Table 2.

Skeletal Phenotype in Individuals With TSHB, TSHR, SECISBP2, THRA, and THRB Mutations

Mutation	Genotype	Systemic Thyroid Status	Skeletal Phenotype	Refs.
TSHB loss-of-function (non-goitrous congenital hypothyroidism type 4; OMIM no. 275100)
TSHBQ49X/Q49X	Premature stop	Low T4, T3, and TSH	T4 replacement from birth	328
	TSH deficiency		BMD normal in two children at 7 y and 10 y
TSHR loss-of-function (non-goitrous congenital hypothyroidism type 1; OMIM no. 275 200)
TSHRP52A/I167N	1) Impaired function	Normal T4	Normal growth and bone age (14 y)	334
	2) Severely impaired function	Elevated TSH 20×	(Without T4 treatment)
TSHRR109Q/W546X	1) Impaired function	Normal T4	Normal growth and bone maturation (3 y)	333
	2) Frameshift/premature stop	Elevated TSH 50×	(Without T4 treatment)
TSHRA553T/A553T	Reduced cell surface expression	Hypoplastic thyroid	Normal birth length and head circumference	331
		Low T4	Normal growth (3 y)
		Elevated TSH 250×	(T4 treatment)
TSHRC390W/ fs419X	1) Impaired function	Hypoplastic thyroid	Normal linear growth and bone age (5 y)	332
	2) Frameshift/premature stop	Low T4	(T4 treatment)
		Elevated TSH 40×
TSHRIVS6+3 G>C/fs656X	1) Skipping of exon 6	Severe hypoplasia	Delayed bone age/enlarged fontanelles at birth	336
	2) Frameshift/premature stop	Very low T4	Normal growth (2 y)
		Elevated TSH 200×	(T4 treatment)
TSHRIVS5-1G>A/IVS5-1G>A	Skipping of exon 6	Severe hypoplasia	Enlarged fontanelles at birth	335
		Very low T4 and T3	Normal growth (12 y)
		Elevated TSH 250×	(T4 treatment)
TSHR gain-of-function (non-autoimmune hyperthyroidism; OMIM no. 609152)
TSHRM453T/+	Constitutive activation of cAMP	Goiter	Advanced bone age	539
		High T4 and T3	Normalized after treatment (12 y)
		Suppressed TSH
TSHRM453T/+	Constitutive activation of cAMP	Goiter	Advanced bone age (newborn)	339
		High T4 and T3
		Suppressed TSH
TSHRS505N/+	Constitutive activation of cAMP	High T4 and T3	Bone age advanced by 4 y at 6 mo old	341
		Suppressed TSH	Craniosynostosis
			Treatment improved growth and bone age (4 y)
TSHRT632I/+	Constitutive activation of cAMP	High T4 and T3	Craniosynostosis	344
		Suppressed TSH
TSHRF629L/+	Constitutive activation	Goiter	Advanced bone age	338
		High T4 and T3	Craniosynostosis
		Suppressed TSH	Development normal after treatment (10 y)
TSHRR528H/S281N	1) Polymorphism	High T4 and T3	Birth length 90th centile	343
	2) Constitutive activation of cAMP	Suppressed TSH	Craniosynostosis requiring surgery
TSHRV597L/+	Constitutive activation of cAMP	High T4 and T3	Advanced bone age (9 mo)	340
		Suppressed TSH
TSHRM453T/+	Constitutive activation of cAMP	Goiter	Bone age advanced by 5 y	342
		High T4 and T3	Craniosynostosis and mid-face hypoplasia
		Suppressed TSH	Shortened 5th metacarpals and phalanges
TSHRT32I/+	Constitutive activation	High T4 and T3	Bone age advanced by 4 y	345
		Suppressed TSH	Craniosynostosis requiring surgery
			Treatment stabilized bone age
			(Height: 90th centile at 6 mo but 18th centile at 4 y)
SECISBP2 loss-of-function (Abnormal thyroid hormone metabolism OMIM: 609698)
SECISBP2R540Q/R540Q	Hypomorphic allele with abnormal SECIS binding	High T4 and rT3, low T3	Delayed growth and bone age	346
		Slightly elevated TSH	Normal final height
SECISBP2K438X/IVS8DS+29G-A	1) LoF truncation	High T4 and rT3, low T3	Transient growth retardation	346
