Experience of X-linked hypophosphatemic rickets in the Gulf Cooperation Council countries: case series.

Summary: X-linked hypophosphatemic rickets (XLH), the most prevalent form of inherited hypophosphatemic rickets, is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog, X-linked (PHEX). This case series presents 14 cases of XLH from Gulf Cooperation Council (GCC) countries. The patients' medical history, biochemical and radiological investigative findings, as well as treatment responses and side effects from both conventional and burosumab therapy, are described. Cases were aged 2-40 years at diagnosis. There were two male cases and 12 female cases. All cases were treated with conventional therapy which resulted in a lack of improvement in or worsening of the clinical signs and symptoms of rickets or biochemical parameters. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients' quality of life and adherence to treatment. In the 10 patients treated with burosumab, there was a marked improvement in the biochemical markers of rickets, with a mean increase in serum phosphate of +0.56 mmol/L and tubular maximum phosphate reabsorption (TmP) to glomerular filtration rate (GFR) ratio (TmP/GFR) of +0.39 mmol/L at 12 months compared to baseline. Furthermore, a mean decrease in serum alkaline phosphatase (ALP) of -80.80 IU/L and parathyroid hormone (PTH) of -63.61 pmol/L at 12 months compared to baseline was observed in these patients. Additionally, patients treated with burosumab reported reduced pain, muscle weakness, and fatigue as well as the ability to lead more physically active lives with no significant side effects of treatment. Learning points: Conventional therapy resulted in a suboptimal response, with a lack of improvement of clinical signs and symptoms. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients' quality of life and adherence to treatment. Burosumab demonstrated marked improvements in the biochemical markers of rickets, in addition to reducing pain, muscle weakness, and fatigue. There were no significant side effects associated with burosumab therapy.

Elemental Milk Formula as a Possible Cause of Hypophosphatemic Rickets in Wiedemann-Steiner Syndrome.

Phosphate has a fundamental role in bone mineralization, and its chronic deficiency has multiple negative consequences in the body including defects in bone mineralization that will manifest in children as rickets and osteomalacia. We present here a young boy known to have Wiedemann-Steiner Syndrome with multiple co-morbidities that necessitated gastric tube feeding. The child at 22 months was found to have hypophosphatemia and a high alkaline phosphatase level associated with rachitic skeletal manifestations that were attributed to low phosphate intake and/or gastrointestinal absorption as there was no evidence of excessive phosphate wasting based on appropriate tubular renal re-absorption of phosphate. The primary nutritional source was an elemental amino acid-based milk formula (Neocate®) from 12 months of age. After switching from Neocate® to another elemental amino-acid based milk formula, all biochemical and radiological abnormalities returned to normal, indicating that the Neocate® formula was the possible cause of the patient's low phosphate intake. However, in the literature, this formula-associated effect was only described in a limited number of patients. Whether or not some patient-related factors, such as the very rare syndrome described in our patient, could influence this effect warrants further exploration.

Prevalence of thyroid nodules and characteristics of thyroid ultrasound in children with goiter: a single center experience.

BACKGROUND: Goiter is a common presenting sign of various thyroid diseases in children. Thyroid nodules are clinically and/or radiologically significant findings due to their high malignancy rate. The ultrasound (US) characteristics of pediatric patients with goiter are rarely reported in literature; thus, the purpose of this study is to assess the characteristics of thyroid US and the prevalence of thyroid nodules in pediatric patients with goiter. METHODS: A retrospective review of children and adolescents under the age of 18 (2015-2020) referred for neck ultrasound due to goiter in clinical examination. RESULTS: A total of 262 patients were included with a mean age of 13.77 ± 3.7 years. Thyroid antibodies were positive in 119/262 (45.4%) patients. Thyroid US reported to be abnormal in 210/262 (80%) patients. Thyroid nodule were found in 33.6% (n = 88/262) of patients with goiter and in 41.9% (n = 88/210) of patients with abnormal thyroid US result. Patients with positive antibodies had more of heterogeneity and hypervascularity of the gland on thyroid US (P < 0.001). On the other hand, thyroid nodules were more likely to be presented in patients with negative thyroid antibodies (P = 0.025). The heterogeneity within the thyroid positive group was significantly correlated with increasing TPOAb (P < 0.001) and TSH levels (P < 0.028). Heterogeneity on US had a positive predictive value (P = 0.041), while hypervascularity had low prediction for thyroid nodules (P = 0.022). Age, gender, family history of thyroid diseases, antibodies status and echogenicity in US did not show any significant associations with thyroid nodules. Papillary thyroid carcinoma was diagnosed in six patients and one of these patients was positive for thyroid antibodies. CONCLUSION: Thyroid nodules are quite common in our population. Thyroid nodules were significantly associated with heterogeneity in US. Although, no clinical or biochemical factors could predict the presence of thyroid nodules on thyroid US in our cohort, the absence of thyroid antibodies should lower the threshold for performing thyroid US.

