Microsoft Word - Black Proof 3-23.docx


	
  

Vol	
  3,	
  No	
  1	
  (2015)	
  
ISSN	
  2167-­‐8677	
  (online)	
  

DOI	
  10.5195/d3000.2015.31 	
  	
  

	
  

	
  

	
  

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	
  aggregation	
  of	
  phenotypic	
  expression	
  of	
  premature	
  hair	
  hy-­‐
popigmentation	
  in	
  the	
  craniofacial	
  region	
  
Corey	
  L.	
  Black1	
  
	
  
1	
  University	
  of	
  Pittsburgh	
  School	
  of	
  Dental	
  Medicine,	
  Pittsburgh	
  PA,	
  USA	
  
	
  

Abstract	
  

There	
  are	
  many	
  pa+ents	
  who	
  experience	
  premature	
  hypopigmenta+on	
  of	
  hair,	
  but	
  do	
  not	
  
understand	
  the	
  underlying	
  causes	
  and	
  poten2al	
  dangers	
  associated	
  with	
  them.	
  The	
  causes	
  
range	
  from	
  gene*c	
  predisposi*on	
  to	
  environmental	
  influences	
  such	
  as	
  tobacco	
  use.	
  Prema-­‐
ture	
  hypopigmenta/on	
  of	
  the	
  hair	
  sha2	
  can	
  also	
  be	
  associated	
  with	
  many	
  syndromes;	
  some	
  
which	
  cause	
  dental	
  anomalies.	
  Today,	
  treatment	
  op6ons	
  are	
  limited	
  for	
  pa6ents,	
  although	
  
various	
  studies	
  are	
  being	
  done	
  on	
  mice	
  to	
  target	
  the	
  underlying	
  mechanism	
  of	
  ac4on.	
  Un-­‐
derstanding	
  the	
  differences	
  between	
  all	
  of	
  the	
  possible	
  causes	
  of	
  this	
  par5cular	
  phenotype	
  
can	
   help	
   clinicians	
   be,er	
   iden/fy	
   the	
   symptoms,	
   educate	
   pa/ents,	
   and	
   possibly	
   modify	
  
treatment	
  to	
  suit	
  the	
  needs	
  of	
  each	
  pa1ent	
  on	
  an	
  individual	
  basis.	
  

	
  

	
  
Cita%on:	
  Black,	
  C.	
  (2015)	
  Familial	
  aggrega*on	
  of	
  
phenotypic	
   expression	
   of	
   premature	
   hair	
   hy-­‐
popigmenta!on	
   in	
   the	
   craniofacial	
   region.	
  Den-­‐
!stry	
  3000.	
  1:a001	
  doi:10.5195/d3000.2015.31	
  
Received:	
  March	
  18,	
  2015	
  
Accepted:	
  March	
  ,	
  2015	
  
Published:	
  April	
  7	
  ,	
  2015	
  
Copyright:	
  ©2015	
  Black.	
   This	
   is	
   an	
  open	
  access	
  
ar!cle	
   licensed	
   under	
   a	
   Crea!ve	
   Commons	
  
A!ribu%on	
  Work	
  4.0	
  United	
  States	
  License.	
  
Email:	
  clb196@pi*.edu

	
  
	
  
Introduction	
  
	
  
	
   Determination	
  of	
  the	
  color	
  
of	
  hair	
  is	
  a	
  complicated	
  process.	
  
There	
  are	
  genes	
  that	
  dictate	
  color,	
  
texture,	
  distribution,	
  and	
  number	
  of	
  
stem	
  cells	
  [1].	
  Gray	
  hair,	
  also	
  known	
  
as	
  canities,	
  is	
  a	
  phenotypic	
  manifes-­‐
tation	
  of	
  a	
  process	
  in	
  while	
  melano-­‐
cytes	
  within	
  hair	
  follicles	
  stop	
  pro-­‐
ducing	
  melanin.	
  For	
  unknown	
  rea-­‐
sons,	
  this	
  process	
  occurs	
  with	
  most	
  
individuals	
  as	
  the	
  aging	
  process	
  
proceeds.	
  However,	
  with	
  a	
  fair	
  
number	
  of	
  individuals,	
  the	
  process	
  
of	
  pigmentation	
  of	
  the	
  hair	
  shaft	
  
begins	
  much	
  sooner	
  than	
  the	
  aver-­‐
age	
  individual.	
  	
