Band 34, Heft 10

Background Micropenis is an endocrinological condition that is habitually observed at birth. Diagnosis is made by measuring the stretched penile length, a method established 80 years ago. Discrepancies in the normative data from recent studies raise the need for a current revision of the methodology. Objectives The aims of this systematic review were to compare the different normative data of SPL at birth, to examine the methodological aspects of the technique and to evaluate the independent variables that may be involved. Methods Searches were performed using MEDLINE, EMBASE, Scielo, the Cochrane Library and Web of Science. A combination of the relevant medical terms, keywords and word variants for “stretched penile length”, “penile length”, “penile size”, “newborn” and “birth” were used. Eligibility criteria included normative studies that used the stretched penile length (SPL) measurement on a population of healthy, full-term newborns during the first month of life. The outcomes studied included characteristics of the studies, methodological aspects and independent variables. Results We identified 49 studies comprising 21,399 children. Significant discrepancies are observed between the different studies. Methodological aspects seem to be consistent and similar. The main independent variables appear to be ethnic group and gestational age. Main limitations were the absence of studies of entire world regions such as Europe or South America, and the heterogeneity of the ethnic background that complicates the analysis. Conclusions It seems advisable to suggest the creation of customized reference charts for each specific population instead of resorting to the classic cut-off points.

Objectives Mucopolysaccharidosis III, an autosomal recessive lysosomal storage disorder, is characterized by progressive mental retardation and behavioral problems. Meta-analysis of global mucopolysaccharidosis III epidemiology, which serves as a fundamental reference for public health decision-making, was not available prior to this study. To provide a systematic review and meta-analysis of birth prevalence of mucopolysaccharidosis III in multiple countries. Methods MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of mucopolysaccharidosis III from inception until 1st July, 2020. A checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) was used to assess the quality of all studies involved. Meta-analysis, adopting a random effects logistic model, was performed to estimate pooled birth prevalence of mucopolysaccharidosis III and its subtypes. Results Twenty-five studies screened out of 1,826 records were included for data extraction. The pooled global mucopolysaccharidosis III birth prevalence was 0.76 cases (95% CI: 0.57–0.96) per 100,000 live births. The pooled global birth prevalence of mucopolysaccharidosis III subtypes (A, B, and C) was 0.52 cases (95% CI: 0.33–0.72), 0.21 cases (95% CI: 0.12–0.30) and 0.01 cases (95% CI: 0.005–0.02) per 100,000 live births, respectively. Conclusions Based on the global population size (7.8 billion) and the life span of patients, there would be 12–19 thousand mucopolysaccharidosis III patients worldwide. To our knowledge, this is the first comprehensive systematic review that presented quantitative data fundamental for evidence-based public health decision-making by evaluating global epidemiology of mucopolysaccharidosis III.

Objectives To compare cardiometabolic risk factors of Brazilian children and adolescents with international reference values. Cardiometabolic risk factors constitute the Metabolic Syndrome, whose evaluation is important to assess pediatric populations’ health and potential to experience metabolic disorders. Methods Cross-sectional study that included 2,250 randomly selected children and adolescents (55.6% girls), aged 6 to 17. Cardiometabolic parameters (body mass index [BMI], waist circumference [WC], systolic and diastolic blood pressures [SBP and DBP], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], TC:HDL-C ratio, triglycerides [TG], glucose and peak oxygen uptake [VO 2 peak]), and clustered risk scores were compared to international age- and sex-specific reference values. A clustered risk score was calculated by summing the WC, glucose, SBP, TG, and the TC:HDL-C ratio Z-scores divided by five. A second clustered was calculated including VO 2 peak (inverted) Z-score, but divided by six. Results The clustered risk score, considering the all ages sample, was better in the Brazilian boys (−0.20 [−0.41;0.01] and −0.18 [−0.37;0.01], including or not VO 2 peak, respectively) but not significantly, and worse in girls (0.24 [0.05;0.43] and 0.28 [0.11;0.44], including or not VO 2 peak, respectively) than the international reference. Additionally, Brazilian youth had a statistically better profile in TC, LDL-C, HDL-C, TC:HDL-C ratio, and VO 2 peak (only girls) as well as a worse profile in BMI, WC, SBP, DBP, TG (only girls), and VO 2 peak (only boys). Conclusions The clustered cardiometabolic risk score (including or not VO 2 peak), considering the all ages sample, was better in the Brazilian boys, but not significantly, and worse in girls compared to the international reference.

