Jesús Barreiro

Influence of sex, age and adrenergic pathways on the growth hormone response to GHRP‐6

OBJECTIVE His‐dTrp‐Ala‐Trp‐dPhe‐Lys‐NH2 (GHRP‐6) is a synthetic compound that releases GH in a dose‐related and specific manner in several species including man. To further characterize the effects of GHRP‐6 on GH secretion in normal human subjects, we assessed plasma GH levels following GHRP‐6 administration in normal male adult subjects, normal female adult subjects at different stages of their menstrual cycle and in normal prepubertal male and female children. We also studied the influence of adrenergic pathways on GHRP‐6 induced GH secretion in normal adult male subjects.

High variability in CYP21A2 mutated alleles in Spanish 21‐hydroxylase deficiency patients, six novel mutations and a founder effect

Objective To detect common as well as rare and novel CYP21A mutations in 21‐hydroxylase deficiency patients. To estimate the distribution of mutations and compare them with other European studies. To construct haplotypes linked to a recurrent novel mutation.

High serum leptin levels in children with type 1 diabetes mellitus : Contribution of age, BMI, pubertal development and metabolic status

Children with diabetes mellitus are prone to develop obesity and to experience a delay in onset of the pubertal process. In order to understand the role of leptin in these abnormalities, serum leptin levels were analysed in children with type 1 diabetes mellitus.

Pituitary Stalk Dysgenesis-Induced Hypopituitarism in Adult Patients: Prevalence, Evolution of Hormone Dysfunction and Genetic Analysis

Objectives: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. Design: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. Results: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. Conclusion: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset.

Plasma growth hormone response to growth hormone‐releasing hexapeptide (GH‐RP‐6) in children with short stature

Eighteen children with short stature were evaluated for growth hormone (GH) reserve after pharmacological tests and a single iv injection of GH‐RP‐6. These children were divided into two groups: 10 were diagnosed as having idiopathic GH deficiency by classical stimulation tests (group A) and the remaining 8 (group B) were considered growth‐retarded children with normal GH secretion, following conventional stimulation, but reduced endogenous GH secretion. The results were compared with a group of 12 normal children. As a group, patients in group A showed a lower GH response to GH‐RP‐6, while patients in group B had a similar response as normal controls. However, on an individual basis, a considerable degree of overlapping in responses among the three groups was evident. These data indicate that, on an individual basis, GH‐RP‐6 testing is not of diagnostic value in children suspected of having idiopathic GH deficiency.GH deficiency, GH‐RP‐6, short stature

Hypochondroplasia and acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor receptor 3 gene?

BACKGROUND Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast growth factor receptor 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene. OBJECTIVE AND DESIGN After initial study of the proband, who had been consulted for short stature and who also presented AN, the study was extended to the patients mother and to 12 additional family members. METHODS Clinical, biochemical and radiological studies were performed on the family. In addition, exons 11 and 13 of FGFR3 were analyzed. RESULTS The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. The members with normal phenotypes were non-carriers of the mutation. CONCLUSION This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, p.Lys650Thr. This finding demonstrates the coexistence of both conditions due to the same mutation and it might represent a true complex, which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.

Evolutionary Analyses of Entire Genomes Do Not Support the Association of mtDNA Mutations with Ras/MAPK Pathway Syndromes

Background There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). Methods/Principal Findings The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. Conclusions/Significance As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.

Kallmann's syndrome with a novel missense mutation in the KAL1 gene that modifies the major cell adhesion site of the anosmin-1 protein.

Kallmanns syndrome (KS) refers to the association of hypogonadic hypogonadism and anosmia or hyposmia. The X-linked form of the disease is due to mutations in the KAL1 gene that encodes for the protein anosmin-1. We studied the KAL1 gene in a patient with KS and his family by PCR amplification and direct sequencing. A novel missense mutation (V263G) that modifies the major cell adhesion site of the anosmin-1 protein was identified. Our results suggest that this reported mutation is responsible for KS and might help to elucidate the function of an important area of the anosmin-1 protein.

Imágenes en pediatríaAcantosis nigricans en los síndromes de resistencia grave a la insulinaAcantosis nigricans in severe insulin resistance syndromes

B f n d p Berardinelli-Seip. La lipodistrofia parcial familiar tipo 2 es una enfermedad autosómica dominante caracterizada por la pérdida de grasa en extremidades y nalgas, y acúmulo en cara y sotabarba. La acantosis nigricans (AN) es un signo cutáneo de resistencia a la insulina (RI), que se manifiesta como un oscurecimiento y engrosamiento de la piel. La mayor prevalencia de obesidad entre niños y adolescentes ha hecho que este signo se pueda observar más frecuentemente y debe ser diferenciado de otros cuadros infrecuentes de RI grave no asociados con la obesidad. Los síndromes de Donohue, Rabson-Mendenhall y RI tipo A son trastornos debidos a mutaciones en el receptor de la insulina. El síndrome de Donohue se manifiesta desde el nacimiento con AN, facies de duende, pubertad precoz, escaso panículo adiposo, hipertricosis, retraso del desarrollo e hipoglucemias. El síndrome de RabsonMendenhall1 (fig. 1) se caracteriza por retraso del desarrollo, AN, apiñamiento dental e hipertrofia gingival (fig. 2) y macropene/clitoromegalia. El síndrome de RI tipo A suele

Acantosis nigricans en los síndromes de resistencia grave a la insulina

B f n d p Berardinelli-Seip. La lipodistrofia parcial familiar tipo 2 es una enfermedad autosómica dominante caracterizada por la pérdida de grasa en extremidades y nalgas, y acúmulo en cara y sotabarba. La acantosis nigricans (AN) es un signo cutáneo de resistencia a la insulina (RI), que se manifiesta como un oscurecimiento y engrosamiento de la piel. La mayor prevalencia de obesidad entre niños y adolescentes ha hecho que este signo se pueda observar más frecuentemente y debe ser diferenciado de otros cuadros infrecuentes de RI grave no asociados con la obesidad. Los síndromes de Donohue, Rabson-Mendenhall y RI tipo A son trastornos debidos a mutaciones en el receptor de la insulina. El síndrome de Donohue se manifiesta desde el nacimiento con AN, facies de duende, pubertad precoz, escaso panículo adiposo, hipertricosis, retraso del desarrollo e hipoglucemias. El síndrome de RabsonMendenhall1 (fig. 1) se caracteriza por retraso del desarrollo, AN, apiñamiento dental e hipertrofia gingival (fig. 2) y macropene/clitoromegalia. El síndrome de RI tipo A suele