New developments in the genetic diagnosis of short stature

Jee, Youn Hee; Baron, Jeffrey; Nilsson, Ola

doi:10.1097/mop.0000000000000653

Cited by 42 publications

(26 citation statements)

References 47 publications

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“…Although CNP performs a broader range of biological functions throughout the CNS and peripheral tissues compared with the predominantly cardiovascular roles for ANP and BNP, it is the effects of CNP on endocrine ossification that are best described. Numerous loss-of-function mutations have now been reported in NPPC and NPR2 , leading to profound skeletal dysplasias and short stature [ 8 , 28 , 50 ]. Mouse models of disrupted Nppc and Npr2 essentially phenocopy the clinical signs observed in humans, but in addition, some of these mouse models have reduced pituitary GH, suggesting a positive role for CNP in pituitary GH secretion [ 5 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…CNP is the major natriuretic peptide of the central nervous system [ 1 , 4 ], but has profound effects on growth in peripheral tissues. Targeted disruption of the Nppc or Npr2 genes (encoding CNP and GC-B, respectively) lead to achondroplasia, dwarfism, female infertility and early death [ 5 , 6 ], and these severe growth phenotypes in mice are mirrored by the symptoms of human patients with inactivating mutations in NPR2 and NPPC mutations [ 7 , 8 ]. Biochemical analyses of Nppc - and Npr2 -disrupted mice indicate deficiencies in both growth hormone (GH) and insulin-like growth factor-1 (IGF-I) [ 5 , 6 ], which suggests a potential pituitary-specific role of CNP and GC-B signalling.…”

Section: Introductionmentioning

confidence: 99%

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Natriuretic Peptide Expression and Function in GH3 Somatolactotropes and Feline Somatotrope Pituitary Tumours

Mirczuk

Scudder

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et al. 2021

IJMS

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Patients harbouring mutations in genes encoding C-type natriuretic peptide (CNP; NPPC) or its receptor guanylyl cyclase B (GC-B, NPR2) suffer from severe growth phenotypes; loss-of-function mutations cause achondroplasia, whereas gain-of-function mutations cause skeletal overgrowth. Although most of the effects of CNP/GC-B on growth are mediated directly on bone, evidence suggests the natriuretic peptides may also affect anterior pituitary control of growth. Our previous studies described the expression of NPPC and NPR2 in a range of human pituitary tumours, normal human pituitary, and normal fetal human pituitary. However, the natriuretic peptide system in somatotropes has not been extensively explored. Here, we examine the expression and function of the CNP/GC-B system in rat GH3 somatolactotrope cell line and pituitary tumours from a cohort of feline hypersomatotropism (HST; acromegaly) patients. Using multiplex RT-qPCR, all three natriuretic peptides and their receptors were detected in GH3 cells. The expression of Nppc was significantly enhanced following treatment with either 100 nM TRH or 10 µM forskolin, yet only Npr1 expression was sensitive to forskolin stimulation; the effects of forskolin and TRH on Nppc expression were PKA- and MAPK-dependent, respectively. CNP stimulation of GH3 somatolactotropes significantly inhibited Esr1, Insr and Lepr expression, but dramatically enhanced cFos expression at the same time point. Oestrogen treatment significantly enhanced expression of Nppa, Nppc, Npr1, and Npr2 in GH3 somatolactotropes, but inhibited CNP-stimulated cGMP accumulation. Finally, transcripts for all three natriuretic peptides and receptors were expressed in feline pituitary tumours from patients with HST. NPPC expression was negatively correlated with pituitary tumour volume and SSTR5 expression, but positively correlated with D2R and GHR expression. Collectively, these data provide mechanisms that control expression and function of CNP in somatolactotrope cells, and identify putative transcriptional targets for CNP action in somatotropes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Natriuretic Peptide Expression and Function in GH3 Somatolactotropes and Feline Somatotrope Pituitary Tumours

