Dataset Information

Effects of Burosumab Treatment on Two Siblings with X-Linked Hypophosphatemia. Case Report and Literature Review.

ABSTRACT: X-linked hypophosphatemia (XLH) or vitamin D-resistant rickets (MIM#307800), is a monogenic disorder with X-linked inheritance. It is caused by mutations present in the Phosphate Regulating Endopeptidase Homolog X-Linked (PHEX) gene responsible for the degradation of the bone-derived hormone fibroblast growth factor 23 (FGF23) into inactive fragments, but the entire mechanism is currently unclear. The inactivation of the gene prevents the degradation of FGF23, causing increased levels of FGF23, which leads to decreased tubular reabsorbtion of phosphorus. Clinical aspects are growth delay, limb deformities, bone pain, osteomalacia, dental anomalies, and enthesopathy. Laboratory evaluation shows hypophosphatemia, elevated alkaline phosphatase (ALP), and normal serum calcium levels, whereas parathormone (PTH) may be normal or increased and FGF23 greatly increased. Conventional treatment consists of administration of oral phosphate and calcitriol. Treatment with Burosumab, a monoclonal antibody that binds to FGF23, reducing its activity, was approved in 2018.

Methods

We describe a case of two siblings, a girl and a boy, diagnosed with XLH, monitored by the Genetic Department of the County Emergency Clinical Hospital since 2019. The clinical picture is suggestive for XLH, both siblings exhibiting short stature, lower limb curvature, bone pain, marked walking weakness, and fatigue. Radiological aspects showed marked deformity of the lower limbs: genu varum in the girl, genu varum and valgum in the boy. Laboratory investigations showed hypophosphathemia, hyperphosphaturia, elevated ALP, normal PTH, and highly increased FGF23 in both. DNA analysis performed on the two siblings revealed a nonsense mutation in exone 5 of the PHEX gene: NM_000444.6(PHEX):c.565C > T (p.Gln189Ter).

Results

At the age of 13½ on 7 June 2021, the two children started treatment with Burosumab in therapeutic doses and were monitored clinically and biochemically at regular intervals according to the protocol established by the Endocrinology Commission of the Romanian Health Ministry.

Conclusions

The first results of the Burosumab treatment in the two siblings are extremely encouraging and suggest a favorable long-term evolution under this treatment.

SUBMITTER: Jurca CM

PROVIDER: S-EPMC9407333 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Effects of Burosumab Treatment on Two Siblings with X-Linked Hypophosphatemia. Case Report and Literature Review.

Jurca Claudia Maria CM Iuhas Oana O Kozma Kinga K Petchesi Codruta Diana CD Zaha Dana Carmen DC Bembea Marius M Jurca Sanziana S Paul Corina C Jurca Alexandru Daniel AD

Genes 20220804 8

X-linked hypophosphatemia (XLH) or vitamin D-resistant rickets (MIM#307800), is a monogenic disorder with X-linked inheritance. It is caused by mutations present in the Phosphate Regulating Endopeptidase Homolog X-Linked (PHEX) gene responsible for the degradation of the bone-derived hormone fibroblast growth factor 23 (FGF23) into inactive fragments, but the entire mechanism is currently unclear. The inactivation of the gene prevents the degradation of FGF23, causing increased levels of FGF23, ...[more]

PMID: 36011303

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Project description:BackgroundX-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies.ResultsThirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy.ConclusionTo our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

Project description:BackgroundLPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient's presentation with a reviewed synthesis of the available literature.Case presentationsThe younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic-clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla. His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions.ConclusionsNeurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.

Dataset Information

Effects of Burosumab Treatment on Two Siblings with X-Linked Hypophosphatemia. Case Report and Literature Review.

Methods

Results

Conclusions

Publications

Effects of Burosumab Treatment on Two Siblings with X-Linked Hypophosphatemia. Case Report and Literature Review.

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