Volume 34, Issue 3

Inborn errors of metabolism consist of a heterogeneous group of disorders with various organ systems manifestations, and some metabolic diseases also cause immunological disorders or dysregulation. In this review, metabolic diseases that affect the immunological system and particularly lead to primary immune deficiency will be reviewed. In a patient with frequent infections and immunodeficiency, the presence of symptoms such as growth retardation, abnormal facial appearance, heart, skeletal, lung deformities, skin findings, arthritis, motor developmental retardation, seizure, deafness, hepatomegaly, splenomegaly, impairment of liver function tests, the presence of anemia, thrombocytopenia and eosinophilia in hematological examinations should suggest metabolic diseases for the underlying cause. In some patients, these phenotypic findings may appear before the immunodeficiency picture. Metabolic diseases leading to immunological disorders are likely to be rare but probably underdiagnosed. Therefore, the presence of recurrent infections or autoimmune findings in a patient with a suspected metabolic disease should suggest that immune deficiency may also accompany the picture, and diagnostic examinations in this regard should be deepened.

Objectives To compare the hydration status between children with obesity and normal-weighted children and to determine whether obesity is related to less water consumption. Methods Children aged between 7 and 18 years with obesity (Group 1, n=31) were compared with nonobese healthy volunteers (Group 2, n=30) in terms of body composition analysis, urine density and daily fluid intake. Results The fluid intake per body surface of Group 1 was found significantly less than Group 2 (p<0.001). The urine density was found significantly higher in Group 1 (1020 (10) vs. 1015(10), p<0.001). Subjects in Group 1 had a higher percentage of body fat (p<0.001), lower percentages of total body water and fat-free mass (p=0.007 and <0.001, respectively). While 55% of subjects in Group 1 satisfied the recommended daily fluid intake, this was 80% in Group 2 (p=0.036). The consumption of SSBs was 71% in Group 1 and 20% in Group 2, with higher amount in Group 1 (median 200 vs. 0 mL, p<0.001). Conclusions Children with obesity had less fluid consumption, lower TBW percentages and higher urine density. The results of this cross-sectional study showed that children with obesity were less hydrated than normal weighted children.

Objectives Childhood obesity is a serious medical condition with alarmingly high rates worldwide. There is controversy regarding the relationship between insulin-like growth factor-1 (IGF-1) and pediatric obesity. We investigated the relationship between IGF-1, insulin resistance and metabolic profile with childhood pre-obesity/obesity. Methods The study involved 201 children aged 7–15 years, divided in three groups according to their nutritional status (International Obesity Task Force criteria): normal-weight (n=84), pre-obese (n=82), obese (n=35). Laboratory IGF-1, insulin, fasting blood glucose (FBG), lipid profile, alanine-aminotransferase (ALT), uric acid (UA), anthropometric and body composition parameters were analyzed. Body mass index and IGF-1 standard deviation score (SDS), waist-to-height ratio (WtHR) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score were calculated. Results Pre-obese/obese children had significantly higher IGF-1 SDS, FBG, insulin, HOMA-IR, UA, ALT, triglycerides, and lower high-density lipoprotein cholesterol (HDL-c); obese group had higher WtHR and low-density lipoprotein cholesterol (LDL-c) compared to controls (p<0.05). In obese group, IGF-1 SDS was positively correlated with fat free/muscle mass, total body water (p<0.05) and negatively correlated with LDL-c (p<0.05). In pre-obese/obese HOMA-IR and insulin were positively correlated with age, total body fat (TBF) (p<0.05) and negatively correlated with HDL-c (pre-obese) (p<0.05). Multivariate ordinal logistic regression analyses showed that IGF-1 SDS (OR=1.94; 95%CI: 1.21–3.11), TBF (OR=1.37; 95%CI: 1.21–1.54) were predictors of nutritional status (p<0.001). FBG (OR=42.39; 95%CI: 2.31–77.2) and UA (OR=1.03; 95%CI: 1.01–1.05) were predictors of IR (p<0.001). Conclusions IGF-1 SDS and TBF were predictors of nutritional status. Further studies are required to clarify the role of IGF-1 in pathophysiology of obesity and its comorbidities.