Objectives Antimullerian hormone (AMH) causes regression of the mullerian ducts in the male fetus. The appendix testis (AT) is a vestigial remnant of mullerian duct origin, containing both androgen (AR) and estrogen (ER) receptors. The role of both AMH and AT in testicular descent is yet to be studied. We investigated the possible association of AMH with AT size, the AR and ER, and their expression in the AT, in congenital cryptorchidism. Methods A total of 26 patients with congenital unilateral cryptorchidism and 26 controls with orthotopic testes were investigated, and 21 ATs were identified in each group. AMH and insulin-like three hormone (INSL3) concentrations were measured with spectrophotometry. AR and ER receptor expression was assessed with immunohistochemistry using monoclonal antibodies R441 for AR and MAB463 for ER. For the estimation of receptor expression, the Allred Score method was used. Results AMH concentrations did not present significant differences between patients with congenital cryptorchidism and the controls. Also, no correlation was found between AMH, INSL3, and AT length. Allred scores did not present significant differences. However, expression percentiles and intensity for both receptors presented significant differences. Three children with cryptorchidism and the highest AMH levels also had the highest estrogen receptor scores in the AT. Conclusions No association was found between AMH and the studied major parameters. However, higher AMH concentrations, in combination with higher estrogen receptor scores in the AT, may play a role in cryptorchidism in some children. Larger population samples are needed to verify this observation.

Objectives The use of inhibin B (INHB), anti-Müllerian hormone (AMH) and insulin-like growth factor-1 (IGF-1) in differentiating central precocious puberty (CPP) from non-CPP was evaluated. Methods In total, 115 Chinese girls were recruited (CPP: 44, non-CPP: 71). The diagnostic performance of INHB, AMH and IGF-1 in differentiating CPP from non-CPP was analyzed using receiver operating characteristic (ROC) curves. Results INHB levels were higher in the CPP group than in the non-CPP group (55.56 ± 22.42 vs. 32.97 ± 15.59 pg/mL; p<0.001). AMH levels were similar in the CPP and non-CPP groups (6.63 ± 3.74 vs. 5.70 ± 3.15 pg/mL; p=0.158), and IGF-1 levels were much higher in the CPP group than in the non-CPP group (290.75 ± 79.78 vs. 200.10 ± 54.01 pg/mL; p<0.001). The area under the ROC curve (AUC) was greatest for INHB (0.819, standard error (SE) 0.041), followed by IGF-1 (0.809, SE 0.047) and AMH (0.567, SE 0.057). Among the ROC curves including combinations of these parameters, the AUC for INHB + IGF-1 was 0.849 and that for INHB + AMH was 0.768. Conclusions Serum INHB and IGF-1 measurements could predict positive responses to gonadotropin-releasing hormone (GnRH) analog stimulation in girls with precocious puberty.

Objectives Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH < 7 ng/dL after provocation) have normal IGFI levels. Do children with ISS or those with GHD with variable pretreatment IGFI standard deviation score (IGFISDS) have different IGFI and growth responses to recombinant human growth hormone (rhGH) therapy? Methods We studied the effect of GH therapy (0.035–0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS < −1.5) and compared them with age-matched prepubertal children with ISS (n=10) and GHD (n=17) who had normal pretreatment IGFISDS. An untreated group of children with ISS (n=12) served as a control group. Results At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035–0.06 mg/kg/day) IGFISDS increased significantly in both groups (p<0.05). Both had significantly increased HtSDS (catch-up growth). The increase in the HtSDS and WGPD were significantly greater in the lower pretreatment IGFISDS group. The IGFSDS, BMISDS, HtSDS and difference between HtSDS and mid-parental HtSDS were significantly greater in the rhGH treated groups vs. the not treated group. In the GHD groups (normal and low IGFISDS), after 1 year of GH therapy (0.03–0.05 mg/kg/day), the HtSDS increased significantly in both, (p<0.01). The WGPD and increment in BMI were significantly greater in children who had low pretreatment IGFISDS. There was a significant increase in the IGFSDS in the two treated groups (p<0.05), however, the WGPD was greater in the pretreatment low IGFISDS. Conclusions IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion.

