History of insulin treatment of pediatric patients with diabetes in Korea

The year 2021 is the centennial of insulin discovery. The discovery of insulin changes diabetes mellitus from a death sentence to a manageable disease. It became a historical turning point in the lives of people with diabetes. Since the first use of insulin in a patient in 1922, insulin and its analogs have been remarkable in saving the lives of people with diabetes. As insulin began to be used as a drug, it was introduced to, and used in Korea until now. This review briefly summarizes the history of insulin treatment in Korean children and adolescents with diabetes.

Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver–Russell Syndrome

Background@#Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS. @*Methods@#Twenty-eight patients who met ≥ 3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MSMLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, MEST on chromosome 7q32.2, and MEG3 on chromosome 14q32.2 was performed. @*Results@#. Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N = 14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N = 3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment. @*Conclusions@#NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.

Discrepancies between Glycosylated Hemoglobin and Fasting Plasma Glucose for Diagnosing Impaired Fasting Glucose and Diabetes Mellitus in Korean Youth and Young Adults

BACKGROUND: Glycosylated hemoglobin (HbA1c) has been recommended as a diagnostic test for prediabetes and diabetes. Here, we evaluated the level of agreement between diagnoses based on fasting plasma glucose (FPG) versus HbA1c levels and determined optimal HbA1c cutoff values for these diseases in youth and young adults. METHODS: The study included 7,332 subjects (n=4,129, aged 10 to 19 years in youth group; and n=3,203 aged 20 to 29 years in young adult group) from the 2011 to 2016 Korea National Health and Nutrition Examination Survey. Prediabetes and diabetes were defined as 100 to 125 mg/dL (impaired fasting glucose [IFG]) and ≥126 mg/dL for FPG (diabetes mellitus [DM] by FPG [DMFPG]), and 5.7% to 6.4% and ≥6.5% for HbA1c, respectively. RESULTS: In the youth group, 32.5% with IFG had an HbA1c level of 5.7% to 6.4%, and 72.2% with DMFPG had an HbA1c ≥6.5%. In the young adult group, 27.5% with IFG had an HbA1c level of 5.7% to 6.4%, and 66.6% with DMFPG had an HbA1c ≥6.5%. Kappa coefficients for agreement between the FPG and HbA1c results were 0.12 for the youth group and 0.19 for the young adult group. In receiver operating characteristic curve analysis, the optimal HbA1c cutoff for IFG and DMFPG were 5.6% and 5.9% in youths and 5.5% and 5.8% in young adults, respectively. CONCLUSION: Usefulness of HbA1c for diagnosis of IFG and DMFPG in Koreans aged <30 years remains to be determined due to discrepancies between the results of glucose- and HbA1c-based tests. Additional testing might be warranted at lower HbA1c levels to detect IFG and DMFPG in this age group.

Arterial stiffness in young women with Turner syndrome using cardio-ankle vascular index

PURPOSE: Patients with Turner syndrome (TS) have increased risk of morbidities and mortality related to cardiovascular complications. Cardio-ankle vascular index (CAVI) is a novel method of evaluating arterial stiffness independent of changes in blood pressure. We compared arterial stiffness using CAVI between TS patients and healthy control subjects. METHODS: Nineteen young women with TS (mean, 26.8 years; range, 20.0–35.1 years) and 23 healthy women matched for age and body mass index (BMI) were recruited for CAVI measurements at Seoul National University Hospital between 2010 and 2013. Anthropometric parameters, fasting blood testing and measurements of CAVI were compared between the 2 groups. RESULTS: TS patients were significantly shorter (mean: 150.1 cm vs. 160.7 cm, P<0.001) and had lower body weight (mean: 47.0 kg vs. 55.5 kg, P=0.014) than healthy controls, without difference in BMI. CAVI (6.5±0.6 vs. 6.1±0.6, P=0.039) was significantly higher in TS patients compared to healthy controls. Age was positively associated with CAVI (r=0.403, P=0.008) in univariate analysis. After adjusting for age, TS was associated with CAVI (P=0.006). CONCLUSION: Young women with TS showed increased arterial stiffness measured by CAVI compared to healthy women after adjusting for age, suggesting inherent vasculopathy in TS patients.

