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Vitamin D-dependent rickets, type 1(VDD1)

MedGen UID:
124344
Concept ID:
C0268689
Disease or Syndrome
Synonyms: VDD1; VITAMIN D DEPENDENCY, TYPE 1; Vitamin D-Dependent Rickets, Type I
SNOMED CT: Vitamin D-dependent rickets, type 1 (67049004); Calcidiol 1-monooxygenase defect (67049004); Pseudo-vitamin-D-deficient rickets (67049004); 1-alpha-hydroxylase deficiency (67049004); Pseudodeficiency rickets (67049004); Pseudovitamin D-resistant rickets (67049004); PDDR - Pseudovitamin D deficiency rickets (67049004); 25-Hydroxycholecalciferol-1-hydroxylase deficiency (67049004); Vitamin D-dependent rickets type I (67049004); VDDR I - Vitamin D-dependent rickets type I (67049004); Pseudovitamin D deficiency rickets (67049004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Monarch Initiative: MONDO:0009924
OMIM®: 264700; 609506
Orphanet: ORPHA289157

Definition

Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.

The signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.

Hair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.

In vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels. [from MedlinePlus Genetics]

Clinical features

From HPO
Bone pain
MedGen UID:
57489
Concept ID:
C0151825
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.
Generalized aminoaciduria
MedGen UID:
339863
Concept ID:
C1847868
Finding
An increased concentration of all types of amino acid in the urine.
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.
Tibial bowing
MedGen UID:
332360
Concept ID:
C1837081
Finding
A bending or abnormal curvature of the tibia.
Enlargement of the wrists
MedGen UID:
325479
Concept ID:
C1838663
Finding
Enlargement of the ankles
MedGen UID:
333151
Concept ID:
C1838664
Finding
Fibular bowing
MedGen UID:
869374
Concept ID:
C4023801
Anatomical Abnormality
A bending or abnormal curvature of the fibula.
Subperiosteal bone resorption
MedGen UID:
1380263
Concept ID:
C4476534
Anatomical Abnormality
Loss of bone mass occurring beneath the periosteum (the periosteum is the connective-tissue membrane that surrounds all bones except at the articular surfaces). This process may create a serrated and lace-like appearance in periosteal cortical bone.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hypocalcemic seizures
MedGen UID:
340985
Concept ID:
C1855841
Disease or Syndrome
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a condition of being easily bothered or annoyed.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Rickets
MedGen UID:
48470
Concept ID:
C0035579
Disease or Syndrome
Rickets is divided into two major categories including calcipenic and phosphopenic. Hypophosphatemia is described as a common manifestation of both categories. Hypophosphatemic rickets is the most common type of rickets that is characterized by low levels of serum phosphate, resistance to ultraviolet radiation or vitamin D intake. There are several issues involved in hypophosphatemic rickets such as calcium, vitamin D, phosphorus deficiencies. Moreover, other disorder can be associated with its occurrence such as absorption defects due to pancreatic, intestinal, gastric, and renal disorders and hepatobiliary disease. Symptoms are usually seen in childhood and can be varied in severity. Severe forms may be linked to bowing of the legs, poor bone growth, and short stature as well as joint and bone pain. Hypophosphatemic rickets are associated with renal excretion of phosphate, hypophosphatemia, and mineral defects in bones. The familial type of the disease is the most common type of rickets.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Difficulty standing
MedGen UID:
69136
Concept ID:
C0241237
Sign or Symptom
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
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.
Sparse bone trabeculae
MedGen UID:
371538
Concept ID:
C1833324
Finding
Thin bony cortex
MedGen UID:
318844
Concept ID:
C1833325
Finding
Abnormal thinning of the cortical region of bones.
Bulging epiphyses
MedGen UID:
371540
Concept ID:
C1833329
Finding
A morphological abnormality of epiphyses whereby they are abnormally outwardly curving (protuberant).
Flat occiput
MedGen UID:
332439
Concept ID:
C1837402
Finding
Reduced convexity of the occiput (posterior part of skull).
Deformed rib cage
MedGen UID:
374021
Concept ID:
C1838659
Anatomical Abnormality
Malformation of the rib cage.
Metaphyseal irregularity
MedGen UID:
325478
Concept ID:
C1838662
Finding
Irregularity of the normally smooth surface of the metaphyses.
Bulging of the costochondral junction
MedGen UID:
338492
Concept ID:
C1848538
Finding
Abnormal outward curving (protuberance) of the junction of ribs and costal cartilage.
Widely patent fontanelles and sutures
MedGen UID:
336570
Concept ID:
C1849300
Finding
An abnormally increased width of the cranial fontanelles and sutures.
Enlargement of the costochondral junction
MedGen UID:
346535
Concept ID:
C1857180
Finding
Abnormally increased size of the costochondral junctions, which are located between the distal part of the ribs and the costal cartilages, which are bars of hyaline cartilage that connect the ribs to the sternum.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Femoral bowing
MedGen UID:
347888
Concept ID:
C1859461
Finding
Bowing (abnormal curvature) of the femur.
Delayed epiphyseal ossification
MedGen UID:
351324
Concept ID:
C1865200
Finding
Abdominal wall muscle weakness
MedGen UID:
867169
Concept ID:
C4021527
Finding
Decreased strength of the abdominal musculature.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
An abnormally decreased phosphate concentration in the blood.
Elevated circulating parathyroid hormone level
MedGen UID:
167805
Concept ID:
C0857973
Finding
An abnormal increased concentration of parathyroid hormone.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
Developmental hypoplasia of the dental enamel.
Delayed eruption of teeth
MedGen UID:
68678
Concept ID:
C0239174
Finding
Delayed tooth eruption, which can be defined as tooth eruption more than 2 SD beyond the mean eruption age.
Secondary hyperparathyroidism
MedGen UID:
9368
Concept ID:
C0020503
Disease or Syndrome
Secondary hyperparathyroidism refers to the production of higher than normal levels of parathyroid hormone in the presence of hypocalcemia.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVVitamin D-dependent rickets, type 1

