Publications by authors named "Stephen H LaFranchi"

31 Publications

Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction.

Front Endocrinol (Lausanne) 2021 15;12:666207. Epub 2021 Jun 15.

Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Sciences University, Portland, OR, United States.

Maternal thyroid hormone crosses the placenta to the fetus beginning in the first trimester, likely playing an important role in fetal development. The fetal thyroid gland begins to produce thyroid hormone in the second trimester, with fetal serum T4 levels gradually rising to term. Full maturation of the hypothalamic-pituitary-thyroid (HPT) axis does not occur until term gestation or the early neonatal period. Postnatal thyroid function in preterm babies is qualitatively similar to term infants, but the TSH surge is reduced, with a corresponding decrease in the rise in T4 and T3 levels. Serum T4 levels are reduced in proportion to the degree of prematurity, representing both loss of the maternal contribution and immaturity of the HPT axis. Other factors, such as neonatal drugs, e.g., dopamine, and non-thyroidal illness syndrome (NTIS) related to co-morbidities contribute to the "hypothyroxinemia of prematurity". Iodine, both deficiency and excess, may impact thyroid function in infants born preterm. Overall, the incidence of permanent congenital hypothyroidism in preterm infants appears to be similar to term infants. However, in newborn screening (NBS) that employ a total T4-reflex TSH test approach, a higher proportion of preterm babies will have a T4 below the cutoff, associated with a non-elevated TSH level. In NBS programs with a primary TSH test combined with serial testing, there is a relatively high incidence of "delayed TSH elevation" in preterm neonates. On follow-up, the majority of these cases have transient hypothyroidism. Preterm/LBW infants have many clinical manifestations that might be ascribed to hypothyroidism. The question then arises whether the hypothyroxinemia of prematurity, with thyroid function tests compatible with either non-thyroidal illness syndrome or central hypothyroidism, is a physiologic or pathologic process. In particular, does hypothyroxinemia contribute to the neurodevelopmental impairment common to preterm infants? Results from multiple studies are mixed, with some randomized controlled trials in the most preterm infants born <28 weeks gestation appearing to show benefit. This review will summarize fetal and neonatal thyroid physiology, thyroid disorders specific to preterm/LBW infants and their impact on NBS for congenital hypothyroidism, examine treatment studies, and finish with comments on unresolved questions and areas of controversy.
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http://dx.doi.org/10.3389/fendo.2021.666207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239410PMC
June 2021

Outcome of Newborn Screening for Congenital Adrenal Hyperplasia at Two Time Points.

Horm Res Paediatr 2020 13;93(2):128-136. Epub 2020 Jul 13.

Doernbecher Children's Hospital, Oregon Health and Science University, Portland, Oregon, USA.

Background/aims: Screening newborns for congenital adrenal hyperplasia (CAH) is problematic owing to the dynamic changes in serum 17-hydroxyprogesterone (17-OHP) levels following birth. Our study objectives were to determine the accuracy of screening, severity of CAH, and biochemical and clinical outcomes of cases detected by our program which collects specimens at 2 time periods following birth.

Methods: We reviewed all CAH cases detected in the Northwest Regional Newborn Screening Program from 2003 through 2017. Comparison was made of screening and confirmatory serum 17-OHP, neonatal, maternal, and follow-up auxologic data, steroid treatment doses, and 21-hydroxylase genotype in cases detected on the first versus second test.

Results: Out of 164 cases of CAH, 25% were detected on the second screen. Infants detected on the second test had a lower screening 17-OHP (147 vs. 294 ng/mL), lower confirmatory serum 17-OHP (7,772 vs. 14,622 ng/dL), and were more likely to have simple virilizing CAH. There were no identifiable neonatal or maternal factors associated with detection on the second test. 21-Hydroxylase genotypes overlapped in first versus second screen cases.

Conclusion: Early collection of specimens necessitated by early discharge resulted in milder CAH cases falling below the screening 17-OHP cutoff. In our program 25% of cases were detected on a routine second screen.
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http://dx.doi.org/10.1159/000508075DOI Listing
July 2021

Congenital Hypothyroidism: Inside Ireland's Incline.

Pediatrics 2018 10;142(4)

Doernbecher Children's Hospital, Portland, Oregon and Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon

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http://dx.doi.org/10.1542/peds.2018-2262DOI Listing
October 2018

Newborn Screening in the US May Miss Mild Persistent Hypothyroidism.

J Pediatr 2018 01;192:204-208

Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA; Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA. Electronic address:

Objective: To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life.