Objectives The development of continuous glucose monitoring (CGM) systems has allowed for identification of blood sugar variations and trends in real-time that is not feasible with conventional self-monitoring of blood glucose. However, there is inconsistent data to show that the use of CGM leads to better glycemic control as measured by Hemoglobin A1c (HbA1c) in pediatric patients with type 1 diabetes mellitus. Our study aimed to compare the average HbA1c level in the 1–2 years prior to starting a CGM to the average HbA1c level in the 1–2 years immediately following CGM initiation in a sample of 1–20 year olds with type 1 diabetes mellitus. Methods Participants were 90 youth (ages 1–20) followed for type 1 diabetes care at our institution who used a CGM for at least a 6 month time period. We performed a retrospective chart review to obtain up to four HbA1c values pre and post-CGM initiation each. We evaluated pre- and post-CGM initiation changes in mean HbA1c via dependent samples t-tests using IBM SPSS 24.0. Results The mean HbA1c was 8.7% pre-CGM and decreased to 8.27% 9–12 months after CGM initiation in the overall sample. A statistically significant decrease in HbA1c was seen in patients who used multiple daily injections (p=0.02), those with a pre-CGM HbA1c greater than 9% (p=0.01), and those with a diabetes duration of 5–10 years (p=0.02). Conclusion CGM use was associated with a decrease in HbA1c over time which was statistically significant in some subgroups.

Objective To characterize the age of ovarian failure in Turner Syndrome (TS) patients by karyotype. Methods Retrospective cohort study of individuals with TS at an academic university hospital. Subjects were seen in TS Clinic at UNC Hospital between 2014 and 2018. Individuals were analyzed by karyotype category (45X, 45X/46XX mosaicism, miscellaneous) and percentage of 45X cells. Age at follicle-stimulating hormone> 30 was defined as the age at loss of ovarian function. Results A total of 79 patients were identified after excluding individuals with unknown ovarian function and those with Y chromosome material. Thirty-eight percent were 45X monosomic, 62% were 45X/46XX mosaic or miscellaneous karyotypes. Fifty-five of 79 (70%) patients had evidence of ovarian failure, median age of failure 11 years (IQR: 4,12). Ovarian failure was more prevalent among individuals with 45X karyotype (100%). The median age of ovarian failure for 45X patients (n=30) was 10 years old, which is significantly younger than other karyotypes (n=49), with a median of 15 years, p<0.01. Linear regression analysis found that 1 percentage point increase in 45X cells in the peripheral karyotype is associated with a 0.09 year decrease in age of ovarian failure (p value=0.01). Only 9% of individuals were referred for fertility counseling. Conclusions There is a lower prevalence of ovarian failure among individuals with mosaic TS karyotypes, and referral rate for fertility counseling of patients with TS is low. These findings are in line with published literature. The finding that percentage of 45X cells in peripheral karyotype is associated with earlier age of ovarian failure is novel and warrants further investigation in a larger prospective cohort.

Background There is no data regarding the interrelationships of circulating Makorin Ring Finger Protein-3 (MKRN3), Kisspeptin (KISS1), and Neurokinin B (NKB) concentrations during minipuberty in humans. Objective To determine temporal changes in circulating concentrations of MKRN3, KISS1, NKB, and gonadotropins and investigate interrelationships between them in healthy full-term (FT) and preterm (PT) infants during minipuberty period. Methods A prospective study of 6-month follow-up performed. Eighty-seven healthy newborns, 48 FT (19 boys/29 girls), and 39 PT (21 boys/18 girls) (gestational age 31–37 weeks), were included. Blood samples were taken at 7 days (D7), 2 months (M2), and 6 months (M6) of age. Serum MKRN3, KISS1, NKB, LH, FSH, total testosterone (TT), and estradiol (E2) concentrations were measured. Results Seventy infants completed the study. MKRN3, KISS1, and NKB concentrations were similar in FT girls and boys. PT boys and girls also had similar concentrations of MKRN3, KISS1, and NKB. FT babies had significantly higher NKB concentrations than PT babies at D7, M2, and M6. MKRN3 and KISS1 concentrations do not differ between FT and PT babies. A strong positive correlation was found between MKRN3 and KISS1 at each time point and in all groups. FSH, LH, TT/E2 concentrations decrease while those of MKRN3 and KISS1 have a trend to increase toward the end of minipuberty. No correlation was detected between gonadotropins and MKRN3, KISS1, NKB concentrations. Conclusion Strong positive correlation demonstrated between KISS1 and MKRN3 suggests that interrelationship between molecules controlling minipuberty is not similar to those at puberty.