  Hair	
  is	
  said	
  to	
  gray	
  
prematurely	
  when	
  it	
  occurs	
  before	
  
the	
  age	
  of	
  20	
  in	
  whites,	
  25	
  in	
  Asians	
  
and	
  30	
  in	
  Africans	
  [1].	
  There	
  have	
  

been	
  many	
  proposed	
  causes	
  of	
  gray	
  
hair	
  including	
  stress,	
  cigarette	
  
smoking,	
  nutritional	
  deficiencies,	
  
genetics,	
  and	
  a	
  variety	
  of	
  syn-­‐
dromes. 	
  It	
  is	
  important	
  for	
  a	
  clini-­‐
cian	
  to	
  understand	
  the	
  many	
  possi-­‐
bilities	
  of	
  this	
  phenotype	
  in	
  order	
  to	
  
be	
  able	
  to	
  identify	
  patients	
  who	
  may	
  
display	
  premature	
  canities.	
  
	
  
	
  Case	
  Report	
  
	
   	
  	
  
	
   An	
  18-­‐year-­‐old	
  African	
  
American	
  male,	
  individual	
  II.2	
  (Fig-­‐
ure	
  1)	
  began	
  to	
  experience	
  canities	
  
prior	
  to	
  college	
  admission	
  in	
  July	
  of	
  
2007.	
  The	
  patient	
  noticed	
  two	
  gray	
  
hairs	
  in	
  the	
  center	
  of	
  his	
  scalp.	
  Be-­‐
lieving	
  that	
  they	
  may	
  have	
  been	
  
caused	
  by	
  stress,	
  he	
  left	
  them	
  alone	
  
and	
  started	
  to	
  use	
  stress	
  reduction	
  

techniques	
  such	
  as	
  exercise	
  and	
  
constant	
  breaks	
  when	
  studying.	
  He	
  
also	
  started	
  to	
  take	
  a	
  multi-­‐vitamin	
  
to	
  ensure	
  that	
  the	
  presentation	
  of	
  
the	
  gray	
  hairs	
  was	
  not	
  due	
  to	
  a	
  B-­‐12	
  
or	
  iron	
  deficiency.	
  However,	
  as	
  the	
  
years	
  progressed,	
  the	
  number	
  of	
  
gray	
  hairs	
  continued	
  to	
  increase	
  at	
  a	
  
rate	
  of	
  approximately	
  10-­‐15	
  hairs	
  
per	
  year.	
  At	
  the	
  age	
  of	
  22,	
  the	
  phe-­‐
notypic	
  expression	
  of	
  the	
  gray	
  hairs	
  
extended	
  to	
  his	
  facial	
  hair,	
  including	
  
a	
  few	
  hairs	
  along	
  the	
  jaw	
  line	
  and	
  a	
  
significant	
  amount	
  extending	
  across	
  
the	
  anterior	
  region	
  of	
  the	
  neck.	
  
Within	
  a	
  span	
  of	
  8	
  years,	
  the	
  num-­‐
ber	
  of	
  hypopigmented	
  hairs	
  in-­‐
creased	
  from	
  2	
  to	
  approximately	
  80	
  
(Figure	
  2).	
  



