Hae Woon Jung

Pediatric patients with multifocal papillary thyroid cancer have higher recurrence rates than adult patients: a retrospective analysis of a large pediatric thyroid cancer cohort over 33 years

CONTEXT Large-sample studies with long-term follow-up data are limited for pediatric patients with thyroid cancer. OBJECTIVE Secular changes in clinicopathological characteristics and outcomes in pediatric patients with thyroid cancer were investigated and compared with those of adults. DESIGN AND PATIENTS A retrospective review of 150 pediatric patients with thyroid cancer managed between 1980 and 2013 was conducted. The long-term outcomes of 124 patients followed up for 12 months or longer were evaluated. Predictors of recurrence-free survival (RFS) in pediatric patients with papillary thyroid cancer (ped-PTC group) were compared with those of 3071 adult patients. RESULTS The proportion of small tumors (<1 cm) increased from 9.0% before 2010 to 36.8% after 2010 (P < .001); however, neither pathological presentations such as multifocality, extrathyroidal extension (ETE), lymph node (LN) metastasis, or lung metastasis nor the RFS rate changed over time. The 5- and 10-year recurrence rates were 14.5% and 34.4% in pediatric patients, respectively. In respective analyses of the ped-PTC group and patients of all ages with papillary thyroid cancer (all ages group), the rates of ETE, LN metastasis, and lung metastasis were higher with younger age (all P for trend <.05). RFS was lower in the pediatric than the adult patients aged 20-54 years (P < .005) and was comparable with that of older patients (≥ 55 y). Only tumor multifocality and size predicted recurrence in the ped-PTC group (P < .05), whereas LN metastasis and ETE also predicted recurrence in the all-ages group (P < .01). Among patients in the all-ages group with multifocal tumors, pediatric patients had the lowest RFS (P < .05). CONCLUSIONS The pathological characteristics and recurrence rates of pediatric thyroid cancer have not changed over 33 years. Although younger patients present with more advanced disease, multifocality rather than age at diagnosis predicted recurrence. Recurrence was higher in pediatric than adult patients with multifocal papillary thyroid cancer.

No influence of parental origin of intact X chromosome and/or Y chromosome sequences on three-year height response to growth hormone therapy in Turner syndrome

Purpose Whether parental origin of the intact X chromosome and/or the presence of Y chromosome sequences (Yseq) play a role in three-year height response to growth hormone (GH) were investigated. Methods Paternal (Xp) or maternal (Xm) origin of X chromosome was assessed by microsatellite marker analysis and the presence of hidden Yseq was analyzed. The first-, second-, and third-year GH response was measured as a change in height z-score (Z_Ht) in Turner syndrome (TS) patients with 45,Xp (n=10), 45,Xm (n=15), and 45,X/46,X,+mar(Y) (Xm_Yseq) (n=8). Results The mean baseline Z_Ht did not differ according to Xp or Xm origin, however the mean baseline Z_Ht was higher in the Xm_Yseq group than in Xm group, after adjusting for bone age delay and midparental Z_Ht (P=0.04). There was no difference in the height response to GH between the 3 groups. The height response to GH decreased progressively each year (P<0.001), such that the third-year increase in Z_Ht was not significant. This third-year decrease in treatment response was unaffected by Xp, Xm, and Xm_Yseq groups. Increasing GH dosage from the second to third-year of treatment positively correlated with the increase in Z_Ht (P=0.017). Conclusion There was no evidence of X-linked imprinted genes and/or Yseq affecting height response to 3 years of GH therapy. Increasing GH dosages may help attenuate the decrease in third-year GH response in TS patients with 45,X and/or 46,X/+mar(Y).

The serum concentrations of perfluoroalkyl compounds were inversely associated with growth parameters in 2-year old children

The relationship between the serum concentrations of perfluoroalkyl compounds (PFCs) and growth parameters was investigated in 2-year-old Korean children. The study included 361 children aged 2years (192 boys and 169 girls; 22-27months), born at term appropriate-for-gestational-age, who visited between 2012 and 2013. Growth parameters of height and weight, and serum samples were collected from 2-year-old children. Four PFCs (perfluorohexane sulfonic acid [PFHxS], perfluorooctane sulfonic acid [PFOS], perfluorooctanoic acid [PFOA], and perfluorononanoic acid [PFNA]), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), and perfluoroheptanoic acid (PFHpA) were detected in >99, 93.4, 89.8, and 74.2% of the serum samples, respectively. The duration of breastfeeding was positively associated with the serum concentrations of ln-transformed PFHxS, PFOS, PFHpA, PFOA, PFNA, PFDA, and PFUnDA (all P<0.001). Height at 2years of age was inversely related to PFHxS, PFOS, PFOA, PFNA, and PFDA concentrations (adjusted β per ln unit [95% confidence interval, CI]: -0.84 [-1.26, -0.42], -0.77 [-1.27, -0.15], -0.91 [-1.36, -0.47], -0.48 [-1.40, -0.51], and -0.44 [-0.77, -0.10] cm, respectively), after adjusting for age, sex, and midparental height. Weight at 2years of age was inversely associated with PFNA (adjusted β per ln unit [95% CI]: -0.32 [-0.48, -0.15] kg), after adjusting for age, sex, and parental BMI. In conclusion, the serum concentrations of PFCs were inversely associated with growth parameters in 2-year-old children.

CD4+FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome

Objective We investigated whether the frequency, phenotype, and suppressive function of CD4+FOXP3+ regulatory T cells (Tregs) are altered in young TS patients with the 45,X karyotype compared to age-matched controls. Design and Methods Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4–35.9 years) and healthy controls (n = 16) were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (–) (n = 7) and TS (+) (n = 17). Tregs sorted for CD4+CD25bright were co-cultured with autologous CD4+CD25− target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function. Results Despite a lower frequency of CD4+ T cells in the TS (-) and TS (+) patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively), both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively). There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+CD25− T cells was significantly impaired in the TS (–) and TS (+) patients compared to controls (P = 0.003 and P = 0.041). Meanwhile, both the TS (–) and TS (+) groups had lower frequencies of naïve cells (P = 0.001 for both) but higher frequencies of effector memory cells (P = 0.004 and P = 0.002) than did the healthy control group. Conclusions The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells.

Long-term endocrine outcome of suprasellar arachnoid cysts

OBJECTIVE Due to their distinct location, suprasellar arachnoid cysts are known to cause a wide variety of problems, such as hydrocephalus, endocrine symptoms, and visual abnormalities. The long-term outcome of these cysts has not been elucidated. To find out the long-term outcome of suprasellar arachnoid cysts, a retrospective review of the patients was performed. The neurological and endocrine symptoms were thoroughly reviewed. METHODS Forty-five patients with suprasellar arachnoid cysts, with an average follow-up duration of 9.7 years, were enrolled in the study. A comprehensive review was performed of the results of follow-up regarding not only neurological symptoms but also endocrine status. The outcomes of 8 patients who did not undergo operations and were asymptomatic or had symptoms unrelated to the cyst were included in the series. RESULTS Surgery was most effective for the symptoms related to hydrocephalus (improvement in 32 of 32), but endocrine symptoms persisted after surgery (4 of 4) and required further medical management. More surprisingly, a fairly large number of patients (14 of 40; 1 was excluded because no pre- or postoperative endocrine evaluation was available) who had not shown endocrine symptoms at the time of the initial diagnosis and treatment later developed endocrine abnormalities such as precocious puberty and growth hormone deficiency. The patients with endocrine symptoms detected during the follow-up included those in both the operated (n = 12 of 32) and nonoperated (n = 2 of 8) groups who had been stable during follow-up since the initial diagnosis. CONCLUSIONS This study implies that patients with suprasellar arachnoid cysts can develop late endocrine problems during follow-up, even if other symptoms related to the cyst have been successfully treated. Hence, patients with these cysts need long-term follow-up for not only neurological symptoms but also endocrine abnormalities.

Factors Associated with the Presence and Severity of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Korean Children and Adolescents

The aim of this study was to identify the risk factors for presence and severity of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in Korean children and adolescents. A retrospective chart review of children and adolescents newly diagnosed with T1DM was conducted in seven secondary and tertiary centers in Korea. Eligible subjects were < 20 years of age and had records on the presence or absence of DKA at the time of T1DM diagnosis. DKA severity was categorized as mild, moderate, or severe. Data were collected on age, height, body weight, pubertal status, family history of diabetes, delayed diagnosis, preceding infections, health insurance status, and parental education level. A total of 361 patients (male 46.3%) with T1DM were included. Overall, 177 (49.0%) patients presented with DKA at T1DM diagnosis. Risk factors predicting DKA at T1DM diagnosis were age ≥ 12 years, lower serum C-peptide levels, presence of a preceding infection, and delayed diagnosis. Low parental education level and preceding infection increased the severity of DKA. These results suggest that alertness of the physician and public awareness of diabetes symptoms are needed to decrease the incidence and severity of DKA at T1DM diagnosis.

Unfavorable Course of Subclinical Hypothyroidism in Children with Hashimoto’s Thyroiditis Compared to Those with Isolated Non-Autoimmune Hyperthyrotropinemia

Subclinical hypothyroidism (SCH) is a common problem in pediatric population, and the natural history of SCH varies depending on its etiology. Whether Hashimoto’s thyroiditis (HT) negatively affects the natural course of SCH was investigated in pediatric patients without concomitant diseases. Predictors for levothyroxine medication were also evaluated. Medical records of 109 children with SCH (91 girls, 5−18 years) diagnosed between 2005 and 2014 were retrospectively reviewed. Patients were classified into HT (n = 37) and isolated non-autoimmune hyperthyrotropinemia (iso-NAHT, n = 72). During median 2 years of follow-up, only 10.1% of SCH patients eventually initiated levothyroxine, and HT patients showed a higher probability of requiring levothyroxine medication than iso-NAHT patients (21.6% vs. 4.2%). Underlying HT independently predicted deterioration of thyroid function, leading to levothyroxine medication (hazard ratios [HRs], 4.6 vs. iso-NAHT, P = 0.025). High titers of anti-thyroglobulin antibodies (TGAbs) predicted later medication in the HT group (HRs, 28.2 vs. normal TGAbs, P = 0.013). Most pediatric SCH showed benign and self-remitting courses. Underlying HT significantly increases the risk for levothyroxine medication, especially with high titers of TGAbs.

The Role of Overweight and Obesity on Bone Health in Korean Adolescents with a Focus on Lean and Fat Mass

As the associations between pediatric overweight/obesity and bone health remain controversial, we investigated the effects of overweight/obesity as well as lean mass (LM) and fat mass (FM) on bone parameters in adolescents. Bone parameters were evaluated using dual-energy X-ray absorptiometry (DXA) data of 982 adolescents (aged 12–19 years) from the Korea National Health and Nutrition Examination Survey (2009–2010). Z-scores for LM, FM, bone mass, bone mineral density (BMD), and bone mineral apparent density (BMAD) using Korean pediatric reference values were used for analysis. Adolescents with overweight/obesity had significantly higher bone mass and density of the total-body-less-head (TBLH), lumbar spine, and femur neck than underweight or normal-weight adolescents (P < 0.001) after adjusting for vitamin D deficiency, calcium intake, and insulin resistance in both sexes. LM was positively associated with bone parameters at all skeletal sites in both sexes (P < 0.001). FM was negatively related to TBLH BMD in boys (P = 0.018) but was positively associated to BMD and BMAD of the lumbar spine and femur neck in girls. In conclusion, overweight/obesity and LM play a positive role in bone health in adolescents. The effect of FM on bone parameters is sex- and site-specific.

Contributions of CAG repeat length in the androgen receptor gene and androgen profiles to premature pubarche in Korean girls.

The CAG repeat length of the androgen receptor (AR) gene, which exhibits an inverse relationship to AR sensitivity, might influence the development of the pubarche along with hyperandrogenemia. There are ethnic differences in the AR CAG repeat length, however, no Asian studies on premature pubarche (PP) have been reported, including Korea. Our objectives were to examine the hormone levels and AR CAG repeat length, and to assess their contributions to PP in Korean girls. Subjects with PP (n=16) and normal pubarche (NP, n=16), and normal controls (NC, n=16) were enrolled. The levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), and free testosterone (FT) were checked. The methylation-weighted (MW) average CAG repeat lengths were analyzed. The median ages at pubarche were 7.4 and 8.9 years in the PP and NP groups, respectively, and the levels of 17-OHP, DHEAS, and FT were similar in both groups. The PP group exhibited a higher DHEAS:DHEA ratio than the NP group (P=0.014). The medians of the MW average CAG repeat length of the AR gene were 22.4 for all subjects and did not differ among the PP (22.3), NP (22.4), and NC (22.2) groups. The AR CAG repeat lengths in the PP and NP groups did not correlate with DHEAS or FT levels. These results suggest that the AR CAG repeat length was not involved in the development of PP in Korean girls. However, excessive adrenal androgen levels, particularly those caused by increased sulfotransferase activity, might be important in the pathogenesis of PP.

A lack of association between vitamin D-binding protein and 25-hydroxyvitamin D concentrations in pediatric type 1 diabetes without microalbuminuria

Purpose Vitamin D deficiency is reported to be more common in type 1 diabetes patients and might be associated with the increased urinary loss of vitamin D binding protein (VDBP) consequent to impaired 25-hydroxyvitamin D (25(OH)D) circulation. We aimed to evaluate the possible increased urinary loss of VDBP, a correlation between VDBP and circulating 25(OH)D level, and risk factors influencing low vitamin D level in pediatric type 1 diabetes patients without microalbuminuria. Methods This is a cross-sectional study of subjects who visited Seoul National University Children’s Hospital between January and March 2013. Forty-two type 1 diabetes patients and 29 healthy controls were included. Biochemical parameters including serum and urine VDBP concentrations were analyzed. Results There was no significant difference in the frequency of vitamin D deficiency or serum 25(OH)D level between the 2 groups. The serum and urine VDBP concentrations did not show any difference between the 2 groups. Serum 25(OH) D level did not correlate with serum or urine VDBP. Multivariate regression analysis revealed that daylight outdoor hours (β=2.948, P=0.003) and vitamin D intake (β=2.865, P=0.003) affected the 25(OH)D level; the presence of type 1 diabetes or urinary VDBP excretion was not significant. Conclusions In pediatric type 1 diabetes patients, urinary VDBP excretion did not contribute to low serum 25(OH)D level in the setting of normoalbuminuria. The factors associated with 25(OH)D level during winter periods were daylight outdoor hours and vitamin D intake. Further studies including both micro- and macroalbuminuria patients with type 1 diabetes are warranted.