Timing of Puberty and Late Pubertal Height in Saudi Schoolboys: Riyadh Puberty Study II.

Objective: Puberty has a significant contribution to the final height. Therefore, it is crucial to understand the normal variations in the onset and tempo of puberty in a specific population. In this study, we aimed to provide normative data on the timing of puberty and late pubertal height (LPH) in Saudi schoolboys in Riyadh. Methods: This is a cross-sectional field study (2011-2013) including Saudi schoolboys (grades 1-12; aged 6 to 19 years). Schools were chosen to represent the population from urban and rural areas in the Riyadh region. Pubertal maturity staging for gonads was assessed by measuring testicular size using a Prader orchidometer and assessing the Tanner staging of pubic hair. The marginal mean age was calculated using regression analysis. Results: We recruited 1086 schoolboys. The estimated mean age of pubertal onset at G2 was 11.8 (95% CI 11.60-12.0) years, for gonadal development at G3 was 13.2 (95% CI 12.9-13.5), G4 = 15.0 (95% CI 14.7-15.2), and G5 = 16.1 (95% CI 15.9-16.3) years, and for pubic hair stage 2 (PH2) was 12.6 (95% CI 12.4-12.9) years. The estimated time from G2/PH2 to G5/PH5 was 4.3 and 3.9 years, respectively. At the onset of puberty, the mean height was 144.7 cm and it reached 167.8 cm at G5 with a pubertal height gain of 23.1 cm. Conclusion: Our data present the norms of the timing of puberty and LPH in Saudi schoolboys. Saudi adolescent males are shorter than some European and American comparatives mainly due to shortness during childhood. However, they could have shorter LPH than Turkish, Greek, Thai, and Japanese due to a less pubertal height gain.

Postoperative intensive care management and residual endocrinopathy of pediatric supratentorial brain tumors: a retrospective cohort study.

OBJECTIVES: Endocrinopathy can occur as a postoperative sequel in children treated for supratentorial tumors (STTs). We assessed prediction of a residual hypothalamic/pituitary insufficiency (HPI) in these patients and factors associated with prolonged length of hospital stay (LOS). METHODS: This is a retrospective cohort study of children who had surgery for STTs in two tertiary centers in Saudi Arabia (2009-2019). We assessed PICU postoperative management and risk of HPI. Data were analyzed using SPSS V24.0 and a logistic regression model for a prediction of a prolonged LOS. RESULTS: Data included 55 children (1-18 years, mean 9.5 ± 4.9 years) who required STT surgeries, 32 (54%) females. Craniopharyngioma (27.3%) was the commonest STTs and 20% of patients had initial symptoms of HPI. PICU management included the use of different types of intravenous fluids (IVFs) and medications such as steroids and desmopressin (DDAVP). An early postoperative DI was reported in 21.8% (n=12/55). Residual HPI included 24 (43.6%) presumed cortisol deficient and 18 (32.7%) central DI patients. Risk factors for postoperative HPI were female gender, age <6 years, headache and preoperative pituitary symptoms. LOS (Median=25.5 ± 12.2 days) was significantly prolonged in patients who required two or more doses of DDAVP [B=13; 95% CI= (1.7-24.3) days] and reduced in patients who had suspected preoperative HPI [B=-19.6; 95% CI= (-31.1, -8.2) days]. CONCLUSIONS: Prediction of postoperative HPI in pediatric STTs enhances an early initiation of treatment in PICU and reduces LOS. A meticulous use of IVF and medications supervised by a multidisciplinary team is essential for a favorable outcome.

