Abstract: Background: Bisphosphonates (Pamidronate and Zoledronic acid) mainly used for the treatment of childhood osteoporosis such as osteogenesis imperfecta have been associated with adverse effects ranging from acute phase response, hypocalcemia, musculoskeletal pain and up to serious side effects such as osteonecrosis of the jaw. In this report, we describe the prevalence of hypocalcemia among Saudi children treated with Zoledronic acid. Method: The biochemical profile of 13 Saudi children with osteogenesis imperfecta treated with Zoledronic acid was reviewed. The bone profile including calcium and phosphorus levels were monitored before and 4-24 hours after Zoledronic acid administration. The annual total Zoledronic acid dose was 0.1 mg/kg/year. Results: Post therapy, 46% of the treated children had mild hypocalcemia and 15% had mild hypophosphatemia. None of the children had hypocalcemic or hypophosphatemic signs or symptoms. No reports of seizure or tetany or muscle spasm. Conclusion: Hypocalcemia associated with Zoledronic acid administration is common, however mild. Close monitoring and calcium supplementation might be needed.

Abstract: Introduction: This retrospective cohort study aimed to describe the articular manifestations in Saudi children with X-linked hypophosphatemic rickets (XLHR). Materials and Methods: The medical records of children with XLHR were retrospectively reviewed. The diagnosis of XLHR was confirmed biochemically by low serum phosphorus and elevated alkaline phosphatase, radiologically by the evidence of active rickets and genetically by phosphate-regulating gene with homology to endopeptidases (PHEX) gene mutations. Results: Twenty-two patients with XLHR (10.8 years + 4.9) were enrolled. All children were followed at King Faisal Specialist Hospital & Research Center for a mean duration of 8.7 years (+3.7). Clinically, all patients had disproportionate short stature (-2.5 standard deviation +1.3) with varying degrees of skeletal deformities, including genu varum in 68%, genu valgum in 18%, coxa vara in 14%, bowing of tabia in 32%, and history of fractures in 32% of children. Hearing impairment was noted in two children. Biochemically, all patients showed increased urinary phosphate loss with hypophosphatemia 0.67 mmol/l (+0.15) and elevated serum alkaline phosphatase levels 522 IU/l (+133). Genetically, hemizygous PHEX mutation (C746F) was reported in seven patients. Radiologically, four children had osteoarthritis and three had enthesopathies. Four patients craniosynostosis. All children were on oral inorganic phosphate salts (50–70 mg/kg/day), combined with 1,25(OH)2D3 (alfacalcidol or calcitriol, 30–40 ng/kg/day). Conclusion: Patients with XLHR frequently present with varying degrees of joint deformities that are not completely resolved with either medical or surgical treatment. Long-term skeletal complications of XLHR that present in adults are less common in children and adolescents.

Abstract: Background: Poor or non-adherence to growth hormone (GH) therapy is the most vital factor that could affect the growth potential of the individual. Aim: To assess the adherence and growth outcomes in growth hormone-deficient children treated with recombinant human growth hormone (r-hGH) via easypod™. Methods: The medical records of children with primary isolated GH deficiency and treated with r-hGH via easypod™ were retrospectively analyzed. The primary endpoint was to assess the mean rate of treatment adherence. Secondary endpoints were to study the changes in height, height standard deviation (SD) score, height velocity, and height velocity SD score after one-year of r-hGH treatment and the impact of adherence on the growth outcomes. Results: The mean age of the children included in this study was 10 years (age range: 8 to 11 years). Adherence to the r-hGH varied from 74-98% (mean 87%). Annular height velocity, the height SD score, and Insulin growth factor-1 level were 2 - 4 cm, -6.2 SD to -2.1 SD, and 22 to 218 ng/ml, respectively before initiation of the therapy, and reaches to 5 - 8 cm, -5.4 SD to -1.25 SD, and 85 to 545 ng/ml after one-year of r-hGH therapy. A good correlation between adherence and height was observed (r=0.85, p 〈 0.01). Conclusion: We found an acceptable adherence to r-hGH treatment among children with primary isolated GH deficiency. We also found a significant relationship between drug adherence and improved growth outcomes.

Abstract: Background: The majority of osteogenesis imperfecta (OI) cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. Patients with OI may have blue sclerae, dentinogenesis imperfecta, and growth deficiency. Zoledronic acid is a third-generation bisphosphonate which was reported to inhibit osteoclast-mediated bone resorption, improve bone density, and reduce incidence of fractures. Aim: To describe the radiographic features of cyclic Zoledronic acid administration on the growing skeleton in children with OI and to report the efficacy of Zoledronic acid on bone mineral density. Methods: We retrospectively reviewed the radiographs of 11 children treated with Zoledronic acid. The age of these children ranged from one to 13 years. Zoledronic acid was administrated intravenously at 6 months intervals at the Pediatric Endocrinology Day Medical Unit, King Faisal Specialist Hospital and Research Centre, and Security Forces Hospital, Riyadh, Kingdom of Saudi Arabia for 2 years. Results: During the course of treatment, a gradual increase in bone density was observed. The baseline mean lumbar BMDz score was -4.9SD + 1.3, which improved to a mean score of -2.7SD + 1.1, and a mean whole body BMDz score was -2SD +1.2 and improved to a mean score of -1.1SD + 1.3 by the end of therapy. Post treatment, there were multiple sclerotic metaphyseal bands seen in all children in the long bones paralleling to the growth plates and corresponding to the number of treatment cycles. Conclusion: Intravenous Zoledronic acid in children with osteogenesis imperfecta improved the bone mineral density and resulted in permanent sclerotic metaphyseal bands.