Objectives Brain MRIs are considered essential in the evaluation of children diagnosed with growth hormone deficiency (GHD), but there is uncertainty about the appropriate cut-off for diagnosis of GHD and little data about the yield of significant abnormal findings in patients with peak growth hormone (GH) of 7–10 ng/mL. We aimed to assess the frequency of pathogenic MRIs and associated risk factors in relation to peak GH concentrations. Methods In this retrospective multicenter study, charts of patients diagnosed with GHD who subsequently had a brain MRI were reviewed. MRIs findings were categorized as normal, incidental, of uncertain significance, or pathogenic (pituitary hypoplasia, small stalk and/or ectopic posterior pituitary and tumors). Charges for brain MRIs and sedation were collected. Results In 499 patients, 68.1% had normal MRIs, 18.2% had incidental findings, 6.6% had uncertain findings, and 7.0% had pathogenic MRIs. Those with peak GH<3 ng/mL had the highest frequency of pathogenic MRIs (23%). Only three of 194 patients (1.5%) with peak GH 7–10 ng/mL had pathogenic MRIs, none of which altered management. Two patients (0.4%) with central hypothyroidism and peak GH<4 ng/mL had craniopharyngioma. Conclusions Pathogenic MRIs were uncommon in patients diagnosed with GHD except in the group with peak GH<3 ng/mL. There was a high frequency of incidental findings which often resulted in referrals to neurosurgery and repeat MRIs. Given the high cost of brain MRIs, their routine use in patients diagnosed with isolated GHD, especially patients with peak GH of 7–10 ng/mL, should be reconsidered.

Objectives Patients with celiac disease had significantly decreased bone mineral density even in patients with no gastrointestinal symptoms. Only few bone studies are available on pediatric patients with celiac disease. Methods Forty-six patients underwent measurement of areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) before the initiation of gluten-free diet. Anthropometric, laboratory and DXA measurements at baseline and at sixth month of the treatment were compared. Results The frequency of low aBMD Z-score (≤−1 SDS) in both or any site was found to be 78.2% in this study. Of 16 patients with an aBMD Z-score of <−2 SDS five gained more than 1 SDS, and one gained more than 2 SDS. Nine of 20 patients with an aBMD Z-score of <−1 SDS completely normalized. Conclusions The results of the study showed that low BMD is common in children with celiac disease at the time of diagnosis and could improve in a short period of six months with a strict gluten-free diet and adequate supplementation of calcium and vitamin D.

Background During 1978–1981 the Japanese Standards Association conducted a national survey to collect 64 distinct body measurements for Japanese children and adults. During 1978–1981, the prevalence of childhood obesity was relatively low yet the population was well nourished in Japanese children. The aim of this study is to construct waist circumference and waist circumference to stature ratio reference centile curves for Japanese preschool children. Methods We utilized 1978–1981 national survey data on body sizes. There are 4937 boys and 4758 girls age 0–6 years for waist circumference measurements. Waist circumference was measured at the level of the umbilicus. Using LMS method, centile curves were constructed for waist circumference and waist circumference to stature ratio. These reference values were compared with those of Dutch, Swedish and Turkish children. Results Centile reference curves were made for clinical and epidemiological use. Japanese children had smaller waist circumference centile values as compared to waist circumference measured at the midpoint of the lowest rib cage and the iliac crest of Dutch, Swedish and Turkish children. However, Japanese children had comparable waist circumference to stature ratio centile values to those of Dutch and Turkish children. Conclusions This study presents the first age-, sex-, and ethnicity-specific reference values for waist circumference and waist circumference to stature ratio in Japanese preschool children.

Objectives While growth charts depicting 7 percentile lines for height and weight are useful for healthcare workers and pediatricians, endocrinologists need indication-specific z score cutoffs to plan investigations and treatment. The current Indian charts do not offer lower percentile/z scores (−2.25, −2.5, and −3 z score) lines. Also, increasing prevalence of childhood overweight and obesity necessitates a quick screening of nutritional status without calculations while using the same growth chart. Our objectives were to produce extended and user-friendly growth charts for 0–18-year-old Indian children that depict −2.25, −2.5, and −3 z score height lines in addition to the standard 7 lines and to add a quick BMI assessment tool as an inset. Methods LMS values from IAP 2015 growth charts (5–18 years) and WHO 2006 MGRS charts (<5 years) were used to generate −2.25, −2.5, and −3 z score height lines (1.2, 0.6, and 0.1 percentiles, respectively) from 0–18 year for boys and girls. These newly generated lines were added to standard 7 (3, 10, 25, 50, 75, 90, 97) percentile lines for height charts. In addition, modified BMI quick screening tool was incorporated as an inset. Results The extended height charts (with 10 lines), standard (7 lines) weight charts, and quick BMI assessment tool are presented in a single unified chart for use by endocrinologists. Conclusions These charts will help in defining specific height z score cutoffs as well as screen for overweight and obesity without any calculations in Asian Indian children.

