Volume 35, Issue 2

Objectives To review the published literature regarding disorders of sex development (DSD) in Africa which will highlight clinical characteristics, and challenges of evaluation and treatment of DSD. Content We performed systematic review of articles published on DSD in Africa between January 2001 and December 2020. Summary Eighteen studies involving 1980 patients from nine countries were analyzed. Overall mean age at presentation was 9.3 years (range 1 day–33 years) with 52.5 and 45.1% reared as females and males, respectively, prior to presentation. Following evaluation however, 64% were assigned female sex, 32.1% were assigned male sex, and 21.8% of the cases required sex reassignment. Only 7 (38.9%) of the publications reported medical treatment of DSD, 4 (22.2%) reported on psychosocial management and 5 (27.8%) documented multidisciplinary team management. Barring regional variations, the documented challenges of management include delayed presentation, loss to follow up, financial challenges, and lack of facilities for care of DSD. Comparison of the cases managed in the last decade (2011–2020) with those managed in the earlier decade (2001–2010) showed a trend towards earlier presentation and reduced rate of sex reassignment in the last decade. However, the challenges persisted. Outlook Barring regional differences, a high proportion of DSD in Africa may have delayed presentation with inappropriate sex of rearing, inadequate evaluation and need for sex reassignment. Specific efforts to improve time to diagnosis, patient evaluation, improvement of healthcare funding, and collaboration with more developed countries may improve the care of patients with DSD in Africa.

Objectives Lack of systematic evaluation of short stature results in unnecessary work-up on one hand while missing pathology on the other. We have developed a mobile application that guides work-up based on age, auxology (height, BMI, and corrected standard deviation score), and skeletal maturation with an aim of reducing the diagnostic errors. Aim of this study is to develop and validate a mobile application for point of care evaluation of short stature. Methods The application was developed (n=400) and validated (n=412) on children and adolescents (2–18 years of age) presenting to our Pediatric Endocrinology Clinic with short stature. Height standard deviation score thresholds determining the need for workup were derived from Receiver Operating Characteristics (ROC) curve. Student’s t-test and ROC curves were used to identify the most appropriate parameter differentiating constitutional delay of growth and puberty (CDGP) from pathological and nutritional from endocrine causes. The validation of the application involved comparing the application predicted and clinical diagnosis at each step of the algorithm. Results The mobile application diagnosis was concordant with clinical diagnosis in 408 (99.0%) with discordance in four (two with CDGP labeled as growth hormone deficiency [GHD] and two with GHD labeled as CDGP). Conclusions Mobile application guided short stature assessment has a high concordance with the clinical diagnosis and is expected to help point of care short stature evaluation.

Objectives There is limited evidence about the inflammatory potential of diet and cardiometabolic risk in children. The aim of this study was to evaluate the association between the Children’s Dietary Inflammatory Index (C-DII) with cardiometabolic risk factors in Turkish adolescents from 10 to 17 years. Methods Participants aged 10–17 years, who completed a 24-h dietary recall, from which C-DII scores were calculated, were include in this cross-sectional study. Lipid profile, glycemic parameters, high-sensitivity C-reactive protein (hs-CRP), liver enzymes, thyroid-stimulating hormone (TSH), and uric acid were analyzed in blood samples. Sociodemographic characteristics and sedentary behavior were assessed using a semi-structured questionnaire. We compared the distributions of anthropometric, biochemical, and blood pressure measurement levels associated with cardiometabolic risk factors by the median of C-DII with linear regression. Results The mean sample C-DII was −0.16 ± 2.31 and ranged from −3.22 to +4.09. Higher median C-DII scores, indicating a more pro-inflammatory diet among children, were associated with higher blood pressure and body mass index (BMI). However, the C-DII was modestly directly associated with fasting insulin, fasting blood glucose, and waist circumference. The area under the receiver operating curve of C-DII in predicting hs-CRP was found to be quite high (0.864, 95% CI: 0.795–0.933). Conclusions Consuming a pro-inflammatory diet in adolescence was associated with alterations in cardiometabolic risk factors, especially with systolic blood pressure, diastolic blood pressure, and BMI.

Objectives Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. Methods The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010–2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979–1992). Individuals with the height standard deviation score <−1.0, the bone age (BA)/chronological age (CA) ratio <0.8 at first visits, and without other identifiable causes of short stature were extracted from the record of OCGH. Similarly, individuals meeting the height and bone age criteria were extracted from the OGR record. The pubertal growth onset was auxologically determined as the upward shift from the prepubertal growth curve fitted to a quadratic function. Earlier-than-expected onset was defined as the onset earlier than the population average +1 year. Results From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. Conclusions Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

Objectives Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population. Methods We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5′-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP. Results We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease. Conclusions A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.

