An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor α.
BACKGROUND
The first human cases (female, age 6 y; father and daughter, ages 47 and 11 y, respectively) with growth retardation/short stature, skeletal dysplasia, constipation, and defective thyroid receptor α (TRα) have been recently described.


OBJECTIVE
A 45-year-old, short, overweight female with cognitive impairment, epilepsy, and constipation was investigated.


METHODS
Clinical, biochemical, and radiological assessment and THRA sequencing were undertaken. The patient's thyroid status and her biochemical and physiological parameters were evaluated at baseline and after T4 therapy.


RESULTS
The patient exhibits disproportionate short stature, macrocephaly, low free T4/free T3 ratio and rT3 levels, together with subnormal heart and basal metabolic rate. She is heterozygous for a novel frameshift/premature stop (Ala382ProfsX7) THRA mutation, generating a mutant TRα with constitutive corepressor binding and negligible coactivator recruitment, which inhibits its wild-type counterpart in a dominant-negative manner-both in vitro and in mutation-containing patient blood mononuclear cells studied ex vivo. Her alertness and constipation responded to T4 therapy, which readily suppressed TSH levels, raised basal metabolic rate, and normalized elevated muscle creatine kinase, but cardiac parameters (heart rate, contractility) remained relatively refractory. The patient and a previous childhood case showed reduced red cell mass with macrocytosis unresponsive to T4 therapy.


CONCLUSIONS
Clinical (short stature, macrocephaly, constipation) and biochemical (low free T4/free T3 ratio, subnormal rT3) findings that are congruent with previous cases and newly recognized features (epilepsy) in this adult female with defective TRα define a shared phenotype in TRα-mediated resistance to thyroid hormone, with differential tissue responses to T4 treatment.
University of Cambridge, Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom. kkc1@medschl.cam.ac.uk.
Carla
C
Moran
Nadia
N
Schoenmakers
Maura
M
Agostini
Erik
E
Schoenmakers
Amaka
A
Offiah
Anna
A
Kydd
George
G
Kahaly
Susan
S
Mohr-Kahaly
Odelia
O
Rajanayagam
Greta
G
Lyons
Nicholas
N
Wareham
David
D
Halsall
Mehul
M
Dattani
Stephen
S
Hughes
Mark
M
Gurnell
Soo-Mi
SM
Park
Krishna
K
Chatterjee
D004351:Drug Resistance / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism / Q000627:therapeutic use*
D037021:Thyroid Hormone Receptors alpha; D013974:Thyroxine