Microsoft Word - 75 2017.docx   Vol  5,  No  1  (2017)   ISSN  2167-­‐8677  (online)   DOI  10.5195/d3000.2017.75           http://dentistry3000.pitt.edu     New  articles  in  this  journal  are  licensed  under  a  Creative  Commons  Attribution  4.0  United  States  License.     This  journal  is  published  by  the  University  Library  System,  University  of  Pittsburgh  as  part  of  its  D-­‐Scribe  Digital  Publishing  Program  and  is  cosponored   by  the  University  of  Pittsburgh  Press.     Familial  inheritance  of  TMD:  a  case  report   Maria  Genello1      1University  of  Pi.sburgh,  School  of  Dental  Medicine Abstract   The  TMJ  is  a  joint  that  can  perform  both  hinge  and  sliding  mo'ons  and  whose  proper  func'oning  depends  on  the  ac-­‐ !ons  of  the  joint  and  joint  capsule,  the  muscles  of  mas!ca!on,  and  the  condi!on  and  ac&on  of  the  mandibular  con-­‐ dyle.   If  any  of  these  components  deviate  from  their  normal  structure  or  func0on,  then  TMD  can  result.  There  have   been  many  reported  contribu"ng  factors  to  TMD  development,  many  of  which  include  environmental  influences  such   as  bruxism,  trauma,  and  other  oral  habits.  However,  a  gene7c  component  can  also  play  a  role.  This  paper  reports  a   case  of  TMD  occurring  within  three  consecu3ve  genera3ons  of  a  family  and  explores  the  possibility  of  this  disorder   exhibi!ng  familial  inheritance.  Members  of  the  family  affected  all  displayed  manifesta'ons  of  joint  laxity  in  other  are-­‐ as   of   the   body,  migraines,   pain,   and   had   smaller   craniofacial   dimensions  with   a   narrower  mandible.   These   factors   were  found  to  have  a  gene/c  influence  and  these  genes  can  also  be  -ed  to  TMD,  thus  suppor-ng  the  argument  that   the  cases  of  TMD  seen  in  this  family  are  in  fact  due  to  inheritance.  If  TMD  can  be  shown  to  have  a  gene;c  component   and  be   inherited,   then  dental  prac//oners  would  be  able  to   iden/fy  high  risk  pa,ents  and  help  to  modify  environ-­‐ mental  factors  early  on  in  order  to  help  prevent  the  onset  of  TMD  in  those  individuals.   Cita%on:  Genello,  M.  (2017)  Familial  inheritance   of  TMD:  a  case  report.  Den$stry  3000.  1:a001   doi:10.5195/d3000.2017.75   Received:    May  15,  2017   Accepted:    May  26,  2017   Published:    June  16,  2017   Copyright:   ©2017   Genello,   M.   This   is   an   open   access   ar!cle   licensed   under   a   Crea!ve   Com-­‐ mons   A"ribu!on   Work   4.0   United   States   Li-­‐ cense.   Email:  mkg35@pi).edu   Introduction   The  TMJ  is  a  unique  bilateral   joint  that  connects  the  mandible  to   the  temporal  bone  [1].  It  performs   both  hinge  and  sliding  motions  which   allows  a  person  to  talk,  chew,  yawn,   and  open  the  mouth.  Some  of  the   component  parts  of  the  TMJ  include   the  mandibular  condyle,  the  glenoid   fossa  of  the  temporal  bone,  the  artic-­‐ ular  eminence  which  the  condyle   slides  down,  the  articulating  disc  be-­‐ tween  the  condyle  and  temporal   bone,  and  the  joint  capsule.  During   function,  the  condyle  glides  forward   from  the  fossa  and  down  the  articular   eminence.  The  disc  remains  between   the  condyle  and  these  other  elements   in  order  to  act  as  a  shock  absorber   [1].  A  disorder  of  the  TMJ,  termed   TMD,  can  affect  one  or  both  of  the   joints.  Manifestations  of  TMD  in-­‐ clude,  but  are  not  limited  to,  pain  in   the  face,  limited  movement  and  stiff-­‐ ness  of  the  jaw,  locking  of  the  jaw,   and  popping  or  clicking  of  the  joint   upon  opening  [1].  The  cause  of  TMD   has  been  attributed  to  many  different   factors,  a  large  portion  being  envi-­‐ ronmental.  These  include  trauma,   bruxism,  and  other  oral  habits.  