ACTION Teens Saudi Arabia: Perceptions, attitudes, motivators, and barriers among adolescents living with obesity, caregivers, and healthcare professionals in Saudi Arabia.

Obesity is predicted to affect approximately one-quarter of children/adolescents in Saudi Arabia by 2030, but there is limited evidence regarding the perceptions, attitudes, behaviours, and barriers to effective obesity care for adolescents living with obesity (ALwO), caregivers of ALwO, and healthcare professionals (HCPs). We report data from 500 ALwO (aged 12-<18 years), 500 caregivers, and 200 HCPs surveyed in Saudi Arabia as part of the global, cross-sectional ACTION Teens study (NCT05013359). Nearly all respondents recognized that obesity has a strong impact on overall health (ALwO 88%; caregivers 85%; HCPs 90%). Most ALwO and caregivers were aware of the ALwO's obesity status (95% and 99%, respectively) and worried about weight impacting the ALwO's future health (both ≥99%), and social media was their most commonly used source of weight-management information (60% and 53%, respectively). Among ALwO and caregivers who had discussed weight with an HCP in the past year, most experienced ≥1 negative feeling following their most recent discussion (61% and 59%, respectively). Although 81% of HCPs felt motivated to help their ALwO patients lose weight, 57% believed weight loss was completely the ALwO's responsibility (compared with only 37% of ALwO and 35% of caregivers). This may reflect the finding that only 24% of HCPs had received advanced training in obesity/weight management after medical school. Overall, while respondents had similar perceptions of the impact of obesity, we found HCPs' attitudes towards weight loss were not aligned with those of ALwO and caregivers, suggesting a need for improved communication and obesity education.

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.

25-Hydroxylase vitamin D deficiency in 27 Saudi Arabian subjects: a clinical and molecular report on CYP2R1 mutations.

Vitamin D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly, inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, to review cases with 25-hydroxylase deficiency and describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.

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.

Outcome of COVID19 in Patients With Osteogenesis Imperfecta: A Retrospective Multicenter Study in Saudi Arabia.

Background: Although genetic diseases are rare, children with such conditions who get infected with COVID-19 tend to have a severe illness requiring hospitalization. Osteogenesis imperfecta (OI) is a rare genetic disorder of collagen resulting in fractures and skeletal deformities. Kyphoscoliosis, restrictive lung disease, and pneumonia worsen the prognosis of patients with OI. The use of bisphosphonate improves bone mineral density (BMD) and reduces fractures in OI. There is no literature describing the impact of COVID-19 in patients with OI. Methodology: A retrospective multi-center study was performed in three hospitals in Jeddah and Riyadh, Saudi Arabia, from March 1st, 2020, until August 31st, 2021, aiming to evaluate the outcome of COVID-19 in patients with OI. Demographics, vaccination status, underlying kyphoscoliosis, functional status, use of bisphosphonate, BMD, and COVID-19 severity, and course were recorded for all patients. Results: Twelve cases of confirmed COVID-19 were identified among 146 patients with OI. 9 (75%) of patients were less than 18 years, 6 (50%) were male, 5 (41%) had kyphoscoliosis, and 5 (41%) were wheelchair-bound. 6 (50%) received bisphosphonate, and 7(58%) had normal BMD. All patients had mild disease and did not require hospitalization. None of OI the patients with COVID-19 were fully vaccinated before the infection, and some were ineligible for vaccination. Conclusion: Patients with OI and COVID-19 in our study recovered without complications, unlike patients with other genetic diseases. Young age and mild illness contributed to the favorable outcome. Half of the patients received bisphosphonate and had normal BMD.

A high rate of novel CYP11B1 mutations in Saudi Arabia.

Despite ethnic variation, 11 ß-hydroxylase deficiency (11ß-OHD) has generally been considered the second most common subtype of congenital adrenal hyperplasia (CAH). We report a high rate of novel mutations in this gene (CYP11B1) in patients from Saudi Arabia. We studied 16 patients with 11ß-OHD from 8 unrelated families. DNA was isolated from peripheral blood. The 9 exons and exon-intron boundaries of CYP11B1 were PCR-amplified and directly sequenced. The novel mutations were functionally characterized using subcloning, in vitro mutagenesis, cell transfection and 11-deoxycortisol: cortisol conversion assays. Six mutations were found in these 8 unrelated families. Three of these mutations are completely novel and two have just been recently described as novel mutations from the same population. These include a single nucleotide insertion mutation in codon 18 (c.53_54insT) leading to frameshift and truncation in 4 siblings, a novel mutation (c.1343G>C, p.R448P) in 3 unrelated families, a novel mutation (c.1394A>T, p.H465L) in 2 siblings, a novel mutation (c.617G>T, p.G206V) in 1 patient, and a recently described non-sense novel mutation (c.780G>A, p.W260X) in another patient. Out of the 6 mutations described in this report, only one mutation (p.Q356X) was reported previously. In vitro functional testing of the 3 missense and nonsense novel mutations revealed complete loss of the 11 hydroxylase activity. We conclude that 11 ß-OHD in Saudi Arabia has a unique genotype with a high rate of novel mutations. The novel p. R448P mutation is the most common mutation in this highly inbred population.

