RT Book, Section
A1 Schafer, Alan J.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1184072922
T1 Campomelic Dysplasia/Autosomal Sex Reversal/SOX9
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1184072922
RD 2024/04/19
AB Campomelic  dysplasia  (CD)  is  a  rare,  dominant,  and  usually  neonatal  lethal  chondrodysplasia  clinically  and  radiologically  defined  by  a  number  of  skeletal  and  extraskeletal  phenotypes,  the  most  conspicuous  of  which  is  angulation  of  the  long  bones.  Bent  or  bowed  limbs  occur  in  other  skeletal  malformation  syndromes  and  are  not  pathognomonic  for  CD.  Major  diagnostic  radiologic  features  include  bowed  or  angulated  femora  and  tibiae,  hypoplastic  scapulae,  vertically  narrow  iliac  wings,  and  nonmineralized  thoracic  pedicles.  No  single  feature  is  diagnostic,  but  each  of  these  appears  with  high  frequency,  and  no  other  syndrome  has  this  combination  of  features.  Additional  common  radiologic  features  are  facial  hypoplasia,  abnormal  cervical  vertebrae,  slender  ribs,  11  pairs  of  ribs,  small  chest,  dislocated  hips,  a  variety  of  pelvic  abnormalities,  and  short  first  metacarpal.  Common  clinical  features  include  micrognathia,  respiratory  distress,  flat  nasal  bridge,  pretibial  dimples,  macrocephaly,  and  talipes  equinovarus.More  than  two-thirds  of  46,XY  campomelic  dysplasia  patients  are  sex  reversed,  developing  as  phenotypic  females  due  to  a  failure  to  form  testes.  The  degree  of  sex  reversal  can  vary,  with  the  most  common  outcome  being  normal  phenotypic  female  with  dysgenic  ovaries.Dominant  mutations  in  the  transcription  factor  SOX9  are  responsible  for  both  the  skeletal  and  the  sex  development  phenotypes.  Mutation  analysis  and  functional  assays  suggest  that  the  phenotypes  result  from  haploinsufficiency  due  to  loss-of-function  mutations  of  a  single  SOX9  allele.  SOX9  mutations  apparently  do  not  cause  sex  reversal  in  the  absence  of  CD  skeletal  defects.SOX9  appears  to  be  a  critical  component  of  the  developmental  pathways  of  both  cartilage  formation  and  testis  formation,  functioning  independently  in  the  development  of  these  two  dissimilar  tissues.  SOX9  mutations  cause  a  loss  of  protein  function  that  leads  to  a  failure  to  propagate  the  appropriate  developmental  signals  in  both  chondrogenic  tissue  and  the  indifferent  gonad.Expression  of  SOX9  is  the  earliest  marker  of  cartilage  differentiation  and  is  required  for  cartilage  formation.  The  SOX9  protein  is  expressed  during  embryonic  chondrogenesis  and  directly  regulates  type  II  collagen  gene  expression  in  chondrocytes.  SOX9  may  also  be  directly  involved  in  regulation  of  type  XI  collagen,  which  is  coexpressed  with  type  II  collagen,  both  collagens  being  essential  for  normal  cartilage  development  and  skeletal  morphogenesis.  In  chimeric  mice,  cells  with  homozygous  deletions  of  Sox9  are  excluded  from  all  cartilages  and  do  not  express  chondrocyte-specific  markers,  showing  the  essential  role  of  Sox9  in  chondrogenesis  and  cartilage  formation.During  mouse  gonadal  development,  Sox9  is  expressed  in  both  XX  and  XY  embryos  in  the  undifferentiated  genital  ridge.  In  XY  embryos,  Sox9  is  up-regulated  coincident  with  the  onset  of  expression  of  Sry,  the  Y  chromosome  testis  determination  factor,  and  continues  to  be  expressed  at  high  levels  in  developing  testes,  with  expression  limited  to  the  Sertoli  cells.  At  the  corresponding  time  in  XX  embryos,  Sox9  expression  is  down-regulated.  This  is  the  earliest  difference  in  gene  expression  known  between  males  and  females  other  than  that  of  Sry  itself.  SOX9  appears  to  act  as  a  partner  of  SF1  in  activating  the  Sertoli  cell-specific  expression  of  anti-Müllerian  hormone  (AMH),  a  hormone  that  promotes  regression  of  the  Müllerian  ducts,  the  primordia  of  female-specific  sex  organs.  The  timing  and  ...