Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives

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Abstract

There is a wide spectrum of craniofacial bone disorders and dysplasias because embryological development of the craniofacial region is complex. Classification of craniofacial bone disorders and dysplasias is also complex because they exhibit complex clinical, pathological, and molecular heterogeneity. Most craniofacial disorders and dysplasias are rare but they present an array of phenotypes that functionally impact the orofacial complex. Management of craniofacial disorders is a multidisciplinary approach that involves the collaborative efforts of multiple professionals. This review provides an overview of the complexity of craniofacial disorders and dysplasias from molecular, clinical, and management perspectives.

Highlights

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Craniofacial disorders are genetically and phenotypically heterogeneous.
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Most craniofacial disorders are rare and have different inheritance patterns.
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Prominent localized craniofacial disorders and dysplasia have systemic components.
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Some craniofacial disorders can present syndromically or in isolation.
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Treatment of craniofacial disorders requires a multidisciplinary approach.

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Most cited references 186

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Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

M. Tartaglia, E. L. Mehler, R. Goldberg … (2001)

Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.

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The RASopathies.

Katherine Rauen (2013)

The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.

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Neurofibromatosis type 1

David Gutmann, Rosalie E Ferner, Robert H. Listernick … (2017)

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

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Author and article information

Contributors

Sunday O. Akintoye

Mel Mupparapu

Journal

Journal ID (nlm-ta): Bone Rep

Journal ID (iso-abbrev): Bone Rep

Title: Bone Reports

Publisher: Elsevier

ISSN (Electronic): 2352-1872

Publication date PMC-release: 01 March 2024

Publication date Collection: March 2024

Publication date (Electronic): 01 March 2024

Volume: 20

Electronic Location Identifier: 101747

Affiliations

[a ]Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States of America

[b ]University of Ibadan and University College Hospital Ibadan, Ibadan, Nigeria

[c ]Department of Oral Pathology & Oral Medicine, University of Nigeria Teaching Hospital, Ituku-Ozalla, Nigeria

Author notes

[* ]Corresponding author. akintoye@ 123456upenn.edu

Article

Publisher Item ID: S2352-1872(24)00014-7 Publisher ID: 101747

DOI: 10.1016/j.bonr.2024.101747

PMC ID: 10985038

PubMed ID: 38566929

SO-VID: 4c96ef92-c29b-458c-b547-0d75407b7d57

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 22 December 2023

Date revision received : 27 February 2024

Date accepted : 29 February 2024

Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives

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Most cited references 186

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

The RASopathies.

Neurofibromatosis type 1

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Contributors

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Article

History

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