Erhan Hüseyin CÖMERT, Emine Seda GÜVENDAĞ GÜVEN, Süleyman GÜVEN

Joubert Sendromunun Tüm Ekzom Dizim ile Prenatal Tanısı

Joubert sendromu (JS), ilk olarak Marie Joubert tarafından tanımlanmıştır. Siliyopatiye ait genlerin nedensel mutasyonu ile karakterize, otozomal resesif geçişli kalıtımsal bir hastalıktır. 27 yaşında bir kadın, prenatal yapılan ultrasonografide renal kist saptanması üzerine ileri araştırma için kliniğimize sevk edildi. Ayrıntılı ultrasonografik incelemede fetal polikistik böbrek gözlendi. Korion villus örneklemesinde INPP5E mutasyonu mevcuttu.Gebeliğin 23. haftasında yapılan ultrasonografide vermis hipoplazisi, polikistik böbrek ve molar diş bulgusu mevcuttu. Bu bulguların başta joubert sendromu olmak üzere sendromik bir durum olduğu düşünüldü. MRI incelemesindeki vermis hipoplazisi, posterior fossa genişlemesi ve bilateral polikistik böbrek gözlendi ve radyolog bu durumu Dandy-Walker'a bağlı olduğu bildirildi, fakat molar diş bulgusuna dikkat etmediği anlaşıldı ve tekrar konsülte edildi. Aileye prognoz hakkında bilgi verildi ve terminasyon seçeneği sunuldu