Volume 33, Issue 7

With this review, we aim to focus the attention on some established as well as new concepts for the metabolic syndrome (MetS) in children and adolescents spanning from definition to recommendations for the diagnostic approach. Even though there is no international commonly used definition of the metabolic syndrome in children and adolescents, all definitions include obesity as precondition for the development of MetS even in children. Obesity is one of the major cardiometabolic risk factors and it is strongly linked to other metabolic diseases like hyperlipidemia, hyperinsulinemia as well as hypertension. The metabolic syndrome is commonly known as a constellation of the mentioned morbidities. Pediatricians and researchers agree that early diagnosis and early interventions of the MetS are important to improve the prevention of cardiovascular disease and type 2 diabetes in adulthood. However, this requires appropriate screening tools for children and adolescents at risk for the MetS and its comorbidities. Due to controversies regarding the definition of MetS and the lack of consensus thresholds for the single components in children and adolescents, there is no internationally accepted diagnostic pathway for MetS available. However, several consensus statements and national guidelines for the assessment of obesity and its comorbidities in children and adolescents are available. Obesity seems to be the driving factor for the development of the other risk factors of MetS. In order to avoid conflicts concerning the definition of overweight and obesity, we recommend using the WHO definition of overweight (one standard deviation body mass index for age and sex and obesity; two standard deviations body mass index for age and sex) in children and adolescents.

Cystic fibrosis (CF) is a highly prevalent autosomal recessive disorder that is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene (7q31.2), which encodes the CFTR chloride-anion channel that is expressed in several tissues. Life expectancy has increased significantly over the past few decades due to therapeutic advances and early diagnosis through neonatal screening. However, new complications have been identified, including CF-related diabetes (CFRD). The earliest detectable glycemic abnormality is postprandial hyperglycemia that progresses into fasting hyperglycemia. CFRD is associated with a decline in lung function, impairments in weight gain and growth, pubertal development, and increased morbidity and mortality. Annual screening with oral glucose tolerance test is recommended beginning at the age of 10, and screenings are recommended for any age group during the first 48 h of hospital admission. Fasting plasma glucose levels ≥126 mg/dL (7.0 mmol/L) or 2-h postprandial plasma glucose levels ≥200 mg/dL (11.1 mmol/L) that persist for more than 48 h are diagnostic criteria for CFRD. Under stable health condition, the diagnosis is made when laboratory abnormalities in accordance with the American Diabetes Association criteria are detected for the first time; however, levels of HbA1c <6.5% do not rule out the diagnosis. Treatment for CFRD includes insulin replacement and a hypercaloric and hyperproteic diet that does not restrict carbohydrates, fats or salt, and diabetes self-management education. The most important CFRD complications are nutritional and pulmonary disease deterioration, though the microvascular complications of diabetes have already been described.

Background Accumulating evidence suggests a relationship between sleep alterations and overweight/obesity in children. Our aim was to investigate the association of sleep measures other than obstructive sleep apnea or sleep duration with overweight/obesity and metabolic function in children. Methods We conducted a prospective cohort study in school- aged children (aged 5 to 8 years, prepubertal, and 12 to 15 years, pubertal) with overweight/obesity and normal-weight children. All children underwent a standardized in-laboratory polysomnography followed by a fasting blood assessment for glucose and metabolic testing. Subjective sleep measures were investigated by a 7-day sleep diary and questionnaire. We analyzed prepubertal and pubertal groups separately using logistic regression and partial correlation analyses. Results A total of 151 participants were analyzed. Overweight/obese children had significantly higher odds for arousal index (prepubertal children: 1.28, Confidence interval (CI): 1.06, 1.67; pubertal children: 1.65, CI: 1.19, 2.29) than normal-weight children, independent of age and gender. In prepubertal children, arousal-index was positively associated with C-peptide (r=0.30, p=0.01), whereas Minimum O2 saturation was negatively associated with triglycerides (r=−0.34, p=0.005), adjusting for age and sex. However, associations were attenuated by further adjustment for body mass index standard deviation scores (BMI-SDS). In pubertal children, higher level of apnea-hypopnea-index and pCO2 predicted increased lipoprotein (a) levels (r=0.35, p=0.03 and r=0.40, p=0.01, respectively), independent of age, sex, and BMI-SDS. A negative association was found between pCO2 and high-density lipoprotein (HDL)-cholesterol (r=−0.40, p=0.01). Conclusions Overall, we report that sleep quality as measured by arousal index may be compromised by overweight and obesity in children and warrants attention in future intervention programs.

