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Noonan Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
NS/LAH has similar features to Noonan syndrome, but differs from the latter by its growth hormone deficiency, distinctive hyperactive behavior, loose anagen hair, darkly pigmented skin with eczema or ichthyosis, hypernasal voice, and more mitral valve dysplasia and cardiac septal defects. Molecularly, NS/LAH is attributed to germline mutations (e.g., 4A→G, p.Ser2Gly) in the SHOC2 gene, which encodes a protein (SHOC2) consisting of almost entirely of leucine-rich repeats. Acting as a scaffold protein linking RAS to RAF1, SHOC2 binds RasGTP and mediates protein phosphatase 1C (PP1C) translocation to the cell membrane, facilitating PP1C dephosphorylation of residue S259 of RAF1. SHOC2 p.Ser2Gly mutation erroneously adds a 14-carbon saturated fatty acid chain, myristate, to the N-terminal glycine of SHOC2, and causes aberrant translocation of SHOC2 to the cell membrane instead of the nucleus, thus prolonging PP1C dephosphorylation of RAF1 and sustaining the MAPK pathway activation [16].
Hair dysplasias
Published in Pierre Bouhanna, Eric Bouhanna, The Alopecias, 2015
Juan Ferrando, L. Alheli Niebla, Gerardo A. Moreno-Arias
Genetics. Gene mutations have been reported in SHOC2 and KRT75.77,78 The former encodes leucine-rich repeat-containing protein, which participates in protein–protein interaction during cascade activation of kinases (RAS/ERK MAP). This mutation is responsible for Noonan-like syndrome with loose anagen hair. KRT75 encodes a family of type 2 keratins that participate in the formation of hair and nails. Its mutation causes pseudo-folliculitis barbae and loose anagen hair. Genes have been identified in 10q.25 and 12q.13, respectively.
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
NS patients usually appear with ocular alignment and motility disorders, including strabismus, absence of normal stereopsis, limited ocular motility, or nystagmus. The findings in existing literature indicate that strabismus is a common ocular manifestation. It may usually present as exotropia or esotropia, while vertical or mixed disorders seem to be seldom. In addition, the limited ocular motility may present as limited abduction, limited adduction, or limited elevation. Possibly, the genetic basis is responsible for the frequency of nystagmus among NS patients.12,14–18 Alfieri et al14 reported nystagmus in patients harboring SOS1 or PTPN11 mutations, with a higher prevalence in the SOS1 group. Marin et al.18 reported no cases of nystagmus in a cohort of patients with PTPN11 mutation. van Trier et al.17 observed nystagmus in two patients in their prospective study; one with PTPN11 mutation and one with BRAF mutation associated with poor vision and infantile sensory nystagmus. In a large retrospective study,12 nystagmus seemed to be associated with almost all identified genes, though visual impairment was mainly found in patients with SHOC2 or KRAS mutations.
Neuro-Ophthalmic Literature Review
Published in Neuro-Ophthalmology, 2018
David Bellows, Noel Chan, John Chen, Hui-Chen Cheng, Peter MacIntosh, John H. Pula, Michael Vaphiades, Konrad P. Weber, Sui Wong
Noonan syndrome (NS) is an autosomal dominant disorder with variable phenotype, including short stature, congenital heart defects, and ophthalmological abnormalities. Different mutations in coding genes leading to dysregulation of the Ras/mitogen-activated protein kinase pathway can cause NS. The authors describe a retrospective review of 105 NS patients in the Netherlands. Sixty eight were under the age of 18 years. The primary outcome of the study was presence of ocular abnormalities in NS population. Seven patients were visually impaired, mainly attributable to binocular optic nerve abnormalities and manifest nystagmus related to RAF1, SHOC2, and KRAS gene mutations. Twenty-eight patients had amblyopia. Refractive errors included myopia, hyperopia, and astigmatism. Ten patients had high refractive errors.
Heterotaxy Syndrome with Increased Nuchal Translucency and Normal Karyotype Associated with Complex Systemic Venous Return. Ultrasound Diagnosis with Autopsy Correlation
Published in Fetal and Pediatric Pathology, 2022
Gabriele Tonni, Maria Paola Bonasoni, Gianpaolo Grisolia, Maria Bellotti, Edward Araujo Júnior
A 32-year-old mother, with a previous miscarriage at 6 weeks (G2P0), was referred at 11 weeks’ gestation for suspected cystic hygroma. The scan was carried out using a Voluson E6 (GE, Milwaukee, WI) apparatus equipped with transabdominal 2 D/3D multifrequency RAD 4-8 D volumetric probe. The fetus presented with CRL (crown rump length) of 46.8 mm (11w5d) and BPD (biparietal diameter) of 18 mm. The skull was normal with symmetric choroid plexuses. NIHF with increased NT (nuchal translucency of 7.7 mm, > 99th centile) were seen together with episodes of sinus bradycardia (defined as fetal heart rate < 120 bpm). Fetal karyotyping by chorionic villus sampling (CVS) was performed at 12w2d together with a-CGH analysis after signed informed consent. During the procedure, recurrence of sinus bradycardia (111 bpm) was detected before and after CVS. Fetal and parental a-CGH revealed in the fetus a partial microduplication of the long arm of chromosome 22 inherited from the father (arr[GRCh37] 22q13.1 encompassing 140 kb from position 37,629,237 to the position 37,773,556). 22q11.2 deletion syndrome, also known as Di George syndrome, was excluded and screening for Noonan syndrome revealed no mutations in PTPN11 gene as well as SOS1, RAF1, RIT1, LZTR1, BRAF and SHOC2 genes. Maternal contamination of fetal DNA was excluded. Follow up scans were planned at 16 and 19 weeks and expert consultation in fetal echocardiography at remote site was sought using telemedicine. Ultrasound showed a right-sided stomach while the spleen was not visible, a dilated coronary sinus due to persistent left superior vena cava (PLSVC), large VSD, both ventricles morphologically appearing as left ventricles with myocardial hypertrophy and overriding aorta. The pulmonary trunk arose from the right-sided ventricle with a potential diagnosis of corrected transposition of the great artery (cTGA). ASVR consisted of interrupted inferior vena cava (IVC) with azygos continuation (Figure 1A–E). A left hetorotaxy syndrome associated with complex CHD with a large VSD, sinus bradycardia and ASVR was prompted.