Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

Role of the pituitary-bone axis in skeletal pathophysiology.

PURPOSE OF REVIEW: Embedded within textbooks for decades is the hard fact that releasing hormones from the anterior pituitary, namely, follicle-stimulating hormone, thyroid-stimulating hormone and adrenocorticotropic hormone, stimulate master hormone secretion from target endocrine organs. We propose a paradigm shift in endocrine physiology, which is that these hormones act by design on bone directly, also now considered an endocrine organ. RECENT FINDINGS: Complementary investigations using mouse genetic and cell biological approaches reveal that follicle-stimulating hormone and thyroid-stimulating hormone act on bone cells directly to regulate bone remodeling and bone mass. Thyroid-stimulating hormone inhibits bone remodeling, whereas follicle-stimulating hormone stimulates it. We also find that the posterior pituitary hormone oxytocin is anabolic to the skeleton. SUMMARY: An ambitious extrapolation is that a plurality of pituitary hormones acts in concert as part of a 'pituitary-bone' axis to regulate skeletal integrity in health and disease. When dysregulated master hormone levels during hypogonadism and hyperthyroidism cause altered pituitary hormone secretion through hypothalamic feedback, the latter hormones contribute to the skeletal loss.

Oxytocin deficiency impairs maternal skeletal remodeling.

We have reported that the posterior pituitary hormone, oxytocin (OT), known for its effects in inducing parturition, lactation and social bonding, is also a skeletal hormone. Here, we demonstrate that OT plays a key role in enabling maternal skeletal mobilization during pregnancy by enhancing the formation of bone resorbing osteoclasts. Osteoclast formation ex vivo is thus diminished in pregnant mothers with genetic OT-deficiency. OT(-/-) pups at day E20 also show a defect in trabecular bone. microCT measurements reveal normal bone volume, but increased trabecular numbers, suggesting that trabeculae in OT(-/-) pups are hypomineralized. We suggest that OT facilitates intergenerational transfer of calcium ions from a pregnant mother to the pups.