medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2020.01.13-23medgen-764Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHСовременные возможности пренатальной и постнатальной диагностики синдрома Фринса: собственные наблюдения и обзор литературыThe possibilities of prenatal and postnatal Fryns syndrome diagnostics: patients presentations and overviewРумянцеваН. В.RumiantsevaN. V.

Румянцева Наталья Владимировна

Минск

Rumiantsеva Natalia

Minsk

rumiantseva@inbox.ruХурсО. М.KhursO. M.

Минск

Minsk

НовиковаИ. В.NovikovaI. V.

Минск

Minsk

ВенчиковаН. А.VenchikovaN. A.

Минск

Minsk

ЗобиковаО. Л.ZobikovaO. L.

Минск

Minsk

ГУ «Республиканский научно-практический центр «Мать и дитя» Министерства здравоохранения Республики БеларусьБеларусьRepublican Scientific Practical Centre «Mother and Child», Ministry of Health, BelarusBelarus2020060520201911323Copyright © Румянцева Н.В., Хурс О.М., Новикова И.В., Венчикова Н.А., Зобикова О.Л., 20202020Румянцева Н.В., Хурс О.М., Новикова И.В., Венчикова Н.А., Зобикова О.Л.Rumiantseva N.V., Khurs O.M., Novikova I.V., Venchikova N.A., Zobikova O.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/764

Синдром Фринса (СФ, OMIM#194050) – редкое аутосомно-рецессивное заболевание с неустановленным генетическим дефектом и высокой летальностью, манифестирует характерным комплексом врожденных пороков развития (ВПР), включающим диафрагмальную грыжу (ДГ). Представлен обзор литературы по фенотипическим признакам и диагностическим критериям синдрома, приведены клинико-генеалогические данные опубликованных семейных наблюдений, ультразвуковые (УЗ) и патоморфологические характеристики плодов с СФ.

Цель исследования

Цель исследования: проанализировать пренатальные УЗ, клинические и патоморфологические характеристики 12 пациентов с СФ, выявленных в Беларуси за период 2009-2018 гг. и представить результаты ретроспективного анализа репродукции семей. Материалы и методы. Проведено медико-генетическое консультирование 10 семей. Все беременные прошли комбинированный пренатальный скрининг. Выполнены пре- и постнатальный анализы кариотипов (GTG-banding), патоморфологическое исследование 10 абортированных плодов и 2 умерших младенцев.

Результаты и обсуждение

Результаты и обсуждение. Фенотипические проявления у всех пациентов соответствовали диагностическим критериям СФ. Среди пренатальных УЗ признаков в 1 триместре при 5 беременностях установлено расширение воротникового пространства; во 2 триместре у 11 плодов выявлена ДГ, у одного – омфалоцеле, в 4 случаях – другие аномалии развития. Грубые черты лица отмечены у живорожденных и плодов. Гипоплазия легких установлена у всех пациентов, редкие аномалии (легочной секвестр, кистозно-аденоматозный порок, аплазия доли) – в 5 случаях. Характерные дефекты терминальных фаланг и/или ногтевых пластинок отмечены в 11 наблюдениях, у 3 сибсов выявлены редкие пороки – полидактилия кистей, эктродактилия стоп. Среди ассоциированных аномалий развития наблюдались расщелина неба, аринэнцефалия, гидроцефалия, комбинированный порок сердца, омфалоцеле, дивертикул Меккеля, аномалии почек, двурогая матка и гипоспадия. В семейном наблюдении у 3 сибсов отмечено высокое сходство фенотипических проявлений. Анализ исходов беременностей в 10 семьях свидетельствует об отягощенном акушерском анамнезе. Из 29 беременностей в 12 случаях потомство имело СФ, 4 завершились спонтанным абортом, 11 – рождением здоровых детей, при 2 текущих беременностях ВПР у плодов не выявлены.

Заключение

Заключение. Клинический диагноз СФ устанавливается при соответствии комплекса ВПР принятым диагностическим критериям после исключения хромосомного дисбаланса. При обнаружении у плода ДГ – ведущего диагностического признака, следует проводить целенаправленный поиск ассоциированных аномалий. Полидактилия и эктродактилия могут рассматриваться в качестве элементов фенотипического спектра СФ.

Fryns syndrome (FS, OMIM#194050) is a rare lethal autosomal recessive disorder with unknown genetic defect, manifested the distinct complex of the multiply congenital abnormalities (MCA), including diaphragmatic hernia. There was made the world literature overview for the FS phenotypic features, clinical and genealogical data of the published familial cases, ultrasound and morphological characteristics of affected fetuses.

