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Genetics and metabolic disorders
Published in Jagdish M. Gupta, John Beveridge, MCQs in Paediatrics, 2020
Jagdish M. Gupta, John Beveridge
Achondroplasia is autosomal dominant (80% of cases represent new mutations). The risk to the offspring of an affected person will be 1 in 2 for each pregnancy. Consanguinity does not increase the risk in offspring unless both parents are affected. If both parents have achondroplasia, there is a 1 in 4 chance that an offspring will be unaffected. Complete penetrance implies that those who do not show the phenotype do not carry the mutation and therefore cannot pass it on. The gene responsible for the disorder has recently been identified as the fibroblast growth factor receptor-3 (FGFR-3), with almost all affected individuals carrying the same mutation. Prenatal diagnosis is now possible by DNA analysis.
The respiratory system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
These are commonly central tumours, in main or segmental bronchi, and they often present earlier than other types of carcinoma because of obstructive symptoms. However, in recent years they have increasingly been seen in the periphery of the lung, which may reflect changing smoking behaviour. The tumour is solid and greyish/white, and may show cavitation. These tumours arise from the bronchial epithelium through a process of squamous metaplasia through dysplasia to squamous carcinoma in situ, and these changes may be seen adjacent to the invasive tumour. The tumour is composed of large cells with squamous differentiation characterized by keratinization and/or intercellular bridges (Figure 8.31). Squamous cell carcinoma shows a diverse range of mutations including losses in chromosomes 3p, 9p, and 17p, corresponding to losses of tumour suppressor genes including CDKN2A and TP53, which occur early in tumour evolution. In addition, amplification of the fibroblast growth factor receptor gene, FGFR1, is seen in many cases and may be a target for therapy.
Disorders of bone and connective tissue
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The milder disorder, hypochondroplasia, is allelic to achondroplasia; ‘compound heterozygotes’ have been recorded when one parent has achondroplasia and the other hypochondroplasia. Although most patients with hypochondroplasia have few physical problems and are mentally normal, a small number of cases with mental retardation have been reported. Also allelic to both conditions is the severe thanatophoric dysplasia. All three conditions are caused by (distinct) variants in one of the fibroblast growth factor receptor genes (FGFR3).
Early Prenatal Ultrasound and Molecular Diagnosis of Apert Syndrome: Case Report with Postmortem CT-Scan and Chondral Plate Histology
Published in Fetal and Pediatric Pathology, 2022
Gabriele Tonni, Gianpaolo Grisolia, Maurizia Baldi, MariaPaola Bonasoni, Vladimiro Ginocchi, Liliam Cristine Rolo, Edward Araujo Júnior
A 36-year-old mother, gravida 2, para 1, with a previous uneventful pregnancy, underwent routine second trimester scan at 19 weeks of gestation using both a Voluson E6 (GE, Milwaukee, WI) and a Samsung WS80A (Seul, South Corea) apparatuses equipped with a transabdominal 2 D/3D multifrequency 2.5-5.0 MHz probes. A premature closure of the cranial sutures together with a wide metopic suture and bregmatic fontenelle and turribrachicephaly was seen by both 2D and 3D ultrasound in multiplanar mode and using skeleton mode (Figure 1A,B). Using a gradient light 3 D application called Realistic Vue™, an associated syndactyly of the left hand was clearly detected (Figure 2A,B). The scan revealed features consistent with a presumptive prenatal diagnosis of craniosynostosis. Amniocentesis performed at 20 weeks demonstrated a 46, XX karyotype. The amniotic fluid α-FP level was within the normal range. A genetic panel was performed comprising mutations in FGFR1 (fibroblast growth factor receptor)(exon 8), FGFR2 (exons 8,10), FGFR3 (exon 7), Twist (exon 1).
Triple-negative breast cancer: promising prognostic biomarkers currently in development
Published in Expert Review of Anticancer Therapy, 2021
Jasmine Sukumar, Kelly Gast, Dionisia Quiroga, Maryam Lustberg, Nicole Williams
The fibroblast growth factor receptors (FGFR) are a family of transmembrane receptors that play an important role in regulating cellular functions including differentiation, proliferation, and angiogenesis. FGFR 1–4 comprises receptor tyrosine kinases, and abnormal signaling contributes to oncogenesis via multiple mechanisms of gene alteration, including point and activating mutations, fusions/rearrangements, and amplifications. In BC cells, FGFR1 amplification is the most frequent aberrancy implicated in tumorigenesis [22]. The prevalence of FGFR1 over-expression was estimated to be 18%, with FGFR1 gene amplification approximately 33%, in a cross-sectional study of TNBC specimens [23]. FGFR2 amplification is relatively less common and occurs in less than 5% of TNBC [22]. While in hormone receptor-positive BC the presence of FGFR1 amplification is consistently associated with a worse prognosis [24], its role in TNBC is more controversial. Some studies indicate no association with prognosis [23,25], while other literature suggests an inferior OS [26]. FGFR2 expression has been correlated with a poor OS [27].
Pubertal growth in height, sitting height and leg length in achondroplasia
Published in Annals of Human Biology, 2021
T. J. Cole, M. del Pino, P. Adamo, V. Fano
Achondroplasia (ACH), an autosomal-dominant disorder, is the most common form of inherited disproportionate short stature, with a worldwide birth prevalence, based on meta-analysis, of 4.6 per 100,000 (Spranger 2012; Foreman et al. 2020). It is caused by a gain of function mutation in the type 3 fibroblast growth factor receptor gene (FGFR3) located on chromosome 4p16.3 (Shiang et al. 1994; Bellus et al. 1995). FGFR3 plays an important role in early mammalian skeletal development, especially in post-embryonic linear bone growth with an inhibition predominantly of endochondral ossification (Foldynova-Trantirkova et al. 2012; Qi et al. 2014). Consequently, children with ACH are born with shorter limbs than non-ACH children, and their limb deficit increases throughout childhood (del Pino et al. 2016; del Pino, Ramos Mejía, et al. 2018).