Frequency and Risk Factors of Diabetic Ketoacidosis in a Specialized Children's Hospital, Riyadh: A Cross-sectional Study.

Objectives: Diabetic ketoacidosis (DKA) is a life-threatening complication and a leading cause of hospitalization in patients with type 1 diabetes mellitus (T1DM). We aimed to assess the risk factors of admissions of children with DKA in a specialized children's hospital to reduce morbidity and inform appropriate prevention and intervention strategies. Methods: We conducted a retrospective review of all DKA admissions at King Abdullah Specialized Children's Hospital, Riyadh (March 2015-December 2017). Data were gathered from newly diagnosed patients with T1DM and known patients ≤ 14 years old with DKA criteria. The main variables were frequency, precipitating factors, and other characteristics of DKA admissions in both groups. Results: A total of 116/562 patients with T1DM (mean age 8.9±3.0 years) had 146 DKA episodes, of which 42/116 (36.2%) were newly diagnosed. The frequency of DKA admissions were 146/562 (26.0%), of which 42/141 (29.8%) were newly diagnosed versus 104/421 (24.7%) known T1DM patients. The majority were 10-14 years old (p ≤ 0.001), and 77.8% were females. Missing insulin was the main cause of DKA (p = 0.001) among known patients with T1DM. Recurrent episodes (n = 30/146, 20.5%) occurred in 15/116 patients and were more common in children ≥ 10 years of age (p = 0.024). The mean length of stay was 2.6±2.0 days and increased with DKA severity (p = 0.008). Conclusions: Most DKA episodes were in patients with known T1DM and missing insulin was the leading cause of DKA. In addition to awareness campaigns to prevent DKA as an initial presentation, intervention strategies should also target high-risk groups of known patients of T1DM such as adolescents and patients with recurrent episodes.

Diagnosis and management of X-linked hypophosphatemia in children and adolescent in the Gulf Cooperation Council countries.

INTRODUCTION: X-linked hypophosphatemia (XLH) is a rare inherited cause of hypophosphatemic rickets and osteomalacia. It is caused by mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX). This results in increased plasma fibroblast growth factor-23 (FGF23), which leads to loss of renal sodium-phosphate co-transporter expression leading to chronic renal phosphate excretion. It also leads to low serum 1,25-dihydroxyvitamin D (1,25(OH)2D), resulting in impaired intestinal phosphate absorption. Chronic hypophosphatemia in XLH leads to impaired endochondral mineralization of the growth plates of long bones with bony deformities. XLH in children and adolescents also causes impaired growth, myopathy, bone pain, and dental abscesses. XLH is the most frequent inherited cause of phosphopenic rickets/osteomalacia. Hypophosphatemia is also found in calcipenic rickets/osteomalacia as a result of secondary hyperparathyroidism. Thus, chronic hypophosphatemia is a common etiologic factor in all types of rickets. RESULTS: There is considerable overlap between symptoms and signs of phosphopenic and calcipenic rickets/osteomalacia. Wrong diagnosis leads to inappropriate treatment of rickets/osteomalacia. Nutritional rickets and osteomalacia are common in the Gulf Cooperation Council countries which include Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain, and Oman. Due to high levels of consanguinity in the region, genetic causes of phosphopenic and calcipenic rickets/osteomalacia are also common. CONCLUSION: This guideline was developed to provide an approach to the diagnosis of XLH, especially where there is no family history of the disease, and that other related conditions are not mistaken for XLH. We also guide the medical management of XLH with conventional treatment and with burosumab, a recombinant human IgG1 monoclonal antibody to FGF23.

Cord blood versus heel-stick sampling for measuring thyroid stimulating hormone for newborn screening of congenital hypothyroidism.

