|Year : 2020 | Volume
| Issue : 4 | Page : 252-255
Turner syndrome associated with cerebellar abnormalities
Tanya T Kitova1, Ekaterina H Uchikova2, Kristina P Kilova3, Veselin T Belovejdov4
1 Department of Anatomy, Histology and Embryology, Plovdiv, Bulgaria
2 Clinic of Obstetrics and Gynecology, University Hospital “St. George”, Plovdiv, Bulgaria
3 Department of Medical Informatics, Biostatistics and E-Learning, Plovdiv, Bulgaria
4 Department of General and Clinical Pathology, Medical University of Plovdiv, Plovdiv, Bulgaria
|Date of Submission||10-May-2019|
|Date of Acceptance||22-May-2020|
|Date of Web Publication||29-Dec-2020|
Dr. Tanya T Kitova
Department of Anatomy, Histology and Embryology, Medical University of Plovdiv, Vasil Aprilov” Street 15A, Plovdiv 4002
Source of Support: None, Conflict of Interest: None
We present an autopsied fetus with Turner syndrome (TS), obtained after a therapeutic abortion at the Clinic of Obstetrics and Gynecology at the University Hospital, Plovdiv, Bulgaria. It was a female fetus weighing 75 g. The chorionic villus sampling followed by karyotyping established monosomy XO. The fetal autopsy confirmed agenesis of the cerebellar vermis and cerebellar hypoplasia. The immunohistochemical study of the brain with S100 protein (S100), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and cluster of differentiation 68 was taken into consideration. The presence of extensive gliosis reaction is proved in the cerebellar structures of TS by the positivity of glial markers: (GFAP) and S100 protein. The quantity of neurons proved by NSE marker is probably associated with the deficiency of differentiation and cell migration caused by inhibition in the development of young cells. The presented case of TS found a new phenotype with cerebellar abnormalities described for the first time.
Keywords: Agenesis of the cerebellar vermis, brain, fetal autopsy, glial marker, immunohistochemical study, Turner syndrome
|How to cite this article:|
Kitova TT, Uchikova EH, Kilova KP, Belovejdov VT. Turner syndrome associated with cerebellar abnormalities. J Anat Soc India 2020;69:252-5
|How to cite this URL:|
Kitova TT, Uchikova EH, Kilova KP, Belovejdov VT. Turner syndrome associated with cerebellar abnormalities. J Anat Soc India [serial online] 2020 [cited 2021 Apr 21];69:252-5. Available from: https://www.jasi.org.in/text.asp?2020/69/4/252/305377
| Introduction|| |
The purpose of this study is to present a unique case of Turner syndrome (TS) associated with cerebellar abnormalities, utilizing modern investigation methods (ultrasound, amniocentesis, karyotype studies, and immunohistochemistry) in additionn to fetopathological autopsy as a final stage of diagnosis, as well as prognosis for future pregnancies
| Case Report|| |
The fetus was acquired from the therapeutic abortion of the first pregnancy of a 19-year-old female, at the Clinic of Obstetrics and Gynecology at the University Hospital “St. George,” Plovdiv, Bulgaria. The control prenatal ultrasound of the fetus found a defect in the posterior cranial fossa [Figure 1], following which a chorionic villus sampling and a karyotype examination were performed. The karyotype was found to be monosomy XO. Informed consent was obtained from both parents. A classical autopsy of the fetus immediately followed by the abortion and histological and immunohistochemical examinations of the brain structures were performed. All specimens were routinely fixed in 10% buffered formaldehyde and embedded in paraffin, and 3.5-μm-thick sections were stained with H and E [Figure 2]. After a longitudinal section of the cerebellum, the slides were selected for an immunohistochemical study by immunoperoxidase staining for S100 protein (S100), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and cluster of differentiation 68 (CD 68) markers using the DAKO immunostainer “Link 48” standard procedure [Table 1].
|Figure 1: (a) Ultrasound of the skull and brain structures. (b) Cystic dilatation of posterior cranial fossa|
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As a control specimen, a cerebellum was used without anomalies of a miscarried fetus at the 16th gestational week. Microphotographs were performed using the Nikon Microphoto-SA microscope (Japan), combined with Camedia-5050Z digital camera (Olympus, Japan). The measurements were performed with the help of the software”DP– Soft” 3.2 (Olympus, Japan). The microscopic field of study is divided by a rectangular grid with a X-horizontal and Y-vertical span. The parameters for this type of measurement and grid size of 20/20 pixels were set. Numerically, cellular densities in each square field (30 grids) of the same 300 mm2 area were counted for each of the three markers for TS [Figure 3].
