The Variant p.Ala84Pro Is Causative of X-Linked Hypophosphatemic Rickets: Possible Relationship with Burosumab Swinging Response in Adults.

Loss of function mutations in the PHEX gene could determine X-linked dominant hypophosphatemia. This is the most common form of genetic rickets. It is characterized by renal phosphate wasting determining an increase in fibroblast growth factor 23 (FGF-23), growth retard, bone deformities and musculoskeletal manifestations. In recent decades, analysis of the PHEX gene has revealed numerous different mutations. However, no clear genotype-phenotype correlations have been reported in patients with hypophosphatemic rickets (XLH). We report two cases of a 28-year-old-male (patient 1) and a 19-year-old male (patient 2) affected by XLH initially treated with phosphate and 1,25-dihydroxyvitamin-D admitted to the Endocrinology unit because of the persistence of muscle weakness, bone pain and fatigue. After phosphate withdrawal, both patients started therapy with burosumab and symptoms ameliorated in three months. However, patient 1's biochemical parameters did not improve as expected so we decided to investigate his genetic asset. We herein describe a possible clinical implication for the missense "de novo" mutation, c.250G>C (p.Ala84Pro) in the PHEX gene, reported in the PHEX database and classified as a variant of uncertain significance (VUS). The clinical implication of this mutation on disease burden and quality of life in adults is still under investigation.

Hashimoto encephalopathy: a case report and a short revision of current literature.

Hashimoto encephalopathy (HE) is a rare but controversial entity encompassing a variety of neuropsychological presentations in the setting of autoimmune thyroid disease. HE, mostly described in adults, with a female­to­male ratio of 4:1, is a relatively rare entity in the pediatric population and probably under recognized as a cause of acute encephalopathy in children and adolescents. A number of pathogenetic mechanisms have been suggested. Female prevalence, presence of autoantibodies, fluctuating course, and response to immunomodulatory therapy suggest the autoimmune nature of the disease. Existing diagnostic criteria for adults require modification to be applied to children and adolescents, who differ from adults in their clinical presentations, clinical findings, autoantibody profiles, treatment response, and long-term outcomes. A combination of neurological findings, positive antithyroid autoantibodies, and responsiveness to steroids is diagnostic of HE. We add a new case of HE in an adolescent girl and review the current HE literature.

A case of Kallmann syndrome associated to a novel missense mutation of the FGFR1 gene.

BACKGROUND: Loss-of-function mutations of fibroblast growth factor receptor 1 gene (FGFR1) have been reported so far. These mutations have been described in the extracellular domain, consisting of three Ig-like domains in the single transmembrane helix and in the intracellular region, containing a tyrosine kinase domain and cause about 10% of all cases of Kallmann syndrome. FRGR1 mutations could be associated with non reproductive phenotype such as cleft palate and dental agenesis and a wide spectrum of reproductive phenotype. CASE REPORT: The patient, 17 years and 11 months old, was a Bulgarian male referred to our Pediatric Endocrinology Unit for pubertal failure and hyposmia. Clinical evaluation revealed a highpitched voice, gynecomastia and obesity. Hormonal study revealed hypogonadotropic hypogonadism. Molecular analysis, performed by Next Generation Sequencing and confirmed by Sanger sequencing, led to the identification of a novel and previously undescribed mutation c.1058 C>G (p. S353C) in heterozygous state on exon 8 of the FGFR1 gene. CONCLUSION: The novel mutation, that we found in a boy with Kallman syndrome, could destabilize the D3 immunoglobulin like receptor domain that is crucial for the FGF-FGFR interaction. (www.actabiomedica.it).