.
A total of 49 subjects born at term of birth weight below the 10th centile were consecutively examined for idiopathic short stature. The first group of subjects (n = 20) with normal GH peaks after pharmacological tests (>8 microg/l) spontaneously reached final height. The second group (n = 29) with abnormal secretion were treated with hGH (20 U/m(2)/week) for 36-84 months. At diagnosis the two groups were of similar height for chronological age and bone age, and had similar target height.
In both groups final height was significantly lower than target height (-0.65 (SEM 0.20) in untreated cases, -0.61 (0.18) in treated cases). Fewer than one third of subjects had a final height above target height. Final height data of untreated and treated cases were not different. In the treated group the best results were obtained by those subjects who improved their height for bone age after three years of therapy.
Our subjects with birth weight below the 10th centile remained as short adults with final height below target height. Treatment with hGH 20 U/m(2)/week in those diagnosed as deficient was not effective, with final results overlapping those of untreated subjects.
Archives of Disease in Childhood 04/2001; 84(4):340-3. · 2.88 Impact Factor