	
  	
  Familial	
  aggrega*on	
  of	
  phenotypic	
  expression	
  of	
  premature	
  hair	
  hypopigmenta/on	
  in	
  the	
  craniofacial	
  region	
  

Vol	
  3,	
  No	
  1	
  (2015)	
  	
  	
  	
  DOI	
  10.5195/d3000.2015.31 	
  

	
  http://dentistry3000.pitt.edu	
  
2	
  

	
   The	
  patient’s	
  medical	
  histo-­‐
ry	
  was	
  negative	
  for	
  any	
  major	
  sys-­‐
temic	
  disease.	
  There	
  were	
  no	
  medi-­‐
cations,	
  other	
  than	
  antibiotics	
  and	
  

multivitamins.	
  He	
  annually	
  visits	
  a	
  
primary	
  care	
  physician	
  and	
  had	
  no	
  
major	
  hospitalizations.	
  The	
  patient	
  
has	
  a	
  family	
  history	
  of	
  cancer,	
  hy-­‐
pertension,	
  and	
  diabetes	
  on	
  the	
  ma-­‐
ternal	
  side.	
  There	
  is	
  a	
  history	
  of	
  
heart	
  and	
  liver	
  disease	
  on	
  the	
  pa-­‐
ternal	
  side.	
  	
  
	
   When	
  examining	
  the	
  family	
  
history	
  of	
  the	
  patient,	
  it	
  appears	
  
that	
  the	
  male	
  progeny	
  within	
  the	
  
immediate	
  generation	
  are	
  affected	
  
by	
  hypopigmentation	
  of	
  the	
  hair	
  
follicles	
  of	
  the	
  craniofacial	
  area.	
  Af-­‐
ter	
  consulting	
  with	
  his	
  father,	
  it	
  was	
  
revealed	
  that	
  the	
  father	
  of	
  the	
  pa-­‐
tient	
  was	
  affected	
  by	
  the	
  same	
  phe-­‐
notype	
  of	
  premature	
  hypopigmen-­‐
tation	
  at	
  the	
  age	
  of	
  20.	
  There	
  was	
  a	
  
similar	
  manifestation	
  of	
  the	
  initial	
  
hypopigmentation	
  appearing	
  in	
  the	
  
scalp	
  and	
  subsequent	
  hypopigmen-­‐
tation	
  in	
  the	
  anterior	
  region	
  of	
  the	
  
neck.	
  	
  
	
   The	
  individual	
  II.1,	
  a	
  direct	
  
male	
  descendant	
  of	
  I.1,	
  also	
  experi-­‐
enced	
  a	
  similar	
  phonotypical	
  mani-­‐
festation.	
  However,	
  the	
  hypopig-­‐

mentation	
  appeared	
  only	
  in	
  the	
  an-­‐
terior	
  neck	
  region	
  and	
  began	
  at	
  the	
  
age	
  of	
  25	
  (Figure	
  2).	
  This	
  may	
  be	
  
explained	
  by	
  variable	
  expressivity	
  

when	
  compared	
  to	
  the	
  early	
  presen-­‐
tation	
  of	
  this	
  phenotype	
  at	
  age	
  18	
  in	
  
individual	
  II.2.	
  Individual	
  II.1	
  also	
  
experienced	
  male	
  pattern	
  baldness	
  
at	
  the	
  age	
  of	
  22.	
  Therefore,	
  it	
  is	
  un-­‐
clear	
  whether	
  the	
  follicles	
  on	
  the	
  
scalp	
  were	
  affected	
  by	
  hypopigmen-­‐
tation.	
  Individual	
  I.1	
  also	
  has	
  anoth-­‐

er	
  son	
  from	
  a	
  previous	
  marriage	
  
who	
  is	
  also	
  affected	
  by	
  hypopig-­‐
mentation.	
  It	
  is	
  unsure	
  at	
  what	
  age	
  
the	
  phenotype	
  was	
  expressed;	
  how-­‐
ever	
  it	
  was	
  before	
  the	
  age	
  of	
  30,	
  

which	
  is	
  considered	
  premature.	
  	
  
The	
  patient’s	
  sister,	
  individual	
  II.3	
  
does	
  not	
  express	
  any	
  symptoms	
  of	
  
hypopigmentation	
  (Figure	
  1).	
  	
