A review of craniofacial and dental findings of the RASopathies

Cao, Hanwen; Alrejaye, Najla; Klein, Ophir D.; Goodwin, Alice F.; Oberoi, Snehlata

doi:10.1111/ocr.12144

Cited by 55 publications

(60 citation statements)

References 33 publications

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“…While isolated growth hormone deficiency is frequently seen in other individuals with NSLH1 (43%), this is the first patient reported with broader manifestations of hypopituitarism. Our patient also had the additional feature of a posterior cleft palate (without cleft lip), which has not been described in other individuals with NSLH or in NS due to mutations in other genes (Cao et al, ; Mallineni et al, ). We recognize that it is possible that the features of cleft palate and hypopituitarism may not be causally related to the SHOC2 mutation.…”

Section: Discussionsupporting

confidence: 60%

“…The clinical features of 84 patients with NSLH1 have been described (Table ) (Bader‐Meunier et al, ; Capalbo, Melis, et al, ; Capalbo, Scala, et al, ; Choi et al, ; Cordeddu et al, ; Ekvall, Hagenäs, Allanson, Annerén, & Bondeson, ; Ferrero et al, ; Garavelli et al, ; Gargano et al, ; Gripp et al, ; Hoban, Roberts, Demmer, Jethva, & Shephard, ; Kane et al, ; Komatsuzaki et al, ; Lo, Wang, Wong, & Lee, ; Mazzanti et al, ; Mazzanti et al, ; Şimşek‐Kiper et al, ; Tafazoli, Eshraghi, Koleti, & Abbaszadegan, ; Takenouchi et al, ; Tartaglia, Zampino, & Gelb, ; Tosti et al, ; Tosti et al, ; Tosti & Piraccini, ; Zmolikova et al, ). With the possible exception of one patient with unusual but not well‐defined palatal anatomy (Kumar, Chandar, Koduri, & Sankireddy, ), posterior cleft palate (CP) has not been reported in individuals with NS or with NSLH (Cao, Alrejaye, Klein, Goodwin, & Oberoi, ; Mallineni, Yung Yiu, & King, ). GHD appears to be both more common and more severe in NSLH1 than in NS (Malaquias et al, ; Mazzanti et al, ; Tamburrino et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

Couser

Keelean‐Fuller

Davenport

et al. 2018

American J of Med Genetics Pt A

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Noonan syndrome (NS), the most common of the RASopathies, is a developmental disorder caused by heterozygous germline mutations in genes encoding proteins in the RAS‐MAPK signaling pathway. Noonan‐like syndrome with loose anagen hair (NSLH, including NSLH1, OMIM #607721 and NSLH2, OMIM #617506) is characterized by typical features of NS with additional findings of macrocephaly, loose anagen hair, growth hormone deficiency in some, and a higher incidence of intellectual disability. All NSLH1 reported cases to date have had an SHOC2 c.4A>G, p.Ser2Gly mutation; NSLH2 cases have been reported with a PPP1CB c.146G>C, p.Pro49Arg mutation, or c.166G>C, p.Ala56Pro mutation. True cleft palate does not appear to have been previously reported in individuals with NS or with NSLH. While some patients with NS have had growth hormone deficiency (GHD), other endocrine abnormalities are only rarely documented. We present a female patient with NSLH1 who was born with a posterior cleft palate, micrognathia, and mild hypotonia. Other findings in her childhood and young adulthood years include hearing loss, strabismus, and hypopituitarism with growth hormone, thyroid stimulating hormone (TSH), and gonadotropin deficiencies. The SHOC2 mutation may be responsible for this patient's additional features of cleft palate and hypopituitarism.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

Couser

Keelean‐Fuller

Davenport

et al. 2018

American J of Med Genetics Pt A

View full text Add to dashboard Cite

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“…RASopathies are individually rare and pleiotropic but are collectively one of the most common causes of developmental disorders. Associated features include neurocognitive impairment, craniofacial dysmorphology, anomalies of the cardiovascular and musculoskeletal systems, cutaneous lesions, and increased risk of tumor formation [6]. For example, variation in HRAS is associated with Costello Syndrome (MIM:218040) and Noonan Syndrome (MIM:609942), variation in KRAS is associated with Cardiofaciocutaneous syndromes (MIM:615278), and variation in NRAS has been observed in probands with RASopathy-associated phenotypes [7].…”

