RT Book, Section
A1 Gelb, Bruce D.
A1 Brömme, Dieter
A1 Desnick, Robert J.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181463844
T1 Pycnodysostosis: Cathepsin K Deficiency
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=1181463844
RD 2024/04/23
AB Pycnodysostosis,  an  inborn  error  of  bone  matrix  degradation,  results  from  the  deficient  activity  of  the  lysosomal  protease,  cathepsin  K,  in  the  osteoclasts  of  affected  individuals.  The  enzymatic  defect  leads  to  a  reduced  ability  of  osteoclasts  to  remove  organic  bone  matrix,  which  causes  defective  bone  growth  and  remodeling.  Partially  degraded  collagen  fibrils  are  found  in  lysosomes  within  osteoclasts  that  are  actively  resorbing  bone.The  disorder  is  transmitted  as  an  autosomal  recessive  trait  by  the  gene  encoding  cathepsin  K,  localized  to  chromosomal  region  1q21.  The  human  cathepsin  K  cDNA  and  genomic  sequences  have  been  isolated,  characterized,  and  used  to  analyze  the  mutations  causing  pycnodysostosis.  All  identified  defects  have  been  point  mutations  in  the  coding  region,  which  obliterate  the  collagenolytic  activity  of  the  mature  enzyme.Clinical  manifestations  include  short  stature,  a  typical  dysmorphic  appearance,  generalized  osteosclerosis,  dysplastic  bones  including  hypoplasia  of  the  distal  phalanges,  clavicles,  and  various  craniofacial  bones,  as  well  as  pathologic  fractures  and  dental  abnormalities.  Associated  complications  include  osteomyelitis  of  the  jaw,  upper  airway  obstruction,  growth  hormone  deficiency,  and  myelophthisis.  Life  span  is  normal,  although  disability  secondary  to  the  orthopedic  problems  may  cause  premature  demise.Diagnosis  is  usually  made  by  clinical  and  radiologic  examinations.  Demonstration  of  cathepsin  K  gene  defects  confirms  the  diagnosis.  Prenatal  diagnosis  can  be  accomplished  by  demonstration  of  the  specific  cathepsin  K  mutation(s)  in  chorionic  villi  or  cultured  amniotic  cells,  or  by  linkage  analysis  for  couples  known  to  be  cathepsin  K  mutation  carriers.Therapy  is  directed  at  preventing  or  ameliorating  the  orthopedic,  dental,  and  medical  complications.  Surgical  intervention  may  be  necessary  for  patients  with  significant  upper  airway  obstruction.  Growth  hormone  repletion  may  improve  linear  growth  for  individuals  with  growth  hormone  deficiency.