Case report: familial hypocalciuric hypercalcemia.

Background: Familial hypocalciuric hypercalcemia (FHH) is a hypercalcemic syndrome that is usually characterized by uncomplicated hypercalcemia and normal longevity. The inheritance pattern is autosomal dominant with high penetrance, and it affects both men and women equally. FHH is caused by mutations that disturb the normal functioning of the calcium-sensing receptor (CaSR) gene. This causes a general lack of sensitivity to calcium, eventually leading to hypercalcemia and low calcium levels in the urine. Case Description: We report a case of a healthy 24-year-old female with longstanding hypercalcemia and a family history indicating asymptomatic hypercalcemia. The patient was also asymptomatic and had no significant past medical or surgical history. Laboratory investigations and the genetic study revealed findings suggestive of FHH subtype 1. Conclusions: The phenotype of FHH is normal, and symptoms of hypercalcemia are usually not present. Patients with FHH and hypoparathyroidism have lower calcium clearance than controls with hypoparathyroidism. This shows that relative hypocalciuria in FHH is not caused by hyperparathyroidism. Since calcium does not appropriately suppress or affect the parathyroid glands in FHH, this means that FHH is a disorder of abnormal transport of extracellular calcium and/or response to it in at least two organs, the parathyroid gland and the kidney. It is quite similar to primary hyperparathyroidism (pHPT) biochemically hence it is important to differentiate this condition from pHPT and hypercalcemia caused by other diseases to avoid any unnecessary surgical or medical intervention.

Modern approaches to the management of homozygous familial hypercholesterolemia in the Middle East and North Africa.

Homozygous familial hypercholesterolaemia (HoFH) is a severe form of FH in which inheritance of two defective or null mutations in genes associated with metabolism of low-density lipoprotein cholesterol (LDL-C) results in extremely high LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) and mortality. Treatment of HoFH comprises a multi-modal approach of statins, ezetimibe, lipoprotein apheresis; and inhibitors of proprotein convertase subtilisin/kexin type, angiopoietin-like protein 3 (ANGPTL3) and microsomal triglyceride transfer protein. These treatments are generally costly, and patients also often require treatment for ASCVD consequent to HoFH. Therefore, in the interests of both economics and preservation of life, disease prevention via genetic screening and counselling is rapidly becoming a key element in the overall management of HoFH. Guidelines are available to assist diagnosis and treatment of HoFH; however, while advancements have been made in the management of the disease, there has been little systematic attention paid to prevention. Additionally, the Middle East/North Africa (MENA) region has a higher prevalence of HoFH than most other regions - chiefly due to consanguinity. This has led to the establishment of regional lipid clinics and awareness programs that have thrown education and awareness of HoFH into sharp focus. Incorporation of principles of prevention, education, awareness, and data from real-world use of existing therapeutics will significantly enhance the effectiveness of future guidelines for the management of HoFH, particularly in the MENA region.

Surgical management of neonatal severe hyperparathyroidism.

BACKGROUND: Neonatal severe hyperparathyroidism (NSHPT) is a rare disease that can be lethal. Most patients require parathyroidectomy. OBJECTIVE: Report experience in managing this severe disease. DESIGN: Retrospective chart review of case series. SETTING: Tertiary health care center. PATIENTS AND METHODS: We reviewed data on patients managed for NSHPT from June 2001 to January 2023. Demographic, clinical, and follow-up data were collected, and descriptive data were generated. MAIN OUTCOME MEASURES: Pre- and postoperative levels of parathyroid hormone (PTH) and serum calcium, and effect of autotransplantation. SAMPLE SIZE: 19. RESULTS: The 13 males and 6 females had a a mean age of 46 days at referral. The mean preoperative parathyroid hormone (PTH) and serum calcium levels were 996 ng/L and 4.54 mmol/L, respectively. Twelve patients underwent ultrasonography preoperatively. Of these, six had prominent glands, while no glands were seen in the other six. A Sestamibi scan was done for 15 patients, of which nine showed negative results and six showed positive results, with three glands observed in the neck and three in the sublingual area. Nineteen patients underwent renal ultrasonography, with nine showing nephrocalcinosis. The mean age at surgery was 5.2 months. Total parathyroidectomy (four glands) was performed in 17 patients, and 15 underwent concurrent auto-transplantation. One patient had three glands removed, in addition to auto-transplantation. Another underwent single gland excision as a redo-surgery after previous surgery elsewhere. The mean postoperative follow-up duration was 6 years. The mean postoperative PTH and calcium levels were 25 ng/L and 1.64 mmol/L, respectively. Ultimately, all the patients were required to initiate calcium and vitamin D supplements, except for two patients who had undergone auto-transplantation. Molecular genetic screening of the calcium-sensing receptor gene reported likely pathogenic/pathogenic mutations in 16 of 19 patients (13 were homozygous, two were heterozygous, one was negative, and data was unavailable for the remaining three patients). CONCLUSIONS: Surgical treatment of NSHPT is effective. Preoperative radiological localization studies did not impact the treatment plan. Auto-transplantation proved ineffective in maintaining independence from medical supplements. LIMITATIONS: The retrospective nature of the study may imply inaccuracybut since the data are gathered from electronic medical records, we believe it is highly accurate. The small sample size limits generalizability.

