Metabolic Impacts of Discontinuation and Resumption of Recombinant Human Growth Hormone Treatment during the Transition Period in Patients with Childhood-Onset Growth Hormone Deficiency

Background@#Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period. @*Methods@#This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption. @*Results@#Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates. @*Conclusion@#GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.

A cell function study on calcium regulation of a novel calcium-sensing receptor mutation (p.Tyr825Phe)

Purpose@#Autosomal dominant hypocalcemia with hypercalciuria is a genetic disease characterized by hypoparathyroidism with hypercalciuria. We discovered a novel variant (p.Tyr825Phe[Y825F]) of the CASR gene in a neonate with congenital hypoparathyroidism and hypercalciuria and conducted a cell function study to determine whether the CASR-Y825F variant was pathogenic. @*Methods@#To perform a functional study on CaSR-Y825F, we constructed expression vectors expressing wild-type (WT) CASR and CASR-Y825F. After transfection of each expression vector into HEK293 cells, we examined alterations in intracellular signaling. Mitogen-activated protein kinase (MAPK) signaling activity of HEK293 cells expressing CASR-WT or CASR-Y825F was determined. Changes in intracellular calcium ions ([Ca2+]i) by extracellular calcium ion ([Ca2+]e) stimulation were quantitatively compared and analyzed. @*Results@#Cells expressing CASR-Y825F showed elevated of MAPK signaling (phospho-ERK [pERK], phospho-JNK [pJNK], phospho-p38 [pp38]) and increased [Ca2+]i levels at low [Ca2+]e stimulation compared with cells expressing CASR-WT. Additionally, [Ca2+]i levels in HEK293 cells expression CASR-WT and CASR-Y825F were determined at 340 nm/380 nm wavelength ratios using Fura-2 AM. At [Ca2+]e concentrations of 2.5 mM and 3 mM, the ratios of CASR-Y825F cells were higher (2.6 and 3.5, respectively) than those of CASR-WT cells (1.04 and 1.40, respectively). @*Conclusion@#This cell function study proved that the CASR-Y825F expressed in HEK293 cells elevated MAPK signaling (pERK, pJNK, pp38) and increased [Ca2+]i to induce hypocalcemia.

A cell function study on calcium regulation of a novel calcium-sensing receptor mutation (p.Tyr825Phe)

Purpose@#Autosomal dominant hypocalcemia with hypercalciuria is a genetic disease characterized by hypoparathyroidism with hypercalciuria. We discovered a novel variant (p.Tyr825Phe[Y825F]) of the CASR gene in a neonate with congenital hypoparathyroidism and hypercalciuria and conducted a cell function study to determine whether the CASR-Y825F variant was pathogenic. @*Methods@#To perform a functional study on CaSR-Y825F, we constructed expression vectors expressing wild-type (WT) CASR and CASR-Y825F. After transfection of each expression vector into HEK293 cells, we examined alterations in intracellular signaling. Mitogen-activated protein kinase (MAPK) signaling activity of HEK293 cells expressing CASR-WT or CASR-Y825F was determined. Changes in intracellular calcium ions ([Ca2+]i) by extracellular calcium ion ([Ca2+]e) stimulation were quantitatively compared and analyzed. @*Results@#Cells expressing CASR-Y825F showed elevated of MAPK signaling (phospho-ERK [pERK], phospho-JNK [pJNK], phospho-p38 [pp38]) and increased [Ca2+]i levels at low [Ca2+]e stimulation compared with cells expressing CASR-WT. Additionally, [Ca2+]i levels in HEK293 cells expression CASR-WT and CASR-Y825F were determined at 340 nm/380 nm wavelength ratios using Fura-2 AM. At [Ca2+]e concentrations of 2.5 mM and 3 mM, the ratios of CASR-Y825F cells were higher (2.6 and 3.5, respectively) than those of CASR-WT cells (1.04 and 1.40, respectively). @*Conclusion@#This cell function study proved that the CASR-Y825F expressed in HEK293 cells elevated MAPK signaling (pERK, pJNK, pp38) and increased [Ca2+]i to induce hypocalcemia.