Aim

Aim. Analysis of the clinical, morphological and prenatal ultrasound data of 12 FS cases, detected in Belarus during 2009-2018 years, and families’ reproduction results.

Material and methods

Material and methods. Genetic counseling of 10 families with affected outcome was performed. All the pregnants underwent the combined (biochemical and ultrasound) screening. Prenatal and postnatal cytogenetical studies (GTG-banding) and the morphological investigations of the 10 aborted fetuses and 2 deceased infants were fulfilled.

Results and Discussion

Results and Discussion. All the patients presented typical FS phenotypic features correlated with the diagnostic criteria. The spectrum of prenatal findings diagnosed at 1-st trimester included nuchal skin enlargement/cystic hygroma (5 cases), at the 2-ed trimester – diaphragmatic hernia (11 cases), omphalocele (1), other malformations (4 fetuses). The facial dysmorphisms (coarse face) were detected in all the patients. Lungs hypoplasia was found in all cases, 5 patients additionally dysplayed other abnormalities: pulmonary sequestration, cystic-adenomatoid malformation, lobular aplasia. Characteristic phalanges and nails hypoplasia or aplasia were registered in 11 cases, 3 sibs presented rare malformations – polydactyly (hands) and ectrodactyly (feet). Associated malformations spectrum included cleft palate, brain abnormalities (ventricular dilatation, arhinencephaly), cardiac defects, omphalocele, Meckel diverticule, hydronephroses, renal cysts, bicornuate uterus and hypospadia. The familial case with 3 affected sibs demonstrated a similarity in main diagnostic criteria. The couples reproduction analysis illulustrated a serious failure. Outcome of 29 pregnancies were as follows: 12 – FS cases, 4 – miscarries at 1-st trimester, 11 – healthy offspring and 2 cases – pregnancies are going on currently (both fetuses without malformations).

Conclusion

Conclusion. Clinical diagnosis of FS may be noted in patients (either fetuses or newborns), which display the conjunction of typical MCA pattern with a normal karyotype. Additional investigations must be used in order to exclude the associated abnormalities if diaphragmatic hernia has been detected in fetus. In our opinion polydactyly and ectrodactyly may be added to the FS phenotypic spectrum.