Munchausen syndrome by proxy: a case report.

BACKGROUND: Inappropriately high levels of insulin secretion can cause the potentially fatal condition of persistent hyperinsulinemic hypoglycemia of infancy. Our paper focuses on another cause of severe hypoglycemia, which can be easily missed. CASE PRESENTATION: An 18-month-old Saudi female was referred to our hospital for further investigation and management of her recurrent hypoglycemic attacks as a case of persistent hyperinsulinemic hypoglycemia of infancy. During admission, we noticed multiple red flags from the history; the mother was insisting on a pancreatectomy, rather than going for a positron emission tomography scan, and most importantly, all hypoglycemic attacks occurred while the mother was around. Consequently, after further investigation, the case was diagnosed as a caregiver-fabricated illness, and the case was referred to the Child Protection Center. CONCLUSIONS: One must have a high index of suspicion to diagnose caregiver-fabricated illness. Physicians should be more attentive to prevent such a disease, which could eventually become lethal if left unnoticed.

Management and clinical outcomes of patients with homozygous familial hypercholesteremia in Saudi Arabia.

We report the incidence, patient characteristic with clinical outcomes in patients with homozygous familial hypercholesterolemia (HoFH) in Saudi Arabia. This is a retrospective and prospective, single center study which included 37 patients 14 years and older enrolled and followed up between 2018-2021 for three years. 46% were females, 78% were offspring of consanguineous marriage. LDLR mutation was in 78% and LDL-C/LDLRAP in 3% of patients. Mean LDL-C at the first presentation was 14.2±3.7 mmol/L, average Dutch lipid score was 20.9±6.24. LDL apheresis was performed on 70% of patients. Most patients were on ezetimibe (92%), high-dose statins ( 84%) and  PCSK9 inhibitors (32%). 48.6% had aortic stenosis, out of which 30% had severe aortic stenosis. Ten underwent aortic valve surgery (5 mechanical valve, 3 Ross procedure, 1 aortic valve repair, 1 bioprosthetic valve) and one had transcatheter aortic valve implantation (TAVI). Coronary artery bypass surgery (CABG) was performed on 32% and percutaneous intervention (PCI) on 11% of patients. HoFH patients have complex diseases with high morbidity and mortality, and benefit from a highly specialized multidisciplinary clinic to address their clinical needs. Although there are several therapeutic agents on the horizon, early diagnosis, and treatment of HoFH remain critical to optimize patient outcomes.

CYP3A4 Mutation Causes Vitamin D-Dependent Rickets Type 3: A Case Report in Saudi Arabia.

Rickets is a childhood disorder of vitamin D deficiency that is characterized by growth retardation and impairment in skeletal mineralization. Vitamin D deficiency is usually due to decreased dietary vitamin D intake, decreased sunlight exposure, or genetic defects. A recurrent gain-of-function missense mutation (p.I301T) in the gene encoding CYP3A4 has been identified as a cause of excessive inactivation of vitamin D metabolites that causes vitamin D-dependent rickets type 3 (VDDR3). We hereby report a case of a six-year-old girl with poor growth and bone deformities, such as genu valgum. In addition, the patient has a strong family history of short stature and bone deformities. She continues to receive multidisciplinary care, and the finding of a heterozygous missense variant in CYP3A4: c.902 T > C; p.Ile301Thr in the CYP3A4 gene confirms the diagnosis of VDDR3. To our knowledge, this is the first case to be reported in Saudi Arabia and the fourth case in the literature. Our findings highlight the importance of vitamin D in those with high activity in CYP3A4 to maintain vitamin D hemostasis, and we need to reach optimal doses to help them maintain their biochemical and radiological finding within the normal range.

