Early corticosteroid treatment in 4 Duchenne muscular dystrophy patients: 14-year follow-up.

INTRODUCTION: Corticosteroid treatment is the standard of care in Duchenne muscular dystrophy (DMD), but the optimal age to initiate treatment and dosage pattern remain a matter of discussion. METHODS: We performed a long-term study of alternate-day corticosteroids in five 2- to 4-year-old DMD patients. The primary outcome measure was prolongation of the ability to walk. RESULTS: One patient lost ambulation at age 10. Four patients, aged 16 to 18 were fully ambulant, and 3 of them could still climb stairs. Respiratory function was moderately reduced in 2. Left ventricular ejection fraction was > 45%. Short stature and delayed puberty were the most relevant side effects. Although the negative impact of corticosteroid treatment on growth rate remained their major concern, parents and patients stated that they preferred corticosteroid therapy. CONCLUSIONS: Long-term corticosteroid treatment is effective in prolonging function but not in recovering lost function, and its early use seems appropriate.

Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young.

The association between maturity onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM) has been rarely described. We report two patients affected by MODY who developed T1DM. Case 1: a 4-yr-old girl referred for glycosuria presented hemoglobin A1c (HbA1c) of 6.6%. Islet cell antibodies (ICA) and anti-glutamic acid decarboxylase (GADA) were initially negative. As her father, uncle and grandmother showed mild hyperglycemia, they were screened for MODY 2. A novel mutation in glucokinase gene was found in the family. Few months later, her glycemic control worsened consistently and she required insulin treatment. A high titer of GADA and ICA was then detected. Six years afterwards insulin requirement is 0.8 U/kg and HbA1c 6.7%. Case 2: a 15-yr-old boy treated for growth hormone deficiency was found with a blood glucose level of 106 mg/dL. HbA1c was 7.2%, ICA and GADA were negative. Family history was positive for autoimmune diseases and type 2 diabetes mellitus. The patient was investigated for MODY 2 and MODY 3, and a mutation of hepatocyte nuclear factor-1 alpha gene was found. The same mutation was found in the mother who had never been referred for hyperglycemia. After 1 yr, due to an unjustified worsening of the metabolic control, autoimmunity was again investigated and a mild positivity was found. He then required insulin therapy and after 5 yr current HbA1c was 8.2%. The diagnosis of MODY does not exclude the risk of developing T1DM. Therefore autoimmunity should be investigated when ordinary treatments fail and metabolic control unexpectedly worsens.

Long-term clinical significance of thyroid autoimmunity in children with celiac disease.

OBJECTIVE: To evaluate the long-term outcome of thyroid function and autoimmunity in a large series of children with celiac disease. STUDY DESIGN: This longitudinal, retrospective study (duration of follow-up, 8.9 +/- 4.0 years) was conducted at the Pediatric Department, University of Bologna, Italy. One hundred thirty-five consecutive patients diagnosed between June 1990 and December 2004 and followed on a gluten-free diet were examined. Inclusion criteria were good dietary compliance and duration of follow-up for at least 3 years. RESULTS: Of 101 patients who never showed positive antithyroid titers during the follow-up, 86 remained euthyroid; 15 showed high thyroid-stimulating hormone values at diagnosis that normalized in 11 cases after 12 to 18 months of gluten withdrawal. Of 31 patients with persistently positive antibody titers, 23 (74%) remained consistently euthyroid during the follow-up and 8 (26%) had a subclinical hypothyroidism. The prevalence of cases with positive antibodies was similar in children with growth retardation or gastroenterological symptoms at diagnosis and different durations of gluten exposure. CONCLUSIONS: The presence of antithyroid antibodies in children with celiac disease has a low predictive value for the development of thyroid hypofunction during the indicated surveillance period. Longer follow-up is needed.

Developmental syndromes: growth hormone deficiency and treatment.