синдром Фринсааутосомно-рецессивный тип наследованиядиафрагмальная грыжагипоплазия/аплазия терминальных фаланг и ногтевых пластинокполидактилияэктродактилияпренатальная диагностикаFryns syndromeautosomal recessive inheritancediaphragmatic herniaphalanges and nails hypoplasia or aplasiapolydactylyectrodactylyprenatal diagnosticsReferencesFryns J.P., Moerman F., Goddeeris P. et al. A new lethal syndrome with cloudy cornea, diaphragmatic defects and distal limb deformities. Hum. Genet. 1979; 50(1): 65–70.Fryns J.P., Moerman F., Goddeeris P. et al. A new lethal syndrome with cloudy cornea, diaphragmatic defects and distal limb deformities. Hum. Genet. 1979; 50(1): 65–70.Ayme S., Julian C., Gambarelli D. et al. Fryns Syndrome: report on 8 new cases. Clin. Genet. 1989; 35(3): 191–201.Ayme S., Julian C., Gambarelli D. et al. Fryns Syndrome: report on 8 new cases. Clin. Genet. 1989; 35(3): 191–201.Schwyzer U., Briner J., Schinzel A. Fryns syndrome in a girl born to consanguineous parents. Acta. Paediatr. Scand. 1987; 76(1): 167–171.Schwyzer U., Briner J., Schinzel A. Fryns syndrome in a girl born to consanguineous parents. Acta. Paediatr. Scand. 1987; 76(1): 167–171.Roy M., Chikkannaiah P., Bali A. Congenital diaphragmatic hernia with hypoplastic lungs, heart, and additional anomalies: A case of? Fryns syndrome. J. NTR. Univ. Health. Sci. 2013; 2(2): 130–132.Roy M., Chikkannaiah P., Bali A. Congenital diaphragmatic hernia with hypoplastic lungs, heart, and additional anomalies: A case of? Fryns syndrome. J. NTR. Univ. Health. Sci. 2013; 2(2): 130–132.Lubinsky M., Severn C., Rapoport J.M. Fryns Syndrome: A new variable multiple congenital anomaly (MCA) syndrome. Am. J. Med. Genet. 1983; 14(3): 461–466.Lubinsky M., Severn C., Rapoport J.M. Fryns Syndrome: A new variable multiple congenital anomaly (MCA) syndrome. Am. J. Med. Genet. 1983; 14(3): 461–466.Moerman P., Fryns J.P., Vandenberghe K. et al. The syndrome of diaphragmatic hernia, abnormal face and distal limb anomalies (Fryns syndrome): report of two sibs with further delineation of this multiple congenital anomaly (MCA) syndrome. Am. J. Med. Genet. 1988; 31(4): 805–814.Moerman P., Fryns J.P., Vandenberghe K. et al. The syndrome of diaphragmatic hernia, abnormal face and distal limb anomalies (Fryns syndrome): report of two sibs with further delineation of this multiple congenital anomaly (MCA) syndrome. Am. J. Med. Genet. 1988; 31(4): 805–814.Bamforth J.S., Leonard C.O., Chodirker B.N. et al. Congenital diaphragmatic hernia, coarse facies, and acral hypoplasia: Fryns syndrome. Am. J. Med. Genet. 1989; 32(1): 93-–99.Bamforth J.S., Leonard C.O., Chodirker B.N. et al. Congenital diaphragmatic hernia, coarse facies, and acral hypoplasia: Fryns syndrome. Am. J. Med. Genet. 1989; 32(1): 93-–99.Alessandri J.L., Cuillier F., Malan V. et al. Fryns syndrome without diaphragmatic hernia, DOOR syndrome or Fryns-like syndrome? Report on patients from Indian Ocean islands. Am. J. Med. Genet. 2014; 164A(3): 648–654.Alessandri J.L., Cuillier F., Malan V. et al. Fryns syndrome without diaphragmatic hernia, DOOR syndrome or Fryns-like syndrome? Report on patients from Indian Ocean islands. Am. J. Med. Genet. 2014; 164A(3): 648–654.Alessandri J.L., Gordon C.T., Jacquemont M.L. et al. Recessive loss of function PIGN alleles, including an intragenic deletion with Fryns syndrome. Eur. J. Hum. Genet. 2018; 26(3): 340–349.Alessandri J.L., Gordon C.T., Jacquemont M.L. et al. Recessive loss of function PIGN alleles, including an intragenic deletion with Fryns syndrome. Eur. J. Hum. Genet. 2018; 26(3): 340–349.McInerney-Leo A.M., Harris J.E., Gattas M. et al. Fryns syndrome associated with recessive mutations in PIGN in two separate families. Hum. Mutat. 2016; 37(7): 695–702.McInerney-Leo A.M., Harris J.E., Gattas M. et al. Fryns syndrome associated with recessive mutations in PIGN in two separate families. Hum. Mutat. 2016; 37(7): 695–702.Slavotinek A.M. Fryns Syndrome: a review of the phenotype and diagnostic guidelines. Am. J. Med. Genet. 2004; 124A(4): 427–433.Slavotinek A.M. Fryns Syndrome: a review of the phenotype and diagnostic guidelines. Am. J. Med. Genet. 2004; 124A(4): 427–433.Lin A.E., Pober B.R., Mullen M.P., Slavotinek A.M. Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells? Am. J. Med. Genet. 