Balkan Journal of Medical Genetics

HIGH RISK OF GESTATIONAL TROPHOBLASTIC NEOPLASIA DEVELOPMENT IN RECURRENT HYDATIDIFORM MOLES WITH NLRP7 PATHOGENIC VARIATIONS
Kocabey M.1,a, Gulhan I.2, Koc A.1,b, Cankaya T.1, Karatasli V.2, Ileri A.3
*Corresponding Author: MD Mehmet Kocabey, Address: Güzelburc District Kıbrıs Street No: 81, 31175 Antioch/Hatay, e-mail: mehmet_kocabey@hotmail.com
page: 45

DISCUSSION

Familial cases of HM were first reported in the early 1980s [9, 10]. Recurrent HMs affect 1.5-9.3% of women with a history of HM and may be associated with autosomal recessive inheritance when encountered in more than one family member [11]. While interspersed normal pregnancies can be seen in recurrent PHM cases, which is generally sporadic, consecutive molar pregnancies are more common in recurrent CHM cases, of which a subgroup is familial [4]. The underlying mechanism has been identified to be the development of varying degrees of ‘erroneous’ paternal imprint markers on maternal chromosomes [12]. Similar loss of imprinting has also been previously demonstrated in choriocarcinomas [13]. To evaluate this recent data in the literature, we investigated the NLRP7 and KHDC3L genes in 3 cases of RHM. A homozygous c.2471+1G>A (rs104895505) pathogenic variation in the NLRP7 gene was detected in two cases. The third case had homozygous c.2571dupC (p.Ile858HisfsTer11, rs766731093) in the 8th exon of the NLRP7 gene. Both variants have been reported previ-ously [11, 14]. All cases had a history of more than two HMs before their genetic testing. However, due to socioeconomic conditions, lack of family history and possibly due to frequent change of specialists during follow-up, HYDM1/HYDM2 investigation was initiated after at least the fourth molar pregnancy. This has led to an increased risk of GTN development, due to repeated attempts of new pregnancies, an increased risk of comorbidities due to repeated curettage, and considerable psychological damage. Therefore, we believe that early genetic counseling should be recommended on a case-by-case basis after the first or first repeated HM, considering criteria such as HM pathological classification, genetic constitution, and family history. During patient evaluation, family history would provide an important indicator in determining the indication for genetic testing. However, another common feature of our cases was the absence of a known family history. The sister of the first case had successful pregnancies. The other cases did not have a sister in the fertile period or any other known family history. Therefore, we think that although family history is important in determining the indication for genetic analysis, it should not be used as the only criterion in RHMs. Post-molar GTN development was encountered in all cases. In the first and third cases, this complication was encountered in the 3rd molar pregnancy and in the second case in the 6th molar pregnancy. Apart from the first pregnancy loss of the first patient, interspersed nonmolar pregnancies were not noticed. Because of the risk of GTNs and the failure to achieve normal pregnancies, we suggest a discussion of in vitro fertilization with oocyte donation in molecularly confirmed cases of HYDM1/2. According to the literature, most of the cases have different genetic variations and frequent mutations that can be called a hotspot have not been identified [15]. To date, 275 variants have been identified in the NLRP7 gene, the majority of which consist of benign, likely benign, silent or unclassified deep intronic variants [16]. Two of the three cases in our series have the same variant and there was no consanguinity between them. None of the patients had any pathogenic KHDC3L variant. As far as we know, only 8 families have been reported from Turkey so far [11, 15, 17, 18]. The variant seen in case three was previously reported in two Turkish families. Therefore, including the 3 families in this study, 3 out of 11 families (27%) carry the c.2571dupC variant, and 2 out of 11 (18%) carry the c.2471+1G>A variant. The lack of any established mutation hotspots and the fact that studies reporting the same mutations coming from different regions of the country suggest a founder effect in the Turkish population. Four or more RHMs were observed in these cases, suggesting that these variants lead to a clinically severe course. Research on a larger scale on this subject among the Turkish population is needed to prove whether there is a founder effect or not. None of the previously reported patients had any KHDC3L variant, which is in accordance with our results.

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