Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha

Louise Koren Dahll; Alexander Bauer Westbye; Kristin Vinorum; Yngve Sejersted; Tuva Barøy; Per Medbøe Thorsby; Sara Salehi Hammerstad

Disclosures

J Endo Soc. 2023;7(8)

Abstract and Introduction

Abstract

Background: Thyroid hormone resistance due to pathogenic variants in thyroid hormone receptor alpha (THRA) is rare and descriptions of patients are sparse. The disorder is probably underdiagnosed as patients may have normal thyroid function tests. Treatment with thyroxine in childhood improves clinical symptoms. However, it is not clear if treatment has beneficial effects if started in adulthood.

Cases: We investigated 4 previously untreated Caucasian adult first-degree-related patients with the THRA c.788C > T, p.(Ala263Val) variant identified by a gene panel for intellectual disability in the index patient. Clinical data and previous investigations were obtained from medical reports.

Results: During childhood and adolescence, short stature, short limbs, metacarpals, and phalanges, and delayed bone age maturation were observed. Delayed motor and language development and decreased intellectual and learning abilities were described. Abdominal adiposity, round face, and increased head circumference were common features. All individuals complained of tiredness, constipation, and low mood. While thyrotropin (TSH) and free thyroxine (FT4) were within the reference range, free triiodothyronine (FT3) was high. FT4/FT3 ratio and reverse T3 were low. Other main features were low hemoglobin and high LDL/HDL ratio.

Conclusion: Investigation of 4 first-degree-related adult patients with untreated resistance to thyroid hormone alpha (RTHα) revealed more pronounced phenotype features and hypothyroid symptoms than previously described in patients treated with levothyroxine from childhood or adolescence. The delay in diagnosis is probably due to normal thyroid function tests. We suggest that THRA analysis should be performed in patients with specific clinical features, as treatment in early childhood may improve outcomes.

Introduction

Thyroid hormones are important regulators of growth and development, metabolic rate, energy homeostasis, heart and bowel function, central nervous system maturation and cholesterol conversion. The THRA and THRB genes encode thyroid hormone receptors (TR), both producing multiple isoforms through alternative splicing. The isoforms TRβ1, TRβ2 and TRα1 bind triiodothyronine (T3) while TRα2 does not bind T3 but acts as an inhibitor by competing for DNA.^[1,2] These nuclear receptors, found in most cells, form monomers, homodimers, or heterodimers with retinoid X receptors at DNA binding sites on target genes (thyroid hormone-responsive elements) and mediate gene regulation by binding of T3.^[3,4]

Pathogenic variants in the receptors are rare but can cause disease due to cellular resistance to T3. The clinical symptoms are receptor specific, because TRα and TRβ are unevenly distributed in the tissues. TRα is the predominant receptor in the central nervous system (CNS), intestines, bone, and cardiac and skeletal muscle, while TRβ is predominant in the hypothalamus, pituitary, retina, cochlea, thyroid gland, liver, and kidneys.^[5,6]

Pathogenic variants in THRB causing resistance to thyroid hormone beta (RTHβ) are suspected if the patient has normal or slightly elevated thyroid stimulating hormone (TSH) and elevated tetraiodothyronine (T4) and freeT4 (FT4). Heterozygous pathogenic variants in THRA are associated with resistance to thyroid hormone alpha (RTHα), causing autosomal dominant nongoitrous congenital hypothyroidism. The receptor translated from the alternative allele causes thyroid hormone resistance by inhibiting wild-type receptor action in a dominant negative manner.

The pathogenic THRA variants described so far are most frequently located in the C-terminal ligand-binding domain (LBD).^[2,7] Nonsense, frame shift, and missense variants close to the C-terminus appear to lead to more severe phenotypic features than missense variants located in the more N-terminal gene segment common to the TRα1 and TRα2 isoforms. A key molecular pathogenic defect may be persistent co-repressor binding, rather than coactivator recruitment per se. The variants associated with the most severe outcomes do not only prevent T3-binding but also coactivator recruitment.^[8–11] The p.(Ala263Val) variant is located in the N-terminal segment of the LBD common to the TRα1 and TRα2 isoforms. This variant is found to cause reduced affinity for T3 which in vitro is overcome by high doses of T3.^[12] Phenotypic variation between patients, and also between family members with the same pathogenic variant in THRA has been reported.^[13]

Here we report available clinical and laboratory characteristics from childhood and onwards of 4 previously untreated adult patients with RTHα. These descriptions may aid pediatricians to identify the disease in patients at an early age.

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Table 1. Clinical and auxological characteristics
	Index patient	Patient 2	Patient 3	Patient 4	*Mother
Age (years)	19	64	26	25	60
Gender	F	M	F	M	F
Weight kg (ref. range)^a	119 (48–77)	97 (NA)	155 (48–77)	111(57–101)	81.7(NA)
Height cm (ref. range)^a,b	165 (154–179)^a	161 (177)^b	163 (154–179)	170(167–194)	165(NA)
Arm span cm (ref. range)^c	160 (166)	157 (162)	158.5 (164)	170(171)	169(166)
Sitting height cm (ref. range)^d	88.6 (82–91)	88.6 (NA)	90.1 (81–90)	91.8(81–92)	82.8(NA)
BMI kg/m² (ref. range)^e	43.8 (18–28)	37.4 (27)	58.0 (18–28)	38.0(17–30)	30.0(26)
Head circumference cm (ref. range)^f	60.1 (52–58)	63.0 (53–59)	60.5 (52–57)	61.0(54–59)	54.5(52–58)
Blood pressure mmHg (ref. range)^g	122/83 (94–136/47–80)	170/114 (101–175/58–100)	118/79 (94–136/47–80)	127/82(103–148/47–83)	126/83(98–175/51–95)
Heart rate bpm (ref. range)^g	57 (51–95)	72 (44–91)	65 (51–95)	68(47–91)	83(46–94)
Shoe size (continental) (predicted size based on height)^h	42 (38)	42 (<39)	42 (38)	44(41)	39(38)