Clinical, endocrinological, and molecular features of four Korean cases of cytochrome P450 oxidoreductase deficiency

Purpose@#Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder caused by mutations in the POR gene encoding an electron donor for all microsomal P450 enzymes. It is characterized by adrenal insufficiency, ambiguous genitalia, maternal virilization during pregnancy, and skeletal dysplasia. In this study, we investigated the clinical, hormonal, and molecular characteristics of patients with POR deficiency in Korea. @*Methods@#This study included four patients with POR deficiency confirmed by biochemical and molecular analysis of POR. Clinical and biochemical findings were reviewed retrospectively. Mutation analysis of POR was performed by Sanger sequencing after polymerase chain reaction amplification of all coding exons and the exon-intron boundaries. @*Results@#All patients presented with adrenal insufficiency and ambiguous genitalia regardless of their genetic sex. Two patients harbored homozygous p.R457H mutations in POR and presented with adrenal insufficiency and genital ambiguity without skeletal phenotypes. The other two patients with compound heterozygous mutations of c.[1329_1330insC];[1370G>A] (p.[I444Hfs*6];[R457H]) manifested skeletal abnormalities, such as craniosynostosis and radiohumeral synostosis, suggesting Antley-Bixler syndrome. They also had multiple congenital anomalies involving heart, kidney, and hearing ability. All patients were treated with physiologic doses of oral hydrocortisone. @*Conclusion@#We report the cases of 4 patients with POR deficiency identified by mutation analysis of POR. Although the study involved a small number of patients, the POR p.R457H mutation was the most common, suggesting founder effect in Korea. POR deficiency is rare and can be misdiagnosed as 21-hydroxylase or 17α-hydroxylase/17,20-lyase deficiency. Therefore, molecular analysis is critical for confirmatory diagnosis.

An Alport syndrome boy with Van Wyk-Grumbach syndrome induced by prolonged untreated congenital hypothyroidism

Alport syndrome (AS) is a rare genetic disorder that causes progressive nephritis and is more common among males. Studies have reported an association between thyroid antibodies and hypothyroidism in patients with AS, but the relevance of this relationship is under debate. Prolonged untreated hypothyroidism induces short stature, abnormal pubertal development, and various other symptoms. However, children with long-standing hypothyroidism rarely present with signs of precocious puberty, or Van Wyk-Grumbach syndrome (VWGS). We report the case of a boy, 8 years and 4 months old, who had VWGS caused by prolonged untreated congenital hypothyroidism and AS. The boy had repeated gross hematuria and proteinuria and was diagnosed with AS by renal biopsy and genetic testing. He had normal renal function but severe growth retardation and hypothyroidism. Obesity, bone age delay, hyperlipidemia, and abnormal increased testicle size were also present due to prolonged untreated hypothyroidism. His thyroid antibody titer elevation was unclear, although ultrasonography and thyroid scanning showed a decrease in thyroid volume. We diagnosed the patient with congenital hypothyroidism caused by thyroid dysgenesis. VWGS was diagnosed due to hypothyroidism, delayed bone age, and pseudoprecocious puberty. To the best of our knowledge, this is the first report of a prepubertal Korean boy with prolonged untreated congenital hypothyroidism complicated by VWGS in AS.

Severe recurrent nocturnal hypoglycemia during chemotherapy with 6-mercaptopurine in a child with acute lymphoblastic leukemia

Various endocrine dysfunctions occur during chemotherapy, including hypoglycemia. However, reports of hypoglycemia associated with 6-mercaptopurine (6-MP) are rare. Herein, we report an 8-year-old boy with severe symptomatic hypoglycemia likely due to 6-MP during chemotherapy. He had been diagnosed with acute lymphoblastic leukemia 3 years previously and was in the maintenance chemotherapy period. Treatment included oral dexamethasone, methotrexate, and 6-MP, of which only 6-MP was administered daily. Hypoglycemic symptoms appeared mainly at dawn, and his serum glucose dropped to a minimum of 37 mg/dL. Laboratory findings showed nothing specific other than increased serum cortisol, free fatty acids, ketone, alanine aminotransferase, and aspartate aminotransferase. Under the hypothesis of hypoglycemia due to chemotherapy drugs, we changed the time of 6-MP from evening to morning and recommended him to ingest carbohydrate-rich foods before bedtime. Hypoglycemia improved dramatically, and there was no further episode during the remaining maintenance chemotherapy period. To the best of our knowledge, this is the first report of this type of hypoglycemia occurring in an Asian child including Korean.

De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.

