TY  - CHAP
M1  - Book, Section
TI  - Vitamin D and Other Calciferols
A1  - Liberman, Uri A.
A1  - Marx, Stephen J.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Normal  calciferol  physiology  includes  activation  through  25-hydroxylation  in  the  liver  and  1α-hydroxylation  in  the  renal  proximal  tubule;  the  most  active  metabolite  is  1α,25-dihydroxyvitamin  D  [1α,25(OH)2D],  which  acts  on  target  tissues  by  a  mechanism  analogous  to  that  of  the  true  steroid  hormones.  Two  distinct  hereditary  defects  have  been  recognized:  (1)  selective  deficiency  (which  implies  normal  concentrations  of  the  immediate  precursor)  and  simple  deficiency  (which  implies  that  other  metabolic  pathways  are  not  abnormal)  of  1α,25(OH)2D,  and  (2)  generalized  resistance  (which  means  that  all  target  tissues  are  affected)  to  1α,25(OH)2D.  Hereditary  defects  in  calciferol  metabolism  or  action  show  all  the  features  of  the  calciferol  deficiency  states  beginning  early  in  life.  These  features  are  intestinal  malabsorption  of  calcium,  hypocalcemia,  secondary  hyperparathyroidism,  increased  renal  clearance  of  phosphorus,  and  hypophosphatemia.  The  combination  of  hypocalcemia  and  hypophosphatemia  results  in  impaired  mineralization  of  bone  (rickets  and  osteomalacia).Hereditary  selective  and  simple  deficiency  of  1α,25(OH)2D  is  an  autosomal  recessive  trait  (MIM  264700).  Patients  respond  to  any  doses  of  calciferol  analogues  that  maintain  normal  circulating  bioactivity  of  equivalents  of  1α,25  (OH)2D.  The  cellular  basis  is  a  deficiency  of  the  renal  25-hydroxyvitamin  D  [25(OH)D]  1α-hydroxylase.Hereditary  selective  deficiency  of  1α,25(OH)2D  also  can  occur  as  part  of  complex  disorders  that  affect  additional  metabolic  pathways  not  related  to  calciferols.  Examples  include  X-linked  hypophosphatemia,  pseudohypoparathyroidism,  and  some  forms  of  Fanconi  syndrome.Hereditary  generalized  resistance  to  1α,25(OH)2D  is  an  autosomal  recessive  trait  (MIM  277440).  The  cellular  basis  is  an  abnormality  in  the  vitamin  D  receptor.  Point  mutations  in  the  vitamin  D  receptor  gene  have  been  implicated  in  almost  every  kindred  studied  and,  depending  on  its  location,  will  affect  DNA  binding,  hormone  binding,  heterdimerization  with  the  retinoid  X  receptors,  or  all  of  the  above.  The  type  of  defect  is  not  correlated  with  the  clinical  features,  and  it  seems  likely  that  each  defect  could  produce  varying  severity  of  clinical  dysfunction.  Approximately  half  of  patients  show  alopecia;  these  are  usually  the  more  severely  affected  patients.  Depending  on  the  severity  of  the  defect,  patients  may  respond  to  treatment  with  (1)  calciferol  analogues  that  allow  for  endogenous  regulation  of  1α,25(OH)2D  production,  (2)  calcium  plus  high  doses  of  calciferol  analogues  that  bypass  25(OH)D  1α-hydroxylase,  or  (3)  extremely  high  doses  of  calcium  orally  or  intravenously  (for  patients  unresponsive  to  maximal  doses  of  all  calciferols).  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/25
UR  - ommbid.mhmedical.com/content.aspx?aid=1181454296
ER  -