Developmental syndromes are characterized by numerous phenotypical signs and malformations. In most of them such as Turner, Noonan, Prader-Willi, Silver-Russel, Williams, Kabuki, Leri-Weill syndrome and skeletal dysplasias, short stature is a common feature. Growth defect is very often related to a defect in cellular growth, but some unknown abnormality in GH action is possible. Recently, the greater availability of recombinant GH has expanded the interest towards GH secretion and therapy also in developmental syndromes. We recognize syndromes associated with GH deficiency (GHD), showing a developmental midline defect such as Pallister-Hall syndrome, septo-optic dysplasia, but many of these conditions do not have a convincing link with GHD. Moreover, some conditions, in particular the well-studied Turner syndrome, that do not have a real GHD, have proven to benefit from GH therapy at supra-physiological doses obtaining a higher final height than the expected one according to the natural history. This has expanded the indications for GH therapy. The aim of our paper is to review the literature on GH secretion, on the effects and costs-benefits of GH therapy in many dysmorphic syndromes, presenting some results of GH secretion and therapy obtained in our experience.

Correlations of phenotype and genotype in relation to morphologic remodelling of the aortic root in patients with Turner's syndrome.

BACKGROUND: Patients with Turner's syndrome are at risk of aortic dilation and dissection. Currently, it is not known whether such dilation is related to associated cardiovascular abnormalities, or to the genetic anomaly itself. METHODS: We studied echocardiographically 107 patients with genetically proven Turner's syndrome, with heterogeneous underlying karyotypes, and without associated cardiac lesions. Their average age was 19.6 plus or minus 8.4 years. We compared the finding with those from 71 age-matched healthy female volunteers. The diameter of the aorta was measured at the level of the basal attachments of the aortic valvar leaflets, the sinuses of Valsalva, the sinutubular junction, and its ascending component. RESULTS: Compared to control subjects, the patients with Turner's syndrome had larger diameters of the aorta at the level of the sinuses of Valsalva, at 23.4+/-4.8 versus 25.5+/-4.1 millimetres (p = 0.0014), the sinutubular junction, at 19.9+/-3.8 versus 23.3+/-4.1 millimetres (p < 0.0001), and the ascending aorta, at 22.3+/-4.9 versus 24.6+/-4.4 millimetres (p = 0.0011). Dilation of the sinutubular junction, found in just over one-quarter of the patients, was more common than dilation of the ascending aorta, the latter found in less than one-tenth. The patients with Turner's syndrome, therefore, presented with remodelling of the aortic root, with relative dilation of the sinutubular junction. The underlying karyotype influenced both the dimensions of the sinutubular junction (p = 0.0054), and the ascending aorta (p = 0.0064), so that patients with the karyotype 45X had larger aortas. The karyotype was the strongest predictor by multivariate analysis for dilation at both these sites (p = 0.0138 and 0.0085, respectively). CONCLUSIONS: Dilation at the sinutubular junction is frequent in patients with Turner's syndrome, and is more common than dilation of the ascending aorta. The syndrome is associated with a remodelling of the aortic root, with prominent dilation of the sinutubular junction. There seems to be a relation between aortic dilation and the underlying genotype.

A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations.

CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date. OBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. DESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. PATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. RESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. CONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.

Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy.

We report on the outcome of intravenous high-dose immunoglobulin (IVIg) treatment in four children with narcolepsy and cataplexy, in whom the early diagnosis and the extreme disease severity were indications for this potentially efficacious therapy. One of four patients showed an objective and persistent improvement in clinical features during and after IVIg treatment. Our data partially support the recent report of the efficacy of IVIg treatment in early diagnosed narcolepsy with cataplexy and support the need for a controlled multicenter clinical trial on IVIg in narcolepsy.

Quality of life, psychological adjustment and metabolic control in youths with type 1 diabetes: a study with self- and parent-report questionnaires.