The autopsy found biometric indicators confirming a fetal age of 16 gestational weeks and intrauterine growth retardation (fetal weight – 75 g). Facial dysmorphia (oblique eye slit, low-set and poorly formed auricles, long philtrum, and microretrognathia) and flat feet were present [Figure 4]a and [Figure 4]b. Macrocephaly, pterygium, cystic hygroma of the neck , and horseshoe kidney malformations were also observed [Figure 4]b and [Figure 4]c. The autopsy of the brain diagnosed cerebellar hypoplasia (weight of cerebellum – 1 g) and agenesis of the cerebellar vermis [Figure 4]d.
|Figure 4: (a) Fetus with Turner syndrome. (b) Facial dysmorphia – oblique eye slit, low-set and poorly formed auricle, and microretrognathia. Cystic hygroma of the neck. (c) Horseshoe kidney malformation. (d) Hypoplasia of the cerebellum, agenesis of the cerebellar vermis|
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Glial fibrillary acidic protein marker
The immunohistochemical study of the cerebellar structures with GFAP marker revealed increased gliosis in the case compared to the control [Figure 5]a and [Figure 5]b. The morphometry established an increased cell expression in TS. Student's t-test revealed a statistically significant difference of expression of the GFAP marker in the case compared to the control [Figure 6] and [Table 2].
|Figure 5: Immunohistochemistry with glial fibrillary acidic protein and S100 markers. (a) Glial fibrillary acidic protein: Turner syndrome. (b) Glial fibrillary acidic protein: control. (c) S100: Turner syndrome. (d) S100: control. The expression of both markers in the cerebellum reveals cellular architecture with increased gliosis in the case with Turner syndrome compared to the control (10 × 40)|
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|Figure 6: Graphic representation of the morphometric results with markers such as glial fibrillary acidic protein, S100, and neuron-specific enolase|
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|Table 2: t-test statistical significance for morphometry of glial fibrillary acidic protein, S100, and neuron-specific enolase markers|
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The expression of the S100 marker in the cerebellum revealed an increased gliosis in the case with TS compared to the control [Figure 5]c and [Figure 5]d. The morphometry established a weaker cell expression in the TS case compared to the control [Figure 6]. Student's t-test did not detect a statistically significant difference for the S100 marker in the case compared to the control [Table 2].
Neuron-specific enolase marker
NSE marker showed higher expression in the control specimen when compared to the case of TS [Figure 7]a and [Figure 7]b. The morphometry established a weaker expression of NSE marker in TS [Figure 6] and [Table 2].
|Figure 7: Immunohistochemistry with neuron-specific enolase and cluster of differentiation 68 markers. (a) Neuron-specific enolase: Turner syndrome. (b) Neuron-specific enolase: control. Neuron-specific enolase marker shows higher expression in the control specimen than in the case of Turner syndrome/CD68 Turner syndrome. (d) Cluster of differentiation 68: control. The lysosomal marker cluster of differentiation 68 is negative in the control specimen, but in the case of Turner syndrome, its expression is focal (10 × 40)|
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Cluster of differentiation 68 marker
The lysosomal marker CD68 is negative in the control specimen, but in the case of TS, its expression is focal. Infiltration of mononuclear inflammatory cells in the fetal cerebellum with TS is increased [Figure 7]c and [Figure 7]d.
| Discussion|| |
Monosomy X is a chromosomal anomaly which represents about 65% of all aneuploidies.
In the present study, the fetal autopsy confirmed agenesis of the cerebellar vermis and hypoplasia. The presence of extensive gliosis reaction is proved in the cerebellar structures of TS by the positivity of both glial markers GFAP and S100. Although only GFAF reaches statistical significance this is important, this is important because GFAP is a predicative molecular signal for the degree of early developmental disturbances of fetal cerebellum.
The NSE marker does not show a statistically significant variation in the quantity of neurons, however, this does not deny the differences in cellular neuro-morphology. It is probably associated with deficiency of differentiation and cell migration, caused by inhibition in the development of young cells.
Cerebellar hypoplasia with glial proliferation suggests a disturbance in brain function, which does not correlate with the statement that there is no mental retardation in TS.
Some authors explain the disturbance in the cerebellar development with intrauterine oxidative stress, while others with the absence of the X chromosome, which leads to a disturbance in the migration of neurons, but only once neuronal migration has been completed in the cortex of the cerebral hemispheres. This explains the inefficiency of neuronal migration in the cerebellum and olive, which means that the process of neuronal migration is affected around the 4th month. The morphogenesis of the cerebellum is impaired by the disturbances in neuronal migration and cell architectonics, long after the closure of the neural tube.
According to the most recent studies, an increased immune reactivity of interleukin 1 and S100 markers is found in degenerative processes, such as Down syndrome and Alzheimer's disease., Similar disturbances are found in Zellweger syndrome and trisomy 21. The association of TS with cerebellar hypoplasia is an additional evidence of a disturbance in the embryonic development of the brain. Although the prognosis for its clinical presentation in the postnatal period is difficult, the questions regarding the necessity of a prenatal genetic study and abortion due to medical reasons in cases of a positive result remain.
| Conclusion|| |
The presented case of TS found new phenotype with cerebellar abnormalities. This phenotype is a result of disturbances in the morphogenesis up to the 16th gestational week of embryonic development, due to impaired neuronal migration and cell architectonics. The most crucial aspect of the prenatal diagnosis remains the karyotype examination, even though chorionic biopsy is associated with an increased risk for the pregnancy.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2]