17alpha-hydroxyprogesterone and cortisol serum levels in neonates and young children: influence of age, gestational age, gender and methodological procedures.

To determine the influence of age, gestational age, gender and methodological protocol on serum 17OHP and cortisol concentrations. 17OHP in non-extracted (NE) and extracted (E) sera was measured by RIA in 319 full-term (FT) (1 d-5 yr) infants, 38 pre-term (PT) and in 19 neonates with classical CAH at diagnosis. 17OHP (NE- and E-) decreased with age in normal children. The extraction procedure significantly reduced 17OHP by eliminating interfering steroids in children < 1 year. Sexual dimorphism was only observed in NE-17OHP. 17OHP in PT was always higher than in FT up to 2 months of age (p < 0.001). Neither NE- nor E-17OHP in CAH overlapped with those of FT or PT (p < 0.001) allowing to omit the extraction procedure to confirm CAH diagnosis. Cortisol levels were within normal range in neonates with CAH, thus not adding useful information about adrenal function. Chronological and gestational age, gender, and extraction for 17OHP measurement are important factors to know when assessing adrenal function during the first year of life.

Abnormal responses to TRH in children born small for gestational age that failed to catch up.

BACKGROUND: Fifteen percent of small for gestational age (SGA) children remain short and undergo thyroid axis evaluations. METHODS: We analyzed data on thyroid assessment of 58 SGA children. Five had primary autoimmune hypothyroidism. In the remaining 53 patients, TSH, free T4 (FT4), antithyroid antibodies and 90-min TRH test results were analyzed. Patients were grouped into G1 (n = 27; normal) and G2 (n = 26; abnormal) according to their response to the TRH test compared with 30 normal children. RESULTS: No differences were found in chronological age, gestational age, or birth weight standard deviation score (SDS) between groups. G2 showed higher SDS BMI at consultation (p < 0.05). FT4 (ng/dl) levels were similar in all groups, while basal TSH levels were statistically different in G2 compared with G1 and controls. In 21 G2 patients treated with thyroxine, FT4 levels did not change, TSH normalized, BMI SDS and height remained unchanged. CONCLUSION: These data suggest that in SGA short children thyroid abnormalities may occur. Some of them may be due to a different setting of the hypothalamic-hypophyseal-thyroid axis during intrauterine life. Intrauterine growth retardation may permanently influence endocrine systems by affecting their programming during development. Further follow-up is needed to confirm these findings and to assess their natural history and potential clinical impact.

[Phenotype variability in Noonan syndrome patients with and without PTPN11 mutation]. / Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11.

INTRODUCTION: Around 50% of Noonan syndrome (NS) patients present heterozygous mutations in the PTPN11 gene. AIM: To evaluate the frequency of mutations in the PTPN11 in patients with NS, and perform phenotype-genotype correlation. PATIENTS: 33 NS patients (23 males). METHODS: DNA was extracted from peripheral blood leukocytes, and all 15 PTPN11 exons were directly sequenced. RESULTS: Nine different missense mutations, including the novel P491H, were found in 16 of 33 NS patients. The most frequently observed features in NS patients were posteriorly rotated ears with thick helix (85%), short stature (79%), webbed neck (77%) and cryptorchidism (60%) in boys. The mean height SDS was -2.7 +/- 1.2 and BMI SDS was -1 +/- 1.4. Patients with PTPN11 mutations presented a higher incidence of pulmonary stenosis than patients without mutations (38% vs. 6%, p< 0.05). Patients with and without mutations did not present differences regarding height SDS, BMI SDS, frequency of thorax deformity, facial characteristics, cryptorchidism, mental retardation, learning disabilities, GH peak at stimulation test and IGF-1 or IGFBP-3 SDS. CONCLUSION: We identified missense mutations in 48.5% of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients.

Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations.

Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We demonstrated that human and mouse mutations of the TPIT gene cause a neonatal-onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. Since identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT-coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.

SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity.

SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1-18.3), mean height sd score (SDS) (sd in parentheses) was -2.85 (1.04), and mean sitting height/height ratio SDS was +3.06 (1.09). Mean birth length SDS was -0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3-11.3) was insignificant with a mean change in height SDS of -0.10 (0.52). Mean height SDS of affected parents was -2.70 (0.85) vs. -0.91 (1.10) in unaffected parents. Height loss due to LWD was estimated calculating delta height defined by actual height SDS minus target height SDS of the unaffected parent(s). In the children, mean delta height SDS was -2.16 (1.06), the loss being greater in girls at -2.30 (1.02) than in boys at -1.72 (1.09) (P = 0.32). In patients with SHOX deletions, it was -2.14 (1.15) vs. -1.67 (0.73) for the SHOX point mutation group (P = 0.38). Mean delta height SDS was -2.26 (0.68) for the girls with early menarche (<12 yr) vs. -2.08 (0.91) for the other postmenarcheal girls (P = 0.72). Height loss in patients with radiologically severe wrist deformities in comparison with those having milder radiological signs was -2.81 (1.01) vs. -1.70 (1.04) (P = 0.03). GH treatment in five children during a median duration of 3.4 yr (range, 1.5-9.8 yr) with a median dosage of 0.23 mg/kg.wk (range, 0.14-0.25) resulted in a mean height SDS gain of +0.82 (0.34). In conclusion, SHOX defects were the main cause of LWD. Growth failure occurred during the first years of life with a mean height loss of 2.16 SDS whereas pubertal growth may only be mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. No statistically significant effects of type of mutation, age of menarche, or sex on height were observed. The effect of GH therapy varied between individuals and needs to be examined in controlled studies.

Pediatric Graves' disease: outcome and treatment.

UNLABELLED: Graves' disease treatment in children and adolescents includes antithyroid drugs (ATD), 131I (RI) or subtotal thyroidectomy (CX), all of which present beneficial effects and disadvantages. OBJECTIVE: To review our experience in the management of pediatric patients with Graves' disease considering the therapeutic strategies used. PATIENTS AND METHODS: Clinical and biochemical data of 116 children (23 boys) aged 11.2 +/- 3.7 years at diagnosis were reviewed. Outcome and remission were evaluated and persistency at 10 years calculated with Kaplan Meier analysis. RESULTS: Initially 113/116 patients received ATD, two RI and one CX. After 10 years of follow up, 38 remitted with ATD, 23 were persistently hyperthyroid with ATD, 38 received RI, one underwent CX, and 13 were lost to follow up. The cumulative proportion with persistent hyperthyroidism at 10 years was 31%. CONCLUSIONS: ATD, although the first choice of treatment, was long-lasting and achieved a low remission rate at 10 years of follow up. Conversely, RI was shown to be a safe, low cost, efficient and definitive alternative for Graves' disease treatment in children and adolescents.

Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis.

Simple childhood obesity is characterized by normal or even accelerated growth in spite of reduced growth hormone (GH) secretion. There are conflicting reports on the effects of obesity upon components of the GH-insulin-like growth factor-I (IGF-I)-IGF binding proteins (IGFBPs) system. In the present study we aimed to determine GH, IGF-I, IGFBP-3 and IGFBP-2 as well as some of the less explored components of this axis (IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments, and total acid labile subunit [ALS]) in 22 obese and 17 age-matched control children. We also evaluated not only total GH binding protein (GHBP) serum levels but also GHBP bound to GH (complexed) in both groups. Obese and control groups strongly differed in BMI (obese: 4.7 +/- 0.36 vs control: 0.37 +/- 0.25 SDS, p <0.0001). In the obese group, we found lower GH serum levels, but normal serum levels of GH-GHBP complex, IGF-I, IGFBP-3, IGF-I/IGFBP-3 molar ratio, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Obese children presented higher total circulating GHBP (6.0 +/- 0.44 vs 2.9 +/- 0.29 nmol/l, p <0.001) and insulin levels (10.5 +/- 1.5 vs 5.1 +/- 0.8 mU/l, p <0.001), while IGFBP-2 (4.6 +/- 0.5 vs 6.6 +/- 0.7%, p <0.05) and the ratio IGFBP-2/IGF-I (0.032 +/- 0.019 vs 0.095 +/- 0.01, p = 0.013) were lower than in controls. BMI and insulin were directly, and IGFBP-2 serum levels inversely, correlated to total GHBP serum levels when multiple regression analysis was performed (r = 0.74, p <0.001). By stepwise regression analysis, insulin (r = -0.37, p <0.05) and BMI (r = -0.52, p <0.01) inversely determined IGFBP-2. In summary, obese children present normal growth in spite of reduced GH secretion, probably because the combination of increased total GHBP and normal GH-GHBP complex serum levels (suggesting increased GH receptor [GHR] number and a normal serum GH reservoir, respectively) allow for the achievement of normal levels of IGF-I, IGFBP-3, IGFBP-3 proteolytic activity, IGFBP-3 plasma fragments and total ALS. Reduced IGFBP-2 serum levels and a lower ratio of IGFBP-2/IGF-I in obese children may suggest an increase of tissue IGF-I bioavailability, thus promoting its action. Normal IGF-I and GH availability may be contributing to maintain normal growth in obese children.