OBJECTIVE: To evaluate self and parent reports on quality of life (QoL) and psychological adjustment of youths with type 1 diabetes, in comparison to a general paediatric population, and identify relationships between disease duration, metabolic control and psychological parameters. RESEARCH DESIGN AND METHODS: Participants included 70 youths with type 1 diabetes and their parents. They were compared with 70 non-diabetic subjects. Data were analyzed in the whole group and in subgroups aged 6-10, 11-13 and 14-18 yr. All cases performed pediatric QoL, Child Behaviour Checklist, filled in by parents, and Youth Self-Report, filled in by youths. Data were compared with haemoglobin A1c (HbA1c) values and disease duration. RESULTS: Self-reports showed a psychological adjustment of youths with type 1 diabetes similar to that of controls. Parent reports showed that parents of children with type 1 diabetes were more worried than those of controls (p < 0.01). Adolescents showed a worse QoL and more frequent psychological disturbances. In this group, for youth and parent reports, HbA1c levels correlated positively with psychological problems (p < 0.05) and negatively with QoL (p < 0.05). Only for parent reports, in the whole group and in subgroups aged 6-10 and 11-13 yr, disease duration correlated positively with psychological adjustment (p < 0.05). CONCLUSIONS: Before adolescence, youths with type 1 diabetes showed only slight problems in psychological adjustment and QoL, with an association with disease duration reported by parents. In adolescence, both youths and their parents reported more emotional and behavioural problems, independent of disease duration. Better metabolic control and psychological well-being seemed directly related.

Prevalence of celiac disease in children with type 1 diabetes mellitus increased in the mid-1990 s: an 18-year longitudinal study based on anti-endomysial antibodies.

Between 1987 and 2004, 331 consecutive children, all newly diagnosed with type 1 diabetes mellitus in our pediatric clinic, underwent repeated serological screening for celiac disease (CD) by means of anti-endomysial antibodies, measured prospectively between 1994 and 2004, and retrospectively, using frozen banked serum, between 1987 and 1993. There were 22 cases (6.6%) of biopsy-proven CD among the 331 diabetic children. The prevalence of CD was significantly (P = 0.015) higher after 1994 (10.6%) than before 1994 (3.3%). The rapid change in the risk of CD among Italian diabetic children that occurred in the mid-1990 s could be related to changes in environmental factors, namely, eating habits and viral infections.

Three novel AMH gene mutations in a patient with persistent mullerian duct syndrome and normal AMH serum dosage.

BACKGROUND: Persistentmullerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. AIM: We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. RESULTS: Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. CONCLUSIONS: The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate.

Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1.

OBJECTIVE: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease caused by mutations in the human mineralocorticoid receptor gene (NR3C2). DESIGN: Aim of the study was to analyze the NR3C2 gene in three Italian patients with clinical signs of renal PHA1 and to evaluate the distribution of the -2G > C, c.538A > G, and c.722C > T single nucleotide polymorphism (SNP) pattern in the PHA1 patients and in 90 controls of the same ethnic origin. METHODS: Analysis of the NR3C2 gene sequence and of the polymorphic SNP markers. Functional characterization of the detected novel NR3C2 mutations utilizing aldosterone-binding assays and reporter gene transactivation assays. RESULTS: One novel nonsense (Y134X) and one novel frameshift (2125delA) mutation were detected. They exhibited no aldosterone binding and no transactivation abilities. No mutation was detected in the third patient. Haploinsufficiency of NR3C2 was ruled out by microsatellite analysis in this patient. The c.722T SNP was detected in 97% of alleles in the Italian population which is significantly different from the general German or US population. CONCLUSIONS: Molecular analysis of the NR3C2 gene in PHA1 patients is warranted to detect novel mutations in order to clarify the underlying genetic cause, which may extend the insight into relevant functional regions of the hMR protein. The effect the different distribution of the c.722T SNP is not clear to date. Further studies are necessary to provide evidence as to a possible advantage of a less sensitive hMR in southern countries.

Effect on adult height of pubertal growth hormone retesting and withdrawal of therapy in patients with previously diagnosed growth hormone deficiency.