Objectives Obesity has often been associated with high low-density-lipoprotein cholesterol (LDL-C) and triglyceride plasma concentrations, known risk factors for diabetes mellitus and cardiovascular disease. Study objective was to evaluate the association of LDL-C and triglyceride plasma concentration with muscle and fat mass in children and adolescents. Methods We analyzed data of the National Health and Nutrition Examination Survey (1999–2004) to estimate lean muscle and fat mass assessed by dual-energy X-ray absorptiometry (DXA) of participants whose lipid profiles had been examined. Fat mass was operationalized by DXA-determined fat mass index (FMI). Muscle mass was assessed by appendicular lean mass index (aLMI). High LDL-C and triglyceride concentration was defined as above 130 mg/dL. Results For the evaluation of the association of LDL-C and triglyceride plasma concentration with LMI and FMI Z-scores, the data of 2,487 children and adolescents (age 8–19 years) (984 females) were eligible. High aLMI showed no association with LDL-C or triglyceride concentration, but high FMI showed significant association with LDL-C and triglyceride plasma concentration in the bivariate regression analysis. Conclusions Isolated muscle mass increase may not be protective against high LDL-C and triglycerides plasma levels in children and adolescents. Thus, exercise may lead to risk factor reduction mainly through fat mass reduction.

Objectives Despite the high prevalence of children with sickle cell anaemia (SCA) in West Africa, there is paucity of data on the height velocity and prevalence of growth failure in SCA patients. With advances in clinical care of SCA patients, could there be a spatial and secular trend in the growth pattern of these children? Hence, the compelling needs to embark on this study. The objectives of the study were to determine the prevalence of growth failure among patients with SCA and its correlation with age, gender and age at diagnosis. Methods A Prospective longitudinal study of a cohort of sickle cell anaemic paediatric patients from Pediatrics SCA Clinic, University of Nigeria Teaching Hospital, Ituku Ozalla. Patients were enrolled over a period of two years using a non-parametric convenient sampling method. Their heights were measured at baseline, three months, six months and at 12 months intervals and subsequently plotted on a standard WHO growth chart. The height velocities at different monthly intervals were calculated and compared with the WHO standard normal linear growth rates) for children (used as control) to identify those with GF. (i.e. <10th percentile). The main outcome measures were the mean height velocities at different months' intervals calculated and compared using the repeated measurement analysis of variance (ANOVA) and the Wilcoxon signed test. Results A cohort of 316 children aged 1–18 years with SCA was evaluated with a male preponderance of 161 (57.4%). The mean age and age at diagnosis were 11.04 ± 5.56 and 4.2 ± 1.7 years, respectively. The prevalence of growth failure and short stature was 84.7%. The burden of GF was highest among post-pubertal participants (94.1%). The most important predictor of growth velocity deficit was age (R 2 =0.045, standard β coefficient = −0.22, t =−03.51, p=0.001). Conclusions The study demonstrated high prevalence of growth failure in children and adolescents with SCA which intensified with advancement in age and older age at diagnosis.

Objectives Growing skeleton is uniquely vulnerable to impaired mineralization in chronic kidney disease (CKD). Continued debate exists about the optimal method to adjust for body size when interpreting dual energy X-ray absorptiometry (DXA) scans in children with CKD given the burden of poor growth. The study aimed to evaluate the clinical usefulness of size-adjustment techniques of lumber-spine DXA measurements in assessing bone mineralization in children with kidney failure on maintenance hemodialysis (HD). Methods Case-control study included 93 children on maintenance HD (9–18 years; 48 males). Participants were subjected to spinal-DXA-scan to obtain areal bone mineral density (aBMD; g/cm 2 ). Volumetric-BMD (vBMD; g/cm 3 ) was mathematically estimated. Z-scores of aBMD for chronological age (aBMD Z-CA ), aBMD adjusted for height age (aBMD Z-HA ), and vBMD Z-score were calculated using mean and SD values of age subgroups of 442 healthy controls (7–18 years). Results In short-for-age CKD patients, aBMD Z-CA was significantly lower than vBMD Z-score , while aBMD Z-HA was significantly higher than aBMD Z-CA and vBMD Z-score . In normal height-for-age CKD patients, no significant difference between aBMD Z-scores and vBMD Z-score was detected. aBMD Z-CA was significantly lower and aBMD Z-HA was significantly higher in short-for-age compared to normal height-for-age patients without significant differences in vBMD Z-score . We observed age-related decrements in the percentage of HD patients with normal densitometric Z-scores, the effect of age was less pronounced in aBMD Z-HA than vBMD Z-score . vBMD Z-score correlated negatively with age, but not with height Z-score . Conclusions Estimated vBMD seems to be a convenient size-adjustment approach of spinal-DXA measurements in assessing BMD especially in older short-for-age children with CKD. aBMD Z-CA underestimates, while aBMD Z-HA overestimates BMD in such patients.