Objectives The standard recommendation of insulin therapy for patients with DKA is the administration of slow continuous intravenous (IV) regular insulin. Currently subcutaneous insulin is being recommended as an alternative treatment of DKA in mild and moderate cases in resource-limited settings. The purpose of this study was to assess the effectiveness and safety of six-hourly subcutaneous regular insulin use for the treatment of DKA among children with type one diabetes mellitus. Methods A retrospective cohort study was conducted among 224 DKA episodes which occurred in 161 children who were treated at St. Paul’s Hospital Millennium Medical College in Addis Ababa, Ethiopia, from November 2015 to November 2020. Results Majority (68.8%) of the episodes occurred in newly diagnosed cases. The median time for urinary ketones clearance was 24 h. DKA severity was found to be the only significant predictor of time to DKA resolution. Only 13 (5.8%) were treated at the pediatric intensive care unit (PICU), and 27 (12.1%) developed complications during management. No death or neurological complications observed. Conclusions The six-hourly subcutaneous regular insulin use was found to be safe and effective alternative to slow IV insulin infusion for the treatment of DKA in a non PICU setting. As it resulted in minimum morbidity and no mortality, we recommend its use in the treatment of DKA irrespective of its severity. It can also decrease the health care cost and patients’ inconvenience.

Objectives NPR2 variants are associated with various short stature and bone dysplasia, such as acromesomelic dysplasia Maroteaux tyoe, individuals with a phenotype similar to Léri–Weill syndrome (LWD), and idiopathic short stature (ISS). However, few studies have reported on the relationship between familial short stature (FSS) and NPR2 variants. This study aimed to explore the relationship between FSS and NPR2 variants through the detection and identification of NPR2 variants in children with FSS, phenotypic description, clear treatment plan, and follow-up of treatment effect. Methods Children who met the FSS diagnostic criteria and had informed consent were included in the study. The trio whole-exome sequencing method (trio-WES) was used to detect and evaluate the NPR2 variants. Results A total of 16 children with short stature were included in this study (pretreatment height ≤ −2 standard deviation (SD) in both the patient and the shorter parent, unknown genetic etiology). NPR2 variants were identified in 12.5%(2/16) of the participants. Patient A was a 6-year-old male and 103.7 cm tall (−3.11SD), while Patient B was a 9-year-old female and 123.2 cm tall (−1.88SD). However, their heights increased after recombinant human growth hormone (rhGH) treatment. The height of patient A increased by 0.36SD six months after treatment while that of patient B increased by 1.22SD after one and a half years of treatment. Conclusions NPR2 variant causes FSS. The growth rate of children significantly improved after rhGH treatment. However, further follow-up study is needed to determine the final height after long-term treatment.

Objectives Coronavirus disease 2019 has caused a major epidemic worldwide, and lockdowns became necessary in all countries to prevent its spread. This study aimed to evaluate the effects of staying-at-home practices on the metabolic control of children and adolescents with type 1 diabetes during the pandemic period. Materials and Methods Eighty-nine patients younger than 18 years old who were diagnosed with type 1 diabetes at least one year before the declaration of the pandemic were included in the study. The last visit data of the patients before and after the declaration of the pandemic, and the frequency of presentation of diabetes-related emergencies from one year after diagnosis of type 1 diabetes to the declaration of the pandemic, and from the declaration of the pandemic to the last visit after the pandemic declaration were compared. Results The total number of patients was 89, and 48 (53.9%) were boys. The mean (± standard deviation [SD]) age at diagnosis was 8.4 ± 3.7 years (boys 7.9 ± 3.6 years; girls 8.9 ± 3.9 years). There was no statistically significant difference when the SD values of the anthropometric measurements, and the glycosylated hemoglobin (HbA1c) and lipid profile tests were compared. However, the frequency of admission to the emergency service related to diabetes was significantly different. Conclusions Although the pandemic did not significantly affect the metabolic and glycemic controls of the children with type 1 diabetes included in this study, an increase in the frequency of diabetes-related emergency admissions was noted.

