A rapid-fire presentation of several papers on Saturday educated me about some very-new aspects of research into pediatric endocrine issues.
Molecular Changes in the aromatase gene in girls with Early Puberty
Dr. Stueve of Keck School of Medicine at the University of Southern California, LA presented work done in conjunction with Mount Sinai School of Medicine. They reminded the audience that both obesity and early thelarche (onset of breast development) are risk factors for estrogen-sensitive breast cancer, presumably due to a longer time spent in an estrogen-exposed status. The enzyme that catalyzes the final step in estrogen formation is called aromatase, or CYP19A1. The hypothesis was that patients with overweight and early thelarche would have less methylation (and therefore increased expression) of the CYP19A1 gene. This investigative team analyzed salivary tissue DNA of 6-8 yo girls with both pubic hair and breast development, and indeed found such an association. In essence, heavier girls with early breast development had DNA with more availability of the aromatase gene to be expressed.
àWould be interesting to see what would happen if these girls lost weight. Would the methylation status of this gene change? Is it static or dynamic?
Optimizing outcomes in preterm, Very-Low Birthweight (VLBW) babies
Work from the German Neonatal Network sought to establish causes for different outcomes in VLBW babies treated with steroids. Steroids called glucocorticoids are dosed in this population to optimize lung development, which is important, though not without its attendant risks. This medication suppresses the immune system in an already vulnerable population, and increase the likelihood for sepsis. The gene for the receptor for this medication (glucocorticoid receptor) was analyzed from 2200 infants, and noted to be different in those with varying alleles.
è Allows for future pharmacogenomics, which is tailoring therapy to a specific patient’s genes. While treatment for the lung maturation would still need to occur, knowledge of the individual patient’s susceptibility to infection may be crucial to minimizing complications and length of NICU stay.
Establishing a new test for Cushing Syndrome in Children
Cushing Syndrome is a rare disorder of cortisol excess. This hormone level varies in a diurnal fashion, high in the morning, and low in evening and overnight. Endocrinologists take advantage of this, and note that one of the first sign of Cushing Syndrome is loss of this diurnal variation, and in adults, measurement of salivary cortisol is an established means to test for this condition. However, to use this convenient test in children (as opposed to the current 24hr urine collection or midnight serum level), one must first establish normal levels. Dr. Rajiv Kumar of Stanford University Medical Center (link) analyzed salivary cortisol of children of normal height referred for short stature to their endocrine clinic who were otherwise healthy, and separated them into those 8yrs and older, and those less than 8. Data were gathered at both bedtime and midnight, and levels were quite close, obviating a need for a later bedtime, kids!
è More normal data makes a diagnostic test robust. One of the presenting signs of Cushing is weight gain, and with the epidemic of obesity in children, it would be nice to have an easier test than 24hr urine to use in special situations when clinical suspicion is higher.
Increasing diagnostic accuracy of newborn screening for CAH
Congenital Adrenal Hyperplasia (CAH) is a rare disease, but in those who go undetected, can be life-threatening at 1-2 weeks of life due to adrenal crisis. For this reason, screening for it is part of the Newborn screen. The cause is a deficiency in 21hydroxylase, which is important in cortisol synthesis, and leads to a buildup of the precursor 17 hydroxyprogesterone (17OHP). Testing should be straightforward, just an elevated level of 17OHP would be indicative. However, 17OHP varies with gestational age, and the test (immunometric assay) is fraught with error, so false positives and false negatives occur, even with “second tier” testing. The investigators considered that perhaps a ratio 17OHP (upstream of 21hydroxylase) to Cortisol (downstream of 21hydroxylase) would provide another parameter help to clarify the presence or absence of disease. Data from the California Department of Public Health was used, and 197 samples were analyzed. Using the ratio of 17OHP/Cortisol, as well as 17OHP/Androstenedione, assignments could be made to “normal”, simple virilizing, CAH carrier, as well as CAH.
è Newborn screening is a powerful tool, but increasing accuracy of the testing, particularly in rare conditions, will aid in prevention of undue worry with false positives, and missed diagnoses in false negatives.
Blog posts from this meeting have been quite Peds-heavy. My plan is to cover thyroid as well, which will be tomorrow’s (well, Wednesday’s, since we’re travelling tomorrow) post. However, I missed some great talks Sunday afternoon due to a gas leak at the Moscone Center.
Instead, our party took the MUNI to Embarcadero to see the Ferry Building, so here are some pictures, enjoy!
A gorgeous heirloom tomato from a market inside the Ferry Building
The Ferry Building on a clear day
The Bay Bridge
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