	2) Splicing defect	Slightly elevated TSH
SECISBP2R128X/R128X	Truncated protein lacking N-terminal	High T4 and rT3, low T3 Normal TSH	Growth retardation and delayed bone age Responsive to T3 treatment	348
SECISBP2R120X/R770X	1) LoF truncation	High T4 and rT3, low T3	Intrauterine growth retardation	347
	2) Impaired SECIS binding	Slightly elevated TSH	Craniofacial dysmorphism
			Bilateral clinodactyly
			Delayed growth and bone age
SECISBP2fs255X/ fs	1) Frameshift/premature stop	High T4 and rT3	Genu valgus	349
	2) Splicing defect	Normal T3	External rotation of the hip
		Normal TSH	Normal final height
SECISBP2C691R/fs	1) Increased proteasomal degradation 2) Splicing defect	High T4 and rT3 Low T3 Normal TSH	Delayed growth T3 treatment improved growth	349
SECISBP2M515fs563X/Q79X	1) Frameshift/premature stop	High T4	Delayed growth and bone age	350
	2) Premature stop	Slightly low T3	GH improved height but not bone age
		Slightly elevated TSH	GH+T3 normalized height and bone age
RTHβ: THRB dominant-negative mutations (non-goitrous congenital hypothyroidism type 6; OMIM no. 614450)
TRβ?/+	Unknown	Goiter	Delayed bone maturation	351
		High T4, T3	Stippled epiphyses
		Nonsuppressed TSH
TRβ?/+	Unknown	Goiter	Normal height and body proportions	360
		High T4, T3	Normal head circumference
		Nonsuppressed TSH	Normal bone age and epiphyses (8 y)
TRβ?/+	Unknown	High T4, T3 and TSH	Short stature and delayed bone age	540
TRβ?/+	Unknown	Goiter	Short stature	377
		High T4, T3	Bone age 3 y at 2.9 y old
		Nonsuppressed TSH	Craniosynostosis (9 y)
			Shortened 4th metacarpals and metatarsals
TRβG345R/+	No T3 binding	Goiter	Normalizing T4 slowed growth	352
		High T4, T3
		Nonsuppressed TSH
TRβΔT337/ΔT337	Dominant-negative TRβ	High T4, T3	Growth retardation	368, 370
	Homozygous single amino acid deletion	Markedly elevated TSH	Delayed bone age
	No T3 binding
TRβ−/−	Deletion of TRβ coding region	High T4, T3	Stippled epiphyses and growth delay	541
		Nonsuppressed TSH
TRβR438H/+	Dominant-negative TRβ	Goiter	Delayed bone age	542
	Missense mutation	High T4 and TSH
TRβC434X/+	Dominant-negative TRβ	High T4, T3	Advanced bone age	376
	C-terminal premature stop	Nonsuppressed TSH
	No T3 binding
TRβR338L/+	Dominant-negative TRβ	High T4, T3	Reduced BMD	375
	Missense mutation	Nonsuppressed TSH
TRβM310L/+	Dominant-negative TRβ	Goiter	Intrauterine growth retardation	366
	Missense mutation	High T4, T3	Delayed bone age
	Reduced T3 affinity	Nonsuppressed TSH	Persistent short stature (17 y)
TRβF438fs422X/+	Potent dominant-negative TRβ	Small goiter	Growth retardation and delayed bone age	367
	Frameshift	Very high T4, T3	Short stature
	C-terminal premature stop	High TSH	Frontal bossing
	No T3 binding
TRβK443fs458X/+	Potent dominant-negative TRβ	High T4, T3 and TSH	Short stature (7 y)	316
	Frameshift
	C-terminal premature stop
	No T3 binding
TRβR429W/+	Normal T3-binding affinity and transactivation	Goiter High T4, T3 Nonsuppressed TSH	Increased osteocalcin and decreased BMD (19 y)	378
TRβG344A/+	Dominant-negative TRβ	High T4	Mild intrauterine growth retardation	364, 543
	Missense mutation	Nonsuppressed TSH	Persistent short stature
	No T3 binding		Delayed bone age
TRβG347A/+	Missense mutation	Goiter	Persistent short stature (21 y)	379
		High T4, T3	Increased bone turnover markers
