Efficacy and safety of burosumab compared with conventional therapy in patients with X-linked hypophosphatemia: A systematic review

ABSTRACT Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: −1.46, 95% confidence interval [CI]: −1.76 to −1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.

Clinical profile of insulinoma: analysis from a tertiary care referral center in India.

Objective To describe the clinical presentation, localization techniques, surgical procedures and outcome in patients with insulinoma. Methods Retrospective analysis of case records of patients diagnosed with insulinoma between January 1993 and June 2009 at a tertiary-care hospital was done. Seventeen patients underwent diagnostic 72-h fast. The sensitivity of computed tomography (CT) of pancreas was judged using intraoperative findings as the gold standard. Results Twenty-six patients (19 women) with mean age 42.2 years (median age 39.5 years) with biochemical/ imaging evidence of insulinoma were included. All patients who underwent 72-h fast developed symptomatic hypoglycemia within 48 h. The sensitivity and positive predictive value (PPV) of CT of pancreas was 68.4% and 92.8%, respectively. Twenty patients underwent surgery, of whom four were operated on without preoperative localization. Four patients had recurrence of symptoms. Of the six patients who were not operated upon, the lesion was localized in four. Conclusion This audit shows that all patients with insulinoma develop hypoglycemia within 48 h of fasting. CT of pancreas localizes the lesion in two thirds of cases and would be a useful initial investigation in patients with suspected insulinoma.

Prepubertal gynecomastia a rare complication of growth hormone therapy.

We report a case of prepubertal gynecomastia diagnosed during growth hormone (GH) treatment. In our patient gynecomastia appeared 6 months after GH was started. This condition appears to be self-limited and benign. In our patient gynaecomastia resolved on its own.

Primary hyperparathyroidism in children and adolescents.

Objective. Primary hyperparathyroidism (PHPT) in children and adolescents is a rare condition. Awareness should improve in order to lower threshold for screening and allow intervention before serious and permanent sequelac occur. Methods. A retrospective analysis of 15 children and adolescents with PHPT (age <20 yr) seen in our clinic between 1993 and 2006. Results. Mean age of patients was 17.73 yr (Range - 13-20, Male-3: Female-12). Average duration of symptoms was 18.87 (range: 0-48) mo. Clinical features at presentation included bone pain (86.67%), proximal myopathy (46.67%), bony deformities (53.33%), fractures (60%), palpable osteitis fibrosa cystica (33.3%), renal calculi (40%), palpable neck swelling (13.3%) and acute pancreatitis (6.67%). None had positive family history or features suggestive of multiple endocrine neoplasia (MEN). After biochemical confirmation, tumor was localised in all prior to surgery. Histopathology confirmed adenoma in all cases. Post-operative hungry bone syndrome occurred in 33.3%. Conclusion. PHPT is more common in females. Presentation of the disease is similar to their adult counterparts except for more severe bone disease and less severe renal disease. MEN and familial non-MEN PHPT do not constitute a major cause of pediatric PHPT as against to worldwide data. The incidence of hyperplasia as a cause of PHPT is rare in our pediatric population.

Pheochromocytoma in children and adolescents.

Eleven subjects aged <20 yr with histologically proven pheochromocytoma between 1987 and 2006 were analyzed. Family history was present in 18%. In 2 patients, pheochromocytoma was part of VHL and in one it was associated with MEN 2. Twenty four hour urine VMA level was elevated in 100% and metanephrine level in 73%. CT/ MRI were showing the tumor in all. Prazosin extended release tablets (maximum 30 mg/day) were used in 73% and doxazosin (maximum 12 mg/ day) in 27%. Intraoperative BP fluctuations were seen in 27%. All were biochemically cured after surgery. Preoperative á blockade with extended release prazosin and doxazosin were effective in controlling perioperative BP fluctuations. Hence these drugs can be used in children and adolescents without fear of postoperative hypotension.

Clinical profile of adrenoleukodysrophy.

X-linked Adrenoleukodystrophy (ALD) is the most common of the peroxisomal disorder and is associated with functional defect of the very long chain fatty acid (VLCFA) oxidation leading to the accumulation of VLCFA in the white matter and adrenal cortex. Retrospective evaluation of medical records of ALD patients were carried out. In all the 5 patients the duration of the symptoms varied from 1-7 years. Most of them presented with Addisonian crisis (4/5) and hyperpigmentation (5/5), white half of them (3/5) had neurological symptoms. All patients had biochemical evidence of the adrenal insufficiency. All siblings of patients should be screened for the possibility of ALD with VLCFA.

