The growth hormone (GH)/insulin-like growth factor (IGF) axis plays fundamental roles during development, maturation, and aging. Members of this axis, composed of various ligands, receptors, and binding proteins, are regulated in a tissue- and time-specific manner that requires precise control that is not completely understood. Some of the most recent advances in understanding the implications of this axis in human growth are derived from the identifications of new mutations in the gene encoding the pregnancy-associated plasma protein PAPP-A2 protease that liberates IGFs from their carrier proteins in a selective manner to allow binding to the IGF receptor 1. The identification of three nonrelated families with mutations in the PAPP-A2 gene has shed light on how this protease affects human physiology. This review summarizes our understanding of the implications of PAPP-A2 in growth physiology, obtained from studies in genetically modified animal models and the PAPP-A2 deficient patients known to date.

Fundamento y objetivo Los niños y adolescentes con síndrome de Down (SD) muestran una mayor incidencia de patología endocrinológica que la población control. Nuestro objetivo ha sido analizar la asociación de patología endocrinológica en una muestra de 1.105 pacientes con SD. Pacientes y método En 1.105 pacientes (0 a 18 años de edad) con SD se analizó retrospectivamente la presencia de patología tiroidea y de diabetes mellitus a lo largo de la infancia y la adolescencia. Resultados: La revisión de 1.105 casos de pacientes con SD seguidos en nuestro Servicio muestra la presencia de endocrinopatías en 222 casos (216 casos de patología tiroidea [19,5%] y 6 casos de diabetes mellitus [0,45%]). El hipotiroidismo primario subclínico se manifestó en 168 pacientes, el hipotiroidismo primario congénito en 15 casos, el hipotiroidismo primario clínico en 24, presentándose hipertiroidismo en 5 casos. Junto a ello, el 16,9% de los pacientes presentaba criterios de obesidad y el 28,2% de sobrepeso. La prevalencia de comorbilidades endocrinológicas en pacientes con SD es elevada respecto a la población general. Conclusiones: El hipotiroidismo subclínico, de base autoinmune en un alto porcentaje de casos y sin predominio por el sexo femenino, es la patología más frecuente en esta serie de pacientes con SD. La elevada frecuencia de patología tiroidea y de diabetes mellitus tipo 1 en estos pacientes aconseja efectuar un seguimiento estrecho de la patología autoinmune en el control clínico de los niños y adolescentes con SD. Background and objective Children and adolescents with Down syndrome (DS) show a greater prevalence of endocrinological abnormalities when compared with the general population. Our aim is to analyze endocrinological abnormalities in 1,105 patients with DS. Patients and methods A review of 1,105 cases of children and adolescents with DS under care in our Department (ages between 0 and 18 years) analyzed retrospectively the presence of thyroid pathology and diabetes mellitus throughout development. Results: Our data indicate the presence of endocrinological abnormalities in 222 patients [216 with thyroid pathology (19.5%) and 6 cases with diabetes mellitus type 1 (0.45%)]. Subclinical primary hypothyroidism was present in 168 cases, congenital primary hypothyroidism in 15 cases, clinical primary hypothyroidism in 24 cases and 5 cases had hyperthyroidism. In addition, 16.9% of these patients exhibit criteria of obesity and 28.2% had overweight. The prevalence of endocrinological comorbidities in children and adolescents with DS is higher than in the general population. Conclusion: Subclinical primary hypothyroidism, due to autoimmune causes in most of the patients, without a higher incidence in females, is the most common endocrinological pathology associated with DS. The high frequency of thyroid pathology and diabetes mellitus type 1 in these patients should induce us to have a closer clinical control of children and adolescents with DS.

Molecular study has become an invaluable tool in the field of RASopathies. Treatment with recombinant human growth hormone is approved in Noonan syndrome but not in the other RASopathies. The aim of this study was to learn about the molecular base of a large cohort of patients with RASopathies, with particular emphasis on patients with pathogenic variants in genes other than PTPN11, and its potential impact on rGH treatment indication. We reviewed the clinical diagnosis and molecular findings in 451 patients with a genetically confirmed RASopathy. HRAS alterations were detected in only 2 out of 19 patients referred with a Costello syndrome suspicion, whereas pathogenic variants in RAF1 and SHOC2 were detected in 3 and 2, respectively. In 22 patients referred with a generic suspicion of RASopathy, including cardiofaciocutaneous syndrome, pathogenic alterations in classic Noonan syndrome genes (PTPN11, SOS1, RAF1, LZTR1, and RIT1) were found in 7 patients and pathogenic variants in genes associated with other RASopathies (HRAS, SHOC2, and PPPCB1) in 4. The correct nosological classification of patients with RASopathies is critical to decide whether they are candidates for treatment with rhGH. Our data illustrate the complexity of differential diagnosis in RASopathies, as well as the importance of genetic testing to guide the diagnostic orientation in these patients.

Linked Content This article is linked to Philpott et al papers. To view these articles, visit https://doi.org/10.1111/apt.14573 and https://doi.org/10.1111/apt.15292.