VDDR 2 ricketes

2. • 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.

3. • 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.
•

4. • 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

5. • 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.

6. • 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

7. • 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).

8. • 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.

9. • 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 .

10. • 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

12. • 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.

14. • 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

15. • Typical signs are observed from
the first few month of life but
could be late.
• rickets .
• Hypocalcemia.
• growth failure
• Alopecia.

16. • fronto-parietal bossing.
• open anterior fontanelle,
• wrist widening,
• Rickety rosary.
• anterior bowing of tibia.
• Harrison groove.
• myopathy.

20. • 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.

21. • 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.

23. • Severe caries.
• enamel hypoplasia
• gingivitis .
• delayed eruption.

24. • 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).

25. • X-ray: Cupping, fraying of metaphysis .
• Generalized osteopenia.
• delay in bone age.
• Renal US: nephrocalcinosis.

28. • 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

29. • Patients with HVDRR without alopecia
are generally more responsive to
treatment with high doses of vitamin D
preparations than patients with
alopecia.

30. • 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.

31. • 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

32. • 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.

33. • 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

34. • 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

35. • 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

36. • 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 .