Objectives The COVID-19 pandemic is a global health problem with high morbidity and mortality. This study aimed to investigate patients who were diagnosed with type 1 diabetes during the pandemic and evaluate the effect of the pandemic on the clinical findings of these patients by comparing them with findings from a year prior. Methods Patients diagnosed with type 1 diabetes mellitus between 2019 and 2021 were separated into two groups: Patients diagnosed prepandemic and those diagnosed during the pandemic. Results The number of newly diagnosed diabetes cases increased from 46 in the prepandemic period to 74 in the pandemic period. The number of cases diagnosed with diabetic ketoacidosis (DKA) in the clinic increased from 58.7 to 91.9%. We found that moderate and severe DKA rates from 18.5 and 14.8% to 23.5 and 22.1%, respectively. Besides, the average HbA1c was higher, while the average bicarbonate was lower in cases diagnosed during the pandemic period compared to the prepandemic period (p=0.048 and p<0.001, respectively). We found that celiac autoantibody positivity antibodies to glutamic acid decarboxylase (anti GAD) positivity, and islet cell antibodies (ICA), ICA and anti GAD positivity coexistence were higher (p=0.045, p=0.008, and p=0.007, respectively) among the patients diagnosed during the pandemic. Conclusions We observed an increase in the number of patients newly diagnosed with type 1 diabetes mellitus, an increase in autoantibody positivity, and higher rates and severity of DKA during the COVID-19 pandemic period compared to the prepandemic period.

Objectives Most patients with type 1 diabetes (T1D) experience a transient phase of partial remission (PR). This study aimed to identify the demographic and clinical factors associated with PR. Methods This was a longitudinal retrospective cohort study of 133 children and adolescents with T1D. PR was defined by the gold standard insulin dose-adjusted hemoglobin A1c (HbA1c) (IDAA1c) of ≤9. Results Remission was observed in 77 (57.9%) patients. At diagnosis, remitters had significantly higher pH (7.3 ± 0.12 vs. 7.23 ± 0.15, p=0.003), higher C-peptide levels (0.45 ± 0.31 ng/mL vs. 0.3 ± 0.22, p=0.003), and they were significantly older (9.3 ± 3.6 years vs. 7.3 ± 4.2, p=0.008) compared with non-remitters. PR developed more frequently in patients without diabetic ketoacidosis (DKA) (p=0.026) and with disease onset after age 5 (p=0.001). Patients using multiple daily insulin regimen were more likely to experience PR than those treated with a twice daily regimen (63.9 vs. 32%, p=0.004). Only age at onset was an independent predictor of PR (OR: 1.12, 95% CI: 1-1.25; p=0.044). Remitters had lower HbA1c levels and daily insulin requirement from diagnosis until one year after diagnosis (p<0.001). PR recurred in 7 (9%) patients. The daily insulin requirement at three months was lower in remitters with PR recurrence compared to those without (0.23 ± 0.14 vs. 0.4 ± 0.17 U/kg/day, p=0.014). Conclusions Addressing factors associated with the occurrence of PR could provide a better comprehension of metabolic control in T1D. The lack of DKA and higher C-peptide levels may influence PR, but the main factor associated with PR presence was older age at onset. PR may recur in a small proportion of patients.

Objectives Questions are emerging concerning the long-term consequences of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, as a possible increase in type 1 diabetes. This study aims to describe the prevalence of anti-SARS-CoV-2 antibodies in children developing type 1 diabetes during this pandemic in Belgium. Methods This observational study included children and adolescents (under 16 years) admitted with new-onset type 1 diabetes. SARS-CoV-2 serology was taken within the first month of diabetes. Results Of the 75 participants, anti-SARS-CoV-2 antibodies were positive in 20% of patients. They had an increased bicarbonate and base excess at diagnosis. Overall 29% of patients presented diabetic ketoacidosis at diagnosis and 9% of them were positive for anti-SARS-CoV-2 antibodies. Insulinoma-associated protein 2 antibodies positivity had significantly higher frequencies in children without anti-SARS-CoV-2 antibodies (49 (81%) vs. 5 (33%), p=0.038). Nine (15%) patients, initially seronegative, have developed anti-SARS-CoV-2 antibodies between the two samples (mean time 8 ± 4 weeks). Conclusions The prevalence of anti-SARS-CoV-2 antibodies in children with newly diagnosed type 1 diabetes (20%) is similar to that found in children without diabetes in Belgium, a country severely affected by this pandemic.