  
	
  
Discussion	
  
	
  
 Today,	
  the	
  exact	
  mechanism	
  
of	
  canities	
  is	
  unknown.	
  However,	
  
when	
  considering	
  the	
  underlying	
  
cause	
  of	
  premature	
  hypopigmenta-­‐
tion,	
  one	
  must	
  consider	
  multiple	
  
mechanisms,	
  encompassing	
  envi-­‐
ronmental,	
  systemic,	
  and	
  genetic	
  
factors.	
  Also,	
  the	
  expressivity	
  of	
  the	
  
phenotype	
  varies	
  for	
  each	
  individu-­‐
al.	
  In	
  this	
  case,	
  there	
  seems	
  to	
  be	
  a	
  
strong	
  genetic	
  link,	
  originating	
  from	
  
the	
  paternal	
  side	
  of	
  the	
  family.	
  
	
   From	
  a	
  genetic	
  standpoint,	
  
premature	
  graying	
  of	
  hair	
  occurs	
  
more	
  commonly	
  without	
  any	
  under-­‐
lying	
  pathology	
  but	
  it	
  is	
  thought	
  to	
  
be	
  inherited	
  in	
  autosomal	
  dominant	
  
pattern	
  [2].	
  It	
  appears	
  that	
  the	
  gen-­‐
otype	
  is	
  one	
  that	
  includes	
  multiple	
  
genes	
  and	
  peptides	
  that	
  affect	
  the	
  
enzymes	
  responsible	
  for	
  melanin	
  
production.	
  	
  
	
   The	
  activity	
  of	
  the	
  tyrosi-­‐
nase	
  enzyme	
  is	
  thought	
  to	
  be	
  crucial	
  
in	
  this	
  process.	
  One	
  study	
  observed	
  

the	
  melanin	
  in	
  albino-­‐mouse	
  hair	
  
follicles.	
  In	
  this	
  study,	
  a	
  point	
  muta-­‐
tion	
  in	
  the	
  tyrosinase	
  gene	
  was	
  cor-­‐
rected	
  in	
  some	
  of	
  the	
  murine	
  folli-­‐
cles	
  with	
  RNA-­‐DNA	
  chimeric	
  oligo-­‐

Figure	
  1.	
  A	
  pedigree	
  shows	
  that	
  the	
  males	
   in	
  generations	
   II	
  and	
   I	
  are	
  affected	
  by	
  
premature	
  hypopigmentation.	
  Individual	
  II.4	
  is	
  also	
  affected,	
  regardless	
  of	
  the	
  fact	
  
that	
  his	
  maternal	
  genome	
  differs	
  from	
  the	
  other	
  progeny	
  in	
  the	
  second	
  generation.	
  
The	
  individual	
  of	
  the	
  case	
  report,	
  II.2	
  is	
  demarcated	
  with	
  a	
  “star”.	
  
	
  

Figure	
  2.	
  The	
  photo	
  on	
  the	
  left	
  is	
  individual	
  II.1	
  shown	
  in	
  the	
  pedigree.	
  The	
  pho-­‐
to	
  on	
  the	
  right	
  is	
  individual	
  II.2.	
  	
  

	
  



	
  	
  Familial	
  aggrega*on	
  of	
  phenotypic	
  expression	
  of	
  premature	
  hair	
  hypopigmenta/on	
  in	
  the	
  craniofacial	
  region	
  

Vol	
  3,	
  No	
  1	
  (2015)	
  	
  	
  	
  DOI	
  10.5195/d3000.2015.31 	
  

	
  http://dentistry3000.pitt.edu	
  
3	
  

nucleotides.	
  A	
  recombinant	
  retrovi-­‐
rus	
  (pLmelSN)	
  from	
  the	
  locus	
  of	
  
Streptomyces	
  Antibioticus	
  genome	
  
was	
  used	
  to	
  induce	
  melanin	
  produc-­‐
tion	
  in	
  vitro	
  [3].	
  These	
  results	
  indi-­‐
cate	
  that	
  the	
  tyrosinase	
  inactivity	
  
may	
  be	
  a	
  possible	
  link	
  to	
  hair	
  hy-­‐
popigmentation	
  and	
  some	
  factors	
  
may	
  cause	
  the	
  premature	
  inactiva-­‐
tion	
  of	
  these	
  enzymes.	
  	