Study Design: All NBS programs in the US were contacted and asked to provide information on their NBS protocols, TSH cutoffs, and whether these cutoffs were age adjusted.

Results: Of 51 NBS programs, 28 request a repeat specimen if the initial eluted serum TSH concentration is mildly increased (between the cutoff and a median upper limit of 50 mU/L), whereas 14 programs perform a routine second screen in all infants. Although these specimens are typically collected between 1 week and 1 month of life, 16 of the 28 programs with a discretionary second test and 8 of 14 programs with a routine second test do not have age-adjusted TSH cutoffs after the first 48 hours of life.

Conclusions: There is variation in NBS practices for screening for congenital hypothyroidism across the US, and many programs do not adjust the TSH cutoff beyond the first 2 days of life. Samples are processed when received from older infants, often to retest borderline initial results. This approach will miss congenital hypothyroidism in infants with persistent mild TSH elevations. We recommend that all NBS programs provide age-adjusted TSH cutoffs, and suggest developing a standard approach to screening for congenital hypothyroidism in the US.
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http://dx.doi.org/10.1016/j.jpeds.2017.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823276PMC
January 2018

Detecting Congenital Central Hypothyroidism by Newborn Screening: Difficulty in Distinguishing from Congenital Thyroxine-Binding Globulin Deficiency.

Horm Res Paediatr 2017 14;88(5):331-338. Epub 2017 Sep 14.

Background/aims: Congenital central hypothyroidism (CH-C) can be detected on newborn screening (NBS) by programs using thyroxine (T4)-reflex thyroid-stimulating hormone (TSH) test approach. CH-C must be distinguished from T4-binding globulin (TBG) deficiency. We sought to determine whether thyroid function tests reliably separate CH-C from TBG deficiency.

Methods: We analyzed NBS and serum free and total T4, T3 resin uptake (T3RU) or TBG, and TSH for infants in the Northwest Regional NBS Program (NWRSP) between the years 2008 and 2015 with either CH-C or TBG deficiency.

Results: We discovered a significant overlap in T3RU and TBG levels amongst 21 cases of CH-C and 250 cases of TBG deficiency. Mean serum TBG levels were lower in CH-C cases (20.3 µg/mL, range 14.2-33.3) than what is reported in healthy infants (28.6 µg/mL, range 19.1-44.6). Serum free T4 was lower in CH-C cases than TBG deficiency but did not always differentiate between the two conditions.

Conclusion: CH-C benefits from detection on NBS but must be distinguished from TBG deficiency. The diagnosis of CH-C rests solely on subnormal serum free T4, but is supported by the demonstration of other pituitary hormone deficiencies. As an overlap exists, serum TBG (or T3RU) levels do not play a role in the diagnosis of CH-C.
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http://dx.doi.org/10.1159/000479367DOI Listing
July 2018

Characterization of Thyroid Abnormalities in a Large Cohort of Children with Down Syndrome
.

Horm Res Paediatr 2017 3;87(3):170-178. Epub 2017 Mar 3.

Background/aims: Thyroid disease is a common comorbidity in individuals with Down syndrome (DS), but historical studies have multiple limitations. We assessed thyroid abnormalities in a large cohort of children with DS.

Methods: Retrospective records review from a single institution. Calculated prevalence of common thyroid abnormalities and associations with common comorbidities.

Results: Among 508 patients, 120 (24%) had a thyroid-related diagnosis, the majority having elevated thyrotropin treated with levothyroxine. A Kaplan-Meier estimate projects that 50% have thyroid disorder by adulthood, with 20% of hypothyroidism diagnosed before the age of 6 months. When tested, approximately 50% had positive antithyroid antibodies, though this rate was 100% in overt hypothyroidism. There was no association between congenital or acquired hypothyroidism and common comorbidities.

Conclusion: Thyroid disease in DS is more common and occurs earlier than in the general population, and is often transient. Thyroid disease is unrelated to gender, obesity, or other comorbidities. Apart from overt hypothyroidism, much of hypothyroidism in DS appears unrelated to autoimmunity; we recommend checking of antithyroid antibodies only in select cases. An additional screen for thyroid disease between the newborn screen and the 6-month well-child visit will detect early cases of hypothyroidism who passed their newborn screen.
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http://dx.doi.org/10.1159/000457952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483988PMC
May 2017

Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA.

Horm Res Paediatr 2016 6;86(3):169-177. Epub 2016 Sep 6.

