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Pedigree Analysis of Constitutional Delay of Growth and Maturation: Determination of Familial Aggregation and Inheritance Patterns

Department of Medicine (I.L.S., J.N.H., M.R.P.), Division of Endocrinology, Children’s Hospital, and Department of Genetics (J.N.H.), Children’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; Center for Genome Research (J.N.H.), Whitehead/MIT, Cambridge, Massachusetts 02139; and Department of Pediatrics (M.R.P.), Division of Pediatric Endocrinology and Metabolism, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Mark R. Palmert, M.D., Ph.D., Division of Pediatric Endocrinology and Metabolism, Rainbow Babies and Children’s Hospital, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: mrp13{at}po.cwru.edu

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 2 SD beyond the mean) and relaxed criteria (pubertal delay 1 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.

This work was supported by Lawson Wilkins Genentech Clinical Scholar Award (to M.R.P.) and NIH Grants K23-RR15544 (to M.R.P.) and RR-002172 (to Children’s Hospital General Clinical Research Center). J.N.H. is a recipient of a Burroughs Wellcome Career Award in Biomedical Science.

Abbreviations: CD, Constitutional delay of growth and maturation; , relative risk for pubertal delay; _p, relative risk for pubertal delay among parents of probands.

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