Context Childhood obesity is defined based on body mass index (BMI) criteria. Asian adults have more abdominal adiposity as compared to Western people for an equivalent BMI. Similarly, children who are non-obese/overweight by BMI criteria may have abdominal obesity. It is important to identify and target this population to reduce future cardiovascular risk. Objective To evaluate and inter-relate the prevalence of obesity subtypes (generalized and abdominal) in school going adolescents. Methods A randomized cross-sectional community based study was conducted, which was carried out in 13 schools of Chandigarh, a North Indian city. 10,037 school going adolescents of age 10–18 years were evaluated. Results The prevalence of overweight and generalized obesity in present study was 9.3 and 4.9% respectively. Generalized obesity was observed in 4.2% of males and 5.7% of females (p-Value = 0.001). The abdominal obesity was noted in 5.4% of children and its prevalence increased progressively with age. The prevalence was highest in 16–18 years age-group (7.6%, p<0.001). 39.3% of abdominally obese subjects were not obese by BMI criteria, while prevalence of abdominal obesity in nonobese adolescents was 2.24%. It was more prevalent in females (3.7%) than males (3%, p=0.025). Prevalence of obesity was 7.9 and 1.8% in private and government schools respectively (p<0.001). Conclusions Abdominal obesity is more prevalent than generalized obesity and shows increasing trend with age. Interestingly, over one third of centrally obese adolescents are not obese by BMI criteria. This underlines the importance of waist circumference measurement in addition to BMI while assessing obesity.

Objectives To determine the clinical utility of the estimated glucose disposal rate (eGDR) for predicting metabolic syndrome (MetS) in children and adolescents with type-1 diabetes (T1D). Methods Modified criteria of the International Diabetes Federation were used to determine MetS in children and adolescents between 10 and 18 years of age with T1D. The eGDR, a validated marker of insulin sensitivity, was calculated in two different ways using either the waist-to-hip ratio (WHR) or waist circumference (WC). Receiver operating characteristic (ROC) curve analysis was performed to ascertain cut-off levels of the eGDR to predict MetS. Results A total of 200 patients (52% male) with T1D were enrolled in the study. The prevalence of MetS was 10.5% (n: 21). Lower eGDR levels, indicating greater insulin resistance, were found in T1D patients with MetS when compared to those without (6.41 ± 1.86 vs. 9.50 ± 1.34 mg/kg/min) (p < 0.001). An eGDR WHR cut-off of 8.44 mg/kg/min showed 85.7% sensitivity and 82.6% specificity, while an eGDR WC cut-off of 8.16 mg/kg/min showed 76.1% sensitivity and 92.1% specificity for MetS diagnosis. The diagnostic odds ratio was 28.6 (7.3–131.0) for the eGDR WHR cut-off and 37.7 (10.8–140.8) for the eGDR WC cut-off. Conclusions The eGDR is a mathematical formula that can be used in clinical practice to detect the existence of MetS in children and adolescents with T1D using only the WC, existence of hypertension, and hemoglobin A1c levels. An eGDR calculated using the WC could be a preferred choice due to its higher diagnostic performance.

Background Physiologic hyperglycemia of puberty is a major contributor to poor glycemic control in youth with type 1 diabetes (T1D). This study’s aim was to determine the effectiveness of continuous glucose monitoring (CGM) to improve glycemic control in pubertal youth with T1D compared to a non-CGM cohort after controlling for age, sex, BMI, duration, and insulin delivery methodology. The hypothesis is that consistent CGM use in puberty improves compliance with diabetes management, leading to increased percentage (%) time in range (TIR 70–180 mg/dL ) of glycemia, and lowering of HbA1c. Methods A longitudinal, retrospective, case-controlled study of 105 subjects consisting of 51 T1D controls (60.8% male) age 11.5 ± 3.8 y; and 54 T1D subjects (48.1% male) age 11.1 ± 5.0 y with confirmed CGM use for 12 months. Pubertal status was determined by Tanner staging. Results were adjusted for baseline HbA1c and diabetes duration. Results HbA1c was similar between the controls and the CGM group at baseline: 8.2 ± 1.1% vs 8.3 ± 1.2%, p=0.48 respectively; but was significantly lower in the CGM group 12 months later, 8.2 ± 1.1% vs. 8.7 ± 1.4%, p=0.035. Longitudinal change in HbA1c was similar in the prepubertal cohort between the control- and CGM groups: −0.17 ± 0.98% vs. 0.38 ± 1.5%, p=0.17. In contrast, HbA1c increased with advancing age and pubertal status in the pubertal controls but not in the pubertal CGM group: 0.55 ± 1.4 vs −0.22 ± 1.1%, p=0.020. Percent TIR was inversely related to HbA1c in the CGM group, r=-0.6, p=0.0004, for both prepubertal and pubertal subjects. Conclusions CGM use significantly improved glycemic control in pubertal youth with T1D compared to non-CGM users.

