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Vitamin D-dependent rickets type II with alopecia(VDDR2A)

MedGen UID:
90989
Concept ID:
C0342646
Disease or Syndrome
Synonyms: GENERALIZED RESISTANCE TO 1,25-DIHYDROXYVITAMIN D; HYPOCALCEMIC VITAMIN D-RESISTANT RICKETS; PDDR IIA; PSEUDOVITAMIN D-DEFICIENCY, TYPE IIA; RICKETS, HEREDITARY VITAMIN D-RESISTANT; RICKETS-ALOPECIA SYNDROME; VDDR2A; Vitamin D-dependent rickets, type 2A; VITAMIN D-DEPENDENT RICKETS, TYPE 2A, WITH OR WITHOUT ALOPECIA; VITAMIN D-RESISTANT RICKETS WITH END-ORGAN UNRESPONSIVENESS TO 1,25-DIHYDROXYCHOLECALCIFEROL
SNOMED CT: Vitamin D-dependent rickets type II with alopecia (237894002); Vitamin D-dependent rickets type IIa (237894002); Rickets - alopecia syndrome (237894002); VDDR IIa - Vitamin D-dependent rickets IIa (237894002)
 
Gene (location): VDR (12q13.11)
 
Monarch Initiative: MONDO:0010186
OMIM®: 277440

Definition

Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and a discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.

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.  https://medlineplus.gov/genetics/condition/vitamin-d-dependent-rickets

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.
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.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
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 tendency to become 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
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.
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.
Bowing of the legs
MedGen UID:
1807399
Concept ID:
C5574706
Finding
A bending or abnormal curvature affecting a long bone of the leg.
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.
High serum calcitriol
MedGen UID:
1619023
Concept ID:
C4531136
Finding
An increased concentration of calcitriol in the blood. Calcitriol is also known as 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3.
Carious teeth
MedGen UID:
8288
Concept ID:
C0011334
Disease or Syndrome
Caries is a multifactorial bacterial infection affecting the structure of the tooth. This term has been used to describe the presence of more than expected dental caries.
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.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Alopecia universalis
MedGen UID:
120481
Concept ID:
C0263505
Disease or Syndrome
Alopecia areata is a common disorder that causes hair loss. "Alopecia" is a Latin term that means baldness, and "areata" refers to the patchy nature of the hair loss that is typically seen with this condition.\n\nIn most people with alopecia areata, hair falls out in small, round patches, leaving coin-sized areas of bare skin. This patchy hair loss occurs most often on the scalp but can affect other parts of the body as well. Uncommonly, the hair loss involves the entire scalp (in which case the condition is known as alopecia totalis) or the whole body (alopecia universalis). Other rare forms of alopecia areata, which have different patterns of hair loss, have also been reported.\n\nAlopecia areata affects people of all ages, although it most commonly appears in adolescence or early adulthood. Hair loss occurs over a period of weeks. The hair usually grows back after several months, although it may fall out again. In some cases, unpredictable cycles of hair loss followed by regrowth can last for years. In addition to hair loss, some affected individuals have fingernail and toenail abnormalities, such as pits on the surface of the nails.\n\nThe hair loss associated with alopecia areata is not painful or disabling. However, it causes changes in a person's appearance that can profoundly affect quality of life and self-esteem. In some people, the condition can lead to depression, anxiety, and other emotional or psychological issues.
Abnormality of the skin
MedGen UID:
1845238
Concept ID:
C5848159
Anatomical Abnormality
An abnormality of the skin.
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  

Professional guidelines

PubMed

Takeda E, Kuroda Y, Saijo T, Naito E, Kobashi H, Yokota I, Miyao M
Pediatrics 1987 Jul;80(1):97-101. PMID: 3037475

Recent clinical studies

Etiology

Ozer S, Uluşahin A, Ulusoy S, Okur H, Coşkun T, Tuncali T, Göğüş A, Akarsu AN
Prog Neuropsychopharmacol Biol Psychiatry 2004 Mar;28(2):255-66. doi: 10.1016/j.pnpbp.2003.10.002. PMID: 14751420

Diagnosis

Kumar V, Kumar M, Yadav M
Ann Trop Paediatr 2010;30(4):329-33. doi: 10.1179/146532810X12858955921357. PMID: 21118628
Sultan Al-Khenaizan, Vitale P
Int J Dermatol 2003 Sep;42(9):682-5. doi: 10.1046/j.1365-4362.2003.01816.x. PMID: 12956677
Arase S, Sadamoto Y, Kuwana R, Nakanishi H, Fujie K, Takeda K, Takeda E
J Dermatol Sci 1991 Sep;2(5):353-60. doi: 10.1016/0923-1811(91)90029-w. PMID: 1742246

Therapy

Kumar V, Kumar M, Yadav M
Ann Trop Paediatr 2010;30(4):329-33. doi: 10.1179/146532810X12858955921357. PMID: 21118628
Takeda E, Kuroda Y, Saijo T, Naito E, Kobashi H, Yokota I, Miyao M
Pediatrics 1987 Jul;80(1):97-101. PMID: 3037475

Clinical prediction guides

Ozer S, Uluşahin A, Ulusoy S, Okur H, Coşkun T, Tuncali T, Göğüş A, Akarsu AN
Prog Neuropsychopharmacol Biol Psychiatry 2004 Mar;28(2):255-66. doi: 10.1016/j.pnpbp.2003.10.002. PMID: 14751420

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