Section: Introductionmentioning

confidence: 99%

De novomutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

Hiatt

Neu

Ramaker

et al. 2018

Preprint

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60Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group 61 of Mendelian diseases known as RASopathies, but the matrix of genotype-phenotype 62 relationships is still incomplete, in part because there are many RAS-related proteins, 63 and in part because the phenotypic consequences may be variable and/or pleiotropic. 64Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 65 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small 66 GTPase. All probands present with speech and motor delays, and most have intellectual 67 disability, low weight, short stature, and facial dysmorphism. The observed rate of de 68 novo RALA variants in affected probands is significantly higher (p=4.93 x 10 -11 ) than 69 expected from the estimated mutation rate. Further, all de novo variants described 70 here affect conserved residues within the GTP/GDP-binding region of RALA; in fact, six 71 alleles arose at only two codons, Val25 and Lys128. We directly assayed GTP hydrolysis 72 and RALA effector-protein binding, and all but one tested variant significantly reduced 73 both activities. The one exception, S157A, reduced GTP hydrolysis but significantly 74 increased RALA-effector binding, an observation similar to that seen for oncogenic RAS 75 variants. These results show the power of data sharing for the interpretation and 76 analysis of rare variation, expand the spectrum of molecular causes of developmental 77 disability to include RALA, and provide additional insight into the pathogenesis of78 human disease caused by mutations in small GTPases.79 80 81 5 82 Author Summary 83 While many causes of developmental disabilities have been identified, a large number of 84 affected children cannot be diagnosed despite extensive medical testing. Previously 85 unknown genetic factors are likely to be the culprits in many of these cases. Using DNA 86 sequencing, and by sharing information among many doctors and researchers, we have 87 identified a set of individuals with developmental problems who all have changes to the 88 same gene, RALA. The affected individuals all have similar symptoms, including 89 intellectual disability, speech delay (or no speech), and problems with motor skills like 90walking. In nearly all of these cases (10 of 11), the genetic change found in the child was 91 not inherited from either parent. The locations and biological properties of these 92 changes suggest that they are likely to disrupt the normal functions of RALA and cause 93 significant health problems. We also performed experiments to show that the genetic 94 changes found in these individuals alter two key functions of RALA. Together, we have 95 provided evidence that genetic changes in RALA can cause DD/ID. These results will 96 allow doctors and researchers to identify additional children with the same condition, 97 providing a clinical diagnosis to these families and leading to new research 98 opportunities. 99 100 101 Developmental delay and intellectual disabili...

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“…12 Diseases seen as a result of mutations in genes encoding Ras/mitogen activated protein kinase (Ras/MAPK) pathway are called RASopathies and Neurofibromatosis is one of these diseases. 13 Neurofibromin is a cytoplasmic protein and is expressed in neurons, Schwann cells, oligodendrocytes and leukocytes. It is a multifunctional enzyme and regulates intracellular activities like RAS-Cyclic AMP pathway, ERK/ MAP kinase cascade, adenylyl cyclase enzyme function and cytoskeleton formation.…”

Section: Discussionmentioning

confidence: 99%

A Sublingual Neurofibroma: A Case Report

Altan¹,

Erdil²,

Akbulut³

2019

ERD

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Neurofibromatosis is a genetically inherited, autosomal dominant disorder. Deletions or mutations on chromosomes 17 and 22 precipitate to neurofibromatosis and there are genetically two types of the it as Type 1 and Type 2. Neurofibromatosis Type 1 is relevant with the abnormalities on chromosome 17.In the affected population, the incidence of oral manifestation is as high as 92%, and the tongue is the most common involved site. Due to the lack of neurofibromin, which is encoded by the NF1 gene located on chromosome 17 and acts as a tumor suppressor protein, neurofibromas are frequently diagnosed on the tongue as nodular growths or diffuse macroglossia in the oral cavity.In this case report we aim to present our approach of treatment with intent to meet patient's preprosthetic demands by performing an incisional biopsy on a sublingual neurofibroma and review the current literature in terms of diagnostic criteria, clinical features, accompanying impairments and treatment modalities. ÖzNörofibromatozis genetik olarak aktarılan, otozomal dominant bir hastalıktır. Hastalığın oluşumuna 17. Ve 22. kromozomlardaki delesyonlar (silinme) veya mutasyonlar sebep olmakta ve hastalığın tip 1 ve tip 2 olmak üzere iki türü bulunmaktadır. Nörofibromatozis Tip 1, 17. kromozomdaki anomalilerden kaynaklanmaktadır.Etkilenen popülasyonda oral bulguların görülme sıklığı %92'ye kadar yükselmektedir. Dil, oral bölgede en sık etkilenen organdır. Hasta bireylerde, tümör baskılayıcı bir protein olan ve 17. kromozom üzerinde yer alan, NF1 geni tarafından kodlanan nörofibromin üretilmediği için oral kavitede sıklıkla dilde nodüler büyümeler şeklinde veya diffüz makroglossi tarzında nörofibromalar görülmektedir.Bu olgu sunumunda, Nörofibromatozis Tip 1 tanılı hastada bir sublingual nörofibromaya insizyonel biyopsi ile preprotetik amaçlı tedavi yaklaşımımızı sunmayı ve mevcut literatürü tanı kriterleri, klinik özellikler, eşlik eden bozukluklar ve tedavi yöntemleri açısından gözden geçirmeyi amaçladık.

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A review of craniofacial and dental findings of the RASopathies

Cited by 55 publications

References 33 publications

Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

De novomutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay

A Sublingual Neurofibroma: A Case Report

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