  
	
   Because	
  the	
  hair	
  cycle	
  and	
  
growth	
  process	
  are	
  complicated,	
  it	
  
makes	
  it	
  difficult	
  to	
  study	
  specific	
  
aspects	
  of	
  the	
  cycle	
  –	
  especially	
  
melanin	
  production.	
  However,	
  oth-­‐
er	
  genes	
  are	
  thought	
  to	
  be	
  involved	
  
in	
  this	
  very	
  complex	
  process.	
  It	
  is	
  
suspected	
  that	
  mice	
  deficient	
  in	
  Bcl-­‐
2	
  and	
  Bcl-­‐x	
  genes	
  are	
  normal	
  at	
  
birth	
  but	
  develop	
  gray	
  hair	
  after	
  a	
  
few	
  weeks	
  [2].	
  Also,	
  a	
  germ	
  line	
  mu-­‐
tation	
  in	
  Syntaxin	
  17	
  gene	
  in	
  horses	
  
causes	
  premature	
  gray	
  hair	
  in	
  the	
  
homozygous	
  genotype	
  [4].	
  Based	
  on	
  
the	
  patient’s	
  medical	
  and	
  family	
  his-­‐
tory,	
  there	
  seems	
  to	
  be	
  a	
  strong	
  ge-­‐
netic	
  link	
  to	
  the	
  cause	
  of	
  this	
  partic-­‐
ular	
  phenotype.	
  
	
  
	
   There	
  are	
  many	
  diseases,	
  
deficiencies,	
  and	
  syndromes	
  that	
  
have	
  been	
  linked	
  to	
  premature	
  hy-­‐
popigmentation	
  of	
  hair.	
  Some	
  of	
  
these	
  include	
  Vitiligo,	
  Werner’s	
  
syndrome,	
  thyroid	
  disease,	
  vitamin	
  
B12,	
  iron,	
  and	
  calcium	
  deficiencies.	
  
One	
  syndrome,	
  known	
  as	
  Book’s	
  
syndrome,	
  contains	
  hypodontia	
  and	
  
premature	
  graying	
  as	
  phenotypic	
  
traits	
  [2].	
  Clinicians	
  should	
  be	
  
aware	
  of	
  this	
  syndrome	
  and	
  its	
  pos-­‐
sible	
  physical	
  manifestations.	
  The	
  
patient	
  has	
  no	
  known	
  syndromes	
  or	
  
deficiencies.	
  Therefore,	
  it	
  is	
  unlikely	
  
that	
  this	
  is	
  the	
  cause	
  of	
  the	
  pheno-­‐
type.	
  
	
   The	
  environment	
  can	
  also	
  
play	
  a	
  crucial	
  role	
  in	
  early	
  hy-­‐
popigmentation	
  of	
  hair.	
  Studies	
  
suggest	
  that	
  there	
  is	
  a	
  significant	
  
association	
  between	
  tobacco	
  use	
  
and	
  aging	
  on	
  graying	
  of	
  hair	
  [5].	
  
Another	
  study	
  suggests	
  that	
  prema-­‐

ture	
  graying	
  of	
  the	
  hair	
  is	
  associated	
  
with	
  premature	
  cardiovascular	
  dis-­‐
ease.	
  It	
  should	
  probably	
  be	
  regard-­‐
ed	
  as	
  a	
  coronary	
  risk	
  factor	
  and	
  
used	
  to	
  identify	
  patients	
  at	
  in-­‐
creased	
  risk	
  [5].	
  These	
  environmen-­‐
tal	
  influences	
  should	
  be	
  explained	
  
to	
  patients	
  who	
  may	
  not	
  contain	
  
such	
  relevant	
  knowledge.	
  Since	
  car-­‐
diovascular	
  disease	
  is	
  present	
  in	
  the	
  
family	
  medical	
  history,	
  it	
  should	
  be	
  
explained	
  to	
  the	
  patient	
  that	
  there	
  
may	
  be	
  a	
  possible	
  link	
  between	
  
premature	
  canities	
  and	
  heart	
  dis-­‐
ease.	
  Hence,	
  future	
  testing	
  should	
  
be	
  done.	
  
