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Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations
Korcan Demir1, Anja L M van Gucht1, Muammer Büyükinan1
1Division of Pediatric Endocrinology (K.D.), Faculty of Medicine, Dokuz Eylül University, 35340, Balcova, Izmir, Turkey; Division of Pediatric Endocrinology (B.Ö.), Dr Behçet Uz Children's Hospital, 35210 İzmir, Turkey; Department of Internal Medicine (A.L.M.v.G., M.E.M., W.E.V., R.P.P., T.J.V.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands; Division of Pediatric Endocrinology (M.B., G.Ç.), Tepecik Education and Research Hospital, 35170, İzmir, Turkey; Department of Psychiatry (Y.A.), Hacettepe University, 06532 Ankara, Turkey; Division of Pediatric Endocrinology (V.N.B.), Eskisehir State Hospital, 26060, Eskisehir, Turkey; and Division of Pediatric Endocrinology (G.Ç., B.D.), Katip Çelebi University, 35620 İzmir, Turkey.
Context:
Recently several patients with resistance to thyroid hormone (RTH)-α due to T3 receptor-α (TRα) mutations were identified. The phenotype of these patients consists of varying degrees of growth impairment, delayed bone, mental and motor development, constipation, macrocephaly, and near-normal thyroid function tests.
Objective:
The objective of the study was to describe the clinical phenotype of three new families with RTHα and thereby gain more detailed knowledge on this novel syndrome.
Design, Setting, And Participants:
RTHα was suspected in three index patients from different families. Detailed clinical and biochemical assessment and imaging and genetic analyses were performed in the patients and their relatives. In addition, functional consequences of TRα mutations were investigated in vitro.
Results:
We studied 22 individuals from three families and identified 10 patients with heterozygous TRα mutations: C380fs387X, R384H, and A263S, respectively. The frame-shift mutation completely inactivated TRα, whereas the missense mutations produced milder defects. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental, and motor development, whereas the seven patients in family 3 had only mild clinical features. The most frequent abnormalities were anemia, constipation, and a delay in at least one of the developmental milestones. Serum free T3 ranged from high-normal to high and serum free T4 and rT3 from normal to low. TSH levels were normal in all patients.
Conclusions:
This large case series underlines the variation in the clinical phenotype of RTHα patients. RTHα should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T3, low/normal free T4, and normal TSH.
Insights
Resistance to thyroid hormone-alpha (RTHα) presents with varied symptoms due to T3 receptor-alpha (TRα) mutations. This study details three new families, highlighting the spectrum of RTHα clinical features and genetic underpinnings.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Resistance to thyroid hormone-alpha (RTHα) is a rare genetic disorder caused by mutations in the T3 receptor-alpha (TRα) gene.
- The clinical presentation of RTHα can vary widely, making diagnosis challenging.
Observation:
- This study investigated three new families with suspected RTHα, involving 22 individuals.
- Genetic analysis identified 10 patients with heterozygous TRα mutations (C380fs387X, R384H, A263S).
- Functional studies revealed that the frame-shift mutation inactivated TRα, while missense mutations caused milder defects.
Findings:
- Clinical severity correlated with mutation type, ranging from severe growth and developmental impairment to mild features.
- Common abnormalities included anemia, constipation, and delayed developmental milestones.
- Thyroid function tests showed high/high-normal free T3, low/normal free T4, and normal TSH levels.
Implications:
- This case series emphasizes the phenotypic variability of RTHα.
- RTHα should be considered in patients with hypothyroidism symptoms and specific thyroid function test patterns.
- Further research into TRα mutations can improve understanding and management of RTHα.
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