Thyroid Function During the Fetal and Neonatal Periods.

Thyroid hormones are essential during infancy and childhood for growth and brain development. The formation and maturation of the newborn's hypothalamic-pituitary-thyroid axis begin in utero with fetal dependence on maternal thyroid hormones early in the pregnancy. As the fetal thyroid gland begins to produce thyroid hormones in the second trimester, the reliance decreases and remains at lower levels until birth. After birth, the detachment from the placenta and the change in thermal environment lead to a rapid increase in circulating thyroid-stimulating hormone in the neonate within hours, resulting in subsequent increases in thyroxine and triiodothyronine concentrations. Preterm infants may have lower thyroxine concentrations because of an immature hypothalamic-pituitary-thyroid axis at the time of birth and premature discontinuation of transference of maternal thyroid hormones. Similarly, infants with critical illness unrelated to the thyroid gland may have lower thyroxine levels. Infants born to mothers with Graves' disease are at risk for hypothyroidism and hyperthyroidism, which is related to the placental transfer of maternal autoantibodies, as well as antithyroid medications. An understanding of the normal embryology and physiology of the fetal and neonatal thyroid will help in evaluating a newborn for thyroid disorders.

Adrenoleukodystrophy in the era of newborn screening.

PURPOSE OF REVIEW: Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular dysfunction. The present review is intended to describe the current knowledge of the pathophysiology of ALD and provide an update regarding newborn screening, diagnosis, monitoring, and treatment. RECENT FINDINGS: New York State initiated newborn screening for ALD on December 30, 2013. Successful ALD newborn screening has led to its addition on other state newborn screens and recommendations for universal screening. Initial incidence reports, based on newborn screening, suggest ALD may be more common than previously described. The Pediatric Endocrine Society has published guidance for monitoring newborn males with ALD and case reports suggest biochemical adrenal insufficiency can be present during early infancy. Allogeneic hematopoietic stem cell transplant and gene therapy have been effective at halting the progression of cerebral ALD. SUMMARY: Early diagnosis and monitoring for progression of ALD can prevent adrenal crisis and treat the cerebral form of the disease. Initial guidelines for surveillance are likely to evolve as newborn screening not only aids in early detection and therapeutic interventions for ALD, but also expands our knowledge of the natural history of ALD.

Intrathyroidal Thymic Tissue in an Adolescent with Graves' Disease: Case Report and Review of Current Literature.

Intrathyroidal thymic tissue (ITT) is a benign entity found in children and young adolescents that often mimics a concerning thyroid nodule with microcalcifications on ultrasound. It is challenging for the clinician to distinguish between these two entities, which may lead to unnecessary invasive procedures. We report an adolescent female patient with Graves' disease who underwent total thyroidectomy for a thyroid nodule concerning for malignancy for which the surgical pathology ultimately revealed ITT. As ITT is rarely found beyond childhood, the concurrent Graves' disease may have led to persistence of thymic tissue in this patient. Several sonographic features can help in differentiating ITT from a concerning thyroid nodule. Once identified, ITT should be followed by serial imaging with anticipation of decreasing size or complete resolution over time.

Early Onset Primary Adrenal Insufficiency in Males with Adrenoleukodystrophy: Case Series and Literature Review.

The lifetime risk for adrenal insufficiency in male children with adrenoleukodystrophy (ALD) is estimated at 80%-86%. Prior to newborn screening, male children with ALD were identified by family history or after symptom development. These young patients with ALD and adrenal insufficiency support newborn screening for ALD.

Limb anterior-posterior polarity integrates activator and repressor functions of GLI2 as well as GLI3.

Anterior-posterior (AP) limb patterning is directed by sonic hedgehog (SHH) signaling from the posteriorly located zone of polarizing activity (ZPA). GLI3 and GLI2 are the transcriptional mediators generally utilized in SHH signaling, and each can function as an activator (A) and repressor (R). Although GLI3R has been suggested to be the primary effector of SHH signaling during limb AP patterning, a role for GLI3A or GLI2 has not been fully ruled out, nor has it been determined whether Gli3 plays distinct roles in limb development at different stages. By conditionally removing Gli3 in the limb at multiple different time points, we uncovered four Gli3-mediated functions in limb development that occur at distinct but partially over-lapping time windows: AP patterning of the proximal limb, AP patterning of the distal limb, regulation of digit number and bone differentiation. Furthermore, by removing Gli2 in Gli3 temporal conditional knock-outs, we uncovered an essential role for Gli2 in providing the remaining posterior limb patterning seen in Gli3 single mutants. To test whether GLIAs or GLIRs regulate different aspects of AP limb patterning and/or digit number, we utilized a knock-in allele in which GLI1, which functions solely as an activator, is expressed in place of the bifunctional GLI2 protein. Interestingly, we found that GLIAs contribute to AP patterning specifically in the posterior limb, whereas GLIRs predominantly regulate anterior patterning and digit number. Since GLI3 is a more effective repressor, our results explain why GLI3 is required only for anterior limb patterning and why GLI2 can compensate for GLI3A in posterior limb patterning. Taken together, our data suggest that establishment of a complete range of AP positional identities in the limb requires integration of the spatial distribution, timing, and dosage of GLI2 and GLI3 activators and repressors.

Sonic hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain.

Astrocytes are an essential component of the CNS, and recent evidence points to an increasing diversity of their functions. Identifying molecular pathways that mediate distinct astrocyte functions, is key to understanding how the nervous system operates in the intact and pathological states. In this study, we demonstrate that the Hedgehog (Hh) pathway, well known for its roles in the developing CNS, is active in astrocytes of the mature mouse forebrain in vivo. Using multiple genetic approaches, we show that regionally distinct subsets of astrocytes receive Hh signaling, indicating a molecular diversity between specific astrocyte populations. Furthermore, we identified neurons as a source of Sonic hedgehog (Shh) in the adult forebrain, suggesting that Shh signaling is involved in neuron-astrocyte communication. Attenuation of Shh signaling in postnatal astrocytes by targeted removal of Smoothened, an obligate Shh coreceptor, resulted in upregulation of GFAP and cellular hypertrophy specifically in astrocyte populations regulated by Shh signaling. Collectively, our findings demonstrate a role for neuron-derived Shh in regulating specific populations of differentiated astrocytes.