Objective To evaluate the eating behavior of obese adolescents and its association with biochemical, anthropometric and peptide YY (PYY) measures. Methods Fifty-one obese adolescents received counseling for weight management at 12 monthly appointments. Fasting serum PYY levels, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), insulin and glucose levels, waist circumference (WC) and results from the Three-Factor Eating Questionnaire (TFEQ-21) were assessed. Results Over one year there was a significant increase in PYY levels (p = 0.026), reduction in TC (p = 0.003), TG (p = 0.022), BMI (p = 0.002), BMI z-score (p < 0.001) and WC (p = 0.003). During this period there was a decrease in the uncontrolled eating score (UE), illustrating that adolescents displayed more self-control (p = 0.008) at the end of the study; however, this result was independent of BMI and BMI z-score (p = 0.407). The reduction in UE was associated with a significant improvement in insulin levels (r s = 0.326; p = 0.020). The reduction in UE was also associated with lower levels of blood glucose (r = 0.332; p = 0.017), and the increase of cognitive restriction, with the reduction of insulin insulin (r s = −0.294; p = 0.036) and TG (r = −0.368; p = 0.008) and an increase in Cognitive Restraint. Conclusions Our results show that after a year of monitoring weight loss, adolescents had more controlled eating behaviors, increased PYY levels, and reduced weights.

Background Little has been published about hyperthyroidism in children from Sudan or Africa. In limited resource countries, lack of facilities and sociocultural factors might make international diagnosis and management guidelines difficult to follow. We aimed to determine the magnitude of autoimmune hyperthyroidism, clinical presentation, diagnosis, management and its outcome in Sudan. Method Records of all patients diagnosed as Graves’ disease (GD) or Hashitoxicosis (HTx) were reviewed and missing data filled by interviewing patients and/or their families. Data including age, sex, clinical presentation, investigations, management and outcome were obtained. Results Eighty-eight patients, 80 with GD (F:M = 4.7:1) and 8 with HTx (F:M = 7:1), were diagnosed at 11.8 ± 3.05 and 11.23 ± 2.78 years, respectively (p = 0.52). GD patients were diagnosed based on presence of exophthalmos (66.25%), positive thyroid receptor autoantibodies (12.5%), prolonged illness duration (8.75%) or remission failure to only B blocker (16.25%). All GD patients were started on carbimazole and cumulative remission rate was 11.8%, 32.4% and 41.2% by end of the second, third and fourth year respectively, however it plateaus after that. While 12 GD patients underwent surgery, only three opted for radioiodine ablation. Conclusion Hyperthyroidism is not an uncommon problem. In absence of laboratory facilities, differentiation between GD and HTx can be made based on clinical grounds. Continuation of medical treatment for 4 years can increase the remission rate to 41.2%. In Sudan, surgery is the preferred method of definitive therapy.

Objectives Limited data on the evolution of thyroid disorders (TD) in Down syndrome (DS) are available. We characterized the timing, prevalence, and dynamics of TD in patients with DS during a long-term follow-up. Methods We retrospectively evaluated 91 children and adolescents with DS (12.5 ± 8.3; follow-up 7.5 ± 6.2). Children were monitored at birth, 6, and 12 months of age and twice a year thereafter. Thyroid status and autoimmunity were periodically investigated. Results TD were detected in 73.6% of patients, in particular congenital hypothyroidism (CH), autoimmune thyroid diseases (ATD) and subclinical hypothyroidism (SH) were recorded in 16.4, 31.8, and 25.3%, respectively. CH was diagnosed at newborn screening in 86.7% of cases and in the first 6 months of life in the remaining 13.3%; the condition was persistent in 61.5% of patients. In more than 30% of CH cases, glandular hypoplasia was also revealed. In the ATD group, 63.1% of patients with Hashimoto’s disease (HD, 82.6%) were treated with levothyroxine and subjects with Graves’ Disease (GD, 17.4%) started therapy with methimazole. DS with SH were treated in 42.1% of cases. A thyroid hypogenic echopattern, without autoantibody positivity was identified in 27.6% of SH patients. Conclusions The high prevalence and evolution of TD in SD requires frequent monitoring starting in the first months of life. CH can be misdiagnosed at screening. In DS subjects, there is a high prevalence of ATD and non-autoimmune diseases with early antibody-negative phases should not be excluded.

