Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings.

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency due to the homozygous PCK1 variant has recently been associated with childhood-onset hypoglycemia with a recognizable pattern of abnormal urine organic acids. In this study, 21 children and 3 adult patients with genetically confirmed PEPCK-C deficiency were diagnosed during the years 2016 to 2019 and the available biochemical and clinical data were collected. All patients were ethnic Finns. Most patients (22 out of 24) had a previously published homozygous PCK1 variant c.925G>A. Two patients had a novel compound heterozygous PCK1 variant c.925G>A and c.716C>T. The laboratory results showed abnormal urine organic acid profile with increased tricarboxylic acid cycle intermediates and inadequate ketone body production during hypoglycemia. The hypoglycemic episodes manifested predominantly in the morning. Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors. Five patients presented with neonatal hypoglycemia. Hypoglycemic seizures occurred in half of the patients (12 out of 24). The first hypoglycemic episode often occurred at the age of 1-2 years, but it sometimes presented at a later age, and could re-occur during school age or adulthood. This study adds to the laboratory data on PEPCK-C deficiency, confirming the recognizable urine organic acid pattern and identifying deficient ketogenesis as a novel laboratory finding. The phenotype is expanded suggesting that the risk of hypoglycemia may continue into adulthood if predisposing factors are present.

Kallmann syndrome in a patient with Weiss-Kruszka syndrome and a de novo deletion in 9q31.2.

Patients with deletions on chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2. The deletion breakpoints (determined with whole-genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with the patient's Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole-exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2) but did not suppress its expression. In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.

Recombinant Human FSH Treatment Outcomes in Five Boys With Severe Congenital Hypogonadotropic Hypogonadism.

CONTEXT: Recombinant human FSH (r-hFSH), given to prepubertal boys with hypogonadotropic hypogonadism (HH), may induce Sertoli cell proliferation and thereby increase sperm-producing capacity later in life. OBJECTIVE: To evaluate the effects of r-hFSH, human chorionic gonadotropin (hCG), and testosterone (T) in such patients. DESIGN AND SETTING: Retrospective review in three tertiary centers in Finland between 2006 and 2016. PATIENTS: Five boys: ANOS1 mutation in two, homozygous PROKR2 mutation in one, FGFR1 mutation in one, and homozygous GNRHR mutation in one. Prepubertal testicular volume (TV) varied between 0.3 and 2.3 mL; three boys had micropenis, three had undergone orchidopexy. INTERVENTIONS: Two boys received r-hFSH (6 to 7 months) followed by r-hFSH plus hCG (33 to 34 months); one received T (6 months), then r-hFSH plus T (29 months) followed by hCG (25 months); two received T (3 months) followed by r-hFSH (7 months) or r-hFSH plus T (8 months). MAIN OUTCOME MEASURES: TV, inhibin B, anti-Müllerian hormone, T, puberty, sperm count. RESULTS: r-hFSH doubled TV (from a mean ± SD of 0.9 ± 0.9 mL to 1.9 ± 1.7 mL; P < 0.05) and increased serum inhibin B (from 15 ± 5 ng/L to 85 ± 40 ng/L; P < 0.05). hCG further increased TV (from 2.1 ± 2.3 mL to 8.6 ± 1.7 mL). Two boys with initially extremely small testis size (0.3 mL) developed sperm (maximal sperm count range, 2.8 to 13.8 million/mL), which was cryopreserved. CONCLUSIONS: Spermatogenesis can be induced with gonadotropins even in boys with HH who have extremely small testes, and despite low-dose T treatment given in early puberty. Induction of puberty with gonadotropins allows preservation of fertility.

Serum 25-Hydroxyvitamin D, Plasma Lipids, and Associated Gene Variants in Prepubertal Children.