2005; 139(3): 186–193.Lin A.E., Pober B.R., Mullen M.P., Slavotinek A.M. Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells? Am. J. Med. Genet. 2005; 139(3): 186–193.Pellissier M.C., Philip N., Potier A. et al. Prenatal diagnosis of Fryns’ syndrome. Prenat. Diagn. 1992; 12(4): 299–303.Pellissier M.C., Philip N., Potier A. et al. Prenatal diagnosis of Fryns’ syndrome. Prenat. Diagn. 1992; 12(4): 299–303.Ramsing M., Gillesen-Kaesbach G., Holzgreve W. et al. Variability in the phenotypic expression of Fryns syndrome: a report of two sibships. Am. J. Med. Genet. 2000; 95(5): 415–424.Ramsing M., Gillesen-Kaesbach G., Holzgreve W. et al. Variability in the phenotypic expression of Fryns syndrome: a report of two sibships. Am. J. Med. Genet. 2000; 95(5): 415–424.Vargas J.E., Cox G.F., Korf B.R. Discordant phenotype in monozygotic twins with Fryns syndrome. Am. J. Med. Genet. 2000; 94(1): 42–45.Vargas J.E., Cox G.F., Korf B.R. Discordant phenotype in monozygotic twins with Fryns syndrome. Am. J. Med. Genet. 2000; 94(1): 42–45.Pratap A., Agrawal A., Raja S. et al. Fryns syndrome: a lethal mesoectodermal birth defect with variable expression in a pair of monozygotic twins. Singapore Med. J. 2007; 48(4): 106.Pratap A., Agrawal A., Raja S. et al. Fryns syndrome: a lethal mesoectodermal birth defect with variable expression in a pair of monozygotic twins. Singapore Med. J. 2007; 48(4): 106.Nirmaladevi M., Kurup S., Ajitha E.V. Fryns syndrome in monozygotic twins – a case report with review of literature. Int. J. Morphol. 2012; 30(1): 56–60.Nirmaladevi M., Kurup S., Ajitha E.V. Fryns syndrome in monozygotic twins – a case report with review of literature. Int. J. Morphol. 2012; 30(1): 56–60.Arora К., Thukral А., Das R.R. et al. Fryns syndrome: a lethal birth defect with variable phenotypic expressions in siblings. Indian J. Pediatr. 2014; 81(6): 614–616.Arora К., Thukral А., Das R.R. et al. Fryns syndrome: a lethal birth defect with variable phenotypic expressions in siblings. Indian J. Pediatr. 2014; 81(6): 614–616.Samueloff A., Navot D., Birkenfeld A., Schenker J.G. Fryns syndrome: a predictable, lethal pattern of multiple congenital anomalies. Am. J. Obstet. Gynecol. 1987; 156(1): 86–88.Samueloff A., Navot D., Birkenfeld A., Schenker J.G. Fryns syndrome: a predictable, lethal pattern of multiple congenital anomalies. Am. J. Obstet. Gynecol. 1987; 156(1): 86–88.Dentici M.L., Brancati F., Mingarelli R., Dallapiccola B. A 6-years old child with Fryns syndrome: further delineation of the natural history of the condition in survivors. Eur. J. Med. Genet. 2009; 52(6): 421–425.Dentici M.L., Brancati F., Mingarelli R., Dallapiccola B. A 6-years old child with Fryns syndrome: further delineation of the natural history of the condition in survivors. Eur. J. Med. Genet. 2009; 52(6): 421–425.Peron A., Bedeschi M.F., Fabietti I. et al. Prenatal and postnatal findings in five cases of Fryns syndrome. Prenat. Diagns. 2014; 34(12): 1227–1230.Peron A., Bedeschi M.F., Fabietti I. et al. Prenatal and postnatal findings in five cases of Fryns syndrome. Prenat. Diagns. 2014; 34(12): 1227–1230.Новикова И.В., Ковалев С.И., Мараховская Э.И. Семейный случай синдрома Фринса у двух плодов II триместра. Пренатальная диагностика. 2018; 17(2): 164–169.Novikova I.V., Kovalev S.I., Marahovskaya E.I. Semejnyj sluchaj sindroma Frinsa u dvuh plodov II trimestra. [Familial case of Fryns syndrome in two fetuses in second trimester]. Prenatal’naya diagnostika [Prenatal diagnostics] 2018; 17(2): 164–169. (In Russ.)Ильина Е.Г., Новикова И.В., Ершова А.А. и др. Три случая синдрома Фринса, диагностированных пренатально в городе Минске за один месяц. Медицинская генетика. 2010; (5): 44–47.Il’ina E.G., Novikova I.V., Ershova A.A. i dr. Tri sluchaya sindroma Frinsa, diagnostirovannyh prenatal’no v gorode Minske za odin mesyac. [Three cases of Fryns syndrome prenatally diagnosed in Minsk during one month]. Medicinskaya genetika [Medical genetics] 2010; (5): 44–47. (In Russ.)Bulas D.I., Saal H.M., Allen J.F. et al. Cystic hygroma and congenital diaphragmatic hernia: early prenatal sonographic evaluation of Fryns syndrome. Prenat. Diagn. 1992; 12(11): 867–875.Bulas D.I., Saal H.M., Allen J.F. et al. Cystic hygroma and congenital diaphragmatic hernia: early prenatal sonographic evaluation of Fryns syndrome. Prenat. Diagn. 