Pediatric Endocrinology, Oregon Health and Science University, Portland, Oreg., USA.

Background/aims: The newborn screening (NBS) program in Oregon, USA, collects two routine specimens in all infants. The aim of our study was to determine the incidence of permanent versus transient congenital hypothyroidism (CH) in infants detected on the first versus second screening test.

Methods: Thyroid function was determined in infants after the age of 3 years diagnosed with CH and born in Oregon between 2005 and 2011. Permanent hypothyroidism was defined as a TSH rise >10 mIU/ml after the first year on treatment or a TSH rise >6 mIU/ml with temporary discontinuation of l-thyroxine after the age of 3 years.

Results: Of the cases detected on the first test, 72 of 87 (83%) were permanent and 15 of 87 (17%) were transient, while of the cases detected on the second test, 5 of 22 (23%) were permanent and 17 of 22 (77%) were transient (OR 16.3, p < 0.001). There was a female preponderance detected on the first screen versus a male preponderance on the second screen. Blood spot and serum thyroid function tests at diagnosis, before treatment, were not meaningfully different between the two groups. The mean l-thyroxine dose at the age of 3 years was greater on the first screen: 61.2 versus 36.6 μg/day.

Conclusions: Infants detected on the second NBS specimen have a higher incidence of transient CH. © 2016 S. Karger AG, Basel.
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http://dx.doi.org/10.1159/000448658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886777PMC
April 2017

Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults.

Thyroid 2015 Jul;25(7):713-5

Department of Pediatrics, Oregon Health and Science University, Portland, Oregon.

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http://dx.doi.org/10.1089/thy.2015.0275DOI Listing
July 2015

Detection of neonates with mild congenital hypothyroidism (primary) or isolated hyperthyrotropinemia: an increasingly common management dilemma.

Expert Rev Endocrinol Metab 2014 May 17;9(3):263-271. Epub 2014 Mar 17.

a Department of Pediatrics (CDRCP), Oregon Health and Science University, 707 SW Gaines St., Portland, OR 97239-3098, USA.

Anywhere from 10% to 40% of neonates detected by newborn screening programs have mild congenital hypothyroidism (thyroid-stimulating hormone [TSH] 6 to 20 mU/l with borderline low free T4) or isolated hyperthyrotropinemia. The increasing frequency of such cases appears to be chiefly the result of lowering screening TSH cutoffs. In some cases, the etiology is a mild form of dysgenesis or dyshormonogenesis; most cases, however, on imaging have gland in situ of unexplained etiology. Re-evaluation after age 3 years shows some with transient hypothyroidism, a minority with permanent hypothyroidism, while the majority have persistent, mild TSH elevation and normal free T4. There is limited data on neurodevelopmental outcome to guide management. In cases where the TSH is trending down and free T4 is normal, we recommend re-checking serum TSH and free T4 at weekly intervals. If serum TSH does not normalize by 4 weeks of age, we recommend treatment, with re-evaluation after age 2-3 years.
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http://dx.doi.org/10.1586/17446651.2014.897607DOI Listing
May 2014

Screening preterm infants for congenital hypothyroidism: better the second time around.

J Pediatr 2014 Jun 20;164(6):1259-61. Epub 2014 Mar 20.

Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, Oregon. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2014.02.031DOI Listing
June 2014

Screening for congenital hypothyroidism: a worldwide view of strategies.

Best Pract Res Clin Endocrinol Metab 2014 Mar 18;28(2):175-87. Epub 2013 Jun 18.

Department of Pediatrics [CDRCP], Doernbecher Children's Hospital, Oregon Health & Science University, 707 SW Gaines St., Portland, OR 97239-3098, USA. Electronic address:

Detection by newborn screening (NBS) and treatment of babies with congenital hypothyroidism (CH) has largely eliminated the intellectual disability caused by this disorder. Lowering of the screening TSH cutoff and changes in birth demographics have been associated with an approximate doubling of the incidence of CH, from 1:3500 to 1:1714. The additional cases detected by lowering of the TSH cutoff tend to have milder hypothyroidism, with imaging often demonstrating a eutopic, "gland in-situ", and some cases turn out to have transient CH. Based on our search for current screening programs, approximately 71 percent of babies worldwide are not born in an area with an established NBS program, despite the existence of screening for over five decades in developed countries. Thus, the majority of babies with CH worldwide are not detected and treated early, such that the economic burden of retardation owing to CH remains a significant public health challenge.
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http://dx.doi.org/10.1016/j.beem.2013.05.008DOI Listing
March 2014

Novel microcephalic primordial dwarfism disorder associated with variants in the centrosomal protein ninein.