Context: The associations of serum 25-hydroxyvitamin D [25(OH)D] with plasma lipids remain controversial in children. Objective: To examine the associations and interactions of 25(OH)D and related gene variants with lipids in children. Design: Cross-sectional. Setting: Kuopio, Finland. Participants: Population sample of 419 prepubertal white children aged 6 to 8 years. Main Outcome Measures: 25(OH)D, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: Serum 25(OH)D was negatively associated with total cholesterol (ß = -0.141, P = 0.004), LDL cholesterol (ß = -0.112, P = 0.023), HDL cholesterol (ß = -0.150, P = 0.002), and triglycerides (ß = -0.104, P = 0.035) adjusted for age and sex. Associations of 25(OH)D with total cholesterol, LDL cholesterol, and HDL cholesterol remained after adjustment for adiposity, physical activity, sedentary behavior, diet, daylight time, and parental education. Children in the highest quartile of 25(OH)D had the lowest total cholesterol (P = 0.022) and LDL cholesterol (P = 0.026) adjusted for age and sex. Cytochrome P450 family 2 subfamily R member 1 (CYP2R1) rs12794714, CYP2R1 rs10741657, and vitamin D binding protein (DBP) rs2282679 were associated with 25(OH)D adjusted for age and sex. CYP2R1 rs12794714 was associated with total cholesterol and LDL cholesterol and C10orf88 rs6599638 with HDL cholesterol adjusted for age, sex, and 25(OH)D. The gene variants did not explain or modify the associations of 25(OH)D with lipids. Conclusions: 25(OH)D was independently and inversely associated with total cholesterol, LDL cholesterol, and HDL cholesterol. CYP2R1 rs12794714, CYP2R1 rs10741657, and DBP rs2282679 were associated with 25(OH)D. CYP2R1 rs12794714 was associated with total cholesterol and LDL cholesterol and chromosome 10 open reading frame 88 (C10orf88) rs6599638 with HDL cholesterol independent of 25(OH)D. None of the gene variants modified the associations of 25(OH)D with lipids. Further studies are needed to detect the mechanisms for the associations of 25(OH)D with lipids.

Body fat mass, lean body mass and associated biomarkers as determinants of bone mineral density in children 6-8years of age - The Physical Activity and Nutrition in Children (PANIC) study.

Lean body mass (LM) has been positively associated with bone mineral density (BMD) in children and adolescents, but the relationship between body fat mass (FM) and BMD remains controversial. Several biomarkers secreted by adipose tissue, skeletal muscle, or bone may affect bone metabolism and BMD. We investigated the associations of LM, FM, and such biomarkers with BMD in children. We studied a population sample of 472 prepubertal Finnish children (227 girls, 245 boys) aged 6-8years. We assessed BMD, LM, and FM using whole-body dual-energy x-ray absorptiometry and analysed several biomarkers from fasting blood samples. We studied the associations of LM, FM, and the biomarkers with BMD of the whole body excluding the head using linear regression analysis. LM (standardized regression coefficient ß=0.708, p<0.001), FM (ß=0.358, p<0.001), and irisin (ß=0.079, p=0.048) were positive correlates for BMD adjusted for age, sex, and height in all children. These associations remained statistically significant after further adjustment for LM or FM. The positive associations of dehydroepiandrosterone sulphate (DHEAS), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), leptin, free leptin index, and high-sensitivity C-reactive protein and the negative association of leptin receptor with BMD were explained by FM. The positive associations of DHEAS and HOMA-IR with BMD were also explained by LM. Serum 25-hydroxyvitamin D was a positive correlate for BMD adjusted for age, sex, and height and after further adjustment for FM but not for LM. LM and FM were positive correlates for BMD also in girls and boys separately. In girls, insulin, HOMA-IR, leptin, and free leptin index were positively and leptin receptor was negatively associated with BMD adjusted for age, height, and LM. After adjustment for age, height, and FM, none of the biomarkers was associated with BMD. In boys, leptin and free leptin index were positively and leptin receptor was negatively associated with BMD adjusted for age, height, and LM. After adjustment for age, height and FM, 25(OH)D was positively and IGF-1 and leptin were negatively associated with BMD. FM strongly modified the association between leptin and BMD. LM but also FM were strong, independent positive correlates for BMD in all children, girls, and boys. Irisin was positively and independently associated with BMD in all children. The associations of other biomarkers with BMD were explained by LM or FM.

Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood wheezing.