Objectives To assess cases with rib fractures in infants under observation for or with an abuse diagnosis, and to compare risk factors with that in infants with fractures but no abuse diagnosis. Methods Design was case-series and register case-control of infants (aged <1 year) with rib fractures. Data was clinical records for the case-series (n = 26) and from national health registers for the case-controls (n = 28 and n = 31). Outcome measures were maternal and perinatal characteristics, reasons for appointment, examination, diagnoses, blood tests, and radiologic findings. Results The case-series had a median age of 70 days. A majority were detected through a skeletal survey for abuse investigation. Sixteen were boys, three were preterm and six were small-for-gestational age. Three carers had noticed popping sound from the chest; no infants showed signs of pain at physical examination. Mean number of fractures was 4.2, and 24 had callus. Bone mineralisation was scarcely reported. Metabolic panel was not uniformly analysed. The register case-control had a median age of 76 days, sharing risk factors such as maternal overweight/obesity, male sex, prematurity, and being small-for-gestational age. Cases more often had subdural haemorrhage, retinal haemorrhage, or long-bone fractures, controls more often had neonatal morbidity, respiratory infection, or a fall accident. Detection of fracture at time of a major surgery (n = 6) and rickets/vitamin D deficiency (n = 5) appeared in both groups, but was delayed among the cases. Conclusions Rib fractures in young infants, diagnosed as abuse, are usually asymptomatic and healing. A substantial proportion had metabolic risk factors, suggesting false positive cases.

Background The impact of gonadotropin-releasing-hormone-analogue (GnRHa) treatment on weight and body composition is controversial. Exploring the nutritional, psychological patterns of this population may aid to clarify this propensity to gain weight. This prospective observational study aimed to evaluate longitudinal changes in adiposity, nutrition and quality of life in girls with central precocious/early-fast puberty (CPP/EFP) during GnRHa treatment. Methods Thirty-two GnRHa-treated girls with CPP/EFP and 27 prepubertal girls (7–10 years) were included in the analysis. Outcome measures assessed at baseline for CPP/EFP and the control groups and during up to two years of GnRHa treatment for the CPP/EFP group, included anthropometrics, body-composition, basal-metabolic-rate (BMR), 3-day food-diaries, child eating-behavior questionnaire, and pediatric quality-of-life questionnaire (PedsQL). Results Girls with CPP/EFP had higher pretreatment BMI-SDS, fat percentages, waist circumference and waist-per-height ( p<0.01 for all), and lower psychosocial functioning than controls (p<0.05). Changes in anthropometric and body composition measurements indicated a gradual increase in adiposity and a decrease in muscle mass (p<0.001 for all). Dynamics in body composition could not be explained by the participants’ self-reported dietary patterns and physical activity levels or by the measured BMR, which revealed an adequate and relatively low energy intake as compared to energy requirements. A gradual decline in physical functioning (PedsQL) after one and two years of GnRHa treatment was observed (p<0.001). Conclusions Our findings highlight the need for comprehensive surveillance in girls with CPP/EFP. Dynamics in weight status and body composition during GnRHa treatment indicate the need for tailored nutritional and physical activity counseling aimed at preventing obesity.

Objectives Coronavirus disease (COVID-19) rapidly spread worldwide in a few months and was declared as a worldwide pandemic by WHO in March 2020. Transient benign hyperphosphatasemia (THI) is a benign condition associated with marked elevation of alkaline phosphatase (ALP) without any other kidney, bone, and liver pathologies. Case presentation Herein, we report a previously healthy 16-month-old female patient who developed a secondary transient benign hyperphosphatasemia associated with SARS-CoV-2. Patient whole family’s SARS-CoV-2 real-time reverse transcription-polymerase chain reaction (RT-PCR) results were positive. Since THI is a diagnosis of exclusion, other reasons that may cause ALP elevation should be ruled out. ALP activity decreased and turned to normal ranges within the following month. THI has been reported to be in association with various conditions. Its relationship with many viruses has been reported previously. Conclusions If ALP elevation is detected in patients with COVID 19 due to the increasing number of infections, THI should be considered if there is no other accompanying pathology.

Objectives Hyperammonemia in a newborn is a serious condition, which requires prompt intervention as it can lead to severe neurological impairment and death if left untreated. The most common causes of hyperammonemia in a newborn are acute liver failure and inherited metabolic disorders. Several mitochondrial disorders have been described as a cause of severe neonatal hyperammonemia. Case presentation Here we describe a new case of adenosine-triphosphate (ATP) synthase deficiency due to m.8528T>C mutation as a novel cause of severe neonatal hyperammonemia. So far six patients with this mutation have been described but none of them was reported to need hemodialysis in the first days of life. Conclusion This broadens the so far known differential diagnosis of severe neonatal hyperammonemia requiring hemodialysis.