A  ge-­‐ netic  component  is  being  explored,   and  many  different  genes  have  been   proposed  as  possible  candidates.     Case  Report   Three  generations  of  a  family   from  northeastern  Pennsylvania  were   analyzed  for  TMD.  The  disorder  ap-­‐ peared  in  each  generation,  and  ap-­‐ peared  to  affect  predominately  the   females  in  the  family.  In  generation   III,  two  males  appear  to  be  affected.   All  of  those  that  report  having   manifestations  of  TMD  have  the   common  feature  of  clicking  and   popping  upon  jaw  opening.  In   generation  one,  (will  refer  to  as   “female  A”),  the  affected  female  A   reports  having  symptoms  of  pop-­‐ ping  and  clicking,  along  with  mild   hip  and  knee  joint  laxity.  She  also   reports  mild  intermittent  jaw  pain   and  headaches.         In  generation  two,   three  females  (females  B,  C,  and  D   respectively)  are  affected  out  of   four,  and  50%  of  the  offspring  are   affected.  The  affected  females  all   report  jaw  clicking  and  popping   upon  opening,  with  female  B  re-­‐ porting  mild  intermittent  head-­‐ aches  and  occasional,  mild  jaw   pain.  Female  C  reports  clicking  and   popping  as  well.  She  suffers  from   migraine  headaches  that  occur   every  few  months.  She  has  laxity   in  her  left  knee  joint,  and  reports   frequent  jaw  pain  that  oftentimes   is  severe.  Her  jaw  mobility  fre-­‐ quently  becomes  restricted,  caus-­‐ ing  her  to  have  limited  opening.   Female  D  reports  clicking  and   popping,  along  with  mild  jaw  dis-­‐ location  when  she  opens  wider   than  her  normal  functional  range   (for  speaking,  chewing,  etc).  She   Familial  inheritance  of  TMD:  a  case  report   Vol  5,  No  1  (2017)        DOI  10.5195/d3000.2017.75    http://dentistry3000.pitt.edu   exhibits  mild  intermittent  jaw   pain.  This  same  female  D  also  re-­‐ ports  laxity  in  her  intervertebral   discs,  and  has  suffered  two   “slipped”  discs.  She  also  reports   more  severe  intermittent  head-­‐ aches.       In  generation  three,   four  members  are  affected,  two  of   which  are  males.  Male  A  is  the  off-­‐ spring  of  female  B,  and  presents   with  only  occasional  mild  clicking   and  popping  upon  opening.  Male   B  is  the  offspring  of  female  C,  and   reports  only  occasional  clicking   and  popping  that  is  mild.  Female   E,  who  is  the  offspring  of  female  C,   presents  with  clicking  and  popping   when  opening  the  jaw,  along  with   severe  left  shoulder  joint  laxity.   She  also  reports  occasional  mod-­‐ erate  headaches  and  mild,  inter-­‐ mittent  jaw  pain.  Female  F,  who  is   the  offspring  of  female  D,  reports   clicking  and  popping,  along  with   occasional  migraine  headaches   and  intermittent,  more  moderate   jaw  pain.  When  opening  past  func-­‐ tional  limits,  the  jaw  often  be-­‐ comes  dislocated.  She  also  exhib-­‐ its  laxity  to  her  intervertebral  discs   and  has  suffered  a  herniation,   along  with  laxity  to  her  hip  joint.     Of  the  affected  individuals,   all  but  male  B  have  smaller  vertical   and  horizontal  craniofacial  meas-­‐ urements,  with  a  narrow  mandi-­‐ ble.  Male  B  exhibits  a  wider,  less   constricted  mandible.       Discussion   TMD  proves  to  be  a  disor-­‐ der  of  variable  expression  and  has   many  different  manifestations.   Many  cases  of  TMD  have  a  strong   environmental  component,  how-­‐ ever,  genetic  elements  to  the  dis-­‐ ease  are  being  studied  and  sug-­‐ gested.  The  TMD  evident  in  this   family  appears  to  have  a  genetic   influence.    When  you  look  at  fig-­‐ ure  1,  one  sees  how  TMD  appears   to  be  present  in  all  three  genera-­‐ tions.  Mainly  females  are  affected,   with  the  ratio  being  6:2  females  to   males.  