Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics

Recently, the first patients with resistance to thyroid hormone alpha (RTHα) due to inactivating mutations in the thyroid hormone receptor alpha (TRα) were identified. These patients are characterized by growth retardation, variable motor and cognitive defects, macrocephaly, and abnormal thyroid function tests. The objective was to characterize a young girl (18 months old) with a mutation in both TRα1 and TRα2, and to study the effects of early levothyroxine (LT4) treatment. The patient was assessed clinically and biochemically before and during 12 months of LT4 treatment. In addition, the consequences of the mutation for TRα1/2 receptor function were studied in vitro. At 18 months of age, the patient presented with axial hypotonia, delayed motor development, severe growth retardation, and abnormally elevated triiodothyronine (T3)/thyroxine (T4) ratios. RTHα was suspected, and concomitantly a c.632A>G/p.D211G missense mutation was identified, affecting both the TRα1 and TRα2 proteins. This mutation was also found in the girl's father. LT4 treatment was started, resulting in a marked improvement of her hypotonia, motor skills, and growth. Functionally, the missense mutation led to decreased transcriptional activity of TRα1, which could be overcome by higher T3 levels in vitro. The mutant TRα1 showed a moderate dominant negative activity on wild type (WT) TRα1. In contrast, WT TRα2 and mutant TRα2 had negligible transcriptional activity and showed no dominant-negative effect over TRα1. This report describes the phenotype of a young RTHα patient with a mild TRα mutation before and during early LT4 treatment. Treatment had beneficial effects on her muscle tone, motor development, and growt

Psychiatric morbidity in children with medically unexplained chronic pain: diagnosis from the pediatrician's perspective.

Contains fulltext : 50167.pdf (publisher's version ) (Open Access)CONTEXT: There is very little general evidence to support the clinical management, particularly diagnosis, of medically unexplained chronic pain (UCP) in children. OBJECTIVE: We sought to assess in children with UCP if clinical characteristics held important by general pediatricians help to accurately diagnose psychiatric morbidity and, alternatively, if the same can be achieved using dedicated questionnaires. METHODS: We used a cross-sectional diagnostic study in a pediatric outpatient clinic of a university hospital. Our participants were 134 patients, aged 8 to 18 years, who were referred for UCP. Performed were (1) diagnostic test reflecting the pediatricians' choice of clinical characteristics and (2) selected questionnaires. Classification was performed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, by a child psychiatrist using the Diagnostic Interview Schedule for Children-Parent Version IV and the Semi-structured Clinical Interview for Children and Adolescents. Results were analyzed by logistic regression. RESULTS: Psychiatric morbidity was present in 80 of the children. A minority had a medical explanation for the pain (15% definite, 17% probable). The clinical diagnostic model included age, social-problem indicators, family structure, parental somatization, and school problems. In the quintile of children in whom this model predicted the highest risk, 93% indeed had psychiatric morbidity at reference testing. In the quintile with the lowest predicted risk, indeed only 27% had psychiatric morbidity. The Dutch Personality Inventory for Youth and the Child Behavior Checklist matched the pediatricians' choice of clinical characteristics. In the quintile of children with the highest predicted risk based on these questionnaires, 89% had psychiatric morbidity. In the quintile with the lowest predicted risk, only 15% had psychiatric morbidity. CONCLUSIONS: A pediatrician-chosen set of clinical characteristics of children with UCP proves useful in diagnosing psychiatric morbidity. Using selected questionnaire screening yields similar results