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Disorders of Keratinization and Other Genodermatoses
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Roselyn Stanger, Nanette Silverberg
Clinical presentation: Costello syndrome is the result of a heterozygous germline mutation in the HRAS gene. Patients with Costello syndrome can have extremely variable phenotypic presentations. Cutaneous findings include lax skin of the hands and feet, deep palmar and plantar creases, curly hair, acanthosis nigricans or even generalized hyperpigmentation, low-set ears, periorificial papillomata, and coarse facial features. Cardiac abnormalities include hypertrophic cardiomyopathy, arrhythmias (e.g., supraventricular tachycardia), and congenital heart defects (e.g., valvar pulmonic stenosis). Patients can also have macrocephaly, hydrocephalus, or cerebellar abnormalities (e.g., Chiari malformations); diffuse hypotonia; and joint laxity. Infants can suffer from failure to thrive, and as they get older, children may have developmental delays, intellectual disabilities, and short stature. As mentioned earlier, patients are at increased risk for malignancies, in particular rhabdomyosarcoma and neuroblastoma in children and transitional cell carcinoma of the bladder in adolescents and young adults.
Costello Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Costello syndrome typically manifests as facial dysmorphism, skin changes, cognitive impairment, cardiac and musculoskeletal defects, along with an increased risk of malignancies as well as sudden death secondary to heart disease [17].
Personalized Medicine in Hereditary Cancer Syndromes
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
The underlying genetic mutations affect different sections of the RAS/RAF/MAPK pathway in each syndrome. Noonan syndrome is associated with mutations in the PTPN11, KRAS, SOS, and RAF1 genes [44]. LEOPARD syndrome is associated with mutations in PTPN11 and RAF1. Patients with Costello syndrome have mutations in the HRAS gene. Patients with cardiofaciocutaneous syndrome have mutations in BRAF, MAP2K1 and MAP2K2, and KRAS [44].
A Narrative Review of the Ocular Manifestations in Noonan Syndrome
Published in Seminars in Ophthalmology, 2022
Evita Evangelia Christou, Paraskevas Zafeiropoulos, Dimitrios Rallis, Maria Baltogianni, Christoforos Asproudis, Maria Stefaniotou, Vasileios Giapros, Ioannis Asproudis
The RASopathies are a clinically defined group of medical genetic syndromes.5,13,20 Regarding the wide spectrum of clinical entities of these syndromes, distinct disorders have been described; (a) neurofibromatosis type 1, (b) Noonan syndrome, (c) Noonan syndrome with multiple lentigines (formerly referred as LEOPARD syndrome), (d) capillary malformation–arteriovenous malformation syndrome, (e) Costello syndrome, (f) cardio-facial-cutaneous syndrome and (g) Legius syndrome. The pathogenesis of RASopathies is associated with germline mutations in genes encoding components or regulators of the RAS/MAPK pathway.5,13,20 The RAS/MAPK pathway is critical for signal transduction through extracellular ligands (growth factors, cell adhesion molecules, cytokines, and hormones) with an essential role in regulating the cell cycle, proliferation, differentiation, and metabolism. Indeed, it plays a vital role in embryonic and postnatal development.
A case of Costello syndrome diagnosed by trio whole exome sequencing
Published in Journal of Obstetrics and Gynaecology, 2022
Helen McDermott, Pallavi Karkhanis, Samantha Doyle, Harsha Gowda
Costello syndrome is associated with pathogenic mutations on the HRAS protein on the short arm of chromosome 11 (p15.5, Online Mendelian Inheritance in Man (OMIM)#218040). Missense variants in this position result in activation of the abnormal protein leading to increased signalling through the Ras-MAPK pathway (Lin et al. 2011). While considered autosomal dominant, often paternally inherited, nearly all known cases arise de-novo. The likelihood in recurrent pregnancies is low but cannot be excluded due to risk of parental germline mosaicism.
Idiopathic polyhydramnios and foetal macrosomia in the absence of maternal diabetes: clinical vigilance for costello syndrome
Published in Journal of Obstetrics and Gynaecology, 2022
Costello syndrome is a rare disorder with intellectual disability, characterised by failure to thrive, short stature, joint laxity, soft skin, and distinctive facial features (Hennekam 2003). This syndrome shows significant clinical overlap with Noonan syndrome, and belongs to the RASopathies, a group of conditions resulting from germline variants affecting the RAS-mitogen activated protein kinase pathway. The p.G12A of HRAS gene in our case is a recurrent variant. Indeed, almost all variants affect either codon 12 or 13 of the protein product, with G12S and G12A occurring in 90.9–95.0% of variant‐positive patients (Rauen 2007; Gripp et al. 2019). Foetal overgrowth and polyhydramios were prominent in our case. Prenatal overgrowth syndromes include relatively few conditions, that is, Sotos syndrome, Simpson–Golabi–Behmel syndrome, Beckwith–Wiedemann syndrome, and Costello syndrome. Sotos syndrome is caused by a deletion or mutation in the NSD1 gene, which maps to 5q35 (Faravelli 2005). Foetuses with Sotos syndrome may manifest with increased NT, macrocephaly, polyhydramnios, foetal overgrowth, renal abnormalities, and central nervous system abnormalities (Thomas and Lemire 2008). Simpson-Golabi-Behmel syndrome is an X-linked recessive disorder with variants of CXORF5 or GPC3 gene on chromosome X (Magini et al. 2016). Foetuses may present with macrosomia, polyhydramnios, cystic hygroma, hydrops fetalis, increased nuchal translucency (NT), craniofacial abnormalities, visceromegaly, renal anomalies, congenital diaphragmatic hernia, polydactyly, and a single umbilical artery. Beckwith-Wiedemann syndrome is an imprinting disorder with the region 11p15 involved. Foetuses may manifest with macrosomia, polyhydramnios, macroglossia, omphalocele, placentomegaly, a long umbilical cord, echogenic kidneys, and pancreatic cystic dysplasia (Barisic et al. 2018; Shieh et al. 2019). Since these syndromes are rare, an increased awareness of them among obstetricians will improve their prenatal detection rates.