Pedigree analysis of constitutional delay of growth and maturation: Determination of familial aggregation and inheritance patterns

To investigate the genetic basis of constitutional delay of growth and maturation (CD), 41 families of CD probands underwent interviews regarding pubertal timing, and 12 additional families had history data analyzed from medical records. The family histories of the 53 probands (40 boys and 13 girls) were assessed for pubertal delay using both strict criteria (pubertal delay greater than or equal to2 SD beyond the mean) and relaxed criteria (pubertal delay greater than or equal to1 SD beyond the mean). These pedigrees were compared with 25 control pedigrees. Mean age of menarche was 14.3 +/- 1.4 yr for mothers of CD probands vs. 12.7 +/- 1.4 yr for mothers of controls (P < 0.0001). Thirty-eight percent of CD mothers met the strict 2 SD criteria, and an additional 29% met the relaxed 1 SD criteria for pubertal delay. By contrast, among the control mothers, 12% met the strict and an additional 8% met the relaxed criteria (P < 0.0001 for comparison with CD mothers). CD fathers were also more likely than the control fathers to have a history of pubertal delay. For first-degree relatives, the estimated relative risk of meeting the 2 SD and 1 SD criteria for delay in CD vs. control pedigrees were 4.8 and 4.9, respectively; estimated relative risk for second-degree relatives were 3.2 and 4.4, respectively. Inheritance patterns varied, but many families showed an apparent autosomal dominant pattern, with or without incomplete penetrance. Although many genes may underlie CD, the inheritance patterns suggest that there are also single genes with major effects whose penetrance is likely affected by genetic or environmental modifiers. The future identification of these major and modifying genes is an exciting prospect that would improve our understanding of the factors that regulate human pubertal timing and modulate the human reproductive endocrine axis.