J Clin Endocrinol Metab 2012 Nov 29;97(11):E2140-51. Epub 2012 Aug 29.

Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.

Context: Microcephalic primordial dwarfism (MPD) is a rare, severe form of human growth failure in which growth restriction is evident in utero and continues into postnatal life. Single causative gene defects have been identified in a number of patients with MPD, and all involve genes fundamental to cellular processes including centrosome functions.

Objective: The objective of the study was to find the genetic etiology of a novel presentation of MPD.

Design: The design of the study was whole-exome sequencing performed on two affected sisters in a single family. Molecular and functional studies of a candidate gene were performed using patient-derived primary fibroblasts and a zebrafish morpholino oligonucleotides knockdown model.

Patients: Two sisters presented with a novel subtype of MPD, including severe intellectual disabilities.

Main Outcome Measures: NIN, encoding Ninein, a centrosomal protein critically involved in asymmetric cell division, was identified as a candidate gene, and functional impacts in fibroblasts and zebrafish were studied.

Results: From 34,606 genomic variants, two very rare missense variants in NIN were identified. Both probands were compound heterozygotes. In the zebrafish, ninein knockdown led to specific and novel defects in the specification and morphogenesis of the anterior neuroectoderm, resulting in a deformity of the developing cranium with a small, squared skull highly reminiscent of the human phenotype.

Conclusion: We identified a novel clinical subtype of MPD in two sisters who have rare variants in NIN. We show, for the first time, that reduction of ninein function in the developing zebrafish leads to specific deficiencies of brain and skull development, offering a developmental basis for the myriad phenotypes in our patients.
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http://dx.doi.org/10.1210/jc.2012-2150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485598PMC
November 2012

Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion.

J Pediatr 2012 Oct 27;161(4):760-2. Epub 2012 Jul 27.

Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health & Science University Doernbecher Children's Hospital, Portland, OR 972389, USA.

We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized.
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http://dx.doi.org/10.1016/j.jpeds.2012.05.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354797PMC
October 2012

Approach to the diagnosis and treatment of neonatal hypothyroidism.

J Clin Endocrinol Metab 2011 Oct;96(10):2959-67

Department of Pediatrics, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.

Congenital hypothyroidism, occurring in 1:3000 newborns, is one of the most common preventable causes of mental retardation. Neurodevelopmental outcome is inversely related to the age of diagnosis and treatment. Infants detected through newborn screening programs and started on l-T(4) in the first few weeks of life have a normal or near-normal neurodevelopmental outcome. The recommended starting dose of l-T(4) (10-15 μg/kg · d) is higher on a weight basis than the dose for children and adults. Tailoring the starting l-T(4) dose to the severity of the hypothyroidism will normalize serum T(4) and TSH as rapidly as possible. It is important to obtain confirmatory serum thyroid function tests before treatment is started. Further diagnostic studies, such as radionuclide uptake and scan and ultrasonography, may be performed to determine the underlying cause of hypothyroidism. Because results from these tests generally do not alter the initial treatment decision, however, these diagnostic studies are rarely indicated. The developing brain has a critical dependence on thyroid hormone for the first 2-3 yr of life; thus, monitoring occurs at more frequent intervals than in older children and adults. Serum free T(4) and TSH should be checked at intervals frequent enough to ensure timely adjustment of l-T(4) dosing and to keep serum free T(4) and TSH levels in target ranges. Given the success of early detection and treatment of neonates with congenital hypothyroidism, a public health mandate should be to develop similar programs for the 75% of babies worldwide who are born in areas without newborn screening programs.
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http://dx.doi.org/10.1210/jc.2011-1175DOI Listing
October 2011

Congenital hypothyroidism.

Orphanet J Rare Dis 2010 Jun 10;5:17. Epub 2010 Jun 10.

Department of Pediatrics, Division of Endocrinology, Oregon Health & Science University, 707 SW Gaines Street, Portland, OR, USA.

Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.
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http://dx.doi.org/10.1186/1750-1172-5-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903524PMC
June 2010

Newborn screening strategies for congenital hypothyroidism: an update.

J Inherit Metab Dis 2010 Oct 2;33(Suppl 2):S225-33. Epub 2010 Mar 2.

Department of Pediatrics (CDRCP), Division of Endocrinology, Oregon Health & Science University, Portland, OR 97219, USA.

