BACKGROUND: Recent data indicate that the risk of developing a thyroid neoplasm clearly is increased after high‐dose, therapeutic radiation therapy during childhood. To better understand the time course, natural history, and histopathology of thyroid lesions that develop after high‐dose irradiation, the authors undertook a retrospective study of all survivors of childhood and adolescent malignancies who were treated at Memorial Sloan‐Kettering Cancer Center and who developed a clinically apparent thyroid neoplasm.METHODS: The authors searched the data base of the Department of Pediatrics, the hospital‐based tumor registry, and the hospital medical records database for patients with thyroid neoplasms.RESULTS: Thirty‐three patients were identified who developed a thyroid neoplasm after therapeutic radiation. Primary diagnoses were Hodgkin disease (n = 18 patients), non‐Hodgkin lymphoma (n = 10 patients), acute lymphoblastic leukemia (n = 2 patients), acute myeloid leukemia (n = 1 patient), Wilms tumor (n = 1 patient), and neuroblastoma (n = 1 patient). The median age at the time of diagnosis of the primary malignancy was 12.0 years (range, 3.7–18.3 years), the median radiation dose to the thyroid gland was 2400 centigrays (cGy; range, 1000–4200 cGy), and the median interval from the time of radiation therapy until the recognition of thyroid disease was 13.0 years (range, 6.2–30.1 years). Thirteen of 33 thyroid lesions (39%) were malignant (11 papillary carcinomas and 2 follicular carcinomas). Age at diagnosis, gender ratio, and time elapsed since initial treatment did not differ between patients with malignant and benign lesions, but the median radiation dose to the thyroid was lower in patients who had malignant disease compared with patients who had benign disease (2000 cGy vs. 2950 cGy; P = 0.03). Disease was confined to the neck in all patients who had malignant thyroid lesions; after a median follow‐up of 6.5 years (range, 0.9–12 years), none of the patients developed progressive or recurrent disease.CONCLUSIONS: Data from this study suggest that a high proportion of clinically apparent thyroid neoplasms that develop after therapeutic radiation for a childhood malignancy are malignant. However, most of these thyroid malignancies do not appear to behave in an aggressive fashion. Because thyroid neoplasms may not become evident for decades after radiation therapy, all individuals who are at risk require life‐long follow‐up. Cancer 2003;97:2397–403. © 2003 American Cancer Society.DOI 10.1002/cncr.11362

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1^−/−) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.

Context Adrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been implemented in five states with plans to expand to all 50 states in the US. Adrenal insufficiency ultimately develops in most males with ALD but the earliest age of onset is not well established. Objective These clinical recommendations are intended to address screening for adrenal insufficiency in boys identified to have ALD by newborn screen. Participants Seven members of the Pediatric Endocrine Society Drug and Therapeutics & Rare Diseases Committee, with clinical experience treating children with ALD and adrenal insufficiency, and a pediatric endocrinologist and laboratory director were selected to be on the working committee. Consensus Process The authors comprised the working group and performed systematic reviews of the published literature regarding adrenal insufficiency and ALD. The recommendations were reviewed and approved by the larger Pediatric Endocrine Society Drug and Therapeutics & Rare Diseases Committee and then by the Pediatric Endocrine Society Board of Directors. Conclusions There is limited literature evidence regarding monitoring of evolving adrenal insufficiency in male infants and children with ALD. The recommendations suggest initiating assessment of adrenal function at diagnosis with ALD and regular monitoring, in order to identify boys with adrenal insufficiency in a timely manner and prevent life-threatening adrenal crisis. These recommendations are intended to serve as an initial guide, with the understanding that additional experience will inform future guidelines.

BACKGROUND: Understanding the risk for type 2 diabetes (T2D) early in the life course is important for prevention. Whether genetic information improves prediction models for diabetes from adolescence into adulthood is unknown. METHODS: With the use of data from 1030 participants in the Bogalusa Heart Study aged 12 to 18 followed into middle adulthood, we built Cox models for incident T2D with risk factors assessed in adolescence (demographics, family history, physical examination, and routine biomarkers). Models with and without a 38 single-nucleotide polymorphism diabetes genotype score were compared by C statistics and continuous net reclassification improvement indices. RESULTS: Participant mean (± SD) age at baseline was 14.4 ± 1.6 years, and 32% were black. Ninety (8.7%) participants developed T2D over a mean 26.9 ± 5.0 years of follow-up. Genotype score significantly predicted T2D in all models. Hazard ratios ranged from 1.09 per risk allele (95% confidence interval 1.03–1.15) in the basic demographic model to 1.06 (95% confidence interval 1.00–1.13) in the full model. The addition of genotype score did not improve the discrimination of the full clinical model (C statistic 0.756 without and 0.760 with genotype score). In the full model, genotype score had weak improvement in reclassification (net reclassification improvement index 0.261). CONCLUSIONS: Although a genotype score assessed among white and black adolescents is significantly associated with T2D in adulthood, it does not improve prediction over clinical risk factors. Genetic screening for T2D in its current state is not a useful addition to adolescents’ clinical care.