CONTEXT: GH replacement therapy in GH-deficient (GHD) patients is usually continued until adult height despite the fact that most of these subjects display a normal secretion when retested at the end of growth. Puberty is the most likely time for normalization of GH secretion. OBJECTIVES: The objectives of this study are to establish the characteristics and the percentage of the subjects with isolated GHD who normalized secretion at puberty and to compare their statural outcomes with those of the subjects with persistent deficiency treated also after retesting. DESIGN AND SETTING: This was a prospective, nonrandomized, open-label study conducted in a university research hospital. PATIENTS AND INTERVENTION: Sixty-nine subjects (40 male, 29 female) with a diagnosis before puberty of isolated GHD by means of arginine and l-dopa tests were reevaluated with the same tests after at least 2 yr of therapy and after puberty onset. If GH peak at retesting was more than 10 microg/liter, therapy was withdrawn. MAIN OUTCOME MEASURES: Percentage and characteristics of normalized subjects at retesting, outcome of treatment in the subjects treated or untreated to adult height, and factors predictive of growth outcome were measured. RESULTS: At retesting, 44 subjects (63.7%) confirmed a GH peak less than 10 microg/liter (24 of 40 male and 20 of 29 female). Apart from a less delayed bone age at diagnosis in females, the subjects with confirmed GHD were not different at diagnosis from the other group for height deficit at diagnosis, first year growth response to GH, age and height at puberty onset, height, and IGF-I at retesting. Mean adult height was 165.1 +/- 4.5 cm in the male group treated until adult height vs. 164.0 +/- 3.4 cm in the group who suspended therapy at retesting. Mean adult height was 153.2 +/- 4.1 cm in the female group treated until adult height vs. 152.9 +/- 5.2 cm in the group that suspended therapy at retesting. As regards the parameters expressing the final outcome, the only difference was found in the mean increment adult height-target height sd score in favor of the male group treated until adult height. In both sexes, therapy duration and GH levels at diagnosis and at retesting were unrelated to adult height parameters and to height increments during the period of observation. CONCLUSIONS: One third of our GHD subjects diagnosed before puberty presented a normal secretion at puberty. The withdrawal of GH therapy in these subjects after retesting was not associated with a catch down growth, and they obtained an adult height similar to those obtained by the GHD subjects treated until adult height. It seems convenient, in subjects with nonsevere GHD, to retest GH secretion at midpuberty and to withdraw treatment for the subjects that are no longer deficient.

Two novel GnRHR gene mutations in two siblings with hypogonadotropic hypogonadism.

OBJECTIVE: Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course. DESIGN: The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor. METHODS: The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing. RESULTS: Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents. CONCLUSIONS: We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand-receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.

Growth and adult height in atypical coeliac patients, with or without growth hormone deficiency.

OBJECTIVE: To evaluate the effect of a gluten-free diet on growth and adult height, when available, in coeliac children without gastrointestinal symptoms. PATIENTS AND METHODS: Sixty-one coeliac children without gastro-intestinal symptoms were included in the study. The age at diagnosis was 9.50 +/- 3.3 years. Thirty-eight had short stature at diagnosis (< 10th percentile) and 23 had normal stature. Thirty-seven reached adult height. RESULTS: After beginning the diet an increase in growth velocity was seen in 30 patients (responders) (20 with initial short stature), while in 31 patients (18 with short stature) there was no catch-up growth (non-responders). Bone age at diagnosis was significantly more delayed in the responders than in the non-responders. Target height was significantly higher in children with normal stature at diagnosis than those with short stature. Growth hormone (GH) deficiency was found and confirmed after 6-12 months of diet in 12 of the 38 patients (32%) with short stature. In the group of the 30 'short' patients who attained final height, target height was attained or improved in 12 patients (40%): in eight of the 16 (50%) responders and in four of the 14 (29%) non-responders; in eight (all responders) out of 22 (36%) without GH deficiency, and in four out of eight (50%) patients with GH deficiency treated with GH (all non-responders). CONCLUSIONS: In children in whom coeliac disease is diagnosed because of short stature, a gluten-free diet will be successful if at diagnosis there is a delay of bone age and in the first year of diet there is an evident catch-up growth. When this does not occur, i.e. in half of the patients (18 out of 38), it may be because of an associated and transient GH deficiency. In these patients a period of GH replacement therapy as well as a gluten-free diet may improve their final height.

Active and total ghrelin concentrations in the newborn.