Objectives IgG4-related hypophysitis is a novel clinical disease entity, which is typically seen in the sixth decade of life and is typically complicated by hypopituitarism. We describe an adolescent female with IgG4-related hypophysitis with normal pituitary function and summarize the relevant literature. Case presentation A 11.8-year-old girl presented with headache and left VI cranial nerve palsy. MRI brain identified an enlarged pituitary gland. Endocrine investigations revealed normal pituitary function. She underwent a transsphenoidal biopsy of the pituitary gland, and histological examination confirmed the diagnosis of IgG4-related hypophysitis. Serum IgG4 concentrations were normal and no evidence of other organ involvement was found. Although the patient tested strongly positive for TB on an interferon gamma release assay, pituitary biopsy was negative for granuloma formation and acid-fast bacilli (Ziehl-Neelson staining). IgG4-related hypophysitis was treated with oral prednisolone and mycophenolate-mofetil with a good response. Conclusions We describe to the best of our knowledge, the youngest patient in the published literature with IgG4-related hypophysitis presenting without pituitary insufficiency. A literature review identified only five cases of IgG4-related hypophysitis in adolescence. Serum IgG4 concentrations were normal in all, except one of the adolescent patients reported so far, and appear unhelpful in diagnosis in this age group.

Objectives Graves’ disease (GD) is rare in children under age five years. Antithyroid drugs are typically first-line therapy but carry the risks of agranulocytosis and liver dysfunction. Case presentation A male infant with multiple congenital anomalies, left ventricular hypertrophy, and neurologic dysfunction developed GD at five months of life. The presence of chronic hepatitis complicated medical management. Potassium iodide was effective temporarily, but urgent thyroidectomy was required at nine months of age. Postoperatively, the patient developed a thyroid function pattern consistent with impaired pituitary sensitivity to thyroid hormone (TH) that responded to the addition of liothyronine. Exome sequencing revealed a heterozygous de novo duplication of the ATAD3 gene cluster, suggesting a possible mitochondrial disorder. Conclusions This case describes the youngest child to date to be diagnosed with endogenous GD and to successfully undergo definitive treatment with thyroidectomy. An underlying defect in mitochondrial function is suspected, suggesting a potential novel pathophysiologic link to early-onset thyroid autoimmunity. Additionally, this case illustrated the development of impaired pituitary sensitivity to TH following thyrotoxicosis of postnatal onset, which may contribute to our understanding of hypothalamic-pituitary-thyroid (HPT) axis development.

Objectives The efficacy of sodium phenylbutyrate (SPB) for hyperammonemia associated with congenital portosystemic shunt (CPSS) remains unknown. We show the effectiveness of oral SPB. Case presentation Our patient had CPSS with severe hypoplasia of extrahepatic portal veins. At 9 months of age, to assess the efficacy of oral SPB, we evaluated the 24 h fluctuations of venous ammonia levels. In the first two days without SPB, ammonia levels were above 80 μmol/L for half a day. On the third and fourth days, administration of oral SPB three times a day decreased ammonia to acceptable levels, except at midnight. On the fifth day, another oral SPB administration at 8 pm decreased ammonia at midnight. Low levels of branched-chain amino acids, as well as coagulation disturbances, were observed without apparent symptoms. At 12 months of age, he showed normal psychomotor development. Conclusions Oral SPB may be effective for hyperammonemia associated with CPSS.

Objectives To report an unusual case of simultaneous presentation of Addison's and Graves' disease in an adolescent female previously diagnosed with type 1 diabetes (T1D) and Hashimoto's. Case presentation A 15-year-old female with T1D and hypothyroidism presented to the emergency department with altered mental state, fever, and left arm weakness for one day. Clinical work-up revealed coexistent new-onset adrenal insufficiency and hyperthyroidism. Her clinical course was complicated by severe, life-threating multisystem organ dysfunction including neurologic deficits, acute kidney injury, and fluid overload. Thyroidectomy was ultimately performed in the setting of persistent signs of adrenal crises and resulted in rapid clinical improvement. Conclusions Endocrinopathy should be included in the differential diagnosis of altered mental status. This case additionally illustrates the challenges of managing adrenal insufficiency in the setting of hyperthyroidism and supports the use of thyroidectomy in this situation.