Objectives Central diabetes insipidus (DI) is a known complication following surgical resection of a suprasellar mass. There are limited data analyzing the outcomes of a standardized protocol for the management of postoperative DI in the pediatric population. We sought to fill this gap and hypothesized that utilizing a standardized protocol for fluid management (3-bag system) would reduce serum sodium fluctuations in the postoperative period after suprasellar surgery. Methods A retrospective chart review was performed. Patients were identified with the following criteria: age ≤ 18 years, undergoing a surgical procedure for suprasellar mass that also had postoperative DI. The primary outcome was the variability in serum sodium during the first 48 h and between 48 and 120 h postoperatively. Results There were 21 encounters pre-protocol and 22 encounters post-protocol for neurosurgical procedures. Use of the standardized protocol was associated with a lower range of sodium within 48 h postoperatively (p=0.065) and 83% lower odds of hypernatremia (Na>150 mmol/L) within 48 h postoperatively (CI 0.039–0.714) after controlling for age, gender, and prior DI diagnosis. History of DI conferred a lower risk of hypernatremia as well as less sodium fluctuation within 48 h postoperatively. Younger patients, those <9.7 years of age were associated with increased risk of hyponatremia and greater sodium fluctuations during the postoperative period. Conclusions In patients with postoperative DI after suprasellar surgery, using a standardized protocol for fluid management (3-bag system) appears to reduce serum sodium variability in the first 48 h after surgery.

Objectives Adrenal insufficiency (AI) is an overall rare disorder characterized by the chronic need for pharmacotherapy to prevent threat to life. The Pediatric Endocrine Society has recommended the use of clinical action tools to improve patient education and help guide acute management of AI. We aimed to develop and assess an easy-to-use, patient-friendly, evidence-based, personalized pictogram-based adrenal insufficiency action plan (AIAP) to aid in the management of AI in children. Methods Patients/caregivers (P/Cs) responded to surveys which measured the concepts of transparency, translucency, and recall in order to assess the pictograms. Readability was assessed using six formulas to generate a composite readability score. Quality was graded by P/Cs using the Consumer Information Rating Form (CIRF) (>80% rating considered acceptable). Understandability and actionability was assessed by medical librarians using the Patient Education Materials Assessment Tool-Printable (PEMAT-P) (>80% rating was acceptable). Suitability was evaluated by clinicians using the Suitability Assessment of Materials (SAM) instrument (>70% rating considered superior). Results All pictograms met criteria for inclusion in the AIAP. Composite readability score=5.4 was consistent with a fifth-grade level. P/Cs (n=120) judged the AIAP to be of high quality with CIRF rating=85.2%. Three medical librarians rated the AIAP to have 100% understandability and 100% actionability. Thirty-three clinicians completing the SAM generated a suitability rating of 90.0%. Conclusions The AIAP visually highlights individualized care plan components to facilitate optimized preventative and acute AI care. Further investigation will determine if AIAP improves clinical outcomes for patients with AI.

Objectives Insulin resistance may be associated with impaired lung function. The objective of this study was to examine the relationship between insulin resistance and lung function in asthmatic children. Methods We performed a cross-sectional study on asthmatic children aged 6–18 years at Tertiary Care Center, India. Fasting serum glucose and insulin levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) in 90 children. Lung function tests were performed. Spearman correlation was used to assess the relationship between insulin resistance and lung function. Linear regression was done to adjust the potential confounders. Results Insulin resistance was present in 15.5% of patients. We found a statistically significant inverse relationship between HOMA-IR and spirometric parameters such as forced expiratory volume in 1 s/forced vital capacity ratio and forced expiratory flow between 25 and 75% on Spearman correlation. However, adjusted regression for age, gender, and body mass index showed no significant association of lung function parameters with HOMA-IR. Conclusions Insulin resistance may be considered for the decline in lung function in asthmatic children.

Objectives Nutritional rickets (NR) is still an important problem and one which increasing influxes of immigrants are further exacerbating. This study evaluated cases of mostly immigrant children followed up with diagnoses of NR in our pediatric endocrinology clinic. Methods Details of 20 cases diagnosed with NR between 2017 and 2020 were retrieved from file records. Results Twenty (11 male) cases were included in the study. Three (15%) were Turkish nationals and the others (85%) were immigrants. Hypocalcemia and hypophosphatemia were detected in 17 and 13, respectively. Alkaline phosphatase (ALP) values were normal in two cases, while ALP and parathyroid hormone (PTH) values were elevated in all other cases, and PTH levels were very high (473.64 ± 197.05 pg/mL). 25-hydroxyvitamin D levels were below 20 ng/mL in all cases. Patients with NR received high-dose long-term vitamin D or stoss therapy. Six patients failed to attend long-term follow-up, while PTH and ALP levels and clinical findings improved at long-term follow-up in the other 14 cases. Conclusions The elevated PTH levels suggest only the most severe cases of NR presented to our clinic. Clinically evident NR is therefore only the tip of the iceberg, and the true burden of subclinical rickets and osteomalacia remains unidentified. Public health policies should therefore focus on universal vitamin D supplementation and adequate dietary calcium provision, their integration into child surveillance programs, adequate advice and support to ensure normal nutrition, exposure to sunlight, and informing families of the increased risk not only for resident populations but also for refugee and immigrant children.