BACKGROUND: Ghrelin is a peptide with a potent capacity to release GH and other metabolic activities. An acyl modification is indispensable for biological activity. Acylated and desacylated forms of ghrelin are both present in the blood. No data exist about the ratio between active ghrelin and total ghrelin in the first period of life. OBJECTIVE: To investigate whether ghrelin may be involved in physiological roles during fetal life. INFANTS AND METHODS: Ghrelin, growth hormone (GH), and leptin concentrations were measured in cord plasma in 98 newborns of healthy mothers. Acyl-ghrelin and the sum of acylated and desacylated forms of ghrelin (total ghrelin) were measured using specific radioimmunoassays. RESULTS: Acylated ghrelin and total ghrelin did not correlate with birth weight, gestational age, body mass index, head circumference, birth length, leptin or GH in plasma cord blood. CONCLUSIONS: The absence of clinically significant correlations between both active and total ghrelin and GH, leptin or anthropometric data does not enable us to ascribe a precise role to ghrelin in prenatal life.

The glucose area under the profiles obtained with continuous glucose monitoring system relationships with HbA(lc) in pediatric type 1 diabetic patients.

OBJECTIVE: The purpose of this study was to determine whether the continuous glucose monitoring system (CGMS) (MiniMed, Sylmar, CA) 1) is sufficiently representative of the overall metabolic control as assessed by HbA(1c), 2) could be used to identify a particular blood glucose threshold value affecting hemoglobin glycation; and 3) is able to show any relationship between particular glycemic profiles and HbA(1c) levels. RESEARCH DESIGN AND METHODS: Of 44 pediatric patients with type 1 diabetes who wore CGMS devices, 28 subjects were selected for the study. Criteria for inclusion were high levels of HbA(1c) (> or =8%) for more than 1 year or a history of frequent hypoglycemic episodes and a complete CGMS registration for 72 h. Age of the subjects ranged from 5.7 to 24.8 years, the mean duration of disease was 7.63 +/- 4.75 years, and the mean HbA(1c) value was 8.7 +/- 1.3%. CGMS data were downloaded and glucose profiles were analyzed. The area under each glucose profile was calculated by means of a professional digital planimeter. RESULTS: The glucose profiles showed a high frequency of prolonged hyperglycemic periods (80% of subjects) and a low frequency of postmeal glycemic peaks (29% of subjects). Postlunch values were significantly correlated with HbA(1c) levels, but the correlation disappeared when controlling for glucose area values. Glucose area values significantly correlated with HbA(1c) levels both when considered as a whole (40-400 mg/dl; r = 0.53, P = 0.002) and when considered fractioned (40-150, 40-200, 40-250, 40-300 mg/dl), apart from the 40-90 mg/dl partial area. HbA(1c) levels were significantly decreased 3 and 6 months after use of CGMS (P = 0.05 and 0.03, respectively, paired Student's t test). CONCLUSIONS: HbA(1c) levels may be decreased by using the information obtained with the CGMS. Three-day glucose profiles are representative of the overall glucose control, because glucose area values correlate with HbA(1c) levels. The only glucose threshold below which there seems to be no correlation with HbA(1c) is 90 mg/dl. Only glucose area, and not postprandial glucose values, are directly and independently correlated with HbA(1c). Therefore, to improve metabolic control, it is necessary to lower the whole mean 24-h glycemia and not just the postprandial glucose values.

Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of disorders characterized by early onset non-insulin-dependent diabetes mellitus, autosomal dominant inheritance, and primary defect in the function of the beta cells of the pancreas. Mutations in the glucokinase (GCK) gene account for 8%-56% of MODY, with the highest prevalences being found in the southern Europe. While screening for GCK mutations in 28 MODY families of Italian origin, we identified 17 different mutations (corresponding to 61% prevalence), including eight previously undescribed ones. The novel sequence variants included five missense mutations (p.Lys161Asn c.483G>C in exon 4, p.Phe171Leu c.511T>C in exon 5 and p.Thr228Ala c.682A>G, p.Thr228Arg c.683C>G, p.Gly258Cys c.772G>T in exon 7), one nonsense mutation (p.Ser383Ter c.1148C>A in exon 9), the splice site variant c.1253+1G>T in intron 9, and the deletion of 12 nucleotides in exon 10 (p.Ser433_Ile436del c.1298_1309del12). Our study indicates that mutations in the GCK/MODY2 gene are a very common cause of MODY in the Italian population and broadens our knowledge of the naturally occurring GCK mutation repertoire.