It is the purpose of this article to briefly review the initial development and subsequent evolution of newborn screening programs to detect infants with congenital hypothyroidism (CH) and then to provide an update of the advantages and disadvantages of the main test strategies. Pilot programs began screening newborn populations in North America in the mid-1970s using either primary thyroxine (T4)-follow-up thyroid stimulating hormone (TSH) or primary TSH testing. Many programs in the United States and around the world continue to prefer a primary T4-follow-up TSH test strategy. This approach has the advantage of detecting infants with primary CH, as well as cases of hypopituitary hypothyroidism, by follow-up of infants with a T4 below an absolute cutoff or with a persistently low T4 level, necessitating a higher recall rate. With increasing assay sensitivity and specificity, several programs in the United States and worldwide have elected to switch to a primary TSH test strategy. This test strategy has the advantage of detecting primary CH and subclinical hypothyroidism and at a lower recall rate. Programs considering switching to a primary TSH test strategy need to develop age-related TSH cutoffs to maintain an acceptable recall rate. Both test strategies have the potential to detect infants with CH characterized by "delayed TSH rise," but only if they collect a routine or discretionary second specimen, now recommended in low-birth-weight and acutely ill infants. Lastly, a lower TSH cutoff appears to be one of the explanations for the recently described increased incidence of CH.
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http://dx.doi.org/10.1007/s10545-010-9062-1DOI Listing
October 2010

Fetal and neonatal thyroid function: review and summary of significant new findings.

Curr Opin Endocrinol Diabetes Obes 2010 Feb;17(1):1-7

Department of Pediatrics, Division of Endocrinology, Oregon Health and Science University, Portland, Oregon 97239, USA.

Purpose Of Review: The purpose of this review is to briefly summarize current knowledge of fetal and neonatal thyroid function, and then to summarize the most significant new findings over the last year that add to our knowledge of the cause, diagnosis, and management of fetal and neonatal thyroid disorders.

Recent Findings: Significant findings from publications in the last year include a report that inadequate iodine intake during pregnancy exists in many parts of the world. Conversely, maternal exposure to iodinated contrast agents did not affect neonatal thyroid function. A small lowering in the screening of thyroid-stimulating hormone cutoff resulted in nearly a doubling of the birth prevalence of congenital hypothyroidism, but more cases had a thyroid gland 'in situ'. Partial iodination defects are relatively common causes of dyshormonogenesis. Tailoring the initial starting levothyroxine dose to severity of hypothyroidism resulted in rapid normalization of thyroid function. Although consensus guidelines recommend an initial starting dose in the 10-15-mug/kg/day range, the Cochrane collaborative did not find sufficient evidence from randomized controlled trials to confirm the high-dose recommendation. Under or overtreatment of childhood hypothyroidism appears to adversely impact adult cardiovascular function. Adults with congenital hypothyroidism are more likely to have quality of life issues.

Summary: Investigations of the impact of iodine and thyroid hormone transfer continue to improve our knowledge of maternal-fetal thyroid relationships. Screening programs to detect and treat newborns with congenital hypothyroidism have resulted in a dramatic improvement in neurocognitive outcome. Nevertheless, debate continues on the optimal screening test approach and thyroid hormone treatment.
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http://dx.doi.org/10.1097/MED.0b013e328333b0b2DOI Listing
February 2010

Should the levothyroxine starting dose be tailored to disease severity in neonates with congenital hypothyroidism?

Nat Clin Pract Endocrinol Metab 2008 Dec 30;4(12):658-9. Epub 2008 Sep 30.

Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.

Early levothyroxine treatment is crucial to minimize neurocognitive impairment associated with congenital hypothyroidism. In this Practice Point commentary, I discuss the findings, implications, and limitations of the study of Mathai et al. in which neonates with congenital hypothyroidism were treated with variable initial doses of levothyroxine. A high initial levothyroxine dose was used for newborn babies with athyreosis, an intermediate dose for those with ectopic glands, and a low dose for those with dyshormonogenesis. Serum free T(4) levels normalized within 2 weeks, but serum TSH levels within up to 4 weeks. A dose adjustment (mostly a dose reduction) was required in about half of the neonates in the first 2 weeks of life. As Mathai et al. carried out no neuropsychological tests, we do not know if their approach has a more beneficial effect on neurocognitive outcomes than other treatment strategies. Nevertheless, as tailoring the levothyroxine dose to severity rapidly normalized serum free T(4) levels, one would predict a beneficial effect of this approach on neurocognitive outcome.
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http://dx.doi.org/10.1038/ncpendmet0970DOI Listing
December 2008

Pediatric thyroid testing issues.

