Patterns of Inheritance of Constitutional Delay of Growth and Puberty in Families of Adolescent Girls and Boys Referred to Specialist Pediatric Care

Wehkalampi, Karoliina; Widén, Elisabeth; Laine, Tiina; Palotie, Aarno; Dunkel, Leo

doi:10.1210/jc.2007-1786

Cited by 130 publications

(113 citation statements)

References 26 publications

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“…17,28,[104][105][106][107][108] Family history indicative of autosomal inheritance cannot be used as a diagnostic tool, as this feature can be observed in both CHH and CDGP. 109 Adulthood CHH might be diagnosed after adolescence, when patients present for evaluation of infertility or even for osteo poro tic fractures. This delay in diagnosis might be related to missed opportunities to diagnose CHH in adolescence or a reluctance of patients to seek medical evaluation.…”

Section: Adolescentmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Adolescentmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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“…boys, this condition cannot be differentiated from ISS (31). This disorder occurs more frequently in males (18,32), and indeed, in our cohort, the proportion of males was greater in the CDGP group than in the non-CDGP group (77 vs 61%, see Table 1). The fact that on the first evaluation our CDGP patients were older than the non-CDGP patients suggests that they might have reached a height SDS below K2.0 (short stature) later in life, therefore coming in later for medical evaluation.…”

Section: Discussionmentioning

confidence: 52%

“…CDGP is characterized by a significant delay in both BA and adolescent growth spurt (31), which underlies the transient short stature stage, which is seen in affected individuals. Calculated measures of heritability suggest that 50-80% of the variance in pubertal onset is genetically controlled (30,32). CDGP appears to be a multifactorial trait, yet at the same time the inheritance patterns suggests that single genes exert major effects (30).…”

Section: Discussionmentioning

confidence: 99%

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Pugliese-Pires

Fortin

Arthur

et al. 2011

European Journal of Endocrinology

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Background: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective: To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. Subjects and methods: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays. Results: Five different heterozygous point variations in GHSR were identified (c.K6 GOC, c.251GOT (p.Ser84Ile), c.505GOA (p.Ala169Thr), c.545 TOC (p.Val182Ala), and c.1072GOA (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were K2.4 and K2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of K0.7 and K1.4) without treatment. Conclusion: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.

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“…Condition of healthy individuals with pubertal onset delayed by more than 2 standard deviations Repeatedly been shown to cluster in families, often with AD pattern 6 , but pathophysiology and genetic regulation remain unclear Very limited number of rare, high impact genetic variants identified in families with both hypogonadotropic hypogonadism (HH) and DP 7 Our cohort was collected from patients seen under specialist Clinical details of this family revealed them to have typical features of self-limited DP. The proband case was first investigated for growth delay at 12.8yrs, at which time his bone age was 11yrs.…”

Section: Background -Pubertymentioning

confidence: 99%

Mutations in HS6ST1 cause self-limited delayed puberty (DP) in addition to idiopathic hypogonadotropic hypogonadism (IHH)

Howard¹,

Poliandre²,

Storr³

et al. 2015

EJEA

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Puberty is the normal developmental stage when reproductive capacity is attained Disturbances of pubertal timing affect over 4% of the population Deranged pubertal timing has significance for public health in view of the association between early or late puberty and an adverse cardiovascular, metabolic and cancer risk profile 1-3 Background -PubertyCondition of healthy individuals with pubertal onset delayed by more than 2 standard deviations Repeatedly been shown to cluster in families, often with AD pattern 6 , but pathophysiology and genetic regulation remain unclear Very limited number of rare, high impact genetic variants identified in families with both hypogonadotropic hypogonadism (HH) and DP 7Our cohort was collected from patients seen under specialist Paediatric care from Finland between 1982Finland between -2004 Cohort contains 403 affecteds from 170 families and their unaffected relatives (total of 910 individuals)

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Patterns of Inheritance of Constitutional Delay of Growth and Puberty in Families of Adolescent Girls and Boys Referred to Specialist Pediatric Care

Cited by 130 publications

References 26 publications

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Mutations in HS6ST1 cause self-limited delayed puberty (DP) in addition to idiopathic hypogonadotropic hypogonadism (IHH)

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