Cardiac autonomic neuropathy in nonobese young adults with type 1 diabetes

PURPOSE: The aim of this study was to evaluate the prevalence and risk factors for cardiac autonomic neuropathy (CAN) in nonobese nonobese young type 1 diabetes mellitus (T1DM) patients without micro- or macrovascular complications. METHODS: CAN was assessed in 95 patients with T1DM, aged 18–29 years, using standard cardiovascular reflex tests – heart rate response to deep breathing, standing, and the Valsalva maneuver and blood pressure response to standing. Furthermore, power spectral analyses of overall heart rate variability (HRV), standard deviation of NN intervals (SDNN), and total power (TP) were tested with DiCAN. CAN was defined as abnormal results for at least 1 of the 4 cardiovascular reflex tests. RESULTS: The prevalence of CAN was 12.6%. The frequency of one and 2 abnormal reflex tests was 10.5% and 2.1%, respectively. No significant differences were observed in age, sex, mean hemoglobin A(1c) (HbA(1c)) level, and duration of diabetes with respect to presence of CAN. Patients with CAN exhibited lower overall HRV parameters (SDNN and TP) compared with those without CAN even though there was no statistical significance. In multivariable analyses, higher mean HbA(1c) level was significantly associated with lower overall HRV (β=-44.42, P=0.002 for SDNN and β=-2.82, P<0.001 for TP). CONCLUSION: CAN can be detected in 12.6% of young adult T1DM patients even without other micro- or macrovascular complications. Glycemic control is the main determinant to maintain overall HRV and prevent CAN.

Thyroid dysfunction in patients with childhood-onset medulloblastoma or primitive neuroectodermal tumor

PURPOSE: We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). METHODS: The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children’s Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) RESULTS: During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9–4.6 years). Younger age ( < 5 years) at radiation exposure (P=0.014 vs. ≥9 years) and HDCT (P=0.042) were significantly predictive for hypothyroidism based on log-rank test. However, sex, type of tumor, and dose of craniospinal irradiation (less vs. more than 23.4 Gy) were not significant predictors. Cox proportional hazard model showed that both younger age (< 5 years) at radiation exposure (hazard ratio [HR], 3.1; vs. ≥9 years; P=0.004) and HDCT (HR, 2.4; P=0.010) were significant predictors of hypothyroidism. CONCLUSIONS: Three-quarters of patients with pediatric medulloblastoma or PNET showed thyroid dysfunction, and over half had permanent thyroid dysfunction. Thus, frequent monitoring of thyroid function is mandatory in all patients treated for medulloblastoma or PNET, especially, in very young patients and/or high-risk patients recommended for HDCT/ASCR.

The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects / 소아과

Growth charts are curves or tables that facilitate the visualization of anthropometric parameters, and are widely used as an important indicator when evaluating the growth status of children and adolescents. The latest version of the Korean National Growth Charts released in 2007 has raised concerns regarding the inclusion of data from both breastfed and formula-fed infants, higher body mass index (BMI) values in boys, and smaller 3rd percentile values in height-for-age charts. Thus, new growth charts have been developed to improve the previous version. The 2006 World Health Organization Child Growth Standards, regarded as the standard for breastfed infants and children, were introduced for children aged 0–35 months. For children and adolescents aged 3–18 years, these new growth charts include height-for-age, weight-for-age, BMI-for-age, weight-for-height, and head circumference-for-age charts, and were developed using data obtained in 1997 and 2005. Data sets and exclusion criteria were applied differently for the development of the different growth charts. BMI-for-age charts were adjusted to decrease the 95th percentile values of BMI. Criteria for obesity were simplified and defined as a BMI of ≥95th percentile for age and sex. The 3rd percentile values for height-for-age charts were also increased. Additional percentile lines (1st and 99th) and growth charts with standard deviation lines were introduced. 2017 Korean National Growth Charts are recommended for the evaluation of body size and growth of Korean children and adolescents for use in clinics and the public health sector in Korea.

