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

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.

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

“…In the study population, 50-75% of subjects with CDGP have a family history of delayed puberty. As much as 80% of all variation in the timing of puberty is due to genetic factors (11,12).…”

Section: Evaluation Of Delayed Pubertymentioning

confidence: 99%

TRANSITION IN ENDOCRINOLOGY: Induction of puberty

Dunkel

Quinton

2014

117

Puberty is the period during which we attain adult secondary sexual characteristics and reproductive capability. Its onset depends upon reactivation of pulsative GNRH, secretion from its relative quiescence during childhood, on the background of intact potential for pituitary-gonadal function. This review is intended: to highlight those current practices in diagnosis and management that are evidence based and those that are not; to help clinicians deal with areas of uncertainty with reference to physiologic first principles; by sign-posting relevant data arising from other patient groups with shared issues; to illustrate how recent scientific advances are (or should be) altering clinician perceptions of pubertal delay; and finally, to emphasise that the management of men and women presenting in advanced adult life with absent puberty cannot simply be extrapolated from paediatric practice. There is a broad spectrum of pubertal timing that varies among different populations, separated in time and space. Delayed puberty usually represents an extreme of the normal, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP), but organic defects of the hypothalamo-pituitary-gonadal axis predisposing to hypogonadism may not always be initially distinguishable from it. CDGP and organic, or congenital hypogonadotrophic hypogonadism are both significantly more common in boys than girls. Moreover, around 1/3 of adults with organic hypogonadotrophic hypogonadism had evidence of partial puberty at presentation and, confusingly, some 5-10% of these subsequently may exhibit recovery of endogenous gonadotrophin secretion, including men with Kallmann syndrome. However, the distinction is crucial as expectative ('watch-and-wait') management is inappropriate in the context of hypogonadism. The probability of pubertal delay being caused by organic hypogonadism rises exponentially both with increasing age at presentation and the presence of associated 'red flag' clinical features. These 'red flags' comprise findings indicating lack of prior 'mini-puberty' (such as cryptorchidism or micropenis), or the presence of non-reproductive congenital defects known to be associated with specific hypogonadal syndromes, e.g. anosmia, deafness, mirror movements, renal agenesis, dental/digital anomalies, clefting or coloboma would be compatible with Kallmann (or perhaps CHARGE) syndrome. In children, interventions (whether in the form or treatment or simple reassurance) have been historically

“…Children with CDGP have reduced body mass index (BMI) compared with control subjects (9). A number of families with CDGP show a dominant pattern of inheritance and estimates of the heritability of CDGP suggest 50-80% of the variance in pubertal onset may be genetically controlled (10). The altered puberty and body habitus led us to hypothesize that sequence variants in LEP may affect the phenotype in children with CDGP.…”

Section: Introductionmentioning

confidence: 99%

Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene

Murray

Read²,

Banerjee³

et al. 2011

Introduction: Leptin deficiency caused by mutations within the leptin gene (LEP) results in severe early onset obesity, hypogonadism, pubertal delay and immune system abnormalities. Constitutional delay in growth and puberty (CDGP) is a common condition seen in paediatric clinics, in which children present with delayed growth and puberty but usually also have a slim body habitus. We hypothesized that LEP variants may play a role in the phenotype seen in CDGP. Aim: To screen a group of children with CDGP for pathogenic sequence variants in LEP. Patients and methods: Denaturing HPLC was used to screen for LEP sequence variants in DNA samples from 78 children with CDGP (predominantly white males) and 112 control subjects. DNA fragments with a WAVE pattern deviant from wild type were directly sequenced. A STAT3 luciferase reporter assay in human embryonic kidney (HEK293) cells transiently transfected with the leptin receptor was used to test activity of mutant leptin. Results: One child with CDGP was identified to be heterozygous for a novel missense variant (c.68COG), which results in a proline to arginine substitution (p.P23R). This sequence variant was not identified in any of the other control subjects, but was identified in his mother who shared a similar phenotype of slim body habitus, reduced appetite and pubertal delay (menarche aged 15 years). The leptin variant showed similar stability in serum compared with wild type and did not demonstrate increased activity in an in vitro reporter gene assay. Conclusions: This is the first report of a sequence variant within the LEP gene associated with reduced body mass index rather than obesity. We hypothesize that this variant has increased bioactivity in vivo.