• 5 month old girl .

• Product of FT, NSVD.

Consanguineous marriage.

• Found to have alopecia totalis.

• Her elder brother 7 year old boy

diagnosed as case of VDDR2 on

regular IV calcium , oral calcium

phosphate and one alph.

• Also called Hereditary vitamin D–

resistant rickets (HVDRR)

• It was first reported by Brooks et al in

1978.

• is a rare hereditary disease.

• resulting from endorgan resistance to

1,25(OH)2 Vit D3.

•

• it is further classified as Vitamin D

Dependent Rickets:

• Type lla (with alopecia)

• Type llb (without alopecia)

• Prevalence:???

• In saudi Arabia in one study 6.17% of

vitamin D cases in follow up in OPD

where found to have VDDR2

• HVDRR follows an autosomal

recessive pattern of inheritance

• Parents of patients, who are

heterozygous for the mutation, show

no symptoms and have normal bone

development.

• males and females are affected

equally.

• It is caused by a defect in the Vit D

receptor (VDR) gene.

• The defect leads to an increase in the

circulating 1,25(OH)2 Vit D3,

• Active vitamin D, 1,25-dihydroxyvitamin

D is crucial for normal calcium

homeostasis. cellular differentiation,

and immune function

• The vitamin D receptor facilitates the

downstream biological action of 1,25-

dihydroxyvitamin D3 at target tissues.

• Vitamin D receptor is a member of the

steroid-thyroid retinoid receptor gene

super family of nuclear transcription

factors

• The VDR contains an terminus DNA-

binding domain (DBD) and a terminus

ligand-binding domain (LBD).

• Presently, more than 34

heterogeneous mutations have been

identified in the VDR gene as the

cause of HVDRR

• including missense and nonsense

mutations, splice site mutations,

insertions/substitutions, insertions/

duplications, and partial deletions of

VDR gene.

• defects in the vitamin D receptor include

the following:

• 1-Failure of 1,25(OH)2D binding to

available receptors

• 2-A reduction in 1,25(OH)2D receptor

binding sites.

• 3-Abnormal binding affinity .

• 4-Inadequate translocation of

1,25(OH)2D-receptor complex to the

nucleus

• 5- Diminished affinity of the

1,25(OH)2D-receptor complex for the

DNA binding domain secondary to

changes in the structure of receptor

zinc binding fingers

• Mutations in the DNA binding domain

(DBD) prevent the VDR from binding to

DNA causing total 1,25(OH)2D3

resistance .

• mutations in the ligand binding domain

(LBD) may disrupt ligand binding, or

heterodimerization with RXR, or prevent

coactivators from binding to the VDR

and cause partial or total hormone

resistance.

• There is only a single reported case

where investigators failed to detect a

mutation in the VDR

• In this case the authors speculated

that the resistance was due to

abnormal expression of hormone

response element-binding proteins

that prevented the VDR-RXR

complex from binding to vitamin D

response elements in target genes

• Typical signs are observed from

the first few month of life but

could be late.

• rickets .

• Hypocalcemia.

• growth failure

• Alopecia.

• fronto-parietal bossing.

• open anterior fontanelle,

• wrist widening,

• Rickety rosary.

• anterior bowing of tibia.

• Harrison groove.

• myopathy.

• The alopecia can be present at birth, but

usually starts in the first few months of

life

• appears in two-thirds of cases.

• It can be associated with decreased hair

in other body parts, such as the

eyebrows and eyelashes.

• usually unresponsive to VitD treatment,

• Patients with alopecia generally have

more severe resistance to vitamin D.

• The cause of alopecia is postulated to

be the lack of ligand-independent

function of the vitamin D receptor in

keratinocytes which is necessary for

proper anagen initiation.

• Severe caries.

• enamel hypoplasia

• gingivitis .

• delayed eruption.

• The calcium low .

• phosphates low.

• the alkaline phosphatase is quite high

• parathyroid hormone is high.

• 25-hydroxyvitamin D normal

• 1,25-dihydroxyvitamin D high. (3 to 5

times the normal values).

• X-ray: Cupping, fraying of metaphysis .

• Generalized osteopenia.

• delay in bone age.

• Renal US: nephrocalcinosis.

• Treatment of VDDR-II is challenging.

• The response to massive doses of vit

D analogues and oral Ca therapy is

variable and unpredictable.

• The use of intravenous high dose Ca

infusions to cure bone pathology

followed by high dose oral Ca is found

to be an effective mode of treatment

• Patients with HVDRR without alopecia

are generally more responsive to

treatment with high doses of vitamin D

preparations than patients with

alopecia.

• Intravenous calcium therapy bypasses

the calcium absorption defect in the

intestine caused by the lack of action of

the mutant VDR.

• However, in some children receiving

IV calcium, when the IV therapy is

discontinued the syndrome recurs

slowly over time.

• Oral calcium alone has sometimes

been successfully used as a therapy

for HVDRR patients .

• Once the child is older, perhaps when

the skeleton has finished major

growth, oral calcium often suffices to

maintain normocalcemia.

• Spontaneous healing of rickets has

been observed in some HVDRR

patients as they get older

• Therapy may start at daily doses of 2

mcg of 1,25(OH)2D and 1000 mg of

elemental calcium.

• Reported effective doses range from

5000 to 40,000 IU/day for vitamin D,

20 to 200 µg/day for 25(OH)D, and 17

to 20 µg/day for 1,25(OH)2D.

• However, administration of extremely

high doses of 1,25(OH)2D (up to 30 to

60 mcg/day) and calcium (up to 3 g per

day) may be necessary to restore

normocalcemia and to mineralize

depleted bones

• the patient with the R274L mutation, a

contact point for the 1α-hydroxyl group

of 1,25(OH)2D3, was unresponsive to

treatment with 600,000 IU vitamin D; up

to 24 μg/day of 1,25(OH)2D3; or 12

μg/day 1 α(OH)D3

• Serum concentrations of calcium,

phosphorus, alkaline phosphatase,

creatinine, 1,25(OH)2D, and

parathyroid hormone (PTH), and the

urinary calcium/creatinine ratio should

be measured.

• If the biochemical parameters do not

respond, the dose of 1,25(OH)2D

should be gradually increased to reach

serum concentrations of up to 100

times the normal mean value

• Lab:

• bone profile, renal profile,

ca/creatinine ratio. Each visit.

• Treatment :

• IV calcium 1500mg/m2 daily for 5-10

days for 9 hour a day .every month

initially then frequency decreased

accordingly.

• Oral calcium , one alpha , phosphate

in interval .