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A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report.

Babiker AM, Al Gadi I, Al-Jurayyan NA, Al Nemri AM, Al Haboob AA, Al Boukai AA, Al Zahrani A, Habib HA - BMC Res Notes (2014)

Bottom Line: A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration.Both parents are heterozygous carriers of the mutation.Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory).

View Article: PubMed Central - PubMed

Affiliation: Pediatric Department, College of Medicine and King Khalid University Hospital, Riyadh, Saudi Arabia. babikeramir@hotmail.com.

ABSTRACT

Background: Rickets can occur due to Vitamin D deficiency or defects in its metabolism. Three rare genetic types of rickets with different alterations of genes have been reported, including: Vitamin D dependent rickets type 1, Vitamin D dependent rickets type 2 or also known as Vitamin D resistant rickets and 25 hydroxylase deficiency rickets. Vitamin D dependent rickets type 1 is inherited in an autosomal recessive pattern, and is caused by mutations in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. We report here a new mutation in CYP27B1, which lead to Vitamin D dependent rickets type 1.

Case presentation: We report on a 13-month-old Arabic Saudi girl with Vitamin D dependent rickets type 1 presented with multiple fractures and classic features of rickets. A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration. Both parents are heterozygous carriers of the mutation. Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory).

Conclusion: The deleterious effect of this alteration, which was the only mutation detected in the CYP27B1 common gene of Vitamin D dependent rickets type 1 in the proband, and its autosomal recessive inheritance fashion, both support a pathogenic nature of this mutation as the cause of Vitamin D dependent rickets type 1.

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Related in: MedlinePlus

X-ray images at time of presentation showing generalized osteopenia with altered texture (a & b). Humeral metaphysis shows frying with more pronounced lucency (a), and ulnar/radial metaphysis shows frying and cupping of their outline (b) - (white arrows). The cortices are indistinct with coarse fuzzy trabecuale (a & b). Fracture of right clavicle (a), and proximal shaft of the ulna (b) - (black arrows).
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Fig2: X-ray images at time of presentation showing generalized osteopenia with altered texture (a & b). Humeral metaphysis shows frying with more pronounced lucency (a), and ulnar/radial metaphysis shows frying and cupping of their outline (b) - (white arrows). The cortices are indistinct with coarse fuzzy trabecuale (a & b). Fracture of right clavicle (a), and proximal shaft of the ulna (b) - (black arrows).

Mentions: A 13-month-old Arabic Saudi girl, previously well, presented with multiple fractures as a result of minor traumas. She was adequately exposed to sunlight and had normal perinatal, developmental, and nutritional history. She is the only child for first-cousins parents, with no family history of similar problems or metabolic bone disease. Examination revealed normal growth for age, mildly reduced muscle tone, normal teeth, rachitic rosary, Harrison’s sulcus, widening of the wrist and bowing deformity of distal arms and legs. Her head circumference was on the 50th centile for age with a frontal bossing and wide anterior fontanel. She had a swelling, secondary to fracture, over her right clavicle. However, the rest of her skin examination was normal and no other signs, which might suggest physical abuse. Initial investigations showed: low serum calcium and phosphorus, high serum parathyroid hormone (PTH), high serum alkaline phosphatase, a normal serum 25OHD3 which was repeated two times, and inappropriately low normal serum 1,25(OH)2D3 suggesting 1α-hydroxylation defect (Table 1). Radiological workup showed generalized osteopenia with multiple fractures involving the right clavicle, right ulna, left proximal ulna and tibia bones. Disorganization of the growth plate was apparent with classic features of rickets (Figure 2).Table 1


A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report.

Babiker AM, Al Gadi I, Al-Jurayyan NA, Al Nemri AM, Al Haboob AA, Al Boukai AA, Al Zahrani A, Habib HA - BMC Res Notes (2014)

X-ray images at time of presentation showing generalized osteopenia with altered texture (a & b). Humeral metaphysis shows frying with more pronounced lucency (a), and ulnar/radial metaphysis shows frying and cupping of their outline (b) - (white arrows). The cortices are indistinct with coarse fuzzy trabecuale (a & b). Fracture of right clavicle (a), and proximal shaft of the ulna (b) - (black arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232664&req=5

Fig2: X-ray images at time of presentation showing generalized osteopenia with altered texture (a & b). Humeral metaphysis shows frying with more pronounced lucency (a), and ulnar/radial metaphysis shows frying and cupping of their outline (b) - (white arrows). The cortices are indistinct with coarse fuzzy trabecuale (a & b). Fracture of right clavicle (a), and proximal shaft of the ulna (b) - (black arrows).
Mentions: A 13-month-old Arabic Saudi girl, previously well, presented with multiple fractures as a result of minor traumas. She was adequately exposed to sunlight and had normal perinatal, developmental, and nutritional history. She is the only child for first-cousins parents, with no family history of similar problems or metabolic bone disease. Examination revealed normal growth for age, mildly reduced muscle tone, normal teeth, rachitic rosary, Harrison’s sulcus, widening of the wrist and bowing deformity of distal arms and legs. Her head circumference was on the 50th centile for age with a frontal bossing and wide anterior fontanel. She had a swelling, secondary to fracture, over her right clavicle. However, the rest of her skin examination was normal and no other signs, which might suggest physical abuse. Initial investigations showed: low serum calcium and phosphorus, high serum parathyroid hormone (PTH), high serum alkaline phosphatase, a normal serum 25OHD3 which was repeated two times, and inappropriately low normal serum 1,25(OH)2D3 suggesting 1α-hydroxylation defect (Table 1). Radiological workup showed generalized osteopenia with multiple fractures involving the right clavicle, right ulna, left proximal ulna and tibia bones. Disorganization of the growth plate was apparent with classic features of rickets (Figure 2).Table 1

Bottom Line: A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration.Both parents are heterozygous carriers of the mutation.Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory).

View Article: PubMed Central - PubMed

Affiliation: Pediatric Department, College of Medicine and King Khalid University Hospital, Riyadh, Saudi Arabia. babikeramir@hotmail.com.

ABSTRACT

Background: Rickets can occur due to Vitamin D deficiency or defects in its metabolism. Three rare genetic types of rickets with different alterations of genes have been reported, including: Vitamin D dependent rickets type 1, Vitamin D dependent rickets type 2 or also known as Vitamin D resistant rickets and 25 hydroxylase deficiency rickets. Vitamin D dependent rickets type 1 is inherited in an autosomal recessive pattern, and is caused by mutations in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. We report here a new mutation in CYP27B1, which lead to Vitamin D dependent rickets type 1.

Case presentation: We report on a 13-month-old Arabic Saudi girl with Vitamin D dependent rickets type 1 presented with multiple fractures and classic features of rickets. A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration. Both parents are heterozygous carriers of the mutation. Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory).

Conclusion: The deleterious effect of this alteration, which was the only mutation detected in the CYP27B1 common gene of Vitamin D dependent rickets type 1 in the proband, and its autosomal recessive inheritance fashion, both support a pathogenic nature of this mutation as the cause of Vitamin D dependent rickets type 1.

Show MeSH
Related in: MedlinePlus