1992; 12(11): 867–875.Arakeri S.U., Manchanda J. Congenital diaphragmatic hernia associated with Fryns syndrome – an autopsy study. J. Evol. Med. Dent. Scienc. 2012; 1(5): 703–706.Arakeri S.U., Manchanda J. Congenital diaphragmatic hernia associated with Fryns syndrome – an autopsy study. J. Evol. Med. Dent. Scienc. 2012; 1(5): 703–706.Dwivedi T., Hungund B. Fryns syndrome: a rare case report with review of literature. J. NTR. Univ. Health Sci. 2018; 7(2): 147–153.Dwivedi T., Hungund B. Fryns syndrome: a rare case report with review of literature. J. NTR. Univ. Health Sci. 2018; 7(2): 147–153.Manouvrier-Hanu S., Devisme L., Vaast P. et al. Fryns syndrome and erupted teeth in a 24-week-old fetus. Genet. Couns. 1996; 7(2): 131–134.Manouvrier-Hanu S., Devisme L., Vaast P. et al. Fryns syndrome and erupted teeth in a 24-week-old fetus. Genet. Couns. 1996; 7(2): 131–134.Wymersch D.V., Favre R., Gasser B. Use of three-dimensional ultrasound to establish the prenatal diagnosis of Fryns syndrome. Fetal. Diagn. Ther. 1996; 11(5): 335–340.Wymersch D.V., Favre R., Gasser B. Use of three-dimensional ultrasound to establish the prenatal diagnosis of Fryns syndrome. Fetal. Diagn. Ther. 1996; 11(5): 335–340.Sheffield J.S., Twickler D.M., Timmons C. et al. Fryns syndrome: prenatal diagnosis and pathologic correlation. J. Ultrasound. Med. 1998; 17(9): 585–589.Sheffield J.S., Twickler D.M., Timmons C. et al. Fryns syndrome: prenatal diagnosis and pathologic correlation. J. Ultrasound. Med. 1998; 17(9): 585–589.Saliani P., Epstein S., Cohen D. The role of ultrasound in the diagnosis of Fryns syndrome. J. Diagn. Med. Sonogr. 2004; 20(1): 42–45.Saliani P., Epstein S., Cohen D. The role of ultrasound in the diagnosis of Fryns syndrome. J. Diagn. Med. Sonogr. 2004; 20(1): 42–45.Benacerraf B.R., Sadow P.M., Barnewolt C.E. et al. Cleft of the secondary palate without cleft lip diagnosed with three-dimensional ultrasound and magnetic resonance imaging in a fetus with Fryns’ syndrome. Ultrasound Obste.t Gynecol. 2006; 27(5): 566–570.Benacerraf B.R., Sadow P.M., Barnewolt C.E. et al. Cleft of the secondary palate without cleft lip diagnosed with three-dimensional ultrasound and magnetic resonance imaging in a fetus with Fryns’ syndrome. Ultrasound Obste.t Gynecol. 2006; 27(5): 566–570.Yucesoy G., Cakiroglu Y., Caliskan E. Fryns syndrome: case report and review of the literature. J. Clin. Ultrasound. 2008; 36(5): 315–317.Yucesoy G., Cakiroglu Y., Caliskan E. Fryns syndrome: case report and review of the literature. J. Clin. Ultrasound. 2008; 36(5): 315–317.Tosun M., Celik H., Bese E. et al. Prenatal diagnosis of Fryns syndrome: a case report. Gynecol. Obstet. Reprod. Med. 2009; 15(1): 47–49.Tosun M., Celik H., Bese E. et al. Prenatal diagnosis of Fryns syndrome: a case report. Gynecol. Obstet. Reprod. Med. 2009; 15(1): 47–49.Плотко И.С., Федотов В.П., Соболева И.А., Машнев Е.Ю. Пренатальная диагностика редких врожденных пороков и синдромов. XXXII. Синдром Фринса. Пренатальная диагностика. 2009; 8(2): 112–114.Plotko I.S., Fedotov V.P., Soboleva I.A., Mashnev E.Yu. Pre natal'naya diagnostika redkikh vrozhdennykh porokov i sindromov. XXXII. Sindrom Frinsa. [Prenatal diagnosis of rare congenital malformations and mov. XXXII. Frins syndrome. Prenatal'naya diagnostika [Prenatal diagnosis]. 2009; 8 (2): 112–114 (In Russ.)Tatar A., Öztas S., Örs R. A case with Fryns syndrome-like phenotype. AÜTD. 2005; 37: 19-21.Tatar A., Öztas S., Örs R. A case with Fryns syndrome-like phenotype. AÜTD. 2005; 37: 19-21.Brady P.D., Moerman P., De Catte L. et al. Exome sequencing identifies a recessive PING splice mutation as a cause of syndromic congenital diaphragmatic hernia. Eur. J. Med. Genet. 2014; 57(9): 487–493.Brady P.D., Moerman P., De Catte L. et al. Exome sequencing identifies a recessive PING splice mutation as a cause of syndromic congenital diaphragmatic hernia. Eur. J. Med. Genet. 2014; 57(9): 487–493.Saal H.M., Bulas D.I. Ectrodactyly, diaphragmatic hernia, congenital heart defect, and agenesis of the corpus callosum. Clinl. Dysmorphol. 1995; 4(3): 246–250.Saal H.M., Bulas D.I. Ectrodactyly, diaphragmatic hernia, congenital heart defect, and agenesis of the corpus callosum. Clinl. Dysmorphol. 1995; 4(3): 246–250.

The authors declare that there are no conflicts of interest present.