Abstract: Postoperative acute kidney injury (AKI) is a common complication of major gastrointestinal surgery with an impact on short- and long-term survival. No validated system for risk stratification exists for this patient group. This study aimed to validate externally a prognostic model for AKI after major gastrointestinal surgery in two multicentre cohort studies. Methods The Outcomes After Kidney injury in Surgery (OAKS) prognostic model was developed to predict risk of AKI in the 7 days after surgery using six routine datapoints (age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker). Validation was performed within two independent cohorts: a prospective multicentre, international study (‘IMAGINE’) of patients undergoing elective colorectal surgery (2018); and a retrospective regional cohort study (‘Tayside’) in major abdominal surgery (2011–2015). Multivariable logistic regression was used to predict risk of AKI, with multiple imputation used to account for data missing at random. Prognostic accuracy was assessed for patients at high risk (greater than 20 per cent) of postoperative AKI. Results In the validation cohorts, 12.9 per cent of patients (661 of 5106) in IMAGINE and 14.7 per cent (106 of 719 patients) in Tayside developed 7-day postoperative AKI. Using the OAKS model, 558 patients (9.6 per cent) were classified as high risk. Less than 10 per cent of patients classified as low-risk developed AKI in either cohort (negative predictive value greater than 0.9). Upon external validation, the OAKS model retained an area under the receiver operating characteristic (AUC) curve of range 0.655–0.681 (Tayside 95 per cent c.i. 0.596 to 0.714; IMAGINE 95 per cent c.i. 0.659 to 0.703), sensitivity values range 0.323–0.352 (IMAGINE 95 per cent c.i. 0.281 to 0.368; Tayside 95 per cent c.i. 0.253 to 0.461), and specificity range 0.881–0.890 (Tayside 95 per cent c.i. 0.853 to 0.905; IMAGINE 95 per cent c.i. 0.881 to 0.899). Conclusion The OAKS prognostic model can identify patients who are not at high risk of postoperative AKI after gastrointestinal surgery with high specificity. Presented to Association of Surgeons in Training (ASiT) International Conference 2018 (Edinburgh, UK), European Society of Coloproctology (ESCP) International Conference 2018 (Nice, France), SARS (Society of Academic and Research Surgery) 2020 (Virtual, UK).

Abstract: The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular diagnosis is thought to influence acute management. Studies on the clinical utility of RES have been largely limited to outbred populations. Methods Here, we describe our experience with rapid exome sequencing (RES) in a highly consanguineous population. Clinical settings included intensive care units, prenatal cases approaching the legal cutoff for termination, and urgent transplant decisions. Results A positive molecular finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 80 of 189 cases (42%), while 15 (8%) and 94 (50%) received ambiguous (variant of uncertain significance (VUS)) and negative results, respectively. The consanguineous nature of the study population gave us an opportunity to observe highly unusual and severe phenotypic expressions of previously reported genes. Clinical utility was observed in nearly all (79/80) cases with positive molecular findings and included management decisions, prognostication, and reproductive counseling. Reproductive counseling is a particularly important utility in this population where the overwhelming majority (86%) of identified variants are autosomal recessive, which are more actionable in this regard than the de novo variants typically reported by RES elsewhere. Indeed, our cost-effectiveness analysis shows compelling cost savings in the study population. Conclusions This work expands the diversity of environments in which RES has a demonstrable clinical utility.

Abstract: Pseudohypoaldosteronism (PHA) is a condition in which serum aldosterone level is normal or elevated but its action is deficient. Objective This study describes the molecular genetics of PHA 1b in the highly consanguineous population of 2 Arabian Gulf countries, Saudi Arabia and Oman. Methods This study enrolled 22 patients from 13 unrelated families (2 families with 5 patients from Oman and 11 families with 17 patients from Saudi Arabia). All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension. We isolated DNA from peripheral blood and PCR-sequenced all exons and exon-intron boundaries of SCNN1A and, if negative, SCNN1B and SCNN1G using the Dideoxy Chain termination method. Results We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G. All of these mutations were novel except one. SCNN1A mutations were: c.1496A & gt;G, p.Q499R (novel) in 1 patient; c.1453C & gt;T, p.Q485X (novel) in 1 patient; c.1322_1322delA, p.N441Tfs*41 (novel) in 2 patients of 1 family; c.876 + 2 delGAGT (novel) in 3 patients of 1 family; c.203_204 delTC, p.I68Tfs*76 (a known mutation) in 8 patients of 5 families; and whole SCNN1A gene deletion (novel) in 2 patients of 2 families. In addition, a nonsense SCNN1B mutation c.1694C & gt;A, p.S565X (novel) was found in 3 siblings from 1 Omani family, and an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family. Conclusion We characterized a unique genotype of PHA 1b with several novel gene structure–disrupting mutations in SCNN1A, SCNN1B, and SCNN1G in a highly consanguineous population.

