The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry.

Osteogenesis imperfecta (OI) is a rare low-bone mass skeletal Mendelian disorder characterized by bone fragility leading to bone fractures, with deformities and stunted growth in the more severe phenotypes. Other common, nonskeletal findings include blue sclerae and dentinogenesis imperfecta. It is caused mainly by quantitative or structural defects in type I collagen, although dysregulation of different signaling pathways that play a role in bone morphogenesis has been described to be associated with a small fraction of individuals with OI. Recently, a homozygous variant in the translation start site of CCDC134, showing increased activation of the RAS/MAPK signaling pathway, has been reported in three families of Moroccan origin with a severe, deforming form of OI. We report on a 9-year-old Brazilian boy, harboring the same homozygous variant in CCDC134, also presenting severe bone involvement. This report contributes to the phenotypic delineation of this novel autosomal recessive form of OI, which presents with high prevalence of nonunion fractures considered rare events in OI in general. In addition, it expands the phenotype to include base skull anomalies, potentially leading to serious complications, as seen in severe forms of OI. A poor response to bisphosphonate therapy was observed in these individuals. As the variant in CCDC134 leads to dysregulation of the RAS/MAPK signaling pathway, drugs targeted to this pathway could be an alternative to achieve a better management of these individuals.

Tamoxifen Improves Final Height Prediction in Girls with McCune-Albright Syndrome: A Long Follow-Up.

BACKGROUND: McCune-Albright syndrome (MAS) is a genetic disorder characterized by the triad of fibrous dysplasia, skin hyperpigmentation, and autonomous hyperfunction of various endocrine organs. MAS frequently presents in females as precocious puberty (PP). Although many treatments have been proposed, the preservation of final height (FH) in these patients remains a challenge. OBJECTIVES: To evaluate the efficacy of tamoxifen in improving the FH prediction (FHP) in patients with MAS. METHOD: We retrospectively analyzed 8 female patients with MAS who presented with café-au-lait spots and gonadotropin-independent PP. The patients were followed for a mean period of 8.3 years (range: 3-16). RESULTS: All patients were treated with tamoxifen (10-20 mg/day) for 3-8 years (mean ± SD: 5.75 ± 2.05), which resulted in the cessation of vaginal bleeding and the stabilization of bone age maturation. There was a significant difference between the FHP at the beginning of treatment and at the end of treatment (145.1 ± 8.6 cm; Z score -2.84 ± 1.44 cm) and at the last evaluation (157.0 ± 9.2 cm; Z score -0.85 ± 0.54 cm; p < 0.001). CONCLUSION: Our results support a role for tamoxifen in improving the FHP in patients with MAS.

Hypophosphatemic rickets and osteomalacia.

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well.

Severe hypercalcemia in a 9-year-old Brazilian girl due to a novel inactivating mutation of the calcium-sensing receptor.

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are consequent to inactivating mutations of the calcium-sensing receptor (CaR) gene. FHH is usually associated with heterozygous inactivating mutations of the CaR gene, whereas NSHPT is usually due to homozygous inactivation of the CaR gene. FHH is generally asymptomatic and is characterized by mild to moderate lifelong hypercalcemia, relative hypocalciuria, and normal intact PTH, whereas individuals with NSHPT frequently show life-threatening hypercalcemia. In this study, we report a novel inactivating mutation of the CaR gene, identified in a 9-yr-old Brazilian girl who was found to be severely hypercalcemic during investigation of a 6-month history of headaches and vomits. Direct sequencing of the CaR gene from this patient showed a novel homozygous mutation (L13P) in exon 2. Functional characterization by intracellular calcium measurement by fluorometry showed that the mutant receptor had a dose-response curve shifted to the right relative to that of wild type. The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, showed the same mutation in the heterozygous form. The mutation described in this study is the inactivating missense mutation present at the most N-terminal end among the known CaR missense mutations. This study reinforces the fact that patients with homozygous inactivation of the CaR gene may present with severe hypercalcemia in different phases of life.