María Angeles Albisu

Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development.

BACKGROUND Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.

SRD5A2 gene mutations and polymorphisms in Spanish 46,XY patients with a disorder of sex differentiation.

One hundred and forty-six index patients with 46,XY DSD in whom gonads were confirmed as testes were consecutively studied for a molecular diagnosis during the period 2002-2010. AR gene was analysed in all patients as the first candidate gene, yielding a mutation in 42.5% of cases and SRD5A2 gene was analysed as the second candidate gene, resulting in the characterization of 10 different mutations (p.Y91D, p.G115D, p.Q126R, p.R171S, p.Y188CfsX9, p.N193S, p.A207D, p.F219SfsX60, p.R227Q and p.R246W) in nine index patients (6.2% of the total number of 46,XY DSD patients). One of the mutations (p.Y188CfsX9) has never been reported. In addition, we genotyped SRD5A2 gene p.V89L and c.281+15T>C polymorphisms in 46,XY DSD and in 156 normal adult males and found that patients with SRD5A2 mutations or without a known molecular diagnosis presented a higher frequency of homozygous p.L89, homozygous TT and combined CCTT genotypes compared with controls. This result suggests that 46,XY DSD patient phenotypes may be influenced by SRD5A2 polymorphism genotypes. SRD5A2 gene mutations may not be as infrequent as previously considered in 46,XY DSD patients with variable degrees of external genitalia virilization at birth and normal T production and appears to be the second aetiology in our series.

Longitudinal Pubertal Growth According to Age at Pubertal Growth Spurt Onset: Data from a Spanish Study Including 458 Children (223 Boys and 235 Girls)

BACKGROUND Age at pubertal growth spurt (PGS) onset varies and is sex-dependent. We present anthropometric pubertal growth data for five 1-year interval age maturity groups: very early, early, intermediate, late and very late. METHODS Longitudinal growth study of 458 healthy children (223 boys, 235 girls). Ages at PGS onset and at adult height attainment, total pubertal growth (TPG), and peak height velocity (PHV) were evaluated. PGS begins between the ages of 10 and 15 in boys and 8 and 13 in girls; children were allocated to the corresponding 1-year interval age maturity group. RESULTS For each sex, the earlier the start of PGS onset, the higher were PHV and TPG gain. However, adult heights were similar among the five pubertal maturity groups. Height SDS values for mean values of the very early, early, late and very late maturity groups calculated according to data from the five pubertal maturity groups taken together as a single group differed from zero in both sexes, mainly during the pubertal years for the very early (> +1) and very late (> -1) maturers. These differences disappeared at adult height. CONCLUSIONS Our data might contribute to better clinical evaluation of pubertal growth according to individual pubertal maturity tempo.

Diagnosis and treatment in utero of goiter with hypothyroidism caused by iodide overload

A fetal goiter was detected by ultrasonography in a woman receiving potassium iodide. After this medication was discontinued at 29 weeks, a fetal hypothyroidism was confirmed by cordocentesis, and two doses of levothyroxine were administered by amniocentesis. At 34 weeks repeated cordocentesis showed fetal euthyroidism and ultrasonography shrinkage of the goiter. Growth and development normal at 1 year.

Influencia de la edad de inicio del brote de crecimiento puberal en la talla adulta

Fundamento y objetivo: En ambos sexos la duracion del crecimiento posnatal difiere entre los sujetos sanos debido a diferencias en la edad a la que inician el crecimiento puberal. Sin embargo, poco se conoce sobre la influencia de este hecho en la estatura adulta. Nuestro objetivo ha sido comparar la talla adulta entre cada uno de los 5 grupos madurativos en los que se inicia el crecimiento puberal. Sujetos y metodo: Dos pediatras realizaron un seguimiento longitudinal de 230 personas (115 mujeres y 115 varones) sanas y sin medicaciones cronicas desde el nacimiento hasta la talla adulta. Se midio la estatura 1-3 veces/ano y se obtuvieron las correspondientes curvas de crecimiento. A partir de ellas se evaluaron la velocidad de crecimiento (cm/ano), la edad al inicio del crecimiento puberal (anos), el crecimiento puberal (cm) y la talla adulta (cm). Segun la edad de inicio del crecimiento puberal, los participantes se agruparon en 5 grupos: 8-9 anos (n = 10), 9-10 anos (n = 29), 10-11 anos (n = 45), 11-12 anos (n = 23) y 12-13 anos (n = 8) en las mujeres, y 10-11 anos (n = 10), 11-12 anos (n = 26), 12-13 anos (n = 45), 13-14 anos (n = 27) y 14-15 anos (n = 7) en los varones. Resultados: En ambos sexos se observaron diferencias estadisticamente significativas para la media de las estaturas al inicio del crecimiento puberal (p < 0,01) y para la media del crecimiento puberal total (p < 0,0001) cuando se comparan entre si los 5 grupos madurativos. Sin embargo, estas diferencias no se observaron entre la media de las tallas adultas cuando se comparan los 5 grupos madurativos entre si, ni cuando se comparo cada grupo con el conjunto de la muestra, ni cuando se comparo cada grupo con las medias obtenidas en estudios recientes de crecimiento de la poblacion espanola. En ambos sexos se observo una correlacion positiva y estadisticamente significativa (p # 0,03) entre la talla al inicio del crecimiento puberal y la talla adulta. Sin embargo, esta correlacion no se observo entre las edades de inicio del crecimiento puberal y las correspondientes estaturas adultas. Conclusiones: En ambos sexos, los factores geneticos, pero no la edad al inicio del crecimiento puberal, influyen en la talla adulta. Aunque la duracion del crecimiento posnatal es menor en las personas con maduracion precoz que en aquellas con maduracion mas tardia, las primeras tienen un desarrollo puberal mas prolongado, ganan mas centimetros de altura y finalizan su crecimiento con una estatura adulta similar.