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Vitamin D-dependent rickets, type 3(VDDR3)

MedGen UID:: 1725534
•Concept ID:: C5436733
•: Disease or Syndrome

Synonyms:	VDDR3; VITAMIN D-DEPENDENT RICKETS, TYPE 3

Gene (location): Gene(s) directly associated with this condition or phenotype.	CYP3A4 (7q22.1)

Monarch Initiative:	MONDO:0033640
OMIM®:	619073

Definition

Vitamin D-dependent rickets-3 (VDDR3) is characterized by early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to the parent molecule as well as activated forms of vitamin D (Roizen et al., 2018). For discussion of genetic heterogeneity of vitamin D-dependent rickets, see 264700. [from OMIM]

Clinical features

From HPO

Genu varum

MedGen UID:: 154257
•Concept ID:: C0544755
•: Finding

A positional abnormality marked by outward bowing of the legs in which the knees stay wide apart when a person stands with the feet and ankles together.

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Growth delay

MedGen UID:: 99124
•Concept ID:: C0456070
•: Pathologic Function

A deficiency or slowing down of growth pre- and postnatally.

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Delayed ability to walk

MedGen UID:: 66034
•Concept ID:: C0241726
•: Finding

A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.

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Osteopenia

MedGen UID:: 18222
•Concept ID:: C0029453
•: Disease or Syndrome

Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.

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Metaphyseal cupping

MedGen UID:: 323062
•Concept ID:: C1837082
•: Finding

Metaphyseal cupping refers to an inward bulging of the metaphyseal profile giving the metaphysis a cup-like appearance.

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Flared metaphysis

MedGen UID:: 337976
•Concept ID:: C1850135
•: Finding

The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.

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Bowing of the legs

MedGen UID:: 1807399
•Concept ID:: C5574706
•: Finding

A bending or abnormal curvature affecting a long bone of the leg.

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Hypocalcemia

MedGen UID:: 5705
•Concept ID:: C0020598
•: Disease or Syndrome

An abnormally decreased calcium concentration in the blood.

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Hypophosphatemia

MedGen UID:: 39327
•Concept ID:: C0085682
•: Disease or Syndrome

An abnormally decreased phosphate concentration in the blood.

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Elevated circulating parathyroid hormone level

MedGen UID:: 167805
•Concept ID:: C0857973
•: Finding

An abnormal increased concentration of parathyroid hormone.

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Elevated circulating alkaline phosphatase concentration

MedGen UID:: 727252
•Concept ID:: C1314665
•: Finding

Abnormally increased serum levels of alkaline phosphatase activity.

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Decreased circulating calcifediol concentration

MedGen UID:: 868662
•Concept ID:: C4023064
•: Finding

A reduced concentration of calcifediol in the blood. Calcifediol is also known as calcidiol, 25-hydroxycholecalciferol and 25-Hydroxyvitamin D3.

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Low serum calcitriol

MedGen UID:: 868663
•Concept ID:: C4023065
•: Finding

A reduced concentration of calcitriol in the blood. Calcitriol is also known as 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3.

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Abnormality of limbs
- Genu varum
Abnormality of metabolism/homeostasis
Abnormality of the musculoskeletal system
Abnormality of the nervous system
- Delayed ability to walk
Growth abnormality
- Growth delay

Professional guidelines

PubMed

Clinical characteristics and long-term management for patients with vitamin D-dependent rickets type II: a retrospective study at a single center in Saudi Arabia.

Alsagheir A, Al-Ashwal A, Binladen A, Alhuthil R, Joueidi F, Ramzan K, Imtiaz F
Front Endocrinol (Lausanne) 2024;15:1365714. Epub 2024 May 30 doi: 10.3389/fendo.2024.1365714. PMID: 38872968 Free PMC Article

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

Méaux MN, Harambat J, Rothenbuhler A, Léger J, Kamenicky P, Soskin S, Boyer O, Boros E, D'Anella P, Mignot B, Gebhart M, Vic P, Richard N, Thivichon-Prince B, Francou B, Linglart A, Bacchetta J, Molin A
J Clin Endocrinol Metab 2023 Mar 10;108(4):812-826. doi: 10.1210/clinem/dgac639. PMID: 36321535

Hypercalcemic and hypocalcemic disorders: diagnosis and treatment.

Bell NH
Nephron 1979;23(2-3):147-51. doi: 10.1159/000181625. PMID: 440508

See all (4)

Recent clinical studies

Etiology

The pathophysiology of hypophosphatemia.

Ito N, Hidaka N, Kato H
Best Pract Res Clin Endocrinol Metab 2024 Mar;38(2):101851. Epub 2023 Nov 30 doi: 10.1016/j.beem.2023.101851. PMID: 38087658

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats.

Nishikawa M, Murose N, Mano H, Yasuda K, Isogai Y, Kittaka A, Takano M, Ikushiro S, Sakaki T
Sci Rep 2022 Jul 22;12(1):12517. doi: 10.1038/s41598-022-16819-7. PMID: 35869242 Free PMC Article

Clinical and genetic analysis of two Chinese families with vitamin D-dependent rickets type IA and follow-up.

Li Y, Yuan X, Chen R, Lin X, Shangguan H, Yang X, Zhang Y
Orphanet J Rare Dis 2020 Oct 1;15(1):273. doi: 10.1186/s13023-020-01558-7. PMID: 33004071 Free PMC Article

Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia.

Barron MJ, McDonnell ST, Mackie I, Dixon MJ
Orphanet J Rare Dis 2008 Nov 20;3:31. doi: 10.1186/1750-1172-3-31. PMID: 19021896 Free PMC Article

See all (19)

Diagnosis

The pathophysiology of hypophosphatemia.

