Constitutional bone impairment in Noonan syndrome

Baldassarre, Giuseppina; Mussa, Alessandro; Carli, Diana; Méndez-Vidal, Cristina; Ferrero, Giovanni Battista

doi:10.1002/ajmg.a.38086

Cited by 17 publications

(20 citation statements)

References 61 publications

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“…Increased bone resorption has previously been reported in RASopathies (D. Stevenson et al, 2011; D. A. Stevenson et al, 2008). Specifically, reduced BMD has been documented in NF1 (Heervä et al, 2012; D. A. Stevenson et al, 2007) and anecdotally in NS and CS (Baldassarre et al, 2017; Leoni et al, 2014; White et al, 2005). In NF1 mouse models, a reduced mineral content associated with decreased bone stiffness has been found (Yang et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In 2012, Choudry et al reported a statistically significant reduction in BMD z‐scores and a trend toward significance for BMC z ‐scores in children with NS compared to age‐matched controls (Choudhry et al, 2012). In the same way, Baldassarre et al investigated bone quality via quantitative ultrasound and metabolic bone profiling in a group of 35 patients with NS demonstrating bone impairment in NS (Baldassarre et al, 2017). In CS anecdotal data have been reported dealing with osteopenia or osteoporosis, mostly for adult patients (D. Stevenson et al, 2011; D. A. Stevenson & Yang, 2011; White et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The musculoskeletal phenotype in CS and CFCS has been widely reported (Leoni et al, 2021; D. A. Stevenson & Yang, 2011), and authors described a large overlap of clinical findings. Reduced bone mineral density (BMD) has been documented in NF1, NS, and CS (Baldassarre et al, 2017; Choudhry et al, 2012; Leoni et al, 2014; Reinker et al, 2011; Stevenson et al, 2007; Stevenson et al, 2008). However, no systematic analysis investigating bone assessment in CFCS is currently available.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of bone homeostasis in individuals affected by cardio‐facio‐cutaneous syndrome

Leoni

Viscogliosi

Onesimo

et al. 2021

American J of Med Genetics Pt A

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Cardio‐facio‐cutaneous syndrome (CFCS) is a rare disorder characterized by distinctive craniofacial appearance, cardiac, neurologic, cutaneous, and musculoskeletal abnormalities. It is due to heterozygous mutations in BRAF, MAP2K1, MAP2K2, and KRAS genes, belonging to the RAS/MAPK pathway. The role of RAS signaling in bone homeostasis is highly recognized, but data on bone mineral density (BMD) in CFCS are lacking. In the present study we evaluated bone parameters, serum and urinary bone metabolites in 14 individuals with a molecularly confirmed diagnosis of CFCS. Bone assessment was performed through dual X‐ray absorptiometry (DXA); height‐adjusted results were compared to age‐ and sex‐matched controls. Blood and urinary bone metabolites were also analyzed and compared to the reference range. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFCS patients showed significantly decreased absolute values of DXA‐assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls. BMD z‐scores and t‐scores (respectively collected for children and adults) were below the reference range in CFCS, while normal in healthy controls. These findings confirmed a reduction in BMD in CFCS and highlighted the importance of monitoring bone health in these affected individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of bone homeostasis in individuals affected by cardio‐facio‐cutaneous syndrome

Leoni

Viscogliosi

Onesimo

et al. 2021

American J of Med Genetics Pt A

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“…Ptpn11 mutations lead to increased SHP2 enzymatic activity and altered activation of the Ras/RAF/ERK signaling cascade responsible for Noonan syndrome (NS). NS is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature, and decreased bone mineral density (BMD), 80 , 81 as well as heart disease. 82 , 83 To circumvent the lethality of SHP2 null mutations and study SHP2’s function in the osteoblastic cell lineage, Ptpn11 floxed alleles have been created 13 , 77 and bred with a series of Cre alleles to target osteoblastic cells at various developmental stages.…”