Association between hemoglobin glycation index and cardiometabolic risk factors in Korean pediatric nondiabetic population

PURPOSE: The hemoglobin glycation index (HGI) represents the degree of nonenzymatic glycation and has been positively associated with cardiometabolic risk factors (CMRFs) and cardiovascular disease in adults. This study aimed to investigate the association between HGI, components of metabolic syndrome (MS), and alanine aminotransferase (ALT) in a pediatric nondiabetic population. METHODS: Data from 3,885 subjects aged 10–18 years from the Korea National Health and Nutrition Examination Survey (2011–2016) were included. HGI was defined as subtraction of predicted glycated hemoglobin (HbA1(c)) from measured HbA1(c). Participants were divided into 3 groups according to HGI tertile. Components of MS (abdominal obesity, fasting glucose, triglycerides, high-density lipoprotein cholesterol, and blood pressure), and proportion of MS, CMRF clustering (≥2 of MS components), and elevated ALT were compared among the groups. RESULTS: Body mass index (BMI) z-score, obesity, total cholesterol, ALT, abdominal obesity, elevated triglycerides, and CMRF clustering showed increasing HGI trends from lower-to-higher tertiles. Multiple logistic regression analysis showed the upper HGI tertile was associated with elevated triglycerides (odds ratio, 1.65; 95% confidence interval, 1.18–2.30). Multiple linear regression analysis showed HGI level was significantly associated with BMI z-score, HbA1(c), triglycerides, and ALT. When stratified by sex, age group, and BMI category, overweight/obese subjects showed linear HGI trends for presence of CMRF clustering and ALT elevation. CONCLUSIONS: HGI was associated with CMRFs in a Korean pediatric population. High HGI might be an independent risk factor for CMRF clustering and ALT elevation in overweight/obese youth. Further studies are required to establish the clinical relevance of HGI for cardiometabolic health in youth.

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.

Healthcare access challenges facing six African refugee mothers in South Korea: a qualitative multiple-case study / 소아과

PURPOSE: Following legal reform in 2013, the annual number of asylum seekers entering South Korea has increased from 1,143 in 2012 to 5,711 in 2015. We interviewed six African refugee mothers of young children regarding their health needs and barriers to access maternal child health services. METHODS: We recruited mothers who had visited a clinic for immigrants between July 2013 and August 2015. Participants were African refugee women, aged over 18 years, who had given birth in Korea within the previous 5 years and had come to Korea over a year before recruitment. Interview questions examined participants' experiences in pregnancy and childbirth and concerns regarding their child's health status. Initial data analysis involved all researchers' immersion in the entire collection of transcripts. We then noted recurrent topics and themes and identified similar issues. RESULTS: At the time of giving birth, 5 participants were asylum seekers and one had undocumented status. The following barriers impeded their access to maternal child healthcare: socioeconomic factors (unstable social identity, low economic status, difficulty obtaining health insurance), language barriers (lack of linguistically appropriate health information, limited access to translation services), and cultural barriers (religious and cultural differences). Weak social support also hindered access to healthcare soon after migration; however, social links with the community emerged as a key coping strategy following settlement. CONCLUSION: We identified barriers to maternal and child healthcare and coping strategies among African refugee mothers in Korea. Future research should assess refugees' health status and improve health access and literacy among refugee mothers.

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.

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.

