The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.

We designed a clinical application of glucose to lymphocyte ratio (GLR) as it might be a sensitive parameter to determine the glucose metabolism and behavior of the cancer (i.e., its aggressiveness), and the immunologic status of a patient with cancer. Thus, we investigated the association of GLR with the overall survival (OS) and disease-free survival (DFS) of patients with T2 gallbladder (GB) cancer after curative-intent surgery. The medical records of patients with T2 GB cancer who underwent surgery were retrospectively reviewed. The clinicopathologic characteristics, preoperative complete blood counts, fasting blood glucose, albumin, cholesterol, and follow-up information were collected. A total of 197 patients were included in the study. In multivariate analysis, high GLR (>69.3) was associated with poor OS (HR = 15.249, 95% CI: 4.090-56.849, P = 0.0001) along with R1 status (HR = 1.755, 95% CI: 0.033-0.910, P = 0.033), >3 metastatic lymph nodes (HR = 2.809, 95% CI: 1.403-5.625; P = 0.004), and lymphovascular invasion (HR = 8.041, 95% CI: 2.881-22.442; P = 0.0001). Moreover, high GLR (HR = 3.666, 95% CI: 1.145-11.737, P = 0.029), adjuvant chemotherapy (HR = 6.306, 95% CI: 1.921-20.699; P = 0.002), lymphovascular invasion (HR = 5.464, 95% CI: 1.783-16.746; P = 0.003), and high-grade tumor (HR = 2.143, 95% CI: 1.042-4.407; P = 0.038) were independently associated with DFS. Preoperative GLR is an independent predictor of OS and DFS in T2 GB cancer. Further studies are required to validate these findings.

Congenital growth hormone deficiency is a rare disorder with an incidence of approximately 1 in 4,000 live births. Pituitary development is under the control of a multitude of spatiotemporally regulated signaling molecules and transcription factors. Mutations in the genes encoding these molecules can result in hypopituitarism but for the majority of children with congenital hypopituitarism, the aetiology of their disease remains unknown. The proband is a 5-year-old girl who presented with neonatal hypoglycaemia and prolonged jaundice. No definitive endocrine cause of hypoglycaemia was identified in the neonatal period. She was born of normal size at 42 weeks but demonstrated growth failure with a progressive reduction in height to -3.2 SD by age 4.5 years and failed a growth hormone stimulation test with a peak growth hormone of 4.2 mcg/L. MRI of the pituitary gland demonstrated a hypoplastic anterior lobe and ectopic posterior lobe. Array CGH demonstrated an inherited 0.2 Mb gain at 1q21.1 and a de novo 4.8 Mb heterozygous deletion at 20p12.2-3. The deletion contained 17 protein coding genes including PROKR2 and BMP2, both of which are expressed during embryological development of the pituitary gland. PROKR2 mutations have been associated with hypopituitarism but a heterozygous deletion of this gene with hypopituitarism is a novel observation. In conclusion, congenital hypopituitarism can be present in individuals with a 20p12.3 deletion, observed with incomplete penetrance. Array CGH may be a useful investigation in select cases of early onset growth hormone deficiency, and patients with deletions within this region should be evaluated for pituitary hormone deficiencies.

Anatomic repair has become the preferred option in the subgroup of patients with congenitally corrected transposition of the great arteries with ventricular septal defect and pulmonary obstruction. We report our 14-year experience with this approach. From April 2001 to February 2014, 22 patients with congenitally corrected transposition with ventricular septal defect and pulmonary obstruction underwent anatomic repair. Nineteen patients had a modified Senning-Rastelli procedure, 2 had a Mustard-Rastelli procedure, and one had a hemi-Mustard-Glenn-Rastelli procedure. The mean age was 10.9 years, and 8 (36.4%) patients were male. There were 2 early deaths from sepsis and ventricular failure at 18 and 81 days postoperatively, and 3 late deaths from ventricular failure at 4, 33, and 113 months postoperatively. Left ventricular failure with mitral valve regurgitation was present in 3 of the 5 patients who died. Among the survivors, 3 underwent 4 transcatheter interventions for right ventricular outflow tract obstruction and 3 underwent 4 reoperations for atrial pathway obstruction, left and right ventricular outflow tract obstruction, or residual shunt. At a median follow-up of 64 months (range 14-167 months), 15 of 17 survivors were in functional class I. One patient had severe mitral valve regurgitation and was awaiting valve replacement. Another patient had right ventricular outflow conduit obstruction and was scheduled for reoperation. Results of atrial switch-Rastelli procedures in this subgroup of patients with corrected transposition are satisfactory but still imperfect. Mitral regurgitation might predict a poor outcome. Long-term follow-up is necessary.