Section: Ptps In Osteoblast Development Function and Bone Homeostasismentioning

confidence: 99%

Protein tyrosine phosphatases in skeletal development and diseases

et al. 2022

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Skeletal development and homeostasis in mammals are modulated by finely coordinated processes of migration, proliferation, differentiation, and death of skeletogenic cells originating from the mesoderm and neural crest. Numerous molecular mechanisms are involved in these regulatory processes, one of which is protein posttranslational modifications, particularly protein tyrosine phosphorylation (PYP). PYP occurs mainly through the action of protein tyrosine kinases (PTKs), modifying protein enzymatic activity, changing its cellular localization, and aiding in the assembly or disassembly of protein signaling complexes. Under physiological conditions, PYP is balanced by the coordinated action of PTKs and protein tyrosine phosphatases (PTPs). Dysregulation of PYP can cause genetic, metabolic, developmental, and oncogenic skeletal diseases. Although PYP is a reversible biochemical process, in contrast to PTKs, little is known about how this equilibrium is modulated by PTPs in the skeletal system. Whole-genome sequencing has revealed a large and diverse superfamily of PTP genes (over 100 members) in humans, which can be further divided into cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs. Here, we review current knowledge about the functions and regulatory mechanisms of 28 PTPs involved in skeletal development and diseases; 27 of them belong to class I and II Cys-based PTPs, and the other is an Asp-based PTP. Recent progress in analyzing animal models that harbor various mutations in these PTPs and future research directions are also discussed. Our literature review indicates that PTPs are as crucial as PTKs in supporting skeletal development and homeostasis.

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“…Reduced bone mineral density (BMD) has been documented in both NF1patients and animal models (Elefteriou et al, 2006; Illés et al, 2001; Kuorilehto et al, 2005; Stevenson, Murray, et al, 2008; Wu et al, 2006; Yang et al, 2006; Yilmaz et al, 2007; Yu et al, 2005). Bone assessment has recently been analyzed also in NS and CS (Baldassarre et al, 2017; Choudhry et al, 2012; Leoni et al, 2014; Leoni et al, 2021), whereas a systematic assessment of BMD and bone mineral homeostasis in CFCS is lacking. Of note we recently documented a low BMD occurring in patients with CS, which was associated with a marked reduction of blood 25‐hydroxyvitamin D (25(OH)vitD), suggesting a possible strategy based on supplementation of this vitamin for managing this complication in CS (Leoni et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Bone tissue homeostasis and risk of fractures in Costello syndrome: A 4‐year follow‐up study

Leoni

Bisanti

Viscogliosi

et al. 2021

American J of Med Genetics Pt A

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Costello syndrome (CS) is a neurodevelopmental disorder with a distinctive musculoskeletal phenotype and reduced bone mineral density (BMD) caused by activating de novo mutations in the HRAS gene. Herein, we report the results of a prospective study evaluating the efficacy of a 4-year vitamin D supplementation on BMD and bone health. A cohort of 16 individuals ranging from pediatric to adult age with molecularly confirmed CS underwent dosages of bone metabolism biomarkers (serum/urine) and dual-energy X-ray absorptiometry (DXA) scans to assess bone and body composition parameters. Results were compared to age-matched control groups. At baseline evaluation, BMD was significantly reduced (p ≤ 0.05) compared to controls, as were the 25(OH)vitD levels. Following the 4-year time interval, despite vitamin D supplementation therapy at adequate dosages, no significant improvement in BMD was observed. The present data confirm that 25(OH)vitD and BMD parameters are reduced in CS, and vitamin D supplementation is not sufficient to restore proper BMD values. Based on this evidence, routine monitoring of bone homeostasis to prevent bone deterioration and possible fractures in adult patients with CS is highly recommended. K E Y W O R D S bone metabolism biomarkers, bone mineral density, Costello syndrome, patient-centered care, personalized medicine, RASopathies 1 | INTRODUCTION Costello syndrome (CS, OMIM #218040) is a rare multisystem disorder belonging to a family of syndromes affecting development and growth collectively known as the RASopathies. These rare diseases share the upregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway as a common pathogenetic mechanism (Aoki et al., 2016;Tartaglia & Gelb, 2010). This signaling cascade controls a wide array of cellular processes (e.g., proliferation, migration, Abbreviations: 25(OH)vitD, 25 hydroxy vitamin D; B-ALP, bone alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; CFCS, cardio-facio-cutaneous syndrome; CS, Costello syndrome; DXA, dual-energy X-ray absorptiometry; F-BMD, femur bone mineral density; FFM, fat free mass; FM, fat mass; FN-BMD, femoral neck bone mineral density; L-BMD, lumbar bone mineral density; MAPK, mitogen-activated protein kinase; NF1, neurofibromatosis type 1; NS, Noonan syndrome; PTH, parathyroid hormone; S-BMC, subtotal bone mineral content; S-BMD, subtotal bone mineral density; WBLH, whole body less head.

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Constitutional bone impairment in Noonan syndrome

Cited by 17 publications

References 61 publications

Characterization of bone homeostasis in individuals affected by cardio‐facio‐cutaneous syndrome

Characterization of bone homeostasis in individuals affected by cardio‐facio‐cutaneous syndrome

Protein tyrosine phosphatases in skeletal development and diseases

Bone tissue homeostasis and risk of fractures in Costello syndrome: A 4‐year follow‐up study

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