GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was R0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

Rasopathies are a group of rare disorders characterized by neurocardiofaciocutaneous involvement, and caused by mutations in several genes of the RAS/MAPK pathway. In the present study, we characterized growth parameters, body composition, and nutritional aspects of children and adults (n = 62) affected by these disorders, mainly Noonan syndrome, using an indirect method-anthropometry-and a 24-hr recall questionnaire. The growth parameters in our cohort showed short stature, especially in individuals with RAF1 and SHOC2 mutations, lower obesity rates compared to the control population, and BMI scores highest in individuals with BRAF mutations and lowest in individuals with SHOC2. Body composition showed a compromise in the upper arm muscle circumference, with a statistically significant difference in the z-score of triceps skinfold (P = 0.0204) and upper arm fat area (P = 0.0388) between BRAF and SHOC2 groups and in the z-score of triceps skinfold between RAF1 and SHOC2 (P = 0.0218). The pattern of macronutrient consumption was similar to the control population. Our study is the first to address body composition in RASopathy individuals and the data indicate a compromise not only in adipose tissue, but also in muscle mass. Studies using different techniques, such as dual-energy X-ray absorptiometry or imaging studies, which give a more precise delineation of fat and non-fat mass, are required to confirm our results, ultimately causing an impact on management strategies. © 2016 Wiley Periodicals, Inc.

The 9p trisomy syndrome is a rare condition, clinically characterized by a wide range of dysmorphic features, intellectual disability, and, in most patients, by short stature. Recombinant human growth hormone (rhGH) therapy is still controversial in syndromic disorders, the reason for which it is not currently indicated. Here we report a 7-year-old boy with 9p trisomy syndrome and marked short stature. Results of routine laboratory assessments were normal. IGF1 and IGFBP3 levels were both in the normal range (-1.6 and -0.7 SDS, respectively). GH peak in response to oral clonidine stimulation test was 3.5 μg/L, which is considered a normal response. Chromosomal analysis revealed the karyotype 47,XY, + del(9)(pter-q11:) dn. SNP array data indicated absence of mosaicism [arr 9p24.3-p13.1 (203,861-38,787,480) x3]. By the age of 8.3 years, the patient had persistent short stature (-2.9 SDS) with normal growth velocity (4.9 cm/y; -0.7 SDS), not showing spontaneous catch-up. After 5.6 years of rhGH therapy (50 μg/kg/d), height SDS improved from -2.9 to -1.0. This result suggests that rhGH therapy could be considered for patients with 9p trisomy syndrome who present with short stature. The degree of intellectual disability and the potential for social inclusion should be taken into account when recommending this treatment. Additional studies are needed to establish the benefits of height gain in these patients.

Long-term rhGH treatment with standard doses might be associated with acromegalic features (increased foot size and lower jaw measurements) in patients with GH deficiency who achieved final height, especially in girls. Neither the clinical nor the hormonal parameters, IGF-I and IGFBP-3 levels, were useful to predict the development of these features. Further studies are necessary to analyse the frequency of this side-effect and how to prevent it.

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