Objectives Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is a common autosomal recessive disorder caused by defects in the  CYP21A2  gene. We aimed to determine the prevalence of the most commonly reported mutations among 21-OHD Egyptian patients and correlate genotype with phenotype. Methods Molecular analysis of the CYP21A2 gene was performed for the detection of the six most common point mutations (p.P30L, p.I172N, p.V281L, p.Q318X, the splice site mutation Int2 [IVS2–13A/C>G], and the cluster of three mutations [p.I236N, p.V237E, and p.M239K] designed as CL6). Polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method was performed on 47 unrelated Egyptian 21α-OH deficiency patients and their available parents to detect the presence of the six most common point mutations. Results Screening for the six most common point mutations in CYP21A2 gene, revealed mutations in 87.2% (82/94) of the studied alleles corresponding to 47 Egyptian patients. The most common mutation among the studied cases was IVS2-13C/A>G that was found to be presented in a frequency of 46.8% (44/94). The genotype/phenotype correlations related to null, A, and B groups were with PPV of 100, 55.5, and 83.3%, respectively. Conclusions The described method diagnosed CAH in 80.8% of the studied patients. Good correlation between genotype and phenotype in salt wasting and simple virilizing forms is determined, whereas little concordance is seen in nonclassical one. Furthermore, studying the carrier frequency of 21-OHD among the normal population is of great importance.

Objectives We investigated the quality of life (QOL) in parents of children with late treated phenylketonuria (PKU) and its associated factors. Methods We conducted a cross sectional study in the reference center of inherited metabolic disease in Tunisia. We used the Tunisian version of the 36-item short-form health survey questionnaire (SF-36). We compared variables in the groups with and without impaired QOL and the SF-36 scores between subgroups of parents and children and between our sample and the Tunisian general population based on published data. We looked for associations between SF-36 scores and quantitative variables. Linear regression and logistic binary regression were used for multivariate analysis. Results Sixty-five parents from 42 families participated. QOL was impaired in 61% of them. The mean SF-36 score was 55.3 ± 25.07. The physical component sub-score was higher than that reported in the Tunisian general population (63.66 ± 27.77 vs. 50.11 ± 8.53; p<0.001). The mental component sub-score was comparable to that reported in the Tunisian general population (46.99 ± 25.94 vs. 47.96 ± 9.82; p=0.830). Gender (mothers) (p=0.008), low monthly income (p = 0.027), low education (p=0.011), and autism in PKU children (p = 0.001) were associated with impaired QOL. Conclusions We identified at risk parents for altered quality of life among parents of PKU children. Our findings were used to develop a psychological and social support strategy for at-risk parents and to promote the implementation of newborn screening of this treatable disease in our low-income country.

Objectives To investigate the clinical and genetic characteristics of children with glycogen storage disease type IIIa (GSD IIIa) and to explore the muscle involvement and manifestations of GSD IIIa patients. Methods The clinical data of 11 patients with GSD IIIa diagnosed by genetic testing from 2003 to 2019 were retrospectively analyzed. Results Twenty variants of AGL gene were detected in 11 patients, eight of which were novel variants. Before treatment, the height was significantly backward. All patients had hepatomegaly. Abnormal biochemical indicators were mainly manifested as significantly increased serum liver and muscle enzymes, accompanied by hypertriglyceridemia, hypoglycemia, hyperlactacidemia, slightly elevated pyruvic acid, and metabolic acidosis. After treatment, the height and liver size of the patients were significantly improved. At the same time, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), lactic acid and pyruvic acid in children were significantly decreased, while creatine kinase (CK) was significantly increased. During follow-up monitoring, six patients developed ventricular hypertrophy. Lactate dehydrogenase (LDH) (691.67 ± 545.27 vs. 362.20 ± 98.66), lactic acid (3.18 ± 3.05 vs. 1.10 ± 0.40), and pyruvic acid (64.30 ± 39.69 vs. 32.06 ± 4.61) were significantly increased in patients with ventricular hypertrophy compared with those without ventricular hypertrophy. Conclusions In clinical cases of upper respiratory tract infection or gastrointestinal symptoms accompanied by hypoglycemia, dyslipidemia, metabolites disorders, elevated serum liver, and muscle enzymes, the possibility of GSD IIIa should be vigilant. During treatment monitoring, if lactic acid, pyruvic acid, LDH, and CK rise, it indicates that the disease is not well controlled and there is the possibility of cardiac hypertrophy.