Objectives Primary adrenal insufficiency (PAI) in children is an uncommon condition. Congenital adrenal hyperplasia (CAH) is the commonest cause followed by autoimmune disorders. Diagnosis and management are challenging especially in resource-limited settings. Studies from Africa are scanty and here we describe for the first time the clinical presentation, possible etiologies, and challenges in diagnosis and management of PAI in a large cohort of Sudanese children. Methods This was a descriptive hospital-based study where all patients diagnosed with PAI between 2006 and 2020 were reviewed. The diagnosis was based on clinical presentation, low morning cortisol ± high adrenocorticotropic hormone (ACTH), or inadequate response of cortisol to synacthen stimulation. Challenges faced in diagnosis and management were identified. Results From 422 PAI suspected patients, 309 (73.2%) had CAH, and 33 (7.8%) had PAI-like symptoms and were not furtherly discussed. Eighty patients (19%) had fulfilled the study criteria: 29 had Allgrove syndrome, nine auto-immune polyendocrinopathy syndrome, seven adrenoleukodystrophy, and one had an adrenal hemorrhage. Hyperpigmentation was the cardinal feature in 75 (93.8%) while the adrenal crisis was not uncommon. Lack of diagnostic facilities has obscured the etiology in 34 (42.5%) patients. Conclusions PAI is not uncommon in Sudanese children where genetic causes outweigh the autoimmune ones. Many cases were missed due to nonspecific presentation, lack of awareness, and difficult access to tertiary health care facilities. In addition to the clinical findings, early morning cortisol ± ACTH levels can be used in diagnosis where facilities are limited particularly synacthen stimulation test.

Objectives The aim of the current prospective randomized control study was to assess efficacy, safety, and non-inferiority of a new liquid L-thyroxine formulation dissolved in glycerol and water (T4 ® drops, produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece) in comparison to the standard Tablets form (T4 ® tablets, Uni-Pharma, Athens, Greece) in the substitutive treatment of children with congenital hypothyroidism (CH). Methods Thirty-nine children with CH, aged 3–12 years old, were enrolled in the study, after parental Informed Consent has been obtained, while three patients were lost from follow-up. At baseline, all participants had normal thyroid-stimulating hormone (TSH) and Free T4 values. Patients were randomly subdivided according to the assigned treatment in Group A (n=17)-Tablet Form and Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0, 2, 4, and 6 months. Results TSH values showed a statistically significant difference (p=0.017) between groups only at six months (Group A having higher TSH levels than Group B, albeit within the normal range), while Free T4 levels had no statistical difference throughout the six month study period and were always within the normal range. Moreover, dose adjustments were more frequent in Group A (p=0.038) during the six months. Liquid L-thyroxine substitutive treatment exhibited no statistically significant adverse effects in comparison to the widely used tablets. Conclusions Levothyroxine (LT4) as liquid solution formulation is safe and noninferior to the widely used L -thyroxine Tablets, with less need for dose adjustment, and can therefore be safely used in the treatment of children with CH.

Objectives Recent studies have demonstrated an increase in the frequency of idiopathic central precocious puberty (CPP) during the severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic. We compared the demographic, anthropometric, and clinical characteristics of idiopathic CPP patients diagnosed during a one-year period of the COVID-19 pandemic with the characteristics of patients diagnosed during the same period in the previous three-years. Methods Demographic, clinical, anthropometric, and laboratory data of all patients diagnosed in our Pediatric Endocrinology clinic with idiopathic CPP during a one-year period of the COVID-19 pandemic (April 2020–March 2021) and a three-year period before the pandemic (April 2017–March 2020) were evaluated retrospectively. Results A total of 124 patients (124 girls, zero boys) diagnosed with idiopathic CPP were included in this study. Sixty-six patients in the three-year period before the COVID-19 pandemic (April 2017–March 2020) and 58 patients (46.8%) in the one-year period during the COVID-19 pandemic period (April 2020–March 2021) were diagnosed with idiopathic CPP. Conclusions This study’s findings suggest that the number of girls diagnosed with idiopathic CPP during the one-year study period during the pandemic was more than double that of any of the previous three-years.

