Bone age determination in eutrophic, overweight and obese Brazilian children and adolescents: a comparison between computerized BoneXpert and Greulich-Pyle methods.

BACKGROUND: Bone age determination is usually employed to evaluate growth disorders and their treatment. The Greulich-Pyle method is the simplest and most frequently used type of evaluation, but it presents huge interobserver variability. The BoneXpert is a computer-automated method developed to avoid significant bone age variability among distinct observers. OBJECTIVE: To compare the BoneXpert and Greulich-Pyle methods of bone age determination in eutrophic children and adolescents, as well as in overweight and obese pediatric patients. MATERIALS AND METHODS: The sample comprised 515 participants, 253 boys (159 eutrophic, 53 overweight and 41 obese) and 262 girls (146 eutrophic, 76 overweight and 40 obese). Left hand and wrist radiographs were acquired for bone age determination using both methods. RESULTS: There was a positive correlation between chronological age and Greulich-Pyle, chronological age and BoneXpert, and Greulich-Pyle and BoneXpert. There was a significant increase (P<0.05) in bone age in both the Greulich-Pyle and BoneXpert methods in obese boys when compared to eutrophic or overweight boys of the same age. In girls, there was an increase in bone age in both obese and overweight individuals when compared to eutrophic girls (P<0.05). The Greulich-Pyle bone age was advanced in comparison to that of BoneXpert in all groups, except in obese boys, in which bone age was similarly advanced in both methods. CONCLUSION: The BoneXpert computer-automated bone age determination method showed a significant positive correlation with chronological age and Greulich-Pyle. Furthermore, the impact of being overweight or obese on bone age could be identified by both methods.

Whole Exome Sequencing in Patients With Ectopic Posterior Pituitary.

Context: Ectopic posterior pituitary (EPP), a condition in which the posterior pituitary gland is displaced due to defective neuronal migration, is frequently associated with hypopituitarism. Genetic variants play a role, but many cases remain unexplained. Objective: A large EPP cohort was studied to explore the importance of genetic variants and how they correlate with clinical findings. Methods: Whole exome sequencing was performed on a discovery sample of 27 cases to identify rare variants. The variants that met the criteria for rarity and biological relevance, or that were previously associated with EPP (ROBO1 and HESX1), were then resequenced in the 27 cases plus a replication sample of 51 cases. Results: We identified 16 different variants in 12 genes in 15 of the 78 cases (19.2%). Complete anterior pituitary deficiency was twice as common in cases with variants of interest compared to cases without variants (9/15 [60%] vs 19/63 [30.1%], respectively; Z test, P = 0.06). Breech presentation was more frequent in the variant positive group (5/15 vs 1/63; Z test, P = 0.003). Four cases had variants in ROBO1 and 1 in HESX1, genes previously associated with EPP. The ROBO1 p.S18* variant has not been reported previously; ROBO1 p.Q1227H has not been associated with EPP previously. Conclusion: EPP cases with variants of interest identified in this study were more likely to present with severe clinical disease. Several variants were identified in genes not previously associated with EPP. Our findings confirm that EPP is a multigenic disorder. Future studies are needed to identify additional genes.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development.

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.