Pediatr Endocrinol Rev 2007 Oct;5 Suppl 1:570-7

Department of Pediatrics, Division of Endocrinology, University of Virginia, VA, USA.

Thyroid problems are common in children. While serum thyroid function tests lead to an accurate diagnosis in most patients, unique patient situations can produce misleading results. Total T4 measurements can incorrectly suggest hypothyroidism in congenital thyroid binding globulin (TBG) deficiency and hyperthyroidism in TBG excess, as seen in high estrogen states. Free T4 (FT4) measurement techniques involve either physical separation of unbound thyroxine from serum binding proteins or estimation of FT4 levels in the presence of binding proteins. These estimation techniques are susceptible to under- or over-estimation of FT4 levels when binding proteins are low or high. Other complicating factors arise in the setting of prematurity or systemic non-thyroidal illness (NTI), simulating central hypothyroidism. Thyroid stimulating hormone (TSH) levels in children have a wider normal range than in adults and are affected by drugs and NTI. Additionally, heterophile and anti-T4 or anti-TSH antibodies can interfere with accurate T4 or TSH measurement.
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October 2007

How should we be treating children with congenital hypothyroidism?

J Pediatr Endocrinol Metab 2007 May;20(5):559-78

Department of Pediatrics, Division of Endocrinology, Oregon Health & Science University, Portland, OR 97239, USA.

Early detection by newborn screening and appropriate L-thyroxine treatment leads to normal or near-normal neurocognitive outcome in infants with congenital hypothyroidism. Many newborns with congenital hypothyroidism have some residual thyroid hormone production, and even in those with athyreosis, transplacental passage of maternal thyroid hormone offers some protection for a time. Given the serum T4 half-life of 6 days, the neonatal T4 level will fall and disappear over the first 2-3 weeks of life. Thus, there is a crucial 'window of opportunity' to correct the hypothyroidism and minimize the time the brain is exposed to hypothyroxinemia. While there are few truly prospective, randomized clinical trials investigating treatment parameters, studies measuring IQ outcome support a starting L-thyroxine dose of 10-15 microg/kg/day. Further, studies show that the most severely hypothyroid infants are at risk for a 5-20 point decrease in IQ. Such infants may benefit from a starting dose of 12-17 microg/kg/d, which has been shown to normalize T4 in 3 days and TSH in 2 weeks. Target serum T4 or free T4 levels appear to be higher in the first two weeks of treatment. Infants require more frequent laboratory monitoring, every 1-2 months in the first 6 months and every 3-4 months until age 3 years, as the developing brain has a critical dependence on thyroid hormone in the first 2-3 years of life.
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http://dx.doi.org/10.1515/jpem.2007.20.5.559DOI Listing
May 2007

Androgen replacement in adolescents and young women with hypopituitarism.

J Pediatr Endocrinol Metab 2005 Apr;18(4):355-62

Department of Pediatrics, Doernbecher Children 's Hospital, Oregon Health and Sciences University, Portland, OR 97239, USA.

The aim of this study was to test the hypothesis that young women with androgen deficiency due to hypopituitarism would benefit from androgen replacement in the form of dehydroepiandrosterone (DHEA). Five young women, age 15.2-23.1 years, with panhypopituitarism were studied in a 12-month double blind placebo-controlled crossover trial of DHEA replacement in a dose 50 mg/day (Belmar Pharmacy, Lakewood, CO). All had growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) and antidiuretic hormone deficiencies. Gonadotropin deficiency was complete in three and partial in two. The patients were evaluated at baseline, 6 months and 12 months. Serum hormone levels, body composition, lumbar bone mineral density (BMD), exercise capacity and tests of psychological function were performed. DHEA replacement restored serum DHEA levels to normal, 359.8+/-337 ng/dl (12.5+/-11.7 nmol/l). The Life Situation Survey showed significantly better life satisfaction on DHEA than placebo (110 vs 102, p = 0.05). Trends for improved maximal oxygen uptake (VO2), and decreased percent body fat did not reach statistical significance. In conclusion, androgen replacement with DHEA should be considered in young women with panhypopituitarism. Further studies over longer periods in larger groups of patients are necessary to better evaluate the effects of DHEA replacement on BMD, muscle strength and body composition.
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http://dx.doi.org/10.1515/jpem.2005.18.4.355DOI Listing
April 2005

Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes?