OBJECTIVE: The aim of the study was to evaluate the association between previous use of ICS and bone mineral density (BMD) at school age in a cohort followed after early childhood wheezing. METHODS: As part of a prospective follow-up study after hospitalization for wheezing at <24 months of age, BMD was measured in 89 children at 12.3 (median) years of age. Data on ICS use were collected by interviewing the parents, and this was supplemented with data from patient records. Cumulative doses and the duration of ICS use were calculated. Areal BMD (BMDareal , g/cm(2) ) was measured by dual energy X-ray absorptiometry (DXA), and apparent volumetric BMD (aBMDvol , g/cm(3) ) was calculated, for the lumbar spine and femoral neck. Weight, height and pubertal stage were recorded. FINDINGS: Age, sex, and pubertal stage were significantly associated with BMDareal and aBMDvol of the lumbar spine and BMDareal of the femoral neck. The regular use of ICS for >6 months at age <6 years was associated with a lower BMD of the lumbar spine. A lower BMDareal and aBMDvol of the femoral neck were associated with higher cumulative doses of ICS at age 0-12.3 (median) years. The results were robust to adjustment for age, sex, pubertal stage, height, weight, and use of systemic steroids. CONCLUSION: ICS use during childhood may be related to a decrease in BMD at late school age. It is important to use the lowest possible ICS dose that maintains adequate asthma control.

Overweight does not increase asthma risk but may decrease allergy risk at school age after infantile bronchiolitis.

AIM: Increasing evidence suggests that overweight children are at increased risk of asthma. The association between weight gain and allergy is more complex. The aim was to evaluate the association between overweight or obesity and asthma, allergy, bronchial reactivity or atopic sensitization at school age in children with bronchiolitis in infancy. SUBJECTS AND METHODS: Eighty-one children hospitalized for bronchiolitis at <24 months of age attended control visits at 7.2 and 12.3 years of ages. The visits consisted of medical examinations, weight and height measurements, body mass index (BMI) calculations, skin prick tests and exercise challenge tests. BMI >1.3 SD from age- and gender-specific references meant overweight and BMI >2.0 SD obesity. RESULTS: Current or previous overweight or obesity did not increase the risk of asthma, allergy, bronchial reactivity or atopic sensitization at 7.2 or 12.3 years of age. Previous and current obesity decreased the risk of atopic dermatitis, and current overweight and obesity decreased the risk of sensitization to outdoor allergens at 12.3 years of age. CONCLUSION: Previous or current overweight does not increase asthma or allergy risk but current obesity may decrease allergy risk at school age after bronchiolitis in infancy.

Lung function and overweight in school aged children after early childhood wheezing.

BACKGROUND AND PURPOSE: Recently, obesity has been connected with wheezing, asthma and reduced lung function. Most previous studies have been cross-sectional. The aim of the present follow-up study was to evaluate the association of preceding or current overweight or obesity with lung function at early and late school age after early childhood wheezing. MATERIAL AND METHODS: From the 100 children hospitalized for infection associated wheezing at <24 months of age, 83 attended the control visit at 4.0 years, 82 at 7.2 years and 81 at 12.3 years of age. Flow-volume spirometry was performed in 79 children at 7.2 years and in 80 children at 12.3 years of age. The weight status was assessed by calculating body mass index (BMI) at all visits. Age- and gender-specific BMI standard deviation scores (BMI-SDS) of >1.3 SD and >2.0 SD were defined to mean overweight and obesity, respectively. RESULTS: Overweight at both 7.2 and 12.3 years of age was associated with decreased FEV1 /FVC (forced expiratory volume in 1 sec/forced vital capacity). Overweight and obesity at 7.2 years of age were associated with decreased FEV1 /FVC and MEF50 (maximal expiratory flow at 50% of FVC) at 12.3 years of age. The results were similar by continuous and categorized analyses, being robust to adjustments for viral findings during early childhood wheezing and asthma maintenance medication at school age. CONCLUSION: Overweight and obesity are significant risk factors for reduced lung function at school age after early childhood wheezing. Thus, early-life wheezers should avoid excessive weight gain during childhood.