Objectives To study the efficacy and influence on metabolism of recombinant human growth hormone (rhGH) treatment in short children born small for gestational age (SGA). Methods Retrospective, observational, multicenter study in 305 short children born SGA, treated with rhGH during a mean ± SD of 5.03 ± 1.73 years at a mean ± SD dose of 37 ± 8 μg/kg/day. Auxological and metabolic assessment including glucose and lipids profile were collected. Results Mean ± SD age at the start of treatment was 7.11 ± 2.78 years. Height and weight improved significantly until the end of treatment from mean −2.72 (CI 95% : −2.81 to −2.63) standard deviation score (SDS) to −1.16 (CI 95% : −1.44 to −0.88) SDS and from −1.62 (CI 95% : −1.69 to −1.55) SDS to −0.94 (CI 95% : −1.14 to −0.74) SDS respectively. Mean height gain was 1.27 (CI 95% : 0.99–1.54) SDS. Prepubertal patients showed higher height gain than pubertal children (mean [CI 95% ] = 1.44 [CI 95% : 1.14–1.74] vs. 0.73 [CI 95% : 0.22–1.24], p=0.02). Height gain SDS during treatment negatively correlated with chronological age (CA) and bone age (BA) delay and positively correlated with duration of treatment, height gain during first year of treatment, years on prepubertal treatment and height SDS from target height (TH). Glucose, insulin, and triglycerides increased significantly but remained within the normal range. Total and LDL-cholesterol decreased significantly, and HDL-cholesterol remained unchanged. Conclusions rhGH treatment in short SGA children effectively normalized height in most of the patients and showed a safe metabolic profile. Children who benefit the most are those with greater height SDS distance from TH, BA delay, longer duration of treatment and prepubertal treatment initiation.

Background In 2011, we described 64 girls diagnosed with central precocious puberty (CPP) during 1995–2009. In 2019, the former CPP patients were 16–30 years of age and had been followed-up for 6–20 years after cessation of gonadotropin-releasing hormone analog (GnRHa) treatment. Objectives To determine the menstrual cycle, reproductive function, and long-term sequelae of the former GnRHa-treated and untreated CPP patients. Methods Sixty-seven former CPP women diagnosed during January 1995 to December 2010 were evaluated in 2019 for current menstrual cycle and pregnancy rate and for general health status, weight, height, blood pressure, and metabolic profiles of glucose, lipids, insulin, and testosterone. Results In 2019, the former CPP women averaged 20.7 ± 2.7 years of age (range: 16.5–30). Eighty-three percent had a regular menstrual cycle. Of the 14 married women, six (43%) were fertile with 1–2 children. The untreated women had a significantly higher rate of obesity (BMI >25 kg/m 2 ) than the GnRHa-treated women (72.1% vs. 36.6%, p < 0.01). Two women (3%) had polycystic ovary syndrome (PCOS). Fasting plasma glucose, serum high-density lipoprotein cholesterol (HDL-C), and testosterone levels were normal and similar between the GnRHa-treated and untreated participants. The serum insulin, cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR) levels were higher in the untreated group than the GnRHa-treated group, but without significant differences. Conclusions At a 10–20-year follow-up, our former CPP patients had regular menstruation, normal reproductive function, and normal metabolic outcomes. The low prevalence of PCOS of 3% suggests that CPP is not a risk factor for PCOS, at least during early adulthood.

Background Congenital hyperinsulinism (CH) is the most frequent cause of persistent hypoglycemia in the newborn. Octreotide, a long-acting somatostatin receptor analog (SSRA), is a second line treatment for diazoxide unresponsive CH patients. Although it has been found to be a safe and effective treatment, long-term benefits and side effects, have not been thoroughly evaluated. Case presentation Some authors have indicated that exocrine pancreatic insufficiency (EPI) is a common but under-recognized adverse reaction in adults treated with octreotide. However, no pediatric patient with SSRA-induced EPI has been reported to date. Here we report a case of an infant with diazoxide unresponsive, diffuse CH, caused by a heterozygous pathogenic paternally inherited mutation in the ABCC8 gene (NM_000352.4:c.357del), that developed exocrine pancreatic insufficiency and secondary vitamin K deficiency associated to chronic octreotide therapy. Conclusions We point out the atypical clinical onset with a cutaneous hemorrhagic syndrome, emphasizing the clinical relevance of this potential side effect.