CYP21 genotype, adult height, and pubertal development in 55 patients treated for 21-hydroxylase deficiency.

In a retrospective study we evaluated long-term growth, pubertal developmental patterns to final height (FH), and medication in 55 patients (35 females) affected by 21-hydroxylase deficiency. The patients were classified into 3 groups according to predicted mutation severity: group A (11 women and 9 men), homozygous or compound heterozygous for null or In2 splice mutations [residual enzymatic activity (RA), <1%]; group B (11 women and 4 men), homozygous for I172N or R341P or R426H mutations (RA, approximately 2-3%) or compound heterozygous with any of the group A or B mutations; and group C (13 women and 7 men), homozygous for P30L or V281L or P453S mutations (RA, >30%) or compound heterozygous with any of the group A, B, or C mutations. Three patients showed unclassifiable genotypes. FH was similar in the female groups, whereas male patients in group B were shorter than males in groups A and C. Fifty-five percent of patients in group A, 33% in group B, and 40% in group C reached an FH within 0.5 SD of target height. Four of the 7 patients diagnosed via neonatal screening achieved an FH equal to or above the target height. In the entire group, early diagnosis (<1 yr) improved height outcome. Early diagnosed CAH patients who received lower cortisol equivalent doses during the first year of life reached a better FH. Our results underline the importance of mineralocorticoid therapy, as CAH subjects in groups A and B who did not receive this treatment showed reduced FH. Early diagnosis, the use of more physiological cortisol equivalent dosages during the first year of life, and the extension of mineralocorticoid therapy to all classical patients are shown to improve the auxological outcome. Genotypic analysis helped to interpret the height results of our cases and prospectively may represent a useful tool for improving the therapeutic choice and the height outcome.

Lung function in children with diabetes mellitus.

A cross-sectional study design was undertaken to assess pulmonary function in children with insulin-dependent diabetes mellitus (IDDM), and to establish if there is any relationship with diabetic factors and complications. Thirty-eight children (10 +/- 1.8 years) with IDDM and without clinical or radiological evidence of lung involvement, and 41 healthy age-matched reference subjects, underwent a pulmonary function study. Thirteen (34%) of 38 subjects with IDDM were studied at the onset of their disease. Adjusted values expressed as SD score of forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and the transfer factor for carbon monoxide (TLCO) were found to be significantly lower than in controls (-0.54 +/- 0.87 vs. 0.40 +/- 1.10, P = 0.0008; -0.11 +/- 0.96 vs. 0.52 +/- 1.07, P = 0.01; -1.60 +/- 1.07 vs. -0.57 +/- 1.28, P = 0.001, respectively). These differences also existed in the group investigated at onset of diabetes. Residual volume (RV) and RV/total lung capacity ratio (RV/TLC) were significantly higher in the whole group of patients with IDDM than in controls (-0.20 +/- 0.83 vs. -0.80 +/- 0.88, P = 0.003; and 26 +/- 6.2 vs. 21 +/- 5.0, P = 0.0002, respectively). Seventeen patients (45%) had abnormal pulmonary function (SD score, less than -1.64): 16 subjects had reduced TLCO, 4 had reduced FVC, and in 3 of the 17, both functional indices were abnormal. There was no significant relationship between pulmonary function indices and diabetic factors or complications. The only significant association was between abnormal TLCO and females (P = 0.03), suggesting that sex may be a predisposing factor for the development of pulmonary complications. This study supports the view that the lung is functionally involved in children with IDDM early on in the course of the disease.

High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy.

STUDY OBJECTIVES: We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses. DESIGN: Cross-sectional on consecutive recruitment. SETTING: Hospital sleep center and pediatric unit. PATIENTS: Forty-three children and adolescents with NC versus 52 age-matched obese children as controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74%) and a higher occurrence of precocious puberty (17%) than obese controls (1.9%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence. CONCLUSIONS: NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities and the potential related risks require a multidiagnostic approach and a tailored therapeutic management.