Objectives Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3 . Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity. Case presentaiton In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients. Conclustions Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.

Objectives Hashimoto’s thyroiditis (HT) is characterized by lymphocytic thyroid infiltration. Gradual thyroid failure can occur due to thyroid cell apoptosis. Rarely neurological autoimmunity due to glutamic acid decarboxylase (GAD) antigen can co exist with HT. Case presentation A seven-year-old male presented with tiredness, weight loss, frequent falls, tachycardia, firm thyromegaly, and abnormal gait. Biochemical markers and thyroid ultrasound (TUS) showed autoimmune hyperthyroidism. Methimazole (MMI) was started and continued for 2.2 years. MRI brain was normal and neurological symptoms resolved. At nine years, he became hypothyroid and levothyroxine (LT4) was started. Serial TUS showed progressive thyroid atrophy. At 14.8 years, he developed epilepsy and fourth cranial nerve palsy, and diagnosed with GAD-65 central nervous system disease. At 15.3 years, TUS showed complete atrophy of right lobe with involuting left lobe volume. Conclusions This is an unusual form of atrophic thyroiditis (AT) with coexisting neurological autoimmunity. GAD-65 CNS autoimmunity should be considered in children with AT presenting with neurological signs.

Objectives Aldolase A deficiency also known as glycogen storage disease (GSD) XII, is an ultra rare autosomal recessively inherited GSD, associated with hemolytic anemia and rhabdomyolysis. Case presentation Here, we first report a patient with dermatological findings, hemodialysis requirement for rhabdomyolysis, and a novel likely pathogenic c.971C>T (p.A324V) mutation in the ALDOA gene. Conclusions Episodes of rhabdomyolysis can be triggered by febrile illnesses and catabolic processes. Diagnosis should be confirmed by the mutation analysis of ALDOA gene. Treatment includes management of hemolytic anemia and administration of antipyretics during febrile episodes to avoid hemolysis and rhabdomyolysis.

Objectives Deoxyguanosine kinase (DGUOK) deficiency is one of the leading causes of the mitochondrial DNA-depletion syndromes (MDDS) associated with hepatocerebral involvement. Herein, we present four cases of DGUOK deficiency to emphasize the clinical variability of disease and the challenges in the diagnosis of DGUOK deficiency. Case presentation Hepatomegaly, hyperlactatemia, elevated alpha fetoprotein (AFP), alanine, and transaminase levels were detected in all patients, and cholestasis, coagulopathy, and hypotonia were common findings. All patients had a low birth weight, one patient underwent liver transplantation (LT). Clinical and laboratory findings of two patients and one patient suggested neonatal hemochromatosis and type 1 tyrosinemia, respectively. All patients were diagnosed with DGUOK deficiency by performing molecular genetic analysis. Conclusions Mitochondrial DNA-depletion syndromes should be kept in mind in cases in which hypotonicity, lactic acidosis, and neonatal cholestasis are observed. DGUOK deficiency may present in different clinics suggesting neonatal hemochromatosis or tyrosinemia type 1.

Objectives  Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial features. Case presentation In this case report, we describe the clinical and biochemical characteristics of two siblings with LS, a sister and a brother, and identify a homozygous c.344A> C (p.Asn115Thr) variant in GHR. The sister was 11 years 9 months old with a height of 127.5 cm (-3.86 SDS), and the brother was 14 years 10 months old with a height of 139 cm (-4.27 SDS). Their phenotype did not have features suggesting classical LS. Conclusion In the current literature, there are three cases with the same missense variant. Our cases differ from them in clinical (higher height SDS, mild dysmorphism including a broad forehead, malar hypoplasia, prominent columella and chin, thick lips) and biochemical characteristics. Here, we present the variable expressivity in the two siblings.