This  is  expected,  since  it  is   found  that  females,  especially   those  of  child  bearing  age,  are   more  susceptible  to  developing   TMD  and  have  more  severe  symp-­‐ toms  due  to  hormonal  differences   [2].     If  we  were  to  propose  the   most  common  mode  of  inher-­‐ itance  for  TMD,  it  would  most  like-­‐ ly  be  polygenic  inheritance  with   environmental  influences.  Since   the  TMJ  function  depends  on  a   multitude  of  factors  such  as  masti-­‐ catory  musculature,  articular  disc   formation  and  health,  integrity  of   the  joint  capsule,  shape  and  angle   of  the  condyle,  mandibular  size   and  development,  shape  of  the   glenoid  fossa,  integrity  of  the  car-­‐ tilage,  etc.,  any  variation  in  these   or  other  structures  that  influence   its  function  can  result  in  a  devia-­‐ tion  from  normal  and  lead  to  TMD.   Since  these  traits  are  all  controlled   by  many  and  different  genes  work-­‐ ing  together  in  order  to  achieve   proper  development  and  function,   it  would  be  safe  to  say  that  any   TMD  with  a  strong  genetic  com-­‐ ponent  would  be  polygenic,  mean-­‐ ing  there  would  be  variations  in   multiple  genes  that  influence  the   structures  relevant  to  the  TMJ.   This  can  also  account  for  the  vari-­‐ able  expression  of  TMD.  Since   many  different  genes  can  have   variations  that  lead  to  TMD,  not   just  a  single  gene,  and  different   environmental  factors,  and  not   just  a  single  environmental  factor,   can  aid  in  the  development  of   TMD,  then  the  expression  seen  in   the  population  of  TMD  would  be   variable.     In  this  family’s  case,  there-­‐ fore,  the  inheritance  is  most  likely   polygenic.  Those  affected  appear   to  have  a  myriad  of  symptoms   that  deal  with  different  aspects  of   the  TMJ,  and  the  expression  of   TMD  within  the  family  isn’t  com-­‐ pletely  uniform,  but  is  rather   somewhat  variable,  leading  us  to   believe  in  the  polygenic  theory.   Now,  if  we  are  speaking  in  terms   of  autosomal  dominance  and  re-­‐ cessiveness,  or  X-­‐linked  domi   Figure  1.  Pedigree  of  the  affected  family.  Blue  color  indicates  those  that  have  any  symptoms  pertaining  to   TMD,  whether  they  be  mild,  moderate,  or  severe.  Letters  are  used  as  identifiers  when  discussing  the  case.     Familial  inheritance  of  TMD:  a  case  report   Vol  5,  No  1  (2017)        DOI  10.5195/d3000.2017.75    http://dentistry3000.pitt.edu   nance  and  recessiveness,  it   is  most  likely  an  autosomal  domi-­‐ nant  inheritance  form.  It  appears   in  every  generation,  ruling  out  a   recessive  inheritance  pattern,  and   it  affects  both  males  and  females,   with  the  females  at  a  higher  in-­‐ stance,  leading  one  to  believe  that   it  is  not  X-­‐linked.       Now  that  we  have  estab-­‐ lished  that  it  is  likely  polygenic   with  an  autosomal  dominant  in-­‐ heritance  pattern,  we  must  make   the  case  that  it  is  in  fact  genetic   variations  that  exist  in  this  family   that  are  causing  these  clinical   manifestations  of  TMD,  and  these   variations  are  being  passed  from   one  generation  to  the  next.  The   genetics  behind  pain  perception   and  chronic  pain  have  become  an   area  of  interest  with  regards  to   TMD.  A  few  candidate  genes  have   been  highlighted,  which  includes   the  serotonin  5-­‐HT  transporter   gene  and  the  COMT  gene,  whose   activity  is  inversely  correlated  to   pain  sensitivity  and  the  develop-­‐ ment  of  TMD.  It  was  found  that   nearly  a  third  of  new  TMD  cases   reported  could  be  attributed  to   having  a  variation  in  the  COMT   gene  [2].  In  our  subjects  here,  we   saw  that  pain  was  a  common  fea-­‐ ture  in  all  three  generations,  rang-­‐ ing  from  mild  to  severe.  