Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80-85% of cases, the thyroid gland is absent (agenesis), ectopically located, and/or severely reduced in size (hypoplasia). In the remaining cases, a normal-sized or enlarged thyroid gland is present, but production of thyroid hormones is decreased or absent. If treatment begins in the first month after birth, infants usually develop normally. When thyroid hormone therapy is not initiated within the first two months of life, however, congenital hypothyroidism can cause severe neurologic, mental, and motor damage (cretinism). In the United States and many other countries, all newborns are tested for congenital hypothyroidism.
Studies have shown that 2% of congenital hypothyroidism patients with thyroid dysgenesis have a positive familial history. A segregation analysis led to the conclusion that thyroid developmental abnormalities are compatible with an autosomal dominant mode of inheritance with a low penetrance. Mutations in many genes are known to cause congenital hypothyroidism. Multiple affected individuals have been shown to be heterozygous for mutations in the Paired Box Gene 8 (PAX8 2q12-q14), including individuals with positive family histories.
Mutations in the FOXE1 (9q22) gene have also been associated with congenital hypothyroidism, and Bamforth Lazarus syndrome (BLS). In addition to congenital hypothyroidism, other characteristics of BLS can include bilateral choanal atresia, cleft palate, bifid epiglottis, and spiky or curly hair. Hypothyroidism can be due to athyreosis or a nonfunctional eutopic thyroid. Sequencing of the FOXE1 gene is recommended after a biochemical diagnosis of congenital hypothyroidism that presents with the characteristics listed above. It can be used to confirm the presence of mutations in a proband, identify carriers among the proband's relatives, and provide prenatal diagnosis in families with known mutations.
For patients with suspected congenital hypothyroidism, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.
This test is indicated for:
- Confirmation of a clinical diagnosis of congenital hypothyroidism in individuals who have tested negative for sequence analysis
Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
- Sequence analysis of the PAX8 and FOXE1 genes is available and is required before deletion/duplication analysis.
- Analysis of the PAX8 and FOXE1 genes is also available individually.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.