RESUMO
Although vitamin D deficiency resulting from insufficient sunlight exposure or inadequate dietary vitamin D intake is the most common cause of rickets, mutations in genes involved in vitamin D metabolism can cause genetic forms of rickets termed Vitamin D-Dependent Rickets (VDDR). In 2018, Roizen et al. described a new type of VDDR, named VDDR3, caused by a recurrent missense mutation in the CYP3A4 gene that leads to accelerated inactivation of vitamin D metabolites. Here, we describe the third case of VDDR3 due to the same CYP3A4 mutation in a 2-year-old boy with bone deformities associated with poor growth. As in the previously reported cases, this patient had no family history of rickets. Serial measurements of vitamin D metabolites after a single 150,000 IU dose of cholecalciferol demonstrated an accelerated inactivation of 25(OH)D and 1,25(OH)2D. Significant improvement in growth velocity and healing of bone deformities were achieved after a short period of treatment with 10.000 IU of cholecalciferol daily, showing the importance of early recognition and prompt precision therapy of this condition.
Assuntos
Raquitismo , Deficiência de Vitamina D , Pré-Escolar , Humanos , Masculino , Colecalciferol , Citocromo P-450 CYP3A/uso terapêutico , Raquitismo/tratamento farmacológico , Raquitismo/genética , Vitamina D/metabolismo , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
CONTEXT: Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported. OBJECTIVE: To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations. METHODS: Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients. RESULTS: We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5' untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR. CONCLUSIONS: WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.
Assuntos
Cromograninas/genética , Metilação de DNA , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Deleção de Genes , Pseudo-Hipoparatireoidismo/genética , Adulto , Criança , Metilação de DNA/genética , Éxons/genética , Família , Feminino , Humanos , Masculino , Mães , Adulto JovemRESUMO
OBJECTIVE: McCune-Albright syndrome (MAS) is characterized by a clinical triad of endocrinopathies, café au lait pigmentation, and polyostotic fibrous dysplasia of bone. We hypothesized that children diagnosed with fibrous dysplasia are not routinely being evaluated for coexisting endocrine dysfunction or MAS. Our objective was to prospectively screen subjects with fibrous dysplasia for endocrine disease and G(s)alpha gene (GNAS1 )-activating mutations. STUDY DESIGN: Nine subjects who presented with fibrous dysplasia and were followed in orthopedic clinics were evaluated for other manifestations of MAS. Genomic DNA was isolated from blood, and mutation analysis of GNAS1 was performed. RESULTS: On physical examination, 5 of 9 subjects were found to have café au lait pigmentation. Three of 9 subjects had TSH levels below the normal range. One of these subjects was found to have hyperthyroidism and was treated by total thyroidectomy. GNAS1 mutations were identified in 5 of 9 subjects with either monostotic or polyostotic fibrous dysplasia of bone. CONCLUSIONS: We conclude that a substantial proportion of children being followed for fibrous dysplasia of bone have unrecognized clinical and laboratory features of MAS. These children are at risk for endocrinopathy and should be screened accordingly.