Thyroid 2005 Jan;15(1):60-71

Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon, USA.

A workshop entitled, "The Impact of Maternal Thyroid Diseases on the Developing Fetus: Implications for Diagnosis, Treatment, and Screening," was held in Atlanta, Georgia, January 12-13, 2004. This paper reports on the individual session that examined thyroid inadequacy during gestation as a risk factor for adverse pregnancy and developmental outcomes. For this session the following papers were presented: "Adverse Pregnancy Outcomes"; "Thyroid Physiology in the Fetus"; "New England Data: Cretinism Revisited-Preventing Fetal Brain Damage when Mothers Have Subclinical Hypothyroidism"; "Dutch Data: Pregnancy, Maternal Thyroid (Dys)function and Outcome of the Offspring"; and "Report on the Wales Controlled Antenatal Thyroid Screening Study (CATS); A Prospective RCT." These presentations were formally discussed by invited respondents well as others in attendance. Salient points from this session about which there was agreement include the following. Maternal hypothyroidism is associated with complications of pregnancy and adverse effects on the fetus. These risks are greater in women with overt hypothyroidism compared to subclinical hypothyroidism, and also appear to be increased in women with euthyroid autoimmune thyroid disease. If maternal hypothyroidism is treated adequately, this appears to reduce the risk for adverse outcomes. The demonstration of a pattern of ontogeny of fetal cerebral cortex deiodinases and thyroid hormone receptors, beginning by 7-8 weeks' gestation, is circumstantial evidence that thyroid hormone plays an important role in fetal neurodevelopment. Significant fetal thyroid hormone production and secretion does not begin until approximately 20 weeks' gestation. If there is a significant role for thyroid hormone in fetal neurodevelopment before 20 weeks' gestation, it likely is of maternal origin. Studies demonstrate low levels of thyroxine in the fetal coelomic fluid and blood prior to 12-14 weeks' gestation. Published data consistently document a relationship between maternal thyroid deficiency during pregnancy and problems with neuropsychological development of the offspring.
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http://dx.doi.org/10.1089/thy.2005.15.60DOI Listing
January 2005

A novel presentation of familial glucocorticoid deficiency (FGD) and current literature review.

J Pediatr Endocrinol Metab 2004 Jan;17(1):85-92

Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health & Sciences University, Portland, OR, USA.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder, which manifests as isolated glucocorticoid deficiency with normal mineralocorticoid function. The disease is secondary to ACTH unresponsiveness, with low serum cortisol concentrations in the presence of markedly elevated ACTH levels. Approximately 40% of patients with FGD have an identifiable mutation in the ACTH receptor gene. The typical presentation of FGD includes recurrent hypoglycemia, failure to thrive, and hyperpigmentation prior to 5 years of age. Patients with point mutations in the ACTH receptor gene are noted to be of tall stature. We report a patient with an atypical initial presentation of this condition. Our patient differed from the typical presentation by having late age of onset, short stature, and few symptoms of FGD. Sequence analysis of the ACTH receptor gene showed compound heterozygosity, with two previously reported mutations: S74I and T159K. Her unique presentation further illustrates the phenotypic heterogeneity of this disorder in light of reported mutations.
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http://dx.doi.org/10.1515/jpem.2004.17.1.85DOI Listing
January 2004

Follow-up of newborns with elevated screening T4 concentrations.

J Pediatr 2003 Sep;143(3):296-301

Department of Pediatrics, Oregon Health and Science University, Pediatric Endocrinology, Legacy Emanuel Children's Hospital, and Oregon State Public Health Laboratory, Portland, Oregon, USA.

Objective: To determine the type and incidence of hyperthyroxinemic disorders detected by follow-up of infants with elevated screening total T4 (TT4) values.

Study Design: Infants born in Oregon with a screening TT4 measurement >3 SD above the mean were offered enrollment. Serum TT4, free T4, total T3, free T3, and thyroid-stimulating hormone concentrations were measured in study infants and their mothers.

Results: Over a 20-month period, 101 infants (51 boys) and their mothers enrolled in the study (of 241 eligible infants), from a total screening population of 80,884; 17 infants were identified with persistent hyperthyroxinemia (TT4 >16 microg/dL). Ten had thyroxine-binding globulin excess (1:8088), 5 had evidence for increased T4 binding but not thyroxine-binding globulin excess (1:16,177), and 2 had findings compatible with thyroid hormone resistance (1:40,442); the other 84 infants had transient hyperthyroxinemia. Sequence analysis revealed a point mutation in the thyroid hormone receptor-beta gene in one infant with thyroid hormone resistance; no mutation was identified in the other infant.

Conclusions: Although neonatal Graves' disease occurs in approximately 1 in 25,000 newborn infants, we did not detect any case among 80,884 infants, most likely because their mothers were receiving antithyroid drugs. Although the other hyperthyroxinemic disorders in the aggregate occur frequently (1:4758) and may benefit from detection, in general they do not require treatment.
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http://dx.doi.org/10.1067/S0022-3476(03)00184-7DOI Listing
September 2003

Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome.

J Clin Endocrinol Metab 2003 Aug;88(8):3573-6

Division of Endocrinology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon 97201, USA.

Prader-Willi syndrome (PWS) is characterized by severe obesity, hyperphagia, hypogonadism, and GH deficiency. Unlike individuals with common obesity, who have low fasting-plasma ghrelin concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Treatment with octreotide, a somatostatin agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. This pilot study was performed to determine whether octreotide administration (5 microg/kg.d) for 5-7 d lowers ghrelin concentrations and affects body composition, resting energy expenditure, and GH markers in children with PWS. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P < 0.05). Meal-related ghrelin suppression (-35%; P < 0.001) was still present after intervention but was blunted (-11%; P = 0.19). Body weight, body composition, leptin, insulin, resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. In conclusion, short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. Further investigation is warranted to determine whether long-term octreotide treatment causes sustained ghrelin suppression, changes eating behavior, and induces weight loss in this population.
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http://dx.doi.org/10.1210/jc.2003-030205DOI Listing
August 2003

Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome.

J Clin Endocrinol Metab 2003 May;88(5):2206-12

Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97201, USA.

The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg x d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. GH administration did not impact fasting ghrelin concentration.
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http://dx.doi.org/10.1210/jc.2002-021536DOI Listing
May 2003

Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome.

J Clin Endocrinol Metab 2003 Jan;88(1):174-8

Division of Endocrinology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97201, USA.

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.
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http://dx.doi.org/10.1210/jc.2002-021052DOI Listing
January 2003

Initial treatment dose of L-thyroxine in congenital hypothyroidism.

J Pediatr 2002 Dec;141(6):786-92

Department of Pediatrics, Oregon Health and Sciences University, Oregon State Public Health Laboratories, and Northwest Kaiser Permanente, Portland, Oregon, USA.

Objectives: To determine the optimal initial treatment dose of L-thyroxine in congenital hypothyroidism (CH) by evaluating the time course of rise of thyroxine (T(4)) and free T(4) concentrations into an established "target range" and normalization of thyroid-stimulating hormone (TSH) and to reevaluate the "target range" for T(4) and free T(4) concentrations during the first 2 weeks of CH treatment.

Study Design: Infants of birth weight 3 to 4 kg with CH (n = 47) detected by newborn screening were randomly assigned into three L-thyroxine treatment dose arms: 37.5 microg/day (group 1); 62.5 microg/day for 3 days, then 37.5 microg/day (group 2); and 50 microg/day (group 3). Serum T(4), free T(4), triiodothyronine (T(3)), free T(3), and TSH were measured before treatment and at 3 days and 1, 2, 4, 8, and 12 weeks after treatment.

Results: T(4) and free T(4) concentrations increased into the target range (10 to 16 microg/dL) by 3 days of therapy in infants in groups 2 and 3 and by 1 week in group 1; 50 microg/day (average 14.5 microg/kg/day) provided the most rapid normalization of TSH by 2 weeks. With the use of linear regression analysis of T(4) versus TSH or free T(4) versus TSH plots, the intercept at the lower range of normal for TSH (1.7 mU/L) showed T(4) = 19.5 microg/dL and free T(4) = 5.23 ng/dL.

Conclusions: Initial dosing of 50 microg/day (12-17 microg/kg per day) raised serum T(4) and free T(4) concentrations to target range by 3 days and normalized TSH by 2 weeks of therapy. We recommend consideration of a somewhat higher "target range" of 10 to 18 microg/dL for T(4) and 2 to 5.0 ng/dL for free T(4) during the first 2 weeks of L-thyroxine treatment. After 2 weeks of treatment, the target range drops to 10 to 16 microg/dL for T(4) and 1.6 to 2.2 for free T(4).
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http://dx.doi.org/10.1067/mpd.2002.128887DOI Listing
December 2002
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