Objectives Prader-Willi Syndrome (PWS) is characterised by hyperphagia often leading to obesity; a known risk factor for insulin resistance and type 2 (T2) diabetes. We present a prepubertal girl with PWS who developed diabetes. Case presentation Our case was diagnosed with PWS in infancy following investigation for profound central hypotonia and feeding difficulties. She commenced growth hormone (GH) aged 8 years for short stature and treatment improved linear growth. At age 12 years, she presented with polydipsia, polyuria and vulvovaginitis. She was overweight (BMI SDS +1.43). Diabetes was diagnosed (Blood glucose = 24.2 mmol/L, HbA1c = 121 mmol/mol or 13.2%). She was not acidotic and had negative blood ketones. Autoantibodies typical of type 1 diabetes were negative. She was initially treated with basal bolus insulin regime. GH was discontinued 3 months later due to concerns regarding GH-induced insulin resistance. Off GH, insulin requirements reduced to zero, allowing Metformin monotherapy. However off GH, she reported significant lethargy with static growth and increased weight. Combinations of Metformin with differing insulin regimes did not improve glucose levels. Liraglutide (GLP-1 agonist) and Metformin did not improve glucose levels nor her weight. Liraglutide and Empaglifozin (SGLT-2 inhibitor) therapy used in combination were well tolerated and demonstrated rapid normalisation of blood glucose and improvement in her HbA1c to within target (48 mmol/mol) which was sustained after 6 months of treatment. Conclusions Newer treatments for type 2 diabetes (e. g. GLP-1 agonists or SGLT-2 inhibitors) offer potential treatment options for those with diabetes and PWS when conventional treatments are ineffective. What is new? – DM (Diabetes mellitus) is a rare complication of Prader-Willi Syndrome (PWS) before puberty. – This case demonstrates the challenges of managing PWS and DM including negotiating growth hormone therapy and pubertal induction/augmentation. – Conventional therapies (e. g. oral hypoglycaemic agents and insulin) failed to achieve adequate glycaemic parameters. – Recently developed therapies of Liraglutide (GLP-1) and Empaglifozin (SGLT-2 inhibitor) used combination were well tolerated, led to rapid normalisation of blood glucose and a sustained improvement in HbA1c within target. – This is the first case report describing the use of a GLP-1 agonist and a SGLT-2 inhibitor used in combination in a child with PWS and DM.

Objectives Severe congenital neutropenia (SCN) is a primary immunodeficiency (PID) characterized by persistent severe neutropenia, recurrent infections, and oral aphthous lesions. Severe congenital neutropenia is caused by various genetic defects such as ELANE, GFI, HAX-1, JAGN1, SRP54, and glucose-6 phosphatase catalytic subunit 3 (G6PC3) deficiency. Clinical features of the patients with G6PC3 deficiency vary from neutropenia to several systemic features in addition to developmental delay. Case presentation In this report, we presented three unrelated patients diagnosed with G6PC3 deficiency. All these patients had short stature, prominent and superficial vascular tissue, cardiac abnormalities (Atrial septal defect (secondary), mitral valve prolapse with mitral insufficiency, pulmonary hypertension) and lymphopenia. Patient 1 (P1) and 2 (P2) had urogenital abnormalities, P2 and P3 had thrombocytopenia. Conclusions We have shown that lymphopenia and CD4 lymphopenia do not rarely accompany to G6PC3 deficiency. Characteristic facial appearance, systemic manifestions, neutropenia could be the clues for the diagnosis of G6PC3 deficiency.

Background Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand, which strongly suppresses osteoclasts. Cherubism is a rare autosomal dominant disorder characterized by symmetrical swelling of the jaws, in which the bone is replaced by a fibrous granuloma containing osteoclast-like giant cells. Case presentation We report the efficacy and safety of denosumab treatment in a prepubertal boy with progressive cherubism. The treatment consisting of eight subcutaneous denosumab injections (120 mg/dose) in 6 months not only suppressed the expansion of the osteolytic lesions but also dramatically ossified them. However, a transiently decreased growth rate and rebounded asymptomatic hypercalcemia were associated with the treatment. Conclusions The present case demonstrated the therapeutic potential of denosumab for treatment of cherubism, although adverse effects, especially those on childhood growth, remain obscure. Further studies are needed to establish a safe and effective protocol for denosumab treatment of children.