[Pediatric emergency: adrenal insufficiency and adrenal crisis]. / Emergencia pediátrica: insuficiencia suprarrenal aguda.

Adrenal insufficiency is defined by impaired secretion of adrenocortical hormones. It is classified upon the etiology in primary and secondary. Rapid recognition and therapy of adrenocortical crisis are critical to survival. Patients often have nonspecific symptoms: anorexia, vomiting, weakness, fatigue and lethargy. They are followed by hypotension, shock, hypoglicemia, hyponatremia and hyperkalemia. All patients with adrenal insufficiency require urgent fluid reposition, correction of hypoglycemia and glucocorticoid replacement, in order to avoid serious consequences of adrenal crisis. After initial crisis treatment, maintenance dose of corticoids should be indicated. Mineralocorticoids replacement, if necessary, should also be initiated.

Trisomy of the short stature homeobox-containing gene (SHOX) due to duplication/deletion of the X chomosome: clinical implications on the stature.

BACKGROUND: The karyotypes of 2 patients with abnormal stature and different phenotypes revealed one similar structural abnormality in the X chromosome by conventional cytogenetic studies and fluorescence in situ hybridization analysis (FISH). FISH strongly suggested the presence of two copies of the SHOX gene in the der(X) chromosome. PATIENTS AND RESULTS: Patient 1 is a teenager girl with tall stature, behavioral disturbances and normal pubertal development. The abnormal X chromosome was present in all cells studied. Parent's karyotypes were normal. Patient 2 is a girl with gonadal dysgenesis, mild Turner syndrome phenotype and short stature. The karyotype was a mosaic 45,X/46,X,r(X) and der(X) chromosome presented in most metaphases of the cell lines. Parent's karyotypes were normal. Nearly all duplication of Xp and partial deletion of the long arm (Xq) from Xq27 or Xq21 to Xqter, in cases 1 and 2, respectively, were observed. In both patients, duplication of Xp translocated to deleted Xq occurred leading to a triplication of the pseudoautosomal region 1 (PAR1) where the SHOX gene is located (Xp22.3). CONCLUSIONS: We propose that in some cases of trisomy for the SHOX gene, the effect of overdosage per se may affect the stature, even in patients with preserved ovarian function (case 1), and that estrogen deprivation may not always be a contributor for tall stature (case 2).

Emergencia pediátrica: insuficiencia suprarrenal aguda / Pediatric emergency: adrenal insufficiency and adrenal crisis

La insuficiencia suprarrenal aguda es un cuadro originado por deficiencia mineralocorticoidea o glucocorticoidea, cuyo no diagnóstico y adecuado tratamiento lleva a una emergenciagrave con riesgo para la vida del paciente. Se clasifica en insuficiencia suprarrenal primaria, que presenta en general compromiso glucocorticoideo y mineralocorticoideo, y secundaria,sin deficiencia mineralocorticoidea. Los pacientes pueden no presentar síntomas que alerten precozmente, comoanorexia, náuseas, astenia, vómitos y dolor abdominal. De no corregirse, aparecen hipotensión, hipoglucemia, hiponatremia con hipercaliemia, deshidratación y shock. Es indispensable,aun en caso de duda, corregir la hipovolemia, el desequilibrioelectrolítico y la hipoglucemia, y administrar glucocorticoidesa dosis de estrés. Superada la fase aguda, administrar la dosis de corticoides de mantenimiento y, en caso necesario, añadir mineralocorticoides.