Clinical course of infants with congenital heart disease who developed thyroid dysfunction within 100 days

PURPOSE: We investigated the clinical course of infants with congenital heart disease (CHD) who experienced thyroid dysfunction within 100 days of birth. METHODS: We performed retrospective medical reviews of 54 CHD patients (24 male patients) who underwent a thyroid function test (TFT) between January 2007 and July 2016. Data were collected on birth history, diagnosis of CHD, underlying chromosomal or genetic abnormalities, medication history, surgery, ventilator care, and exposure to iodine contrast media (ICM). Results of neonatal screening tests (NSTs) and TFTs were reviewed. RESULTS: A total of 36 patients (29 transient, 7 permanent) showed thyroid dysfunction. Among the seven patients with permanent hypothyroidism, three had an underlying syndrome, three showed abnormal NST results, and one was admitted to the intensive care unit for macroglossia and feeding cyanosis. We found that infants with transient thyroid dysfunction had a lower birth weight and were more commonly exposed to thyroid disrupting medication and/or ICM. However, these risk factors were not significant. A total of 8 patients with a history of ICM exposure showed thyroid dysfunction. Excluding 3 patients with elevated thyroid stimulating hormone before ICM exposure, 5 patients recovered from transient thyroid dysfunction. CONCLUSIONS: We observed thyroid dysfunction in two-thirds of CHD infants (53.7% transient, 13.0% permanent) who had risk factors and received TFT screening within 100 days, despite normal NSTs. Further studies with larger sample sizes are required to revise the criteria for TFT screening in CHD infants.

Prevalence and Clinical Characteristics of Metabolically Healthy Obesity in Korean Children and Adolescents: Data from the Korea National Health and Nutrition Examination Survey

Metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) are differentiated by the presence of cardiometabolic risk factors (CMRFs) and insulin resistance (IR). This study aimed to evaluate the prevalence and clinical characteristics of MHO in Korean children and adolescents and to investigate the anthropometric, laboratory, and lifestyle predictors of MHO. This study included data from 530 obese subjects, aged 10–19 years, obtained from the Fourth Korea National Health and Nutrition Examination Survey. Subjects were classified into MHO and MUO groups according to the presence of CMRF (MHO(CMRF)/MUO(CMRF)) and degree of IR (MHO(IR)/MUO(IR)). Demographic, anthropometric, cardiometabolic, and lifestyle factors were compared between the groups. Logistic regression analysis and receiver operating characteristic curve analysis were performed to identify factors that predicted MHO. The prevalence of MHO(CMRF) and MHO(IR) in obese Korean youth was 36.8% (n = 197) and 68.8% (n = 356), respectively. CMRF profiles were significantly less favorable in MUO children. Longer and more vigorous physical activity and less protein intake were associated with MHO(CMRF) phenotype. The best predictors of MHO(CMRF) and MHO(IR) were waist circumference (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.77–0.88; P < 0.001) and body mass index (BMI) standard deviation score (OR, 0.24; 95% CI, 0.15–0.39; P < 0.001), respectively. The prevalence of MHO differed depending on how it was defined. To adequately manage obesity in youth, the approach to individuals with MHO and MUO should be personalized due to variation in clinical characteristics. Longitudinal studies are needed to evaluate long-term consequences of MHO.

Nonalcoholic fatty liver disease in long-term survivors of childhood-onset craniopharyngioma

PURPOSE: Hypothalamic obesity in childhood-onset (CO-) craniopharyngioma patients may predispose to nonalcoholic fatty liver disease (NAFLD). This study reviewed the characteristics of NAFLD associated with CO-craniopharyngioma. METHODS: This study retrospectively reviewed 75 patients who underwent surgery for craniopharyngioma while younger than 15 years of age between 2000 and 2016. RESULTS: Elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above 40 IU/L was observed in 51 of the 75 (68%) CO-craniopharyngioma patients. Imaging studies were performed in 32 patients with elevated liver enzymes. The estimated prevalence of NAFLD in CO-craniopharyngioma was 47%. NAFLD was detected in 22 patients (male 59%, 4.3±4.0 years after first surgery). The mean age at the time of the initial operation was 9.1±2.9 years. Six patients (27.3%) were diagnosed within 1 year. Among the 19 patients with initial height and weight data, the body mass index (BMI) z-score (BMI_Z) at the time of diagnosis with NAFLD was 1.37±1.01 (range, -0.75 to 3.18), with 4 patients (18.2%) being overweight and 9 (40.9%) being obese. BMI_Z increased above BMI_Z at the time of the operation in 13 patients (68.4%). The increment in BMI_Z was 1.13 (range, 0.10–2.84). Seventeen patients did not receive growth hormone. An insulin-like growth factor-I level < 3rd percentile was observed in 19 patients. CONCLUSION: NAFLD is common in survivors of CO-craniopharyngioma and may develop earlier. If the ALT or AST is above 40 IU/L, a diagnostic work-up should be started.

