Burosumab therapy in children with x-linked hypophosphatemia

BACKGROUND X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. METHODS In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. RESULTS The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets

Adolescent spinal pain: The pediatric orthopedist's point of view

AbstractIntroductionTen to twenty percent of persons experience spinal pain during growth. Causes are diverse in adolescents, and it is essential to determine etiology rapidly so as to guide optimal management.HypothesisIt is important for the pediatric orthopedist to understand the natural history of conditions inducing spinal pain.Material and methodsA retrospective study included 116 adolescents presenting with spinal pain at the Hôpital Nord (Marseille, France) between January 1, 2009 and January 1, 2014. Malignant tumoral etiologies were excluded. Mean patient age was 13.6 years. Risser ranged between >0 and <5. Interview and clinical examination (skin, spine, neurologic examination, general clinical examination) were systematic; depending on results, complementary examinations (imaging, biology, biopsy) were prescribed.ResultsThere were 32 cases of non-specific adolescent low back pain, 31 of lumbar or thoracolumbar scoliosis, 23 of spinal growth dystrophy (Scheuermann's disease), 13 of isthmic lysis, 5 of spondylolisthesis, 8 of transitional lumbosacral hinge abnormality, 2 of discal hernia, 1 of osteoid osteoma and 1 of eosinophil granuloma. Treatment was often non-operative when diagnosis was sufficiently early. In case of failure, surgery could generally be considered.DiscussionCorrectly indicated non-operative management or surgery changes the natural history of these pathologies. The aim of treatment is to resolve pain in adolescence, as it risks becoming chronic and disabling by adulthood.Level of evidenceIV

Continuous Subcutaneous Recombinant Parathyroid Hormone (1-34) Infusion in the management of childhood Hypoparathyroidism associated with Malabsorption

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Hypoparathyroidism associated with malabsorption can be particularly challenging to manage due to limited and erratic intestinal absorption of calcium and vitamin D analogues, resulting in episodes of hypo- or hypercalcaemia. We evaluated the role of continuous subcutaneous recombinant parathyroid hormone (rhPTH 1–34) infusion (CSPI) in children with hypoparathyroidism associated with intestinal malabsorption resistant to conventional therapy. &lt;b&gt;&lt;i&gt;Method:&lt;/i&gt;&lt;/b&gt; Four patients (8–13 years of age), with symptomatic hypocalcaemia resistant to conventional therapy, were started on CSPI (follow-up 3–8 years) in two paediatric endocrinology units in Europe. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Serum calcium normalized within 48 h of commencing treatment in all 4 patients. An average rhPTH 1–34 dose of 0.4 µg/kg/day resulted in a substantial reduction in symptomatic hypocalcaemia and hypo-/hypercalcaemia-related hospital admissions. An increased alkaline phosphatase activity was noted in the first 6 months on CSPI, indicating an increase in bone turnover. In 2 patients with elevated urinary calcium excretion before CSPI, this normalized in the first year on treatment. No significant side effects were noticed in the short or long term, with patient-reported preference of CSPI over conventional treatment. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; CSPI is a promising and effective treatment option for managing hypocalcaemia and hyperphosphataemia in children with hypoparathyroidism associated with intestinal malabsorption.</jats:p

Congenital imprinting disorders: EUCID.net - a network to decipher their aetiology and to improve the diagnostic and clinical care.

Imprinting disorders (IDs) are a group of eight rare but probably underdiagnosed congenital diseases affecting growth, development and metabolism. They are caused by similar molecular changes affecting regulation, dosage or the genomic sequence of imprinted genes. Each ID is characterised by specific clinical features, and, as each appeared to be associated with specific imprinting defects, they have been widely regarded as separate entities. However, they share clinical characteristics and can show overlapping molecular alterations. Nevertheless, IDs are usually studied separately despite their common underlying (epi)genetic aetiologies, and their basic pathogenesis and long-term clinical consequences remain largely unknown. Efforts to elucidate the aetiology of IDs are currently fragmented across Europe, and standardisation of diagnostic and clinical management is lacking. The new consortium EUCID.net (European network of congenital imprinting disorders) now aims to promote better clinical care and scientific investigation of imprinting disorders by establishing a concerted multidisciplinary alliance of clinicians, researchers, patients and families. By encompassing all IDs and establishing a wide ranging and collaborative network, EUCID.net brings together a wide variety of expertise and interests to engender new collaborations and initiatives

Recent Advances in Imprinting Disorders.

Imprinting disorders (ImpDis) are a group of currently 12 congenital diseases with common underlying (epi)genetic etiologies and overlapping clinical features affecting growth, development and metabolism. In the last years it has emerged that ImpDis are characterized by the same types of mutations and epimutations, i.e. uniparental disomies, copy number variations, epimutations, and point mutations. Each ImpDis is associated with a specific imprinted locus, but the same imprinted region can be involved in different ImpDis. Additionally, even the same aberrant methylation patterns are observed in different phenotypes. As some ImpDis share clinical features, clinical diagnosis is difficult in some cases. The advances in molecular and clinical diagnosis of ImpDis help to circumvent these issues, and they are accompanied by an increasing understanding of the pathomechanism behind them. As these mechanisms have important roles for the etiology of other common conditions, the results in ImpDis research have a wider effect beyond the borders of ImpDis. For patients and their families, the growing knowledge contributes to a more directed genetic counseling of the families and personalized therapeutic approaches.COST (BM1208), Bundesministerium für Bildung und Forschung (Network ‘Imprinting Diseases’, 01GM1513B), German Ministry of research and education (01GM1513B)This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/cge.1282

Identification of novel pathogenic variants and features in patients with pseudohypoparathyroidism and acrodysostosis, subtypes of the newly classified inactivating PTH/PTHrP signaling disorders.

Albright hereditary osteodystrophy (AHO) is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. AHO and pseudohypoparathyroidism (PHP) have been used interchangeably in the past. The term PHP describes end-organ resistance to parathyroid hormone (PTH), occurring with or without the physical features of AHO. Conversely, pseudopseudohypoparathyroidism (PPHP) describes individuals with AHO features in the absence of PTH resistance. PHP and PPHP are etiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gs α) locus (GNAS) in chromosome 20q13. Another less-recognized group of skeletal dysplasias, termed acrodysostosis, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gs α-cyclic adenosine monophosphate-protein kinase A signaling pathway. We describe the clinical course and genotype of two adult patients with overlapping AHO features who harbored novel pathogenic variants in GNAS (c.2273C > G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C > T, p.Ala268Val, NM_002734.4), respectively. We highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses and discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide signaling disorder classification system.Cambridge NIHR Biomedical Research Centr