		Nonsuppressed TSH
TRβA317T/+; TRβR438H/+; TRβP453T/+; TRβP453fs463X/+; TRβN331H/+	Missense mutations Frameshift C-terminal premature stop	High T4, T3 Nonsuppressed or high TSH	Reduced whole body and lumbar spine BMD in adults but not in children	374
RTHα: THRA dominant-negative mutations (nongoitrous congenital hypothyroidism type 6; OMIM no. 614450)
TRα1E403X/+	Dominant-negative TRα1	Low fT4, normal fT3	Disproportionate short stature (6 y)	382
	C-terminal premature stop	Low fT4:fT3 ratio Low rT3 Normal TSH	Epiphyseal dysgenesis and grossly delayed bone age Macrocephaly and patent skull sutures Delayed tooth eruption, defective bone mineralization
TRα1F397fs406X/+	Dominant-negative TRα1	Low fT4 and high fT3	Delayed bone age and persistent short stature (3 y)	384, 385
	Frameshift	Low fT4:fT3 ratio	Macrocephaly/flattened nasal bridge/patent skull sutures
	C-terminal premature stop	Low rT3	Delayed tooth eruption and congenital hip dislocation
		Normal TSH	Brief increased growth after T4 treatment
			Persistent short stature and otosclerosis (47 y)
TRα1A382Pfs389X/+	Dominant-negative TRα1	Normal fT4 and fT3	Disproportionate persistent short stature (45 y)	383
	Frameshift	Low fT4:fT3 ratio	Macrocephaly and cortical bone thickening
	C-terminal premature stop	Low rT3	T4 treatment (10–15 y) increased growth rate
		Borderline elevated TSH
TRα1C392X/+	C-terminal premature stop	Low fT4 High fT3 Low fT4:fT3 ratio Normal TSH	Delayed growth short stature with shortened limbs Macrocephaly/flattened nasal bridge/hypertelorism Micrognathia/elongated thorax/lumbar kyphosis (18 y) T4 treatment did not improve syndrome	388
TRα1E403X/+	Dominant-negative TRα1	Low normal fT4	Delayed growth short stature with shortened limbs	388
	C-terminal premature stop	High normal fT3 Low fT4:fT3 ratio Normal TSH	Macrocephaly/flattened nasal bridge/hypertelorism Elongated thorax/lumbar kyphosis (14 y) T4 treatment did not improve syndrome
TRα1E403K/+	Missense mutation	Low normal fT4 High normal fT3 Low fT4:fT3 ratio Normal TSH	Short stature with shortened limbs Macrocephaly/flattened nasal bridge/hypertelorism Elongated thorax (12 y) T4 treatment did not improve syndrome	388
TRα1P398R/+	Missense mutation	Low normal fT4	Delayed growth with shortened limbs	388
		High normal fT3	Flattened nasal bridge/hypertelorism
		Low fT4:fT3 ratio	Elongated thorax (8 y)
		Low normal TSH	T4 treatment did not improve syndrome
TRαA263V/+	Weak dominant-negative	Low normal fT4	Growth retardation	389
	Missense mutation	High normal fT3	Macrocephaly/broad face/flattened nasal bridge
	Transactivation activity restored by supraphysiological T3	Low fT4:fT3 ratio	Thickened calvarium
	No effect on TRα2 action	Low rT3	T4 treatment improved growth rate
		Normal TSH	Macrocephaly and increased BMD in adult
TRαN359Y/+	Dominant-negative TRα1 Missense mutation with decreased T3 binding and transactivation activity Weak reduction in TRα2 action	Normal fT4 High normal fT3 Low fT4:fT3 ratio Low normal rT3 Low TSH (initially normal)	Growth retardation with shortened limbs Macrocephaly/hypertelorism/micrognathia/broad nose Elongated thorax with clavicular and 12th rib agenesis with scoliosis, ovoid vertebrae, and congenital hip dislocation Humeroradial synostosis and syndactyly	390

Abbreviation: LoF, loss of function.