Abstract: The growth hormone (GH) cascade and the remarkable advances over the past four decades in our knowledge of its components are considered. It is now over 40 years since human pituitary GH (pit-hGH) was purified and the first GH-deficient patient, a 17-year-old male, was successfully treated with pit-hGH. However, the shortage of pit-hGH limited its use and the dose, the biopotency of preparations varied, strict criteria of GH deficiency (GHD) were used for patient selection including peak plasma immunoreactive GH levels after provocative stimuli of 〈 3.5–5 ng/ml, treatment was not infrequently interrupted, the mean age for initiating treatment was often late in childhood (12–13 years) and the growth deficiency severe (height –4 to –6 SDS), and finally pit-hGH therapy was often discontinued when girls attained a height of 5′ and boys 5′5′′. Nonetheless, the effects of pit-hGH were dramatic; the final height SDS increased in isolated GHD to about –2 SDS in boys and –2.5 to –3.0 SDS in girls, and in multiple pituitary hormone deficiencies to between –1 and –2 SDS. Between 1962 and 1985 when the Creutzfeldt-Jakob disease crisis struck, the number of GH-deficient patients treated with pit-hGH increased from about 150 to over 3,000. The advent of biosynthetic GH (rhGH) and its availability to treat large numbers of idiopathic GH-deficient children (the minimum prevalence rate of which in the USA and UK is between 1 in 3,400 and 4,000) dramatically changed this picture in 1985. It is estimated that more than 60,000 patients have been or are now on treatment. With rhGH treatment the attained mean adult height SDS is now about –1.0, and in our experience with the treatment of patients under 4 years of age, final height may exceed the target height. It is now recognized that (a) the replacement dose of rhGH ranges from 0.175 to 0.35 mg/kg/week and should be individualized; (b) dividing this dose into 6 or 7 daily subcutaneous injections is more effective than giving the same total dose in three weekly portions, and (c) final height correlates significantly with pretreatment chronologic age, height SDS and predicted adult height, duration of therapy, birth length, in some studies height SDS and age at start of puberty, weight, and serum GHBP (an indicator of GH receptor mass). Early recognition of GHD is essential for an optimal height outcome. rhGH treatment should not be delayed in children with documented GHD; the greater the height deficit, the lower the probability that target height will be reached. GHD needs to be detected earlier in children with organic hypopituitarism whether due to a developmental defect, neoplasm, radiation, head trauma, or a CNS infection. Early rhGH therapy in neonatal hypopituitarism has resulted in excellent growth responses. As the height prognosis in isolated GHD is not as good (especially in girls) as in GHD associated with gonadotropin deficiency, the use of LHRH agonists to delay puberty or potent aromatase inhibitors to delay skeletal maturation should be considered in selected patients with isolated GHD. When the growth response to rhGH is less than predicted, one must consider: (a) poor compliance; (b) improper preparation of rhGH for administration or faulty injection techniques; (c) the timing of administration; (d) the dose of glucocorticoid in the ACTH-deficient patient; (e) occult hypothyroidism; (f) inadequate nutrition; (g) a chronic illness; (h) neutralizing antibodies to rhGH, and (i) the wrong diagnosis. The major cause of mortality (unrelated to Creutzfeldt-Jakob disease or a CNS neoplasm) is adrenal crisis and hypoglycemia in children with both GH and ACTH deficiency. Major adverse effects of rhGH treatment in children are uncommon and include idiopathic intracranial hypertension, slipped capital femoral epiphysis, and acute pancreatitis. The rhGH is not an added risk for leukemia in the US and Europe in the absence of coexisting risk factors, nor is there a higher risk of recurrence of brain or other neoplasms. Even with the striking effects of rhGH on growth and body composition, there are important quality-of-life issues that need to be addressed. Finally, we need to consider the consequences of discontinuing treatment after adult height is achieved. We interpret the current weight of evidence to favor continued rhGH treatment at a much reduced dose and schedule of administration, with or without an interval of interrupted therapy (the latter has been useful in enabling the adolescent to make a personal judgment). Long-term monitoring including the determination of serial serum IGF-I levels is essential, for example, that the serum IGF-I does not exceed the normal range for age. The potential risk of excessive IGF-I on the growth of mutated cells merits vigilance. In any event, all GH-deficient patients should be reassessed for the presence of GHD as 25–65% of isolated GH-deficient patients have normal GH responses to provocative stimuli on retesting in adolescence and adulthood. New approaches to the treatment of GHD are discussed.