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.

Identification and Treatment of Patients with Homozygous Familial Hypercholesterolaemia: Information and Recommendations from a Middle East Advisory Panel.

We present clinical practice guidelines for the diagnosis and treatment of homozygous familial hypercholesterolaemia (HoFH) in the Middle East region. While guidelines are broadly applicable in Europe, in the Middle East we experience a range of confounding factors that complicate disease management to a point whereby the European guidance cannot be applied without significant modification. Specifically, for disease prevalence, the Middle East region has an established epidemic of diabetes and metabolic syndrome that can complicate treatment and mask a clinical diagnosis of HoFH. We have also a high incidence of consanguineous marriages, which increase the risk of transmission of recessive and homozygous genetic disorders. This risk is further augmented in autosomal dominant disorders such as familial hypercholesterolaemia (FH), in which a range of defective genes can be transmitted, all of which contribute to the phenotypic expression of the disease. In terms of treatment, we do not have access to lipoprotein apheresis on the same scale as in Europe, and there remains a significant reliance on statins, ezetimibe and the older plasma exchange methods. Additionally, we do not have widespread access to anti-apolipoprotein B therapies and microsomal transfer protein inhibitors. In order to adapt existing global guidance documents on HoFH to the Middle East region, we convened a panel of experts from Oman, Saudi Arabia, UAE, Iran and Bahrain to draft a regional guidance document for HoFH. We also included selected experts from outside the region. This panel statement will form the foundation of a detailed appraisal of the current FH management in the Middle Eastern population and thereby provide a suitable set of guidelines tailored for the region.

Surgical management of severe neonatal hyperparathyroidism: one center's experience.

INTRODUCTION: Neonatal severe hyperparathyroidism (NSHPT) is a rare disease that presents early with severe hypercalcemia. We reviewed our experience with NSHPT management at a tertiary-care institution. METHODS: A retrospective chart review was conducted for patients managed for NSHPT over the last 10 years. Demographic, clinical, and follow-up data were collected, and descriptive data were generated. RESULTS: Five patients were managed for NSHPT, 3 females and 2 males, with a mean age of 18 days at presentation. The mean preoperative parathyroid hormone and calcium levels were 3607 ng/L and 3.84 mmol/L, respectively. Preoperative parathyroid gland localization tests were all negative. All patients had a total parathyroidectomy and autotransplantation at a mean age of 65 days, with a mean follow-up of 5.5 years. One patient had normal parathyroid hormone and normal calcium levels 9.5 years after surgery without medication. One patient had normal levels without medication for 2 years then needed calcium and vitamin D supplements thereafter (8.5 years postoperatively). Three patients are still on calcium and vitamin D supplementation 5.5 years, 3.5 years, and 8 months, respectively, after surgery. CONCLUSIONS: Neonatal severe hyperparathyroidism is managed effectively with total parathyroidectomy. Preoperative localization studies are not helpful, and autotransplantation has a modest effect in our experience.

Persistent hyperinsulinaemic hypoglycaemia of infancy in 43 children: long-term clinical and surgical follow-up.