BACKGROUND: Screening for congenital hypothyroidism (CH) using cord blood or heel-stick samples is considered essential for the prevention of long-term complications CH, which include intellectual disability and slow growth. OBJECTIVE: Compare the sensitivity and specificity of cord blood and heel-stick samples for determining thyroid-stimulating hormone (TSH) levels for the detection of CH. DESIGN: Comparative diagnostic accuracy. SETTINGS: Tertiary care center in Riyadh. PATIENTS AND METHODS: The study included all infants who were delivered during the period from May 2011 to May 2013. As part of routine newborn screening, both cord blood and heel-stick samples were collected from each newborn for CH screening by measuring TSH levels. A cord TSH level was considered positive if the concentration of TSH was more than 60 mIU/L and negative if less than 30 mIU/L. Any cord TSH level between 30-60 mIU/L was considered borderline, and free T4 was measured from the same cord sample. The result was considered positive if the free T4 level was below 9 pmol/L. Heel-stick TSH levels more than 20 µU/L were considered positive. All newborns with positive results were recalled and a peripheral venous sample was taken for TSH and free T4 for confirmation. MAIN OUTCOME MEASURES: Sensitivity and specificity, positive and negative predictive values and recall rates. SAMPLE SIZE: 17 729 screened babies. RESULTS: Of 17 729 neonates screened, 7 were diagnosed as having primary CH. All confirmed cases were detected by both cord and heel-stick TSH levels: 88 cord results were positive (sensitivity 100%, specificity 99.6%, with a recall rate of 0.04%) and 305 heel-stick results were positive (sensitivity 100%, specificity 98.3%, with a recall rate of 1.68%). CONCLUSION: Both cord and heel-stick TSH testing detected all cases of CH. Cord testing was superior to heel-stick testing as the recall rate was lower. We think cord TSH testing is preferable when heel-stick is difficult or early discharge is the practice. LIMITATIONS: Retrospective; the timing of newborn screening for TSH sampling was premature. CONFLICT OF INTEREST: None.

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome.

Extra-genital congenital anomalies are often present in cases of hypospadias, but it is unclear whether they have an association with the outcome of hypospadias surgery. The aim of this study was to review all hypospadias cases that had surgery between 2009 and 2015 at a single centre and identify clinical determinants of the surgical outcome. An extra-genital congenital anomaly was reported in 139 (22%) boys and 62 (10%) had more than 1 anomaly. Of the 626 boys, 54 (9%), including 44 with proximal hypospadias, had endocrine as well as limited genetic evaluation. Of these, 10 (19%) had a biochemical evidence of hypogonadism and 5 (9%) had a molecular genetic abnormality. At least 1 complication was reported in 167 (27%) patients, with 20% of complications (most frequently fistula) occurring after 2 years of surgery. The severity of hypospadias and the existence of other anomalies were clinical factors that were independently associated with an increased risk of complications (p < 0.001). In conclusion, complications following surgery are more likely in those cases that are proximal or who have additional extra-genital anomalies. To understand the biological basis of these complications, there is a greater need to understand the aetiology of such cases.

Characteristics of pediatric diabetic ketoacidosis patients in Saudi Arabia.

OBJECTIVES: To evaluate the clinical and biochemical characteristics of children with diabetic ketoacidosis (DKA). METHODS: In this retrospective study conducted between June 2012 and November 2013 at the King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia, we evaluated pediatric DKA admissions from 1995-2008 (Phase 1). From the case files, we obtained information related to patients' age, gender, weight, presenting complaints, serum biochemical profile, and management. RESULTS: This study included 373 DKA admissions with a median age of 11 years (interquartile range [IQR]: 8-13). The patients in the subgroup of age more than 10 years old had the highest proportion of admissions (n=250, 67%, p<0.000). The median duration of diagnosis of diabetes mellitus (DM) was 3 years (IQR: 2-6). New-onset DM was 47%. Predominant precipitating cause was acute illness, mostly viral syndrome in 22% of all cases, and non-compliance to insulin regimen was in 79% of  the diagnosed diabetic cases. Blood glucose, pH, anion gap, serum osmolality, serum potassium, and serum phosphate showed the highest change during the initial 6 hours of management, while trends of serum bicarbonate and blood urea nitrogen demonstrated a predominant change in the initial 12 hours. CONCLUSION: The notable findings in this study, such as, higher mean age of presentation, high rate of non-compliance to insulin as the cause of precipitation, and a high prevalence of abdominal pain at presentation should be followed up with further comparative studies.