Lethal digenic mutations in the K+ channels Kir4.1 (KCNJ10) and SLACK (KCNT1) associated with severe-disabling seizures and neurodevelopmental delay.

A 2-yr-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia, and tonic-clonic seizures that caused the death of the patient. Targeted and whole exome sequencing revealed two heterozygous missense variants: a novel mutation in the KCNJ10 gene that encodes for the inward-rectifying K+ channel Kir4.1 and another previously characterized mutation in KCNT1 that encodes for the Na+-activated K+ channel known as Slo2.2 or SLACK. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4.1 mutation. The mutant and wild-type KCNJ10 constructs were generated and heterologously expressed in Xenopus laevis oocytes, and whole cell K+ currents were measured using the two-electrode voltage-clamp technique. The KCNJ10 mutation c.652C>T resulted in a p.L218F substitution at a highly conserved residue site. Wild-type KCNJ10 expression yielded robust Kir current, whereas currents from oocytes expressing the mutation were reduced, remarkably. Western Blot analysis revealed reduced protein expression by the mutation. Kir5.1 subunits display selective heteromultimerization with Kir4.1 constituting channels with unique kinetics. The effect of the mutation on Kir4.1/5.1 channel activity was twofold: a reduction in current amplitudes and an increase in the pH-dependent inhibition. We thus report a novel loss-of-function mutation in Kir4.1 found in a patient with a coexisting mutation in SLACK channels that results in a fatal disease.NEW & NOTEWORTHY We present and characterize a novel mutation in KCNJ10 Unlike previously reported EAST/SeSAME patients, our patient was heterozygous, and contrary to previous studies, mimicking the heterozygous state by coexpression resulted in loss of channel function. We report in the same patient co-occurrence of a KCNT1 mutation resulting in a more severe phenotype. This study provides new insights into the phenotypic spectrum and to the genotype-phenotype correlations associated with EAST/SeSAME and MMFSI.

Clinical, Endocrine, and Molecular Genetic Analysis of a Large Cohort of Saudi Arabian Patients with Laron Syndrome.

BACKGROUND/AIMS: Laron syndrome (LS) is an autosomal recessive disease characterized by marked short stature and very low serum IGF-1 and IGFBP-3 levels. This study assessed the clinical and endocrine features alongside determining the growth hormone receptor gene (GHR) mutation in Saudi Arabian patients with LS in order to establish whether or not a genotype/phenotype correlation is evident in this large cohort. SUBJECTS AND METHODS: A total of 40 Saudi Arabian patients with a suspected diagnosis of LS were recruited and subjected to a full clinical and endocrine investigation together with direct sequencing of the coding regions of the GHR gene. RESULTS: GHR mutations were identified in 34 patients from 22 separate nuclear families. All 34 molecularly confirmed patients had the typical clinical and endocrinological manifestations of LS. Eleven different mutations (9 previously unreported) were detected in this cohort of patients, all inherited in an autosomal recessive homozygous form. No genotype/phenotype correlation was apparent. CONCLUSION: The identification of pathogenic mutations causing LS will be of tremendous use for the molecular diagnosis of patients in Saudi Arabia and the region in general, with respect to prevention of this disease in the forms of future carrier testing, prenatal testing, premarital screening and preimplantation genetic diagnosis.

Divergent gender identity in three siblings with 46XX karyotype and severely virilizing congenital adrenal hyperplasia caused by a novel CYP11B1 mutation.

OBJECTIVE: To describe conflicting gender identities in three karyotypically female siblings with congenital adrenal hyperplasia (CAH) caused by a novel mutation in the CYP11B1 gene, who were assigned as males at birth and followed up to adulthood. METHODS: We present 3 siblings (16, 14 and 10 years old) who were born with severe genital virilization and raised as males. Clinical examination showed Prader IV to V external genitalia with a stretched penile length of 7 to 11 cm. Adrenocorticotrophic hormone (ACTH) stimulation test showed a stimulated 11 deoxycortisol (11DOC) level of 12,300-18,700 µg/L (normal 0-5 µg/L). Their karyotypes were 46 XX, and they had normal-sized uterus and ovaries on pelvic ultrasound. DNA was isolated from peripheral leukocytes, and polymerase chain reaction (PCR) and direct sequencing revealed a novel CYP11B1 mutation. This mutation leads to a c.53_54 T insertion (c.53_54insT) with frameshift and truncation at c.115 (codon 39) of CYP11B1. RESULTS: Psychological evaluation of the oldest sibling suggested a female gender identity, and she declared herself as female, and female sex was re-assigned after 1 year of psychosocial adjustment. Psychological assessment for the 2 younger siblings and a fourth 46XY sibling with the same condition revealed male gender identities, and they continued their lives as males without significant difficulties. CONCLUSION: Divergent gender identity was observed in three severely masculinized 46XX siblings with CAH who carried the same CYP11B1 mutation and had comparable postnatal and probably prenatal androgen exposure and environmental circumstances. These cases suggest that the basis of gender identity is more complex than chromosomal, biochemical, and genetic constitution.