Turner syndrome, also known as monosomy of the X chromosome, is a chromosomal disorder due to the total (monosomy) or partial absence of an X chromosome in a female individual. Turner syndrome is characterized by a wide phenotypic variability, which includes very serious clinical pictures that are evident even before birth to very blurred pictures in which the diagnosis arrives after puberty.
Detailed clinical description
Turner syndrome is characterized by a very marked phenotypic heterogeneity. One of the most common features seen in affected patients is short stature, which becomes evident within 5 years of life. The other very frequent sign is premature ovarian failure associated with gonadal dysgenesis, so much so that almost all patients are infertile and do not reach puberty, unless under hormone stimulation.
Affected patients often have webbed neck, low posterior hairline and may have eye defects such as strabismus and ptosis.
Among the signs that can be variably identified in Turner syndrome patients, there are congenital cardiac defects (from 30% to 50% of patients) such as coarctation of the aorta or dysfunction of the aortic valve; lymphedema of the hands and feet, even from birth; structural renal abnormalities; skeletal problems such as osteoporosis and scoliosis. In adult women, about 50% develop sensorineural hearing loss.
From a cognitive point of view, most patients have normal intelligence, although in some cases specific learning difficulties may be present.
On the basis of the severity of the clinical picture, diagnosis can be made prenatally, thanks to fetal DNA screening or invasive investigations such as amniocentesis, or in the postnatal period. Rarely, in the presence of very mild symptoms, the diagnosis can occur in adulthood. The diagnosis is suspected from the clinical picture and is confirmed by cytological investigation (karyotype, FISH or array-CGH).
Turner syndrome is one of the most frequent chromosomal abnormalities and has an incidence of about 1/2000-2500 live-born females. It is also the only monosomy compatible with life. However, approximately 99% of conception with karyotype 45, X is spontaneously aborted.
Turner syndrome derives from an error during the formation of gametes, whereby a gamete is nullisomic for a specific chromosome (in this case without the sex chromosome). About 50% of females with Turner syndrome have a 45, X karyotype and in most cases the loss of the chromosome is of paternal origin. A good part of the remaining 50% has mosaicism (a cell line 45, X, plus other different cell lines). Rarely, other chromosomal aberrations have also been found such as the presence of a ring X chromosome, the presence of an isochromosome Xq (an X chromosome formed by the duplication of the long arm and without the short arm) and the deletion of the short arm of the X chromosome.
Turner syndrome in most patients is not hereditary: the total lack of an X chromosome seems to be a completely random event that occurs during gametogenesis and independent of maternal age. In these cases, the syndrome is sporadic and the risk of recurrence in another child is practically absent. In cases of mosaicism, an error occurs in the early stages of cell division after fertilization: even these cases cannot be inherited. Rarely, partial deletions of the X chromosome may be inherited.
Noonan syndrome is part of the differential diagnosis of Turner syndrome. Noonan syndrome is a congenital genetic disorder characterized by features such as webbed neck, low posterior hairline, short stature, and skeletal malformations. Congenital heart defects, malformation of the lymphatic vessels and genitourinary problems are also often present. Noonan syndrome is due to heterozygous mutations in the genes A2ML1, BRAF, KRAS, LZTR1, MAPK1, MRAS, NRAS, PPP1CB, PTPN11, RAF1, RASA2, RIT1, RRAS2, SHOC2, SOS1, SOS2. In only one case, bi-allelic mutations in LZTR1 are associated with Noonan syndrome.
Genetic testing strategy
In case of suspicion of Turner syndrome already in the prenatal period on the basis of ultrasound examination, it is recommended to perform invasive diagnostic tests such as amniocentesis or CVS. In the postnatal period, the diagnostic process includes the execution of the karyotype or other cytological techniques such as array-CGH and FISH.
Cui X, Cui Y, Shi L, Luan J, Zhou X, Han J. A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment. Intractable Rare Dis Res. 2018 Nov;7(4):223-228. doi: 10.5582/irdr.2017.01056. PMID: 30560013; PMCID: PMC6290843.
Samango-Sprouse C, Song SQ, Lin AE, Powell CM, Gropman AL. Klinefelter Syndrome and Turner Syndrome. Pediatr Rev. 2021 May;42(5):272-274. doi: 10.1542/pir.2020-004028. PMID: 33931514.
Paolucci DG, Bamba V. Turner Syndrome: Care of the Patient: Birth to Late Adolescence. Pediatr Endocrinol Rev. 2017 Jun;14(Suppl 2):454-461. doi: 10.17458/per.vol14.2017.pb.turnersyndromecare. PMID: 28647950.