TSHR – Thyroid Hypoplasia

The thyrotropin receptor (TSHR) is essential for thyroid development and hormone synthesis. Biallelic loss-of-function (LOF) mutations in TSHR lead to complete TSH resistance, presenting as severe congenital hypothyroidism (CH) with thyroid hypoplasia at birth (PMID:23154162). Affected neonates exhibit markedly elevated serum TSH and variable free thyroxine (T4) levels. The severity of gland underdevelopment correlates with residual receptor activity and the nature of mutated alleles. Early recognition is critical for prompt management and prevention of neurodevelopmental impairment.

In a pivotal report, a female infant with permanent CH and reduced thyroid volume was compound heterozygous for two LOF variants: c.1217_1234del (p.Asn406_Ile411del) and c.1170T>G (p.Cys390Trp), both of which abrogate cell surface expression and TSH binding (PMID:9329388). The frameshift allele induced intracellular trapping of the receptor, while the missense change disrupted a conserved cysteine, critically reducing ligand affinity. No further segregation beyond parental carrier status was documented.

Functional investigations confirm that LOF TSHR mutations abolish G_s–mediated cAMP signaling, consistent with receptor inactivation. The hyt/hyt mouse model harboring p.Pro556Leu recapitulates severe hypothyroidism and thyroid hypoplasia, supporting a haploinsufficiency mechanism (PMID:8170469). Rescue studies remain limited, but receptor re-expression in cell systems restores signaling capacity.

Clinically, neonates with biallelic LOF mutations are identified by newborn CH screening and ultrasound evidence of thyroid hypoplasia. TSH levels are markedly elevated, while free T4 may range from low-normal to reduced. Heterozygous carriers often display subclinical TSH elevation without hypoplasia. Lifelong L-T4 replacement is mandatory for severe cases to prevent growth failure and cognitive deficits.

Genetic testing for TSHR mutations is recommended in all patients with isolated severe CH and thyroid hypoplasia. Identification of bi-allelic LOF variants informs prognosis, tailors hormone dosing, and enables familial carrier counseling. Asymptomatic carriers benefit from monitoring for subclinical hypothyroidism.

In summary, biallelic LOF mutations in TSHR are causally linked to congenital hypothyroidism with thyroid hypoplasia, warranting a Limited clinical validity classification based on two probands and concordant functional data. Key take-home: early genetic diagnosis of TSHR LOF enables targeted L-T4 therapy and prevents irreversible developmental outcomes.

References

• Journal of clinical research in pediatric endocrinology • 2013 • Current loss-of-function mutations in the thyrotropin receptor gene: when to investigate, clinical effects, and treatment. PMID:23154162
• The Journal of clinical endocrinology and metabolism • 1997 • Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. PMID:9329388
• Molecular endocrinology (Baltimore, Md.) • 1994 • Identification of a point mutation in the thyrotropin receptor of the hyt/hyt hypothyroid mouse. PMID:8170469

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