	
  
Conclusion	
  
	
  
Clinicians	
  must	
  be	
  able	
  to	
  recognize	
  
premature	
  hypopigmentation	
  of	
  
hair	
  and	
  understand	
  the	
  many	
  
causes	
  of	
  it.	
  The	
  ultimate	
  goal	
  is	
  to	
  
know	
  that	
  the	
  hypopigmentation	
  
phenotype	
  can	
  be	
  explained	
  by	
  a	
  
number	
  of	
  factors.	
  In	
  order	
  to	
  un-­‐
derstand	
  the	
  exact	
  cause,	
  clinicians	
  
must	
  ask	
  the	
  appropriate	
  questions,	
  
comprehending	
  that	
  the	
  physical	
  
appearance	
  of	
  a	
  few	
  premature	
  gray	
  
hairs	
  can	
  provide	
  information	
  about	
  
unknown	
  underlying	
  factors.	
  	
  Once	
  
the	
  real	
  cause	
  is	
  known,	
  treatment	
  
may	
  be	
  modified	
  to	
  ensure	
  that	
  the	
  
patient	
  receives	
  the	
  best	
  quality	
  of	
  
care	
  when	
  under	
  the	
  care	
  of	
  that	
  
particular	
  clinician.	
  	
  
	
  
References	
  
	
  
1.	
  Epidemiological	
  and	
  investigative	
  
study	
  of	
  premature	
  graying	
  of	
  hair	
  
in	
  higher	
  secondary	
  and	
  pre-­‐
university	
  school	
  children.	
  Bhat	
  
RM,	
  Sharma	
  R,	
  Pinto	
  AC,	
  Dandekeri	
  
S,	
  Martis	
  J.	
  Int	
  J	
  Trichology.	
  2013	
  
Jan;5(1):17-­‐21.	
  doi:	
  10.4103/0974-­‐
7753.114706.	
  PMID:23960391	
  	
  
	
  
2.	
  Tobin,	
  D.	
  &	
  Trueb,	
  R.	
  (2010).	
  Nat-­‐
ural	
  Hair	
  Graying.	
  In	
  Aging	
  Hair	
  (pp.	
  

208-­‐210).	
  New	
  York,	
  New	
  York:	
  
Springer	
  Science	
  &	
  Business	
  Media.	
  
	
  
3.	
  The	
  hair	
  follicle	
  and	
  its	
  stem	
  cells	
  
as	
  drug	
  delivery	
  targets.	
  Hoffman	
  
RM.	
  Expert	
  Opin	
  Drug	
  Deliv.	
  2006	
  
May;3(3):437-­‐43.	
  Review.	
  
PMID:16640502	
  
	
  
4.	
  Polymorphisms	
  in	
  the	
  syntaxin	
  
17	
  gene	
  are	
  not	
  associated	
  with	
  
human	
  cutaneous	
  malignant	
  mela-­‐
noma.	
  Zhao	
  ZZ,	
  Duffy	
  DL,	
  Thomas	
  
SA,	
  Martin	
  NG,	
  Hayward	
  NK,	
  Mont-­‐
gomery	
  GW.	
  Melanoma	
  Res.	
  2009	
  
Apr;19(2):80-­‐6.	
  doi:	
  
10.1097/CMR.0b013e328322fc45.	
  
PMID:19209086	
  
	
  
5.	
  Premature	
  hair	
  graying:	
  a	
  proba-­‐
ble	
  coronary	
  risk	
  factor.	
  Gould	
  L,	
  
Reddy	
  CV,	
  Oh	
  KC,	
  Kim	
  SG,	
  Becker	
  W.	
  
Angiology.	
  1978	
  Nov;29(11):800-­‐3.	
  
PMID:727561