Ito N, Hidaka N, Kato H
Best Pract Res Clin Endocrinol Metab 2024 Mar;38(2):101851. Epub 2023 Nov 30 doi: 10.1016/j.beem.2023.101851. PMID: 38087658

Vitamin D deficiency in adulthood: Presentation of 2familial cases simulating pseudohypoparathyroidism.

Manero-Azua Á, Pereda A, González Cabrera N, Martínez de Salinas Santamaría MÁ, Cámara Balda A, Pérez de Nanclares G
Med Clin (Barc) 2023 Dec 7;161(11):493-497. Epub 2023 Jul 25 doi: 10.1016/j.medcli.2023.06.009. PMID: 37500374

Clinical spectrum and diagnostic challenges of vitamin D dependent rickets type 1A (VDDR1A) caused by CYP27B1 mutation in resource limited countries.

Aftab S, Khan SA, Malik MI, Imran A, Anjum MN, Saeed A, Qureshi AA, Cheema HA
J Pediatr Endocrinol Metab 2023 Feb 23;36(2):152-157. Epub 2022 Dec 19 doi: 10.1515/jpem-2022-0550. PMID: 36524979

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia.

Barron MJ, McDonnell ST, Mackie I, Dixon MJ
Orphanet J Rare Dis 2008 Nov 20;3:31. doi: 10.1186/1750-1172-3-31. PMID: 19021896 Free PMC Article

See all (26)

Therapy

Vitamin D deficiency in adulthood: Presentation of 2familial cases simulating pseudohypoparathyroidism.

Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review.

Mantoanelli L, de Almeida CM, Coelho MCA, Coutinho M, Levine MA, Collett-Solberg PF, Bordallo AP
Calcif Tissue Int 2023 Apr;112(4):512-517. Epub 2023 Jan 19 doi: 10.1007/s00223-022-01051-2. PMID: 36656330 Free PMC Article

Clinical spectrum and diagnostic challenges of vitamin D dependent rickets type 1A (VDDR1A) caused by CYP27B1 mutation in resource limited countries.

Aftab S, Khan SA, Malik MI, Imran A, Anjum MN, Saeed A, Qureshi AA, Cheema HA
J Pediatr Endocrinol Metab 2023 Feb 23;36(2):152-157. Epub 2022 Dec 19 doi: 10.1515/jpem-2022-0550. PMID: 36524979

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I.

Tahir S, Demirbilek H, Ozbek MN, Baran RT, Tanriverdi S, Hussain K
Horm Res Paediatr 2016;85(5):309-17. Epub 2016 Mar 17 doi: 10.1159/000444483. PMID: 26982175

See all (19)

Prognosis

Clinical characteristics and long-term management for patients with vitamin D-dependent rickets type II: a retrospective study at a single center in Saudi Arabia.

Clinical presentation and molecular genetic analysis of a Sudanese family with a novel mutation in the CYP2R1 gene.

Abdalla AT, Koedam M, Drop SLS, Boot AM, Abdullah MA, van der Eerden BCJ
Gene 2022 Nov 30;844:146809. Epub 2022 Aug 13 doi: 10.1016/j.gene.2022.146809. PMID: 35973571

Clinical and genetic analysis of two Chinese families with vitamin D-dependent rickets type IA and follow-up.

Li Y, Yuan X, Chen R, Lin X, Shangguan H, Yang X, Zhang Y
Orphanet J Rare Dis 2020 Oct 1;15(1):273. doi: 10.1186/s13023-020-01558-7. PMID: 33004071 Free PMC Article

CYP2R1 mutations causing vitamin D-deficiency rickets.

Thacher TD, Levine MA
J Steroid Biochem Mol Biol 2017 Oct;173:333-336. Epub 2016 Jul 27 doi: 10.1016/j.jsbmb.2016.07.014. PMID: 27473561

Incidence and prevalence of nutritional and hereditary rickets in southern Denmark.

Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK
Eur J Endocrinol 2009 Mar;160(3):491-7. Epub 2008 Dec 18 doi: 10.1530/EJE-08-0818. PMID: 19095780

See all (12)

Clinical prediction guides

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

Robust osteogenic efficacy of 2α-heteroarylalkyl vitamin D analogue AH-1 in VDR (R270L) hereditary vitamin D-dependent rickets model rats.

Nishikawa M, Murose N, Mano H, Yasuda K, Isogai Y, Kittaka A, Takano M, Ikushiro S, Sakaki T
Sci Rep 2022 Jul 22;12(1):12517. doi: 10.1038/s41598-022-16819-7. PMID: 35869242 Free PMC Article

CYP2R1 mutations causing vitamin D-deficiency rickets.

Thacher TD, Levine MA
J Steroid Biochem Mol Biol 2017 Oct;173:333-336. Epub 2016 Jul 27 doi: 10.1016/j.jsbmb.2016.07.014. PMID: 27473561

Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I.

Tahir S, Demirbilek H, Ozbek MN, Baran RT, Tanriverdi S, Hussain K
Horm Res Paediatr 2016;85(5):309-17. Epub 2016 Mar 17 doi: 10.1159/000444483. PMID: 26982175

Molecular genetics of vitamin D- dependent hereditary rickets.

Kato S, Yoshizazawa T, Kitanaka S, Murayama A, Takeyama K
Horm Res 2002;57(3-4):73-8. doi: 10.1159/000057955. PMID: 12006701

See all (24)

Recent systematic reviews

Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review.

See all (1)

MedGen

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Vitamin D-dependent rickets, type 3(VDDR3)

Definition

Clinical features

Professional guidelines

PubMed

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Recent systematic reviews

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Practice guidelines

Molecular resources

Consumer resources

Reviews

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