ESPE Abstracts (2019) 92 P3-295

A Novel Pathogenic Mutation of Vitamin-D-Dependent Rickets

Jacopo Norberto Pin1, Micol Cossettini2, Francesco Fabris2, Stefano Martelossi2


1Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova, Italy. 2UOC Pediatria, Ospedale Ca' Foncello di Treviso, Italy


Background: Vitamin-D-dependent rickets 1A (VDDR-1A) is a extremely rare, autosomic recessive genetic form of rickets caused by a defect in vitamin D 1α-hydroxylase enzyme which leads to low levels of 1,25-(OH) vitamin D.

Herein, we report two Moroccan sisters R.E. and N.E. (respectively 3 and 15 months old), born from consanguineous parents, who presented with psychomotor retardation and failure to thrive.

Methods: Biochemical analyses in serum and urine were conducted using the automatic analyzer Cobas immediately after collection. Serum intact PTH was measured by chemiluminescence assay. 25-OH vitamin D and 1,25-(OH) vitamin D levels were measured by enzyme immunoassays.

The entire coding region of CYP27B1, CYP2R1 and VDR genes were sequenced through NGS technology. Relevant genetic variations were resequenced through Sanger technology. The in silico prediction models used were Polyphen2, SIFT, MutationTaster, PHRED, MutationAssssor.

Results: Both sisters showed typical laboratory findings of VDDR-1A including hypocalcemia, hypophosphatemia, elevated ALP and PTH. Further assesments demonstrated normal-elevated levels of 25-OH vitamin D with low 1,25-(OH) 2 vitamin D.

Radiological workup revealed osteopenia, widened and irregular epiphyseal plates and in the older sister rachitic rosary.

We therefore sequenced the entire coding region of genes that has been associated to this clinical condition. Both sisters showed the homozigotic mutation p.Leu169Pro (c.596T>C) of CYP27B1 gene that has never been described before. All prediction models consider this mutation harmful.

Both sisters immediately started 1,25-(OH) Vitamin D supplementation (N.E. took a galenic formulation of Calcium too).

They both showed an adequate but incomplete treatment response with psychomotor retardation improvement, weight gain, normalization of serum Ca and P levels and a significant decrease of PTH and ALP levels.

Conclusion: We report a novel pathogenic mutation of CYP27B1 that leads to VDDR-1A.

An early diagnosis is necessary to prevent serious complications of rickets that are only partially reversible.

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