Severe vitamin D deficiency in preterm infants: maternal and neonatal clinical features / 소아과

PURPOSE: We investigated the vitamin D status of preterm infants to determine the incidence of vitamin D deficiency. METHODS: A total of 278 preterm infants delivered at Kyungpook National University Hospital between January 2013 and May 2015 were enrolled. The serum concentrations of calcium, phosphorous, alkaline phosphatase, and 25-hydroxyvitamin D (25-OHD) were measured at birth. We collected maternal and neonatal data such as maternal gestational diabetes, premature rupture of membranes, maternal preeclampsia, birth date, gestational age, and birth weight. RESULTS: Mean gestational age was 33(+5)+/-2(+2) weeks of gestation and mean 25-OHD concentrations were 10.7+/-6.4 ng/mL. The incidence of vitamin D deficiency was 91.7%, and 51.1% of preterm infants were classified as having severe vitamin D deficiency (25-OHD<10 ng/mL). The serum 25-OHD concentrations did not correlate with gestational age. There were no significant differences in serum 25-OHD concentrations or incidence of severe vitamin D deficiency among early, moderate, and late preterm infants. The risk of severe vitamin D deficiency in twin preterm infants was significantly higher than that in singletons (odds ratio, 1.993; 95% confidence interval [CI], 1.137-3.494, P=0.016). In the fall, the incidence of severe vitamin D deficiency decreased 0.46 times compared to that in winter (95% CI, 0.227-0.901; P=0.024). CONCLUSION: Most of preterm infants (98.9%) had vitamin D insufficiency and half of them were severely vitamin D deficient. Younger gestational age did not increase the risk of vitamin D deficiency, but gestational number was associated with severe vitamin D deficiency.

Vitamin D in Full-term Neonates in Daegu and Gyeongbuk Province of Korea and the Association with Maternal and Neonatal Diseases / 대한주산의학회잡지

PURPOSE: This study aimed to evaluate serum 25-hydroxyvitamin D [25(OH)D3] levels of full-term neonates in Daegu and Gyeongbuk province of Korea to determine the association between maternal and neonatal diseases, known to be affected by low 25(OH)D3 levels. METHODS: Serum 25(OH)D3 levels were evaluated in full-term neonates (n=122) who were born at Kyungpook National University Hospital. Normal full-term neonates (control group, n=38) were classified by sex, season of birth, and delivery mode (normal or caesarean section). Serum 25(OH)D3 levels in neonates (n=84) with maternal diseases (gestational diabetes mellitus, hypothyroidism, pregnancy induced hypertension, premature rupture of membrane and systemic lupus erythematosus) and neonatal diseases (small for gestational age, transient tachypnea of newborn and pneumonia) were compared with those in control group. RESULTS: The mean serum 25(OH)D3 level in the control group was 9.2+/-5.0 ng/mL. There were no statistically significant differences of serum 25(OH)D3 level between the control group and the disease group. In the control group, 63.2% of serum 25(OH)D3 levels referred to vitamin D deficiency, and 34.2% referred to vitamin D insufficiency. In the maternal disease group and the neonatal disease group, 56.1% and 63.0% of serum 25(OH)D3 levels referred to vitamin D deficiency, and 35.0% and 33.3% referred to vitamin D insufficiency. CONCLUSION: High percentages of neonates were found to be deficient or insufficient in vitamin D. Although low 25(OH)D3 levels have previously been associated with maternal and infant diseases, the association was not observed in this study.

Comparison of the Therapeutic Efficacy of Methylprednisolone Pulse Therapy and Oral Steroid Therapy in Children with IgA Nephropathy and HSP Nephritis Combined with Proteinuria

PURPOSE: The purpose of this study was to assess the therapeutic efficacy of methylprednisolone pulse therapy in children with IgA nephropathy and Henoch-Schonlein Purpura (HSP) nephritis combined with proteinuria. METHODS: We retrospectively reviewed the clinical records of 21 patients who were diagnosed with IgA nephropathy and HSP nephritis based on percutaneous renal biopsy. Of the 21 patients, 15 were diagnosed with IgA nephropathy and 6 were diagnosed with HSP nephritis. They had mild to severe proteinuria at the time of diagnosis or during follow-up. Group 1 (n=7) received methylprednisolone pulse therapy three times every couple of months, and Group 2 (n=14) received oral steroid therapy. The follow-up periods for Group 1 and 2 were 14.0 (9-54) months and 26.5 (14-34) months, respectively. There was no significant difference in the follow-up duration between the two groups. RESULTS: The average age at diagnosis and biopsy was lower in Group 1 compared to Group 2, but it was not significantly different. At admission, all patients in both groups had hematuria and 5 patients (71.4%) of Group 1 and 14 patients (100%) of Group 2 had proteinuria. Before treatment, there was no significant difference of spot urine protein/creatinine ratio between the two groups. During follow-up, 7 patients of Group 1 (100%) and 10 patients of Group 2 (71.4%) showed complete improvement of proteinuria and the spot urine protein/creatinine ratio in Group 1 was significantly lower than Group 2. CONCLUSION: In patients with IgA nephropathy and HSP nephritis with proteinuria, methylprednisolone pulse therapy was more effective than oral steroid therapy in the reduction of proteinuria. To investigate the effects on long-term prognosis, large-scale prospective studies are needed.