Pedigree Analysis of Constitutional Delay of Growth and Maturation: Determination of Familial Aggregation and Inheritance Patterns
Ines L. Sedlmeyer,
Joel N. Hirschhorn and
Mark R. Palmert
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 ofgrowth and maturation (CD), 41 families of CD probands underwentinterviews regarding pubertal timing, and 12 additional familieshad history data analyzed from medical records. The family historiesof the 53 probands (40 boys and 13 girls) were assessed forpubertal delay using both strict criteria (pubertal delay 2SD beyond the mean) and relaxed criteria (pubertal delay 1 SDbeyond the mean). These pedigrees were compared with 25 controlpedigrees. Mean age of menarche was 14.3 ± 1.4 yr formothers of CD probands vs. 12.7 ± 1.4 yr for mothersof controls (P < 0.0001). Thirty-eight percent of CD mothersmet the strict 2 SD criteria, and an additional 29% met therelaxed 1 SD criteria for pubertal delay. By contrast, amongthe control mothers, 12% met the strict and an additional 8%met the relaxed criteria (P < 0.0001 for comparison withCD mothers). CD fathers were also more likely than the controlfathers to have a history of pubertal delay. For first-degreerelatives, the estimated relative risk of meeting the 2 SD and1 SD criteria for delay in CD vs. control pedigrees were 4.8and 4.9, respectively; estimated relative risk for second-degreerelatives were 3.2 and 4.4, respectively. Inheritance patternsvaried, but many families showed an apparent autosomal dominantpattern, with or without incomplete penetrance. Although manygenes may underlie CD, the inheritance patterns suggest thatthere are also single genes with major effects whose penetranceis likely affected by genetic or environmental modifiers. Thefuture identification of these major and modifying genes isan exciting prospect that would improve our understanding ofthe factors that regulate human pubertal timing and modulatethe human reproductive endocrine axis.
This work was supported by Lawson Wilkins Genentech ClinicalScholar Award (to M.R.P.) and NIH Grants K23-RR15544 (to M.R.P.)and RR-002172 (to Children’s Hospital General ClinicalResearch Center). J.N.H. is a recipient of a Burroughs WellcomeCareer Award in Biomedical Science.
Abbreviations: CD, Constitutional delay of growth and maturation;, relative risk for pubertal delay; p, relative risk for pubertaldelay among parents of probands.
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