Despite the clinical importance of delayed puberty, the understanding of this condition is hampered by the lack of studies evaluating etiologies and predisposing factors among large case series. We performed a retrospective study of clinical and laboratory data from adolescents (< or =18 yr of age) with delayed puberty who had been seen in our clinic between 1/96 and 7/99 (n = 232 subjects; 158 males and 74 females). Family histories of pubertal timing among primary relatives were classified as negative, having at least a tendency to pubertal delay (development > or =1 SD beyond the mean), or diagnostic of delay (development > or =2 SD beyond the mean). The most common cause of delayed puberty was constitutional delay of growth and maturation (CD), which affected 53% of the subjects (63% of males and 30% of females). The remaining subjects could be divided into four categories: those with an underlying condition associated with delayed, but spontaneous, pubertal development [functional hypogonadotropic hypogonadism (FHH)], 19% of subjects; those with permanent hypogonadotropic hypogonadism, 12% of subjects; those with permanent hypergonadotropic hypogonadism, 13% of subjects; and those without clearly classified disorders, 3% of subjects. Like CD, FHH was male predominant, whereas the other categories either affected both genders equally or were predominantly female. In total, 50 different etiologies led to pubertal delay within our case series. Data permitted classification of family histories of pubertal timing among primary relatives in 95 of 122 of the CD and in 25 of 45 of the FHH cases. Analysis revealed at least a tendency to pubertal delay in 77% of the CD and in 64% of the FHH families and a diagnosis of delay in 38% of the CD and 44% of the FHH families. Both parents contributed to the positive family histories. The rates of positive family histories among the CD and FHH groups were approximately twice those seen among the other subjects in our case series. Among all subjects, those with FHH had the most marked growth delay, and girls had the greater bone age delay. Among the boys and at comparable chronological ages, CD and FHH were characterized by greater delays in pubic hair development and bone age than in the other diagnostic groups. Although CD is typically associated with leanness, 22% of our subjects had a BMI SD score at the 85th percentile or above for chronological age. These overweight subjects differed from the rest of the CD group: bone age was less delayed, and height was less affected. Finally, our analysis suggested a possible association between attention deficit disorder with or without hyperactivity and pubertal delay in our CD and FHH subjects. Our study provides valuable data regarding the variety and frequency of diagnoses that lead to delayed puberty. The results underscore the importance of performing a thorough evaluation and family history in adolescents with delayed puberty. Moreover, the data from our case series provide clues for unraveling the mechanism(s) of idiopathic p...

Despite the clinical importance of delayed puberty, the understanding of this condition is hampered by the lack of studies evaluating etiologies and predisposing factors among large case series. We performed a retrospective study of clinical and laboratory data from adolescents (< or =18 yr of age) with delayed puberty who had been seen in our clinic between 1/96 and 7/99 (n = 232 subjects; 158 males and 74 females). Family histories of pubertal timing among primary relatives were classified as negative, having at least a tendency to pubertal delay (development > or =1 SD beyond the mean), or diagnostic of delay (development > or =2 SD beyond the mean). The most common cause of delayed puberty was constitutional delay of growth and maturation (CD), which affected 53% of the subjects (63% of males and 30% of females). The remaining subjects could be divided into four categories: those with an underlying condition associated with delayed, but spontaneous, pubertal development [functional hypogonadotropic hypogonadism (FHH)], 19% of subjects; those with permanent hypogonadotropic hypogonadism, 12% of subjects; those with permanent hypergonadotropic hypogonadism, 13% of subjects; and those without clearly classified disorders, 3% of subjects. Like CD, FHH was male predominant, whereas the other categories either affected both genders equally or were predominantly female. In total, 50 different etiologies led to pubertal delay within our case series. Data permitted classification of family histories of pubertal timing among primary relatives in 95 of 122 of the CD and in 25 of 45 of the FHH cases. Analysis revealed at least a tendency to pubertal delay in 77% of the CD and in 64% of the FHH families and a diagnosis of delay in 38% of the CD and 44% of the FHH families. Both parents contributed to the positive family histories. The rates of positive family histories among the CD and FHH groups were approximately twice those seen among the other subjects in our case series. Among all subjects, those with FHH had the most marked growth delay, and girls had the greater bone age delay. Among the boys and at comparable chronological ages, CD and FHH were characterized by greater delays in pubic hair development and bone age than in the other diagnostic groups. Although CD is typically associated with leanness, 22% of our subjects had a BMI SD score at the 85th percentile or above for chronological age. These overweight subjects differed from the rest of the CD group: bone age was less delayed, and height was less affected. Finally, our analysis suggested a possible association between attention deficit disorder with or without hyperactivity and pubertal delay in our CD and FHH subjects. Our study provides valuable data regarding the variety and frequency of diagnoses that lead to delayed puberty. The results underscore the importance of performing a thorough evaluation and family history in adolescents with delayed puberty. Moreover, the data from our case series provide clues for unraveling the mechanism(s) of idiopathic p...

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 >or=2 SD beyond the mean) and relaxed criteria (pubertal delay >or=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.

Because GnRH and its receptor (GnRHR) are pivotal regulators of the reproductive endocrine axis and mutations in GNRHR lead to hypogonadotropic hypogonadism, we investigated whether genetic variation in GNRHR or GNRH1 affects pubertal timing in the general population. To screen for missense mutations in these genes that might affect pubertal timing, we resequenced the coding regions of these genes in 48 probands with late but otherwise normal pubertal development. No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development. To search for common variants that might affect pubertal timing, we took a haplotype-based association approach. To identify common haplotypes in these genes, we genotyped 41 SNPs in DNA from commercially available European-derived multigenerational pedigrees and participants in a multiethnic cohort (MEC). Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes. A set of haplotype-tagging SNPs that mark these common haplotypes in all five ethnic groups within the MEC were defined and used to perform association studies among 125 trios (probands with late pubertal development and their parents) and 506 women from the MEC who had early (menarche< 11 yr of age, n = 216) or late (menarche > or = 15 yr of age, n = 290) pubertal development. Three SNPs in GNRHR showed modest association with late pubertal development in the trios; among the 506 women, a different SNP was associated with late menarche, and one rare haplotype was associated with early age of menarche. All of the observed associations were relatively modest and only nominally statistically significant; replication is needed to determine their validity. We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population.