Values outside the reference ranges are marked in bold.
Abbreviations: BMI, body mass index; bpm, beats per minute; F, female; M, male.
^aReference ranges are extracted from available literature. Patient 3 and 4: Height, weight or BMI and range (± 2 SD) from Norwegian 19-year-olds [23].
^bPatient 2 and mother: Mean height of Norwegian military conscripts (by year of birth) (Statistics Norway, table SY 108).
^cPredicted arm span from height [24].
^dSitting height range (mean ± 2 SD) predicted from patient height [25]. Patient 3 and 4 predicted using ratios for age 21 years. Dutch population.
^eBMI [26].
^fHead circumference range (3rd to 97th percentile) of adult females and males [27]. British population.
^gSystolic and diastolic blood pressure and heart rate range (calculated from mean ± 2SD) for the Norwegian HUNT3 (2006–2008) cohort [28]. Index patient compared to age group 20–29 years.
^hEstimated shoe size by height [29] in parenthesis. Conversion of US Women's size to continental size based on a Nike size chart.
*Mother served as control.

Table 2. Thyroid function test results
	Index patient	Patient 2	Patient 3	Patient 4	Mother^a	Reference range
TSH	2.9	0.55	2	1.9	0.82	0.5–3.6 (mU/L)
FT4	15	13	9.6	9.6	19	8.0–21.0 (pmol/L)
FT3	7.8	6.2	6.8	7.2	3.8	2.8–7.0 (pmol/L)
FT4/FT3	1.9	2.1	1.4	1.3	5	See Figure 3
rT3	0.18	0.21	0.11	0.12	0.28	0.26–0.69 (nmol/L)
TT4	125	118	86	84	92	60–150 (nmol/L)
TT3	2.9	2.4	2.8	3	1.3	1.2–2.8 (nmol/L)
TBG	22.6	15.6	17.5	20.3	19	14–31 (mg/L)

Results in bold show low FT4/FT3 ratio and high FT3.
Abbreviations: TSH, thyroid stimulating hormone; T3, triiodothyronine; T4, thyroxine; TBG, thyroxine binding globulin.
^aThe mother served as a control. Reference ranges (RR) for the mother at the local hospital were TSH: 0.27–4.2 mIU/L, FT4: 12–22 pmol/L, FT3: 2.6–5.7 pmol/L.

Table 3. Biochemical characteristics
	Index	Patient	Patient	Patient	Mother^a	Reference ranges
	Patient	2	3	4	Mother^a	Reference ranges
Hemoglobin	11.4	14.1	11.6	13.8	12.3	age ≥ 12 F: 11.7–15.3, M: 13.4–17 g/dL
EVF	0.32	0.42	0.36	0.42	0.38	age ≥ 12 F: 0.35–0.46, M: 0.40–0.50
MCV	88	94	94	90	98	80–100 fL
HbA1C	33	39	44	39	58	20–42 mmol/mol
C-peptide fasting	1749	898	1690	1105	947	300–1480 pmol/L
Total cholesterol	4.7	6.1	5.5	5.2	3.8	age 18–29: 2.9–6.1 age ≥ 50 3.9–7.8 mmol/L
LDL cholesterol	3.25	4.75	4.3	3.55	1.63	age 18–29: 1.5–4.2, age 50–79: 2.1–4.9 mmol/L
HDL-cholesterol	0.97	1.09	0.97	1.33	1.7	F: 1.0–2.7, M: 0.8–2.1 mmol/L
LDL/HDL	3.4	4.4	4.4	2.7	0.96	Recommended ratio: 1–3.5
Lipoprotein (a)	<20	<20	114	131.9	238	>75 nmol/L increase risk of atherosclerosis
Haptoglobin	1.8	2.5	2.2	2.8	1.5	0.4–2.1 g/L
Lactate dehydrogenase	181	290	206	182	121	age 18–69: 105–205 U/L
Total CK (>99% CK-MM)	125	345	173	197	79	F ≥ age 18: 35–210, M: age 18–49:50–400,
						M: age ≥ age 50: 40–280 U/L
CK-MB	2	4	2	2	3	≤5 μg/L
Androstenedione	3.5	2.9	6.9	5	4.6	F: 0.9–7.9, F > 50 years: 0.5–2.9, M: 1.2–4.7 nmol/L
IGF-1	25	16.4	13.1	18.5	9.2	age 19–24: 10–51, age 25–29: 9–34, age ≥ 50: 4–22 nmol/L
SHBG	36	50	28	25	124	F: 23–100, M age < 60: 8–60, age > 60: 15–90 (nmol/L)

Values outside the reference ranges are marked in bold.
Abbreviations: CK-MM/CK-MB, skeletal muscle/cardiac muscle isoenzyme of creatinine kinase; EVF, erythrocyte volume fraction; HbA1C, glycated hemoglobin A1C; IGF-1, insulin-like growth factor-1; MCV, mean corpuscular volume; SHBG, sex hormone–binding globulin.
^aThe mother served as a control. RR for the mother: SHBG (23–150 nmol/L).