TY  - CHAP
M1  - Book, Section
TI  - Thyroid Disorders
A1  - Refetoff, Samuel
A1  - Dumont, Jacques
A1  - Vassart, Gilbert
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  - Synthesis,  storage,  secretion,  delivery,  action,  and  metabolism  of  the  thyroid  hormones  involve  a  complex  sequence  of  molecular  events,  for  which  a  number  of  the  genes  involved  are  known.  Thyroid  diseases  may  result  from  impairments  at  many  steps  in  this  process.  Defects  may  be  classified  as  resulting  from  anomalies  within  the  thyroid  gland  (dyshormonogenesis),  in  the  development  of  the  thyroid  anlage  (thyroid  dysgenesis),  in  the  transport  of  thyroid  hormones,  in  target  tissues  of  thyroid  hormones  (thyroid  hormone  resistance),  or  in  the  regulatory  hypothalamo-pituitary  circuit.Defects  involving  genes  expressed  in  the  thyroid  gland  may  be  responsible  for  a  series  of  different  phenotypes.  Gain  of  function  mutations  of  the  thyrotropin  receptor  cause  autosomal  dominant  toxic  thyroid  hyperplasia,  or  sporadic  (neonatal)  toxic  thyroid  hyperplasia,  depending  on  whether  the  mutation  is  transmitted  from  one  parent  or  is  a  new  mutation.  Loss-of-function  mutations  in  any  of  the  genes  encoding  proteins  implicated  directly  or  indirectly  in  thyroid  hormone  synthesis,  cause  hypothyroidism,  usually  associated  with  goiter  secondary  to  hyperstimulation  by  thyrotropin  (congenital  goiter).  Mutations  of  this  type  have  been  found  in  the  sodium-iodide  symporter  (trapping  defects),  thyroglobulin  (coupling  defects),  and  thyroperoxidase  and  pendrin  (organification  defects).  In  all  these  instances,  transmission  is  autosomal  recessive  and,  except  for  the  last  one,  the  disease  is  nonsyndromic.  Mutations  of  pendrin  cause  hypothyroidism  associated  with  sensorineural  deafness.  Additional  mutations  are  expected  to  be  found  in  the  genes  responsible  for  H2O2  generation  (an  additional  cause  of  organification  defect),  and  in  iodotyrosine  deiodinase.Inadequate  regulation  of  thyroid  function  by  thyrotropin  causes  a  decrease  in  thyroid  function  (synthesis  and  secretion  of  thyroid  hormone)  and  growth  (thyroid  hypoplasia).  This  may  result  from  defects  at  the  hypothalmo-pituitary  level  (central  hypothyroidism),  secondary  to  mutations  in  a  series  of  developmental  genes  (PIT1,  PROP1)  required  for  normal  growth  and  function  of  thyrotrophs.  Mutations  directly  affecting  the  TRH  receptor  or  thyrotropin  beta  genes  also  cause  congenital  hypothyroidism  with  thyroid  hypoplasia.  Similarly,  but  at  the  thyroid  level,  loss-of-function  mutations  of  the  TSH  receptor  gene  cause  variable  levels  of  resistance  to  thyrotropin,  the  more  severe  cases  presenting  with  congenital  hypothyroidism  and  thyroid  hypoplasia.Thyroid  dysgenesis  is  responsible  for  the  majority  of  cases  with  congenital  hypothyroidism  (85%).  It  encompasses  a  series  of  developmental  defects  affecting  the  thyroid  gland,  whose  common  characteristic  is  an  inadequate  amount  of  functional  thyroid  tissue.  The  situation  is  anatomically  (and  probably  genetically)  heterogeneous,  presenting  as  thyroid  aplasia  (agenesis),  hypoplasia,  ectopy,  or  hemiagenesis.  Most  cases  are  sporadic  (~1/3500  newborn)  which  poses  the  unresolved  problem  of  the  genetic  or  environmental  cause  of  the  disease.  In  a  handful  of  cases,  a  mutation  has  been  identified  in  genes  implicated  in  the  development  of  the  gland:  PAX8  and  TTF2.  In  the  latter,  hypothyroidism  is  part  of  a  complex  syndrome  with  choanal  atresia,  cleft  palate,  and  kinky  hairs  (Bamforth  syndrome),  reflecting  the  multiple  sites  of  normal  TTF2  expression.Since  only  free  thyroid  hormones  are  responsible  for  the  effects  on  target  tissues  (including  the  hypothalamus  and  the  thyrotrophs),  mutations  in  the  proteins  implicated  in  the  transport  of  thyroid  hormones  in  the  blood  (thyroid  binding  globulin  (TBG);  transthyretin;  albumin)  are  responsible  only  for  anomalies  of  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1170103757
ER  -