Clinical Characteristics of Children with THRA Mutations: Variable Phenotype and Good Response to Recombinant Human Growth Hormone Therapy.

INTRODUCTION: Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. CASE PRESENTATION: Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range. CONCLUSION: THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.

Lack of association between IL27 gene variants and type 1 diabetes susceptibility.

BACKGROUND: Recently, a new subpopulation of T cells, the Th17 subset, has been implicated in autoimmune diseases. Its development is influenced by IL-27, expressed in macrophages or dendritic cells. IL-27 blockage delays the onset of diabetes in non obese diabetes mouse, but its role in type 1 diabetes (T1D) in human has not been reported yet. The aim of this study was identify variants in the entire coding regions of IL-27 gene, including the 5' proximal region, and their possible association with the disease. METHODS: Those regions were amplified by polymerase chain reaction followed by automatic sequencing and restriction fragments length polymorphisms. The cohort involved 614 individuals - 318 patients with T1D (19.6 ± 11.2 y, 129M/189F) and 296 healthy control subjects (30.3 ± 13.2 y, 131M/165F). RESULTS: We identified eight allelic variants in the 5' proximal and coding regions of IL-27 gene, including two new variants: the c.-324 C>T in the 5' proximal region and the c.521 G>C in exon 5. None of these variants compromised transcription factor binding sites or the protein structure. The frequency of the alleles and genotypes of IL-27 variants did not differ between T1D patients and controls. There was no association between IL27 variants with gender, ethnicity, age at diagnosis of diabetes or presence of pancreatic and extrapancreatic autoantibodies. CONCLUSION: Our findings suggest that allelic variants in IL27 are not associated with susceptibility to T1D in a Brazilian population.

Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability.

OBJECTIVE: Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature. DESIGN AND METHODS: We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants. RESULTS: We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described likely pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2, and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, P = .04). CONCLUSION: In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.