Primary hyperparathyroidism: A clinicopathological experience.

Background: Parathyroid neoplasms form a small percentage of head and neck neoplasms. Primary hyperparathyroidism is caused by parathyroid adenomas, hyperplasia or, rarely, a carcinoma. Materials and Methods: This is a retrospective study of 48 parathyroidectomies received in the Department of Pathology of a major teaching hospital over a period of 10 years. Clinical, biochemical and radiological details were retrieved from medical records. Information regarding routine gross and microscopic examination findings (including frozen section and paraffin sections) was retrieved from departmental records. Results: We had 43 adenomas, three hyperplasias and two carcinomas. The most common age group was 21-30 years. The female:male ratio was 2.5:1. Most patients presented with skeletal manifestations. The pre-operative diagnosis was assisted by ultrasonography in 11 cases, computerized tomography of the neck in 10 cases and sestamibi scans in three cases. Intra-operative parathormone monitoring was performed in one case of adenoma. Frozen section was requested in 28 of 48 cases. There was a discrepancy between frozen section diagnosis and paraffin section diagnosis in two cases. Conclusion: Histopathologic diagnosis is an important guide to decide the type of surgical management. Although pathologic features of parathyroid carcinoma are diagnostically reliable, those of the more commonly encountered lesions of adenoma and hyperplasia may be overlapping and, therefore, indistinctive, more so if only a single gland is available for examination. Because parathyroid lesions are only occasionally encountered by the surgical pathologist, awareness of the spectrum of histologic features along with knowledge of recent trends in diagnosis and surgical management are important.

Prevalence of carbohydrate intolerance of varying degrees in pregnant females in western India (Maharashtra)--a hospital-based study.

This was a study to assess the prevalence of carbohydrate intolerance of varying degrees in pregnant females registered at a tertiary care hospital in western India. Prospective screening of pregnant females was carried out (2005-2007) with oral glucose tolerance test (OGTT) based on American Diabetes Association (ADA) 2005 criteria. One thousand two hundred and twenty-five women with mean age 25.4 years (18-40) of which average risk and high risk were found in 408 (33.3%) and 817 (66.7%) cases respectively. Gestational diabetes mellitus (GDM) was diagnosed in 94 cases (7.7%) while 171(13.9%) had impaired gestational glucose tolerance (IGGT) ie, one value abnormal on 3-hour OGTT, while the combined prevalence of GDM and IGGT was 21.6% (n=265). Prevalence of GDM and IGGT was more in patients with age more than 30 years compared to younger females [GDM: 17.6% versus 6.8% (p=0.00); IGGT : 21% versus 13.4% (p=0.00)]; and in those with body mass index (BMI) >23 compared to BMI<23[GDM: 11.4% versus 8.3% (p=0.0374); IGGT : 22.8% versus 10.5 % (p= 0.0028)]. As the maternal age [odd's ratio {OR} :1.32; confidence interval {CI} (1.20 - 1.55) (p=0.000)] and prepregnancy BMI [OR:1.43; CI (0.65 - 3.14), (p=0.0316)] increases; prevalence of GDM, IGGT increased. There was a non-significant trend of increased GDM and IGGT in patients with family history of diabetes, bad obstetric history, history of macrosomic baby and decreased physical activity. So it is concluded GDM and IGGT affects one-fifth of pregnant females from western India on selective screening with increasing maternal age and BMI being significant risk factors associated.

Thyroid disorders in childhood and adolescence.

Thyroid disorders are common endocrine problem encountered in the paediatric and adolescent age group. Amongst the functional thyroid disorders hypothyroidism is far more common than hyperthyroidism. Though simple goitre is common in this age group, nodular goitre and in particular solitary thyroid nodule are uncommon. Appropriate use of thyroid function test can delineate practically all thyroid disorders. Functional thyroid disorders lend themselves to effective treatment and monitoring strategies. The basic management principles remain similar to adults with thyroid dysfunction; experience in management of paediatric and adolescent thyroid disorders is particularly necessary to safeguard against long term detrimental effects of under-or overtreatment as it can have repercussion on the growth of the child. Prognosis in majority of the children tends to be good provided that timely and appropriate management is undertaken.