Objectives: Gordon syndrome (GS), also known as pseudohypoaldosteronism type II, is a rare tubular disease characterized by hypertension, hyperkalemia, and metabolic acidosis. Its causative genes are CUL3 , KLHL3 , WNK1 , and WNK4 , and they are associated with varying severity of the disease. Herein, we report the first case of GS caused by a CUL3 mutation in a patient with short stature in Korea. Case presentation: A 7-year-old boy had hypertension, metabolic acidosis, and persistent hyperkalemia, which were initially detected during the evaluation of short stature. He was born small for gestational age at late preterm gestation. Laboratory test findings showed hyperkalemia with low trans-tubular potassium gradient, hyperchloremic metabolic acidosis with a normal anion gap, and low plasma renin levels. Genetic analysis revealed a heterozygous de novo mutation in the CUL3 gene (c.1377+1G > C in intron 9). Thus, a diagnosis of GS was made. The results of the endocrine function test (including growth hormone stimulation tests) were normal. After thiazide treatment, the patient’s electrolyte levels were normalized. However, he presented with persistent hypertension and short stature. Conclusions: GS should be considered in children with short stature, hypertension, and hyperkalemia, and early treatment may reduce complications.

Objectives Tyrosinaemia type 1, an inherited disorder of tyrosine metabolism, is usually treated with a tyrosine-defined diet and since 2000 with nitisinone. So far, data about effects of nitisone during pregnancy and breastfeeding are rare. This is the first report of two pregnancies in a patient with tyrosinaemia type 1 while under treatment with nitisinone. Case presentation We here present a 20-year-old female patient with tyrisonemia type 1 receiving treatment with nitisinone and a tyrosine-defined diet since she was diagnosed with tyrosinaemia type 1 at the age of 18 months. During two pregnancies blood concentrations of tyrosine, succinylacetone and nitisinone were measured regularly. Neither infant has tyrosinaemia type 1 and both showed an initial increase in concentrations of tyrosine, succinylacetone and nitisinone. All three metabolites dropped within two weeks after birth. Both were exclusively breastfed for about two weeks. Both children show age-appropriate physical and mental development. Conclusions Nitisinone therapy during pregnancy and the short breastfeeding period did not result in adverse events in our patient or her children. Regular assessments of tyrosine, succinylacetone and nitisinone should be made during pregnancy and the breastfeeding period in both the mother and the infant. For better understanding, in principle, all cases of pregnancy and breastfeeding with tyrosinemia type 1 should be assessed and followed to further evaluate the implications of tyrosinaemia type 1 and its treatment during pregnancy. Additionally, even though experience with breastfeeding is limited, medication with nitisinone is safe and there is no reason to consider breastfeeding unsafe or to not recommend it.

Objectives Myxedema crisis, a fatal complication of severe hypothyroidism, is extremely rare in children and treatment guidelines are lacking. Since availability of intravenous levothyroxine is limited in resource poor settings, myxedema crisis can be treated with oral levothyroxine and/or oral liothyronine (if necessary), in the absence of cardiac risk factors, thus hastening the recovery and significantly decreasing the associated morbidity and mortality. In the background of untreated hypothyroidism, a possible association of ovarian hyperstimulation syndrome (OHSS) and reactive pituitary hyperplasia should be kept in mind, thus preventing unnecessary interventions. Case presentation A 13-year-old girl child with Down syndrome, presented with myxedema crisis, as initial presentation of untreated hypothyroidism. Conclusions Annual screening, timely diagnosis of hypothyroidism, and early initiation of thyroid hormone supplementation will prevent associated physical and neurocognitive morbidity in children, especially those with Down syndrome. Importance of oral liothyronine supplementation in myxedema crisis, has been highlighted in this case report.

Objectives Enzyme replacement therapy (ERT) with alglucosidase alfa (rhGAA) has changed the fatal course of infantile Pompe disease, however, development of anti rhGAA antibodies and infusion-associated reactions (IAR) restrict the tolerability and effectiveness of the treatment. Case presentation We describe a successful concomitant immune tolerance induction (ITI) and desensitization protocols in a cross-reactive immunologic material (CRIM) negative 7-month-old male patient. At the age of 5 months and eighth dose of the ERT, the patient developed IAR and his rhGAA specific IgE was negative however, his rhGAA specific IgG titer was as high as 12,800. ITI therapy to suppress antibody formation and a desensitization protocol was devised to be given concomitantly. At the end of 5-week therapy, his fatigue and weakness improved profoundly and a control antidrug antibody level decreased at 800. At the time of the patient’s follow up, he was still on ERT with desensitization at the age of 15 months without any reactions. Conclusions This is the first report in the literature applying concomitant ITI and desensitization protocols in a CRIM negative infantile-onset Pompe disease patient successfully, hence the importance of the case.