It  is  im-­‐ portant  to  note  that  those  with   more  manifestations  of  the  disor-­‐ der,  such  as  female  C  and  female   F,  experienced  more  severe  pain   than  the  others  that  were  affect-­‐ ed,  indicating  a  possible  correla-­‐ tion  between  pain  sensitivity  and   TMD  severity.     Another  important  finding   in  this  family  and  that  deals  with   chronic  pain  was  the  presence  of   headaches.  Numerous  studies   have  been  done  on  the  association   of  certain  genes  and  headaches.   Through  these  studies,  it  was   found  that  some  of  these  genes   not  only  predisposed  a  person  to   headaches  and  migraines,  but  to   TMD  as  well.  COMT  was  again  part   of  these  studies.  COMT  genetic   variations  were  involved  with  both   migraines  and  TMD.  DRD4  was   another  gene  that  is  involved  with   neurotransmission  and  that  was   associated  with  both  the  presence   of  headaches  and  the  manifesta-­‐ tion  of  TMD  [3].  Another  gene  of   interest  was  the  ESR1  gene,  which   variations  lead  to  the  presence  of   chronic  headaches  and  was  also   associated  with  TMD  manifesta-­‐ tions.  Studies  show  that  up  to  50%   of  migraine  and  chronic  headache   etiology  was  due  to  genetic  vari-­‐ ants  [3].  Headaches  were  present   in  all  female  cases  in  this  family,   and  ranged  from  mild  to  severe.   The  presence  of  this  shared  trait  in   all  of  the  affected  female  individu-­‐ als  could  be  due  to  genetic  varia-­‐ tion,  specifically  a  gene  that  not   only  deals  with  the  presence  of   headaches,  but  can  also  be  associ-­‐ ated  with  TMD  (like  COMT,  DRD4,   and  ESR1),  which  would  explain   the  concurrent  expression  of  both   TMD  and  chronic  headaches  in  all   of  the  affected  female  individuals.     Table  1.  Summary  of  clinical  findings.   Affected   Member   M/F   Clicking/Popping   Headaches   (mild,   mod.,   severe)   Systemic  joint   laxity/location   Pain   (mild,   mod.,   severe)   Movement   restrictions   A   Female   Yes   Yes;  mild   Yes;  hip  and   knee   Yes;  mild   No   B   Female   Yes   Yes;  mild   No   Yes;  mild   No   C   Female   Yes   Yes;  se-­‐ vere   Yes;  knee   Yes;   severe   Yes   D   Female   Yes   Yes;  se-­‐ vere   Yes;  IV  discs   Yes;  mild   yes   A   Male   Yes;  mild  and   occasional   No   No   No   No   B   Male   Yes;  mild  and   occasional   No   No   No   No   E   Female   Yes   Yes;  mod-­‐ erate   Yes;  shoulder   Yes;  mild   No   F   Female   Yes   Yes;  se-­‐ vere   Yes;  hip  and   IV  discs   Yes;   moderate   Yes   Familial  inheritance  of  TMD:  a  case  report   Vol  5,  No  1  (2017)        DOI  10.5195/d3000.2017.75    http://dentistry3000.pitt.edu   A  trait  that  many  of  the  af-­‐ fected  individuals  of  this  family   shared  was  that  of  systemic  joint   laxity.  Joints  affected  ranged  from   the  knee  and  hip  joints,  to  the   shoulder  joint  and  intervertebral   discs.  Systemic  laxity  of  joints  has   a  genetic  component.  There  are   certain  genes  that  control  the   amount  and  type  of  collagen  pro-­‐ duced  in  the  body.  Skin  biopsies  of   patients  with  joint  laxity  found   them  to  have  less  overall  collagen   and  a  higher  ratio  of  type  III  colla-­‐ gen  to  type  III+I  [4].  Those  with   systemic  joint  laxity  and  hypermo-­‐ bility  had  a  higher  incidence  of   TMD.    This  is  due  to  the  fact  that  if   the  joints  in  the  body  are  more   mobile  and  lax,  then  the  capsule   of  the  TMJ  would  also  be  lax,  mak-­‐ ing  the  disc  vulnerable  to  dis-­‐ placement  and  the  condyle  prone   to  hypermobility  [5].  So,  a  genetic   component  can  be  involved  in  the   joint  laxity  and  subsequent  TMD   seen  in  each  generation  of  this   family.   