Timing of Pubertal Onset in Girls and Boys With Constitutional Delay

Jonsdottir-Lewis, Elfa; Feld, Amalia; Ciarlo, Ryan; Denhoff, Erica R.; Feldman, Henry A.; Chan, Yee-Ming

doi:10.1210/clinem/dgab270

Cited by 20 publications

(17 citation statements)

References 29 publications

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“…In those cases where there is no personal or family history that could drive the diagnosis, constitutional delay of puberty is the commonest cause of lack of pubertal signs in a boy reaching the age of 14 years, that is, that corresponding to more than 2 standard deviations from normal pubertal age onset. 32 , 33 The differential diagnosis may prove difficult: basal LH and testosterone levels are usually uninformative and several dynamic tests have been developed with controversial results. 34 Although neglected in males, the FSH-gonadal axis seems to be more informative.…”

Section: The Ontogeny Of the Hypothalamic-pituitary-testicular Axis: Its Importance For The Diagnosis Of Male Hypogonadismmentioning

confidence: 99%

Recent advancement in the treatment of boys and adolescents with hypogonadism

Rey

2022

Therapeutic Advances in Endocrinology

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Clinical manifestations and the need for treatment varies according to age in males with hypogonadism. Early foetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in foetal life presents with micropenis, cryptorchidism and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relative short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective to induce an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.

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Section: The Ontogeny Of the Hypothalamic-pituitary-testicular Axis: Its Importance For The Diagnosis Of Male Hypogonadismmentioning

confidence: 99%

Recent advancement in the treatment of boys and adolescents with hypogonadism

Rey

2022

Therapeutic Advances in Endocrinology

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“…Accordingly, a link can be suggested between different genetic backgrounds and variations in pubertal timing at the site. However, environmental conditions (e.g., socioeconomic status, nutrition and physical activity) can also affect pubertal development (Fricke et al, 2019;Hochberg & Belsky, 2013;Jonsdottir-Lewis et al, 2021;Karapanou & Papadimitriou, 2010;Parent et al, 2003). Pre-Roman societies were hierarchically structured (Naso, 2017) and multifaceted funerary customs in Pontecagnano suggest a complex social stratification (Cinquantaquattro & Pellegrino, 2017).…”

Section: Variability In Pubertal Timingmentioning

confidence: 99%

Puberty in pre‐Roman times: A bioarchaeological study of Etruscan‐Samnite adolescents from Pontecagnano (southern Italy)

Bareggi

Pellegrino

Giuffra

et al. 2022

Intl J of Osteoarchaeology

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Objectives: Puberty is a crucial part of life, representing the biological transition from childhood to adulthood. With the aim of expanding current knowledge of pubertal development and the life course in past populations, this study provides the first investigation of puberty in pre-Roman Italy. Materials and methods: Nine skeletal and dental puberty indicators were assessed in a sample of 84 Etruscan and Samnite individuals (8.0-23.9 years) from Pontecagnano (southern Italy, seventh-fourth centuries BC) to garner insights into the timing and duration of different pubertal stages. Results: Adolescents from Pontecagnano entered puberty at 10-12 years and completed pubertal development at approximately 20-21 years. Menarche occurred between 14 and 17 years. Remarkable variability in pubertal timing and an overall prolonged pubertal tempo were observed. Unexpectedly, females completed puberty at the same age as males. Discussion: The onset and completion of puberty in Pontecagnano are mostly in line with pubertal trends emerging from other bioarchaeological studies and historical sources. The considerable inter-individual variability in pubertal timing seen at the site probably reflects its great sociocultural heterogeneity, whilst the prolonged pubertal tempo could represent an adaptive mechanism in response to environmental disruptors. These may have included endemic diseases characteristic of Pontecagnano's marshy environment and pollutants produced by the Etruscan and Samnite metallurgical industries. Moreover, the role of catch-up growth in favouring better pregnancy outcomes could explain why female puberty appears particularly stretched. The importance of exploring pubertal development in past societies without culturally biased assumptions is emphasised.

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“…Variant filtering and prioritization were performed on B_platform, 2 as previously reported using inhouse pipelines (26). The variant call format (VCF) file was annotated with ClinVar, 3 gnomAD, 4 and dbSNP 5 databases. Candidate variants were selected when minor allele frequency (MAF) was < 1% in gnomAD exomes and genomes in the 1000 Genomes and in Bitgenia's database of over 100 Argentine control individuals.…”

Section: Next-generation Sequencing and Filteringmentioning

confidence: 99%

“…A delay of puberty is diagnosed when no clinical signs of pubertal onset are present by the age of 14 (4). In approximately 2/3 of the cases, this is due to a normal developmental variant called constitutional delay of growth and puberty (5), but this is an exclusion diagnosis and causes of pathologic hypogonadism should be explored. After ruling out general chronic or acute illnesses and primary testicular failure, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, characterized by low testosterone secretion by the testes due to an impaired gonadotropin-releasing hormone (GnRH)/gonadotropin axis function (3,4,(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report

et al. 2022

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Pubertal delay in males is frequently due to constitutional delay of growth and puberty, but pathologic hypogonadism should be considered. After general illnesses and primary testicular failure are ruled out, the main differential diagnosis is central (or hypogonadotropic) hypogonadism, resulting from a defective function of the gonadotropin-releasing hormone (GnRH)/gonadotropin axis. Ciliopathies arising from defects in non-motile cilia are responsible for developmental disorders affecting the sense organs and the reproductive system. WDR11-mediated signaling in non-motile cilia is critical for fetal development of GnRH neurons. Only missense variants of WDR11 have been reported to date in patients with central hypogonadism, suggesting that nonsense variants could lead to more complex phenotypes. We report the case of a male patient presenting with delayed puberty due to Kallmann syndrome (central hypogonadism associated with hyposmia) in whom the next-generation sequencing analysis identified a novel heterozygous base duplication, leading to a frameshift and a stop codon in the N-terminal region of WDR11. The variant was predicted to undergo nonsense-mediated decay and classified as probably pathogenic following the American College of Medical Genetics and Genomics (ACMG) criteria. This is the first report of a variant in the WDR11 N-terminal region predicted to lead to complete expression loss that, contrary to expectations, led to a mild form of ciliopathy resulting in isolated Kallmann syndrome.

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Timing of Pubertal Onset in Girls and Boys With Constitutional Delay

Cited by 20 publications

References 29 publications

Recent advancement in the treatment of boys and adolescents with hypogonadism

Recent advancement in the treatment of boys and adolescents with hypogonadism

Puberty in pre‐Roman times: A bioarchaeological study of Etruscan‐Samnite adolescents from Pontecagnano (southern Italy)

Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report

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