OBJECTIVE: To describe the clinical, surgical, biochemical, radiological and electrophysiological features of 43 Saudi children with persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) who have been followed since 1983. METHODS: Data from 43 patients were retrospectively analysed. PHHI was diagnosed on the basis of high intravenous glucose requirement, high insulin to glucose ratio, negative urinary ketones and normal tandem mass spectrometry. The patients were assessed radiologically by brain magnetic resonance imaging and/or computed tomography and electrophysiologically by brain stem auditory evoked potential, visual evoked response and electroencephalogram. Patients who failed medical therapy received near total pancreatectomy. RESULTS: The patients were severely hypoglycaemic and intolerant to fast. Hypoglycaemic convulsion was the most commonly presenting complaint. Eighteen patients were developmentally delayed and 14 of them had brain atrophy. All patients, except nine, did not respond to medical treatment and underwent surgery. Four pancreatectomized patients developed diabetes and two had malabsorption. One baby had 180 cm resection of gangrenous bowel most likely secondary to octreotide. No common bile duct injury was encountered. One patient was treated medically during childhood and developed diabetes and gained weight during adolescence. CONCLUSION: PHHI is a relatively common and serious disease among Saudi children. Early intervention is necessary to avoid neurological damage in patients who are severely hypoglycaemic and unresponsive to medical therapy. Surgically and probably medically treated patients are at a high risk of developing diabetes, which could be the natural outcome of this disease. Care and spending time during surgery to visualize the common bile duct help in avoiding its injury.

Continuous subcutaneous insulin infusion in type 1 diabetic Saudi children. A comparison with conventional insulin therapy.

OBJECTIVE: To assess the efficacy and effectiveness of continuous subcutaneous insulin infusion (CSII) therapy in type 1 diabetic Saudi children in comparison with conventional insulin (CI) therapy. METHODS: Continuous subcutaneous insulin infusion was initiated in 14 Saudi children with type 1 diabetes mellitus (T1DM) through insulin pump therapy between October 2002 and June 2004. All children were followed at the Diabetes Clinic, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. The patients were initially on CI therapy, which is usually defined as 2 or fewer insulin injections per day before shifting them to CSII. The patients were trained on carbohydrates counting and started on continuously basal insulin infusion aside from the meal and high blood glucose correction insulin boluses. RESULTS: The patients included in the study had T1DM for a mean duration of 6 years. The age of the children ranged from 4-18 years. They were followed on insulin pump therapy for a mean duration of 10 months. There was a significant reduction in hemoglobin A1c, mean blood glucose level, total insulin requirement, frequency of hypoglycemic episodes and frequency of diabetic ketoacidosis (DKA) events during CSII therapy. CONCLUSION: Continuous subcutaneous insulin infusion improved the glycemic control in diabetic Saudi children with decreased frequency of hypoglycemic episodes and DKA events. Long follow-up studies are needed to confirm these results.

The syndrome of septo-optic dysplasia in Saudi children.

OBJECTIVE: To describe the clinical, ophthalmological, endocrinological and radiological features of 10 Saudi children with the syndrome of septo-optic dysplasia and hypothalamic hypopituitarism. METHODS: All patients underwent complete ophthalmological and endocrinological evaluation at the Pediatric Endocrine Clinics, King Faisal Specialist Hospital and Research Center and King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia, from October 1999 through to May 2004. The hormonal evaluation included growth hormone, adrenocorticotrophic hormone, thyroid stimulating hormone, gonadotropin and anti diuretic hormone testing, and the neuroradiological assessment included brain magnetic resonance imaging or computed tomogram scanning, or both. RESULTS: The current age of patients ranged from 18- months to 5-years. The mean age of initial presentation for endocrine evaluation was 14-months. Hormonal studies indicated that all children had multiple pituitary hormone deficiencies (2 or more of the pituitary hormones were deficient). Ten children had growth hormone deficiency, 8 had thyroid stimulating hormone deficiency, 8 had adrenocorticotrophic hormone deficiency, 2 children were suspected to have gonadotropin deficiency and central diabetes insipidus was present in one patient. Pendular nystagmus and impaired vision were common initial signs. All children had bilateral optic nerve hypoplasia. Neuroradiologic findings were variable. Eight children had absent septum pellucidum, 3 had pituitary gland hypoplasia, 2 had pituitary stalk dysplasia (pituitary stalk was either attenuated or not visualized), 2 had absent corpus callosum and one had absent posterior pituitary high intensity signal. All patients were replaced with appropriate hormonal replacement therapy. Two male children had micropenis which responded to testosterone therapy. CONCLUSION: The syndrome of septo-optic dysplasia is commonly associated with hypothalamic hypopituitarism including anterior and posterior pituitary hormonal deficiencies. Early diagnosis of this syndrome is critical as the hormonal deficiencies can be life threatening.