Professional guidelines

PubMed

Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, Bhandare VV, Patil VA, Shah NS, Thomas N, Kunwar A, Bandgar TR
J Pediatr Endocrinol Metab 2021 Dec 20;34(12):1505-1513. Epub 2021 Sep 8 doi: 10.1515/jpem-2021-0403. PMID: 34492747

Recent clinical studies

Etiology

Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, Bhandare VV, Patil VA, Shah NS, Thomas N, Kunwar A, Bandgar TR
J Pediatr Endocrinol Metab 2021 Dec 20;34(12):1505-1513. Epub 2021 Sep 8 doi: 10.1515/jpem-2021-0403. PMID: 34492747
Ban M, Caillier S, Mero IL, Myhr KM, Celius EG, Aarseth J, Torkildsen Ø, Harbo HF, Oksenberg J, Hauser SL, Sawcer S, Compston A
Ann Neurol 2013 Mar;73(3):430-2. Epub 2013 Feb 26 doi: 10.1002/ana.23833. PMID: 23444327Free PMC Article
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
Yamamoto K, Uchida E, Urushino N, Sakaki T, Kagawa N, Sawada N, Kamakura M, Kato S, Inouye K, Yamada S
J Biol Chem 2005 Aug 26;280(34):30511-6. Epub 2005 Jun 22 doi: 10.1074/jbc.M505244200. PMID: 15972816
Hewison M, Zehnder D, Bland R, Stewart PM
J Mol Endocrinol 2000 Oct;25(2):141-8. doi: 10.1677/jme.0.0250141. PMID: 11013342