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.

Two cases of Antley-Bixler syndrome caused by mutations in different genes, FGFR2 and POR

Antley-Bixler syndrome (ABS) is a rare form of syndromic craniosynostosis with additional systemic synostosis, including radiohumeral or radioulnar synostosis. Another characteristic feature of ABS is mid-facial hypoplasia that leads to airway narrowing after birth. ABS is associated with mutations in the FGFR2 and POR genes. Patients with POR mutations present with either skeletal manifestations or congenital adrenal hyperplasia with ambiguous genitalia. We report here two cases of ABS caused by mutations in FGFR2 and POR. Although the patients had craniosynostosis and radiohumeral synostosis in common and cranioplasty was performed in both cases, the male with POR mutations showed an elevated level of 17α-hydroxyprogesterone during newborn screening and was diagnosed with congenital adrenal hyperplasia by adrenocorticotropic hormone stimulation. This patient has been treated with hydrocortisone and fludrocortisone. He had no ambiguous genitalia but had bilateral cryptorchidism. On the other hand, the female with the FGFR2 mutation showed severe clinical manifestations: upper airway narrowing leading to tracheostomy, kyphosis of the cervical spine, and coccyx deformity. ABS shows locus heterogeneity, and mutations in two different genes can cause similar craniofacial and skeletal phenotypes. Because the long-term outcomes and inheritance patterns of the disease differ markedly, depending on the causative mutation, early molecular genetic testing is helpful.

Three Korean patients with Cantú syndrome caused by mutations in ABCC9 and their clinical manifestations

Cantú syndrome (CS, OMIM 239850) is a very rare autosomal dominantly inherited genetic disease characterized by congenital hypertrichosis, neonatal macrosomia, a distinct facial features such as macrocephaly, and cardiac defects. Since the first description by Cantú et al. in 1982, about 50 cases have been reported to date. Recently, two causative genes for CS has been found by using exome sequencing analyses: ABCC9 and KCNJ8 . Most cases of clinically diagnosed CS have resulted from de novo mutations in ABCC9. In this study, we report three independent Korean children with CS resulting from de novo ABCC9 mutations. Our patients had common clinical findings such as congenital hypertrichosis, distinctive facial features. One of them showed severe pulmonary hypertension and hypertrophic cardiomyopathy, which require medical treatment. And, two patients had a history of patent ductus arteriosus. Although two of our patients had shown early motor developmental delay, it was gradually improved during follow-up periods. Although CS is quite rare, there are the concerns about development of various cardiac problems in the lifetime. Therefore, an accurate diagnosis followed by appropriate management and genetic counseling should be provided to CS patients.

Multiple osteoblastomas in a child with Cushing syndrome due to bilateral adrenal micronodular hyperplasias

Adrenocorticotropin-independent adrenal hyperplasias are rare diseases, which are classified into macronodular (>1 cm) and micronodular (≤1 cm) hyperplasia. Micronodular adrenal hyperplasia is subdivided into primary pigmented adrenocortical disease and a limited or nonpigmented form 'micronodular adrenocortical disease (MAD)', although considerable morphological and genetic overlap is observed between the 2 groups. We present an unusual case of a 44-month-old girl who was diagnosed with Cushing syndrome due to MAD. She had presented with spotty pigmentation on her oral mucosa, lips and conjunctivae and was diagnosed with multiple bone tumors in her femur, pelvis and skull base at the age of 8 years. Her bone tumor biopsies were compatible with osteoblastoma. This case highlights the importance of verifying the clinicopathologic correlation in Cushing syndrome and careful follow-up and screening for associated diseases.