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Noonan Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Noonan syndrome is an autosomal dominant disorder characterized by short stature, facial dysmorphism, and congenital heart defects. Molecular mechanisms underlying the development of Noonan syndrome relate to genetic mutations that compromise the functions of the RAS/mitogen-activated protein kinase (MAPK) pathway, with marked developmental and tumorigenic consequences. For this reason, Noonan syndrome and its phenotypic variants, including Noonan syndrome with multiple lentigines (NSML, formally LEOPARD syndrome), Noonan-like syndrome with loose anagen hair (NS/LAH), CBL syndrome (or Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia [JMML]), together with several other disorders, including cardio-facio-cutaneous syndrome (CFCS), Costello syndrome, Legius syndrome, neurofibromatosis type 1 (NF1), and capillary malformation–arteriovenous malformation syndrome (CM-AVM), are collectively referred to as RASopathies (or neuro-cardio-facio-cutaneous syndromes [NCFCS]) (see Chapter 87Table 87.1 in this book for further details) [1–3].
Severe male factor infertility: Genetic consequences and recommendations for genetic testing
Published in David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham, Textbook of Assisted Reproductive Techniques, 2017
Katrien Stouffs, Willy Lissens, Sara Seneca
Very rarely, patients with other mostly syndrome- associated genetic defects may consult at a male infertility clinic. Up to 80% of patients with Noonan syndrome present with oligozoospermia or azoospermia as a result of cryptorchidism (67). The diagnosis is so far based on other symptoms, including small stature, chest deformity, a rather typical facial dysmorphism, and congenital heart disease. Defects in a gene on chromosome 12q24.1, PTPN11, are responsible for approximately 40% of patients with Noonan syndrome (68). Another six genes involved in Noonan syndrome have been identified; all seven known genes account for around 60% of cases. Consequently, more (currently unknown) genes are involved in Noonan syndrome. The autosomal dominant inheritance asks for genetic counseling. Other possible patients may be affected by Aarskog-Scott syndrome with acrosomal sperm defects (69, 70) or Beckwith-Wiedemann syndrome with cryptorchidism (71). Syndromes such as Bardet-Biedl syndrome and Prader-Willi syndrome, both presenting with hypogonadism, are associated with other major symptoms, including (severe) mental retardation, which limit procreation (72–74). Prader-Willi syndrome is an imprinting syndrome resulting from the absence of expression of the paternal alleles in the 15q11-q13 imprinted region (75–77). Other causes of male infertility include deficiencies in enzymes involved in the synthesis of testosterone (64, 66), luteinizing hormone, and luteinizing hormone receptor (78, 79).
Genodermatoses
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Noonan syndrome is an autosomal dominant disorder with an estimated incidence of 1/1000–2500 live births. Hyperpigmentation is variable (mostly café-au-lait spots). Clinically, the most constant criteria are short stature, dysmorphic facial features, congenital heart defects, and chest deformities. Other phenotypical characteristics are thin and woolly or curly hair, hypertelorism, light blue irises, epicanthal folds, high forehead, broad depressed nasal base, posteriorly rotated ears with thickened helix, broad neck, low posterior hairline, widely spaced nipples, and chest defects.
Co-occurrence of incontinentia pigmenti and down syndrome: examining patients’ potential susceptibility to autoimmune disease, autoinflammatory disease, cancer, and significant ocular disease
Published in Ophthalmic Genetics, 2021
David C. Gibson, Natario L. Couser, Kayla B. King
In addition to autoimmune disease, autoinflammatory disease, and cancer, certain genetic conditions have been reported in patients with IP. Klinefelter syndrome is by far the most common among these because the chromosomal complement of Klinefelter syndrome (XXY) allows males with IP to survive past gestation (9). Noonan syndrome has also been reported in a patient with IP (14). This concurrence is interesting because individuals with Noonan syndrome have an increased frequency of autoimmune and autoinflammatory diseases, like SLE, celiac disease, autoimmune thyroiditis, antiphospholipid syndrome, autoimmune hepatitis, and vitiligo. These patients also have a predisposition to certain cancers, like myeloproliferative disorder, juvenile myelomonocytic leukemia (JMML), neuroblastoma, and embryonal rhabdomyosarcoma. In the present case, we describe the second occurrence of Down syndrome reported in a patient with IP.
Fetal hydrops – a review and a clinical approach to identifying the cause
Published in Expert Opinion on Orphan Drugs, 2020
Esther Dempsey, Tessa Homfray, John M Simpson, Steve Jeffery, Sahar Mansour, Pia Ostergaard
There is some evidence of genotype-phenotype correlation within Noonan syndrome. Patients with RIT1 mutations have a much higher incidence of hypertrophic cardiomyopathy (see ‘cardiomyopathies’) (54%) but also perinatal abnormalities (100%), including raised nuchal translucency (67%), polyhydramnios (67%), fetal hydrops (38%), and pleural effusions (62%) [84]. The diagnosis of Noonan syndrome during pregnancy can be enormously helpful. A persistently raised nuchal translucency is a strong predictor of Noonan syndrome [138] and is seen in postnatal life as the neck webbing typical of this condition. If the fetus does not develop significant cardiac compromise, these babies often survive and can go on to lead healthy lives, sometimes with minimal intellectual deficit.
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.