Emergencia pediátrica: insuficiencia suprarrenal aguda / Pediatric emergency: adrenal insufficiency and adrenal crisis

La insuficiencia suprarrenal aguda es un cuadro originado por deficiencia mineralocorticoidea o glucocorticoidea, cuyo no diagnóstico y adecuado tratamiento lleva a una emergenciagrave con riesgo para la vida del paciente. Se clasifica en insuficiencia suprarrenal primaria, que presenta en general compromiso glucocorticoideo y mineralocorticoideo, y secundaria,sin deficiencia mineralocorticoidea. Los pacientes pueden no presentar síntomas que alerten precozmente, comoanorexia, náuseas, astenia, vómitos y dolor abdominal. De no corregirse, aparecen hipotensión, hipoglucemia, hiponatremia con hipercaliemia, deshidratación y shock. Es indispensable,aun en caso de duda, corregir la hipovolemia, el desequilibrioelectrolítico y la hipoglucemia, y administrar glucocorticoidesa dosis de estrés. Superada la fase aguda, administrar la dosis de corticoides de mantenimiento y, en caso necesario, añadir mineralocorticoides.(AU)

Variabilidade do fenótipo de pacientes com síndrome de Noonan com e sem mutações no gene PTPN11 / Phenotype variability in Noonan syndrome patients with and without PTPN11 mutation

INTRODUÇÃO: Aproximadamente 50 por cento dos pacientes com síndrome de Noonan (SN) apresentam mutações em heterozigose no gene PTPN11. OBJETIVO: Avaliar a freqüência de mutações no PTPN11 em pacientes com SN e analisar a correlação fenótipo-genótipo. PACIENTES: 33 pacientes com SN. MÉTODO: Extração de DNA de leucócitos periféricos e seqüenciamento dos 15 exons do PTPN11. RESULTADOS: Nove diferentes mutações missense no PTPN11, incluindo a mutação P491H, ainda não descrita, foram encontradas em 16 dos 33 pacientes. As características clínicas mais freqüentes dos pacientes com SN foram: pavilhão auricular com rotação incompleta e espessamento da helix (85 por cento), baixa estatura (79 por cento), prega cervical (77 por cento) e criptorquidismo nos meninos (60 por cento). O Z da altura foi de -2,7 ± 1,2 e o do IMC foi de -1 ± 1,4. Os pacientes com mutação no PTPN11 apresentaram maior freqüência de estenose pulmonar do que os pacientes sem mutação (38 por cento vs. 6 por cento, p< 0,05). Pacientes com ou sem mutação no PTPN11 não diferiram em relação à média do Z da altura, Z do IMC, freqüência de alterações torácicas, características faciais, criptorquidia, retardo mental, dificuldade de aprendizado, pico de GH ao teste de estímulo e Z de IGF-1 ou IGFBP-3. CONCLUSÃO: Identificamos mutações no PTPN11 em 48,5 por cento dos pacientes com SN, os quais apresentaram maior freqüência de estenose pulmonar.

INTRODUCTION: Around 50 percent of Noonan syndrome (NS) patients present heterozygous mutations in the PTPN11 gene. AIM: To evaluate the frequency of mutations in the PTPN11 in patients with NS, and perform phenotype-genotype correlation. PATIENTS: 33 NS patients (23 males). METHODS: DNA was extracted from peripheral blood leukocytes, and all 15 PTPN11 exons were directly sequenced. RESULTS: Nine different missense mutations, including the novel P491H, were found in 16 of 33 NS patients. The most frequently observed features in NS patients were posteriorly rotated ears with thick helix (85 percent), short stature (79 percent), webbed neck (77 percent) and cryptorchidism (60 percent) in boys. The mean height SDS was -2.7 ± 1.2 and BMI SDS was -1 ± 1.4. Patients with PTPN11 mutations presented a higher incidence of pulmonary stenosis than patients without mutations (38 percent vs. 6 percent, p< 0.05). Patients with and without mutations did not present differences regarding height SDS, BMI SDS, frequency of thorax deformity, facial characteristics, cryptorchidism, mental retardation, learning disabilities, GH peak at stimulation test and IGF-1 or IGFBP-3 SDS. CONCLUSION: We identified missense mutations in 48.5 percent of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients.