Hwal Rim Jeong

Low Frequency of MKRN3 Mutations in Central Precocious Puberty Among Korean Girls

Mutations of MKRN3, the gene encoding makorin RING-finger protein 3, lead to central precocious puberty (CPP). The aim of this study was to investigate mutations of the MKRN3 gene in Korean girls with CPP. Two hundred-sixty Korean girls with idiopathic CPP were included. Auxological and endocrine parameters were measured, and the entire MKRN3 gene was directly sequenced. MKRN3 gene analysis revealed one novel nonsense mutation (p.Gln281 *) and 6 missense variants (p.Ile100Phe, p.Gly196Val, p.Ile204Thr, p.Gln226Pro, p.Lys233Asn, and p.Ser396Arg). The novel nonsense mutation (p.Gln281 *) was a heterozygous C>T nucleotide change (c.841C>T) predicted to result in a truncated protein due to a premature stop codon in the MKRN3 gene. The nonsense mutation (p.Gln281 *) was only identified in one of the girls and her younger brother. Compared to previous reports on MKRN3 mutations in familial and sporadic cases of CPP, the present study reveals a relatively low number of MKRN 3 mutations in Korean girls with CPP. Larger samples of children with CPP and MKRN3 mutations are necessary in order to clarify whether the clinical course of puberty may differ as compared to idiopathic CPP.

Associations between serum vitamin D levels and precocious puberty in girls

Purpose Vitamin D deficiency has been linked to chronic diseases, such as diabetes mellitus, obesity and autoimmune disease. However, data on the vitamin D status and its association with precocious puberty in girls are limited. We aimed to investigate the association between serum 25-hydroxyvitamin D (25OHD) and precocious puberty in girls. Methods A total of 60 girls with central precocious puberty (CPP) and 30 control girls were enrolled. Anthropometric measurement and serum level of 25OHD were estimated for all subjects. Results There was a significant difference in the mean serum 25OHD concentration between the precocious puberty group and the control group (17.1±4.5 ng/mL vs. 21.2±5.0 ng/mL, P<0.05). Forty-two of the 60 girls with CPP (70%) had vitamin D deficiency (defined as serum 25OHD<20 ng/mL) and 18 (30%) had vitamin D insufficiency. Of the 30 girls in the control group, vitamin D deficiency was seen in 13 subjects (43.3%), 15 subjects (50%) had vitamin D insufficiency, and 2 subjects (6.7%) had sufficient serum vitamin D (defined as serum 25OHD>30 ng/mL). Vitamin D deficient girls had a significantly higher odds ratio (OR, 3.05; 95% CI, 1.22-7.57, P=0.021). Conclusion These results showed that vitamin D levels may be associated with precocious puberty. Further studies are required to establish the potential effect of vitamin D status on puberty.

The Association between Bone Age Advancement and Insulin Resistance in Prepubertal Obese Children

OBJECTIVE Obesity is associated with bone age (BA) advancement, but the underlying mechanisms remain unclear. The objective of this study was to investigate the association between BA maturation and insulin levels in obese children. METHODS In this cross-sectional study of 93 prepubertal obese children, anthropometric data and hormonal values were measured. Subjects were divided into 2 groups based on the difference between BA and chronological age (CA) (noted as BA-CA). RESULTS The study population included 39 (41.9%) males and 54 (58.1%) females with a mean age of 7.4±1.5 years. The advanced bone age group defined as BA-CA>1 year (n=44) had significantly higher HOMA-IR and fasting insulin levels, and lower quantitative insulin sensitivity check index (QUICKI). BA-CA was significantly correlated with fasting insulin (r=0.255, P=0.014), HOMA-IR (r=0.230, P=0.027), and QUICKI (r=- 0.301, P=0.003). Also, height SDS was significantly associated with ΔBA-CA (r=0.417, P<0.001). In the multiple regression analysis, HOMA-IR was identified as a significant independent predictor of BA-CA. CONCLUSION Bone age is more advanced in obese children with hyperinsulinemia and insulin resistance. These findings suggest that insulin may affect skeletal maturation.

Multiple Endocrine Neoplasia Type 1 Presenting as Hypoglycemia due to Insulinoma

Multiple endocrine neoplasia (MEN) mutation is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. The incidence of insulinoma in MEN is relatively uncommon, and there have been a few cases of MEN manifested with insulinoma as the first symptom in children. We experienced a 9-year-old girl having a familial MEN1 mutation. She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. At first, she was only diagnosed with insulinoma by abdominal magnetic resonance images of a 1.3 x 1.5 cm mass in the pancreas and high insulin levels in blood of the hepatic vein, but after her father was diagnosed with MEN1. We found she had familial MEN1 mutation, and she recovered hyperinsulinemic hypoglycemia after enucleation of the mass. Therefore, the early genetic identification of MEN1 mutation is considerable for children with at least one manifestation.

The effect of growth hormone treatment on height in children with idiopathic short stature

Abstract Background: Idiopathic short stature (ISS) is short stature of unknown cause. In 2003, the Food and Drug Administration (FDA) approved the use of growth hormone (GH) for ISS. Several studies have evaluated the effect of GH in children with ISS, in whom improved growth velocities and height standard deviation scores (SDS) have been reported. However, clinical variables influence the height improvement. Objective: This study aimed to evaluate the effects of GH treatment on ISS and to analyze clinical factors associated with growth velocity. Materials and methods: This study was conducted retrospectively. Subjects diagnosed with ISS at Ajou University Hospital were divided into two groups, an ISS with GH-treatment group (n=34) and an ISS control group (n=36). All children were prepubertal, and aged <10 years. We reviewed their auxological data, laboratory findings, and bone age. Results: Growth velocity of the GH-treatment group exceeded that of controls by 3.37 cm/year (95% CI, 2.78–3.95). At baseline, the mean SDS for height in the treatment and control groups were equivalent (–2.25±0.29 and –2.22±0.31, respectively). However, after 1 year, the height of the GH-treated group exceeded that of the control group by 0.73 SDS (95% CI, 0.57–0.88). A negative correlation was found between age and growth velocity in the GH-treatment group. Conclusion: GH treatment increased short-term growth velocity and height SDS of Korean children with ISS. Age was identified as the single most important factor correlated with growth velocity in GH treatment.

The changes of subtypes in pediatric diabetes and their clinical and laboratory characteristics over the last 20 years

Purpose We studied the changes in subtypes of diabetes mellitus (DM) in children and evaluated the characteristics of each group over the past 20 years. In addition, we also examined the correlation between the glycated hemoglobin (HbA1c) values at the time of diagnosis and lipid profiles. Methods The patients were divided into 2 groups: there were a total of 190 patients under 20 years of age firstly diagnosed with DM in Ajou University Hospital. The patients in groups I and II were diagnosed from September 1995 to December 2004 and from January 2005 to April 2014, respectively. Results The characteristics were compared between the 2 groups of patients. The result showed an increase in percentage of type 2 diabetes and maturity onset diabetes of the young (MODY) patients between the 2 groups. HbA1c and total cholesterol level had statistical significances to explain increasing the low-density lipoprotein cholesterol level among age, HbA1c, total cholesterol level, and z-scores of weight and body mass index (BMI) in type 2 diabetes. R-square was 0.074. However, z-score of BMI and total cholesterol level, not HbA1c, had statistical significances in type 1 diabetic patients. R-square was 0.323. Conclusion The increase in the proportions of both type 2 diabetes and MODY in the last 10 years needed to be reminded when diagnosing the subtypes of DM, and the dyslipidemia should be attended more as a common problem of pediatric diabetic patients.

Makorin ring finger 3 gene analysis in Koreans with familial precocious puberty

Abstract Background: Precocious puberty is known as an idiopathic, sporadic disease. Recently, specific mutations have been shown to cause familial central precocious puberty (CPP). The makorin ring finger 3 (MKRN3) gene plays a key role in puberty; loss-of-function mutations in the gene trigger familial CPP. To date, most described patients have been Western; few Asians with CPP have been documented. Objective: To identify MKRN3 gene mutations or polymorphisms in Korean patients with familial CPP. Methods: 26 patients with CPP and their parents (total 13 families) were recruited. We measured endocrine and auxological parameters, and sequenced all MKRN3 exons. Results: We found no MKRN3 mutations. Two MKRN3 exon polymorphisms were identified. The g.23566445 C/T polymorphism was found in eight families; a novel single nucleotide polymorphism (SNP) g.23567001 A/C was found in one family. These variants are synonymous SNPs; their functional roles remain unknown. Conclusions: MKRN3 mutation is uncommon in Korean patients with familial CPP. Ethnic variation in the MKRN3 mutational status is thus evident.

Glycogenic hepatopathy in a Korean girl with poorly controlled type 1 diabetes mellitus

Glycogenic hepatopathy (GH) is a rare complication of type 1 diabetes mellitus. We report the case of a 13-year-old diabetic female with poorly controlled blood sugar levels who presented with abdominal pain and distention 1 month in duration. She exhibited tender hepatomegaly, an elevated lipid profile, and elevated serum transaminase levels. Her liver histology was consistent with GH. The pathophysiology and/or underlying genetic background of GH remains unclear. The optimum treatment for GH is optimal glycemic control, and the prognosis is favorable. Clinicians should be aware of the possibility of GH and observe the clinical response to optimal glycemic control prior to invasive investigation.

The association between bone age advancement and insulin in prepubertal children with obesity

Results The study population included 49 (47.6%) males and 54 (52.4%) females with a mean age of 7.6 ± 1.6 years. The advanced bone age group defined as BA-CA>1 year (n=53) had significantly higher HOMA-IR, fasting insulin levels and lower quantitative insulin sensitivity check index (QUICKI). Also, BA-CA was significantly correlated with fasting insulin (r=0.315, P<0.001), HOMA-IR (r=0.288, P<0.001), and QUICKI (r=-0.353, P<0.001). In multiple regression analysis, fasting insulin was identified as significant independent predictors for BA-CA.

Final height after gonadotropin-releasing hormone agonists with or without growth hormone in Korean girls with central precocious puberty and early puberty

Results The mean age at the start of treatment was 8.11 ± 0.70 years in group 1, 8.98 ± 0.38 years in group 2 and 9.46 ± 0.46 years in group 3, respectively. The mean predicted adult height (PAH) SDS at the start of treatment was -1.29 ± 1.16 in group 1, -1.14 ± 0.88 in group 2 and -1.87 ± 1.09 in group 3, respectively. Rate of growth during treatment with GnRHa combined with GH was higher significantly in group 3 (6.89 ± 1.45 cm) than in group 1 (5.27 ± 0.89 cm, p = 0.001) and in group 2 (5.64 ± 0.72 cm, p = 0.022). The mean FH SDS was -0.60 ± 0.88 in group 1, -0.40 ± 1.03 in group 2 and -0.92 ± 0.72, respectively and significantly higher than initial height prediction. For the girls received GnRHa alone, FH SDS was correlated significantly with TH SDS, PAH at the start of treatment, PAH at the discontinuation of treatment. Conclusion After GnRHa treatment in girls with CPP or EP, FH is significantly higher than initial height prediction. GnRHa treatment combined with GH resulted in higher growth rate.