Chromosome 18q deletions (18q-) are survivable autosomal deletions, having an estimated incidence of 1/40,000 live births. Our long-term goals are to 1) comprehensively define the endocrine phenotype, 2) determine the natural history and 3) identify key genes leading to particular phenotypes. This report specifically emphasizes the thyroid phenotype. Medical record review and comprehensive clinical assessment(s) were performed on 120 individuals with 18q- at The Chromosome 18 Clinical Research Center: the largest group of individuals with 18q- ever assembled. Affected subjects ranged in age from 6 weeks to 32 yr at initial assessment. Due to case reports of thyroid dysfunction in 18q deletions, and the well-established association between hypothyroidism and aneusomies, we undertook thyroid testing in all individuals and completed TSH releasing hormone studies on 50 of them. Our studies demonstrated that 12% had hypothyroidism and the results were consistent with primary thyroidal dysfunction. Furthermore, 2 individuals progressed from normal to abnormal over the course of 2 yr. Based on these studies, it appears that, as is the case in other aneusomies, annual thyroid testing, using TSH as a primary screening tool, is indicated. The mechanism of the hypothyroidism is not yet known and the genetic basis has not been delineated.