Another  important  feature   to  note  in  this  particular  family   was  the  smaller  craniofacial  di-­‐ mensions  and  narrower  mandible.   All  of  the  affected  individuals  but   one  have  a  narrower  and  smaller   face.  A  high  score  on  the   Helkimo’s  Clinical  Dysfunction  In-­‐ dex,  which  is  a  tool  used  to  assess   the  presence  and  severity  of  TMD,   was  found  in  patients  with  smaller   vertical  and  horizontal  facial  di-­‐ mensions  [6].  Facial  development   and  size  is  under  strict  genetic   control.  Any  variation  in  these  de-­‐ velopmental  genes  can  cause  vari-­‐ ations  in  the  size  and  shape  of  the   craniofacial  bones  and  their  rela-­‐ tionship  to  each  other,  which  can   lead  to  a  TMD.  The  variations  in   the  gene  pool  of  this  family  for  the   size  and  width  of  the  craniofacial   bones  could  be  a  factor  in  their   shared  TMD.   Conclusion   The  genetic  component  of   TMD,  while  not  as  extensively  ex-­‐ plored  as  the  environmental  as-­‐ pect,  presents  with  some  compel-­‐ ling  support.  Many  candidate   genes  have  been  identified  to  be   associated  with  the  development   of  TMD.  The  family  involved  in  this   case  report  saw  TMD  reported  in   three  consecutive  generations.   There  was  some  variation  in  the   expression  of  the  disorder,  but   most  of  those  affected  had  clicking   and  popping  of  the  joint,  along   with  systemic  joint  laxity,  head-­‐ aches,  and  pain.  Smaller  craniofa-­‐ cial  dimensions  were  also  a  com-­‐ mon  feature  seen.  All  of  these  fea-­‐ tures  have  a  genetic  component   that  can  also  be  tied  to  TMD.   Therefore,  the  conclusion  is  that   the  TMD  seen  in  three  consecutive   generations  of  this  family  is  the   result  of  genetic  variation  and  is   inherited.  Furthermore,  by   demonstrating  a  genetic  basis  for   many  cases  of  TMD,  gene  mapping   can  be  done  in  those  families  or  in   individuals  thought  to  have  a   higher  susceptibility  for  TMD,  and   thus  analyze  the  genes  involved   and  the  risk  of  either  developing  a   TMD  or  the  risk  of  offspring  ac-­‐ quiring  TMD.  If  a  dental  practi-­‐ tioner  is  made  aware  of  a  patient’s   risk  of  TMD,  then  steps  can  be   taken  early  on  to  modify  said  pa-­‐ tient’s  environmental  factors  (such   as  reducing  bruxism,  clenching  of   teeth,  etc.)  in  an  effort  to  try  to   prevent  or  delay  the  onset  of   TMD.     References   1.  TMJ  disorders.  National  Insti-­‐ tute  of  Dental  and  Craniofacial  Re-­‐ search.  [cited  March  4,  2017]   Available  from   https://www.nidcr.nih.gov/oralhe alth/topics/tmj/tmjdisorders.htm# symptoms.     2.  The  many  faces  of  the  genetics   contribution  to  temporomandibu-­‐ lar  joint  disorder.  Oakley  M,  Vieira   AR.  Orthod  Craniofac  Res.  2008   Aug;11(3):125–135.  PMID:   18713149.   3.  Genetic  predictors  of  human   chronic  pain  conditions.  Zorina-­‐ Lichtenwalter  K,  Meloto  CB,   Khoury  S,  Diatchenko  L.  Neurosci-­‐ ence.  2016  Dec;338:36–62.  PMID:   27143481.   4.  Temporomandibular  joint  dys-­‐ function  and  systemic  joint  laxity.   Westling  L.  Swedish  Dental  Journal   Supplement.  1992;81:1-­‐79.  PMID:   1621231   5.  The  role  of  systemic  hypermo-­‐ bility  and  condylar  hypermobility   in  temporomandibular  joint  dys-­‐ function.  Kavuncu,  V.,  Sahin,  S.,   Kamanli,  A.  et  al.  Rheumatol  Int.   2006  Jan;26(3):  257-­‐60.  PMID:   15988598   6.  Temporomandibular  disorders   in  relation  to  craniofacial  dimen-­‐ sions,  head  posture  and  bite  force   in  children  selected  for  orthodon-­‐ tic  treatment.  Liselotte  Sonnesen,   Merete  Bakke,  Beni  Solow.  Eur  J   Familial  inheritance  of  TMD:  a  case  report   Vol  5,  No  1  (2017)        DOI  10.5195/d3000.2017.75    http://dentistry3000.pitt.edu   Orthod.  2001  Apr;23(2):  179-­‐192.   PMID:11398555