MAPK inhibition and growth hormone: a promising therapy in XLH

Fuente, Rocío Aller de la; Gil‐Peña, Helena; Claramunt-Taberner, Débora; Hernández-Frías, Olaya; Fernández-Iglesias, Ángela; Alonso-Durán, Laura; Rodríguez-Rubio, Enrique; Hermida-Prado, Francisco; Anes-González, Gonzalo; Rubio‐Aliaga, Isabel; Wagner, Carsten A.; Santos, Fernando

doi:10.1096/fj.201802007r

Cited by 15 publications

(21 citation statements)

References 33 publications

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“…7 Growth hormone therapy can be beneficial in children with XLH, 9,23,24 and in the Hyp mouse model of XLH. 10 Haffner and colleagues found improved growth rate and median adult height in three children in whom rHGH was initiated before puberty for 3.1−6.3 years. However, the upper/lower ratio was exaggerated in some.…”

Section: Discussionmentioning

confidence: 98%

“…Recombinant human growth hormone (rHGH) therapy has been used with some benefit in patients with XLH and the Hyp mouse model of XLH. 9 , 10 This may be due, in part, to the calcium- and phosphate-sparing effects of GH and IGF1 in the kidneys. 11 – 13 In seven children with idiopathic GH deficiency, intestinal calcium absorption increased during rHGH administration, resulting in a compensatory decrease of PTH and serum 1,25(OH) 2 D, and, thus, was interpreted as direct effect of rHGH at the intestinal lining.…”

Section: Introductionmentioning

confidence: 99%

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Description of a novel SLC34A3.c.671delT mutation causing hereditary hypophosphatemic rickets with hypercalciuria in two adolescent boys and response to recombinant human growth hormone

Dreimane

Chen

Bergwitz

2020

Therapeutic Advances in Musculoskeletal

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Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder characterized by hypophosphatemia, rickets, hyperphosphaturia, elevated 1,25(OH)2D, and hypercalciuria. Mutations in SLC34A3, the gene encoding the sodium-dependent cotransporter NPT2c, have previously been described as a cause of HHRH. Here, we describe two male siblings with rickets and hypercalciuric nephrolithiasis born to unrelated parents, and their response to oral phosphate supplementation and growth hormone therapy. Whole exome sequencing of the oldest brother, and polymerase chain reaction and Sanger sequence analysis of the identified SLC34A3 mutations, was performed for confirmation and to evaluate his siblings and parents. Serum and urine biochemical parameters of mineral homeostasis before and after therapy were evaluated. Whole exome sequencing analysis identified a previously reported heterozygous deletion SLC34A3.g.2259-2359del101bp on the maternal allele, and a novel heterozygous single nucleotide deletion SLC34A3.c.671delT on the paternal allele of the two affected brothers. The parents and the unaffected brother are heterozygous carriers. Recombinant human growth hormone (rHGH) plus oral phosphate in one affected brother improved the renal phosphate leak and resulted in accelerated linear growth superior to that seen with oral phosphate supplementation alone in the other affected brother. Our case study is the first to demonstrate that rHGH can be considered in addition to oral supplementation with phosphorus to improve linear growth in patients with this disorder, and suggests that renal phosphate reabsorption in response to rHGH is NPT2c-independent.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Description of a novel SLC34A3.c.671delT mutation causing hereditary hypophosphatemic rickets with hypercalciuria in two adolescent boys and response to recombinant human growth hormone

Dreimane

Chen

Bergwitz

2020

Therapeutic Advances in Musculoskeletal

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“…The severity of the disease was similar in males and females. Background X-linked hypophosphatemic rickets (XLH) (OMIM 307800) is the most common hereditary rickets (1)(2)(3)(4)(5) with an estimated prevalence of 1:20,000 (6,7). It follows a dominant transmission (8).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population.

Rodríguez-Rubio

Gil‐Peña

Chocrón³

et al. 2020

Preprint

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BACKGROUNDX-Linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading to hypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH. RESULTSThe RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 0 to 9 years of age at the time of diagnosis, and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was -1.89 ± 0.19 SDS and 55% of patients had height SDS below - 2. All cases had hypophosphatemia, serum phosphate being -2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype – phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n=26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis. CONCLUSIONSThis study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.

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“…A recent study in a young hyp mice model demonstrated that the combination of MAPK inhibitor, which heals rickets and improves growth plate organisation, along with GH could be a promising new therapy in treating children with XLH. However, such therapy would need exploration via clinical trials in humans [45].…”

Section: Mapk Inhibitorsmentioning

confidence: 99%

New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management

2020

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X-linked hypophosphataemia (XLH) is due to mutations in phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and represents the most common heritable form of rickets. In this condition, the hormone fibroblast growth factor 23 (FGF23) is produced in excessive amounts for still unknown reasons, and causes renal phosphate wasting and suppression of 1,25-dihydroxyvitamin D, leading to low serum phosphate concentrations. Prolonged hypophosphataemia decreases apoptosis of hypertrophic chondrocytes in growth plates (causing rickets) and decreases mineralisation of existing bone (causing osteomalacia). In contrast to historical conventional treatment with oral phosphate supplements and active vitamin D for the last 50 years, the new anti-FGF23 antibody treatment (burosumab) targets the primary pathology by blocking FGF23, thereby restoring phosphate homeostasis. In this review, we describe the changes in treatment monitoring, treatment targets and long-term treatment goals, including future opportunities and challenges in the treatment of XLH in children.

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MAPK inhibition and growth hormone: a promising therapy in XLH

Cited by 15 publications

References 33 publications

Description of a novel SLC34A3.c.671delT mutation causing hereditary hypophosphatemic rickets with hypercalciuria in two adolescent boys and response to recombinant human growth hormone

Description of a novel SLC34A3.c.671delT mutation causing hereditary hypophosphatemic rickets with hypercalciuria in two adolescent boys and response to recombinant human growth hormone

Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population.

New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management

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