Diagnosis

Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, Bhandare VV, Patil VA, Shah NS, Thomas N, Kunwar A, Bandgar TR
J Pediatr Endocrinol Metab 2021 Dec 20;34(12):1505-1513. Epub 2021 Sep 8 doi: 10.1515/jpem-2021-0403. PMID: 34492747
Zalewski A, Ma NS, Legeza B, Renthal N, Flück CE, Pandey AV
J Clin Endocrinol Metab 2016 Sep;101(9):3409-18. Epub 2016 Jul 11 doi: 10.1210/jc.2016-2124. PMID: 27399352
Donghi V, Di Frenna M, di Lascio A, Chiumello G, Weber G
J Pediatr Endocrinol Metab 2011;24(9-10):801-5. doi: 10.1515/jpem.2011.214. PMID: 22145480
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
Søvik O, Boman H
Acta Paediatr 2008 May;97(5):665-7. doi: 10.1111/j.1651-2227.2008.00722.x. PMID: 18394115

Therapy

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 Nov 5;7:783. doi: 10.1186/1756-0500-7-783. PMID: 25371233Free PMC Article
Donghi V, Di Frenna M, di Lascio A, Chiumello G, Weber G
J Pediatr Endocrinol Metab 2011;24(9-10):801-5. doi: 10.1515/jpem.2011.214. PMID: 22145480
Malloy PJ, Feldman D
Endocrinol Metab Clin North Am 2010 Jun;39(2):333-46, table of contents. doi: 10.1016/j.ecl.2010.02.004. PMID: 20511055Free PMC Article

Prognosis

Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, Bhandare VV, Patil VA, Shah NS, Thomas N, Kunwar A, Bandgar TR
J Pediatr Endocrinol Metab 2021 Dec 20;34(12):1505-1513. Epub 2021 Sep 8 doi: 10.1515/jpem-2021-0403. PMID: 34492747
Zalewski A, Ma NS, Legeza B, Renthal N, Flück CE, Pandey AV
J Clin Endocrinol Metab 2016 Sep;101(9):3409-18. Epub 2016 Jul 11 doi: 10.1210/jc.2016-2124. PMID: 27399352
Zou M, Baitei EY, Alzahrani AS, Parhar RS, Al-Mohanna FA, Meyer BF, Shi Y
Endocrine 2011 Aug;40(1):14-20. Epub 2011 May 21 doi: 10.1007/s12020-011-9489-7. PMID: 21604088
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

Clinical prediction guides

Barizzone N, Pauwels I, Luciano B, Franckaert D, Guerini FR, Cosemans L, Hilven K, Salviati A, Dooley J, Danso-Abeam D, di Sapio A, Cavalla P, Decallonne B, Mathieu C, Liston A, Leone M, Dubois B, D'Alfonso S, Goris A
Ann Neurol 2013 Mar;73(3):433-7. Epub 2013 Mar 11 doi: 10.1002/ana.23834. PMID: 23483640
Zou M, Baitei EY, Alzahrani AS, Parhar RS, Al-Mohanna FA, Meyer BF, Shi Y
Endocrine 2011 Aug;40(1):14-20. Epub 2011 May 21 doi: 10.1007/s12020-011-9489-7. PMID: 21604088
Wang X, Zhang MY, Miller WL, Portale AA
J Clin Endocrinol Metab 2002 Jun;87(6):2424-30. doi: 10.1210/jcem.87.6.8534. PMID: 12050193
Hewison M, Zehnder D, Bland R, Stewart PM
J Mol Endocrinol 2000 Oct;25(2):141-8. doi: 10.1677/jme.0.0250141. PMID: 11013342

Recent systematic reviews

Dodamani MH, Sehemby M, Memon SS, Sarathi V, Lila AR, Chapla A, Bhandare VV, Patil VA, Shah NS, Thomas N, Kunwar A, Bandgar TR
J Pediatr Endocrinol Metab 2021 Dec 20;34(12):1505-1513. Epub 2021 Sep 8 doi: 10.1515/jpem-2021-0403. PMID: 34492747

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