[Noonan syndrome: genetic and clinical update and treatment options]. / Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas.

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies¼. Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.

Differences between patients with isolated GH deficiency based on findings in brain magnetic resonance imaging.

INTRODUCTION: Protocol for prescribing hormone replacement therapy in isolated growth hormone (GH) deficiency includes magnetic resonance imaging of the brain. There is controversy on the frequency of structural pituitary abnormalities and on the importance of abnormal MRI findings on prognosis and response to GH replacement. METHODS: A descriptive, retrospective study of children of both sexes aged 0-14 years, who had undergone brain MRI, diagnosed with isolated GH deficiency at a tertiary hospital in the past 14 years, aimed at reporting the frequency of abnormal MRI findings in isolated GH deficiency, and to establish whether differences exist in height diagnosis and evolution according to MRI findings. MRI findings were also compared with the findings reported in healthy children in order to establish incidence. RESULTS: 96 patients were studied, of whom 74/96 (77%) reached adult age. Abnormal MRI findings were seen in 11.5% of them (8/11 of pituitary origin). No brain or pituitary tumor was seen in any case. Patients with abnormal images had a mean age at treatment start of 8 years, a target height of -0.8SD, and a final height of 1.04SD, while patients with normal MRI findings had an age at treatment start of 10 years old, a target height of -1.44SD, and a final height of -1.75SD, with statistically significant differences. CONCLUSIONS: Patients with abnormal MRI findings show a more favorable response to GH replacement therapy.

Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype.

MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.