Mirczuk

Scudder

Read

et al. 2021

IJMS

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“…This is due to insufficient safety and efficacy data, most often related to the rarity of the particular condition, rendering clinical trials with sufficient numbers of patients challenging. Of note, the medical knowledge of genetic conditions and traits causing short stature has now expanded [5] to a level that almost makes obsolete the term "idiopathic short stature".…”

Section: Human Growth Plate Functionmentioning

confidence: 99%

New developments in the management of achondroplasia

Högler

Ward

2020

Wien Med Wochenschr

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Achondroplasia is the most common form of disproportionate short stature. A dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor receptor 3 (FGFR3) and its downstream mitogen-activated protein kinase (MAPK) signalling pathway. This inhibits chondrocyte differentiation and puts a break on growth plate function, in addition to causing serious medical complications such as foramen magnum and spinal stenosis and upper airway narrowing. A great deal has been learned about complications and consequences of FGFR3 activation and management guidance is evolving aimed to reduce the increased mortality and morbidity in this condition, particularly deaths from spinal cord compression and sleep apnoea in infants and small children. To date, no drugs are licensed for treatment of achondroplasia. Here, we report on the various substances in the drug development pipeline which target elements in molecular disease mechanism such as FGF (fibroblast growth factor) ligands, FGFR3, MAPK signalling as well as the C-type natriuretic peptide receptor NPR-B (natriuretic peptide receptor B).

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“…In recent years there has been a much greater emphasis and interest in genes within the growth plate, some regulating metabolic factors and cycles that subserve growth. Genome-wide association studies (GWAS), targeted gene sequencing and whole exome or genome sequencing abound (102)(103)(104). Although of great interest for primary growth disorders, it is far too early to implicate them in some of the secondary growth disorders, including psychosocial short stature.…”

Section: Dénouemontmentioning

confidence: 99%

Emotional Deprivation in Children: Growth Faltering and Reversible Hypopituitarism

Rogol

2020

Front. Endocrinol.

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Emotional deprivation can lead to growth faltering of infants and children. The mechanism(s) involved differ in that for infants, the major metabolic problem is inadequate energy intake for growth. In young children, it is likely that the emotional deprivation causes a syndrome not only of growth faltering, but with bizarre behaviors, especially with regard to food: hoarding, gorging and vomiting, hyperphagia, drinking from the toilet, and eating from garbage pails. Other disturbed behaviors include, poor sleep, night wanderings, and pain agnosia. The pathophysiology appears to be reversible hypopituitarism, at least for the growth hormone and hypothalamic-pituitary-adrenal axes. The review begins with an historical perspective concerning stress, children and growth and then moves to the issue of hospitalism, where young infants failed to thrive (and died) due to inadequate stimulation and energy intake. Refeeding programs at the end of World Wars I and II noted that some children did not thrive despite an adequate energy intake. It appeared that in addition taking care of their emotional needs permitted super-physiologic (catch-up) growth. Next came the first notions from clinical investigation that hypopituitarism might be the mechanism of growth faltering. Studies that address this mechanism from a number of observational and clinical research studies are reviewed in depth to show that the hypopituitarism was relieved upon removal from the deprivational environment and occurred much too quickly to be due to adequate energy alone. These findings are then compared to those from malnourished children and adoptees from emerging countries, especially those from orphanages where their psychosocial needs were unmet despite adequate caloric intake. Together, these various conditions define one aspect of the field of psychoneuroendocrinology.

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New developments in the genetic diagnosis of short stature

Cited by 42 publications

References 47 publications

Natriuretic Peptide Expression and Function in GH3 Somatolactotropes and Feline Somatotrope Pituitary Tumours

Natriuretic Peptide Expression and Function in GH3 Somatolactotropes and Feline Somatotrope Pituitary Tumours

New developments in the management of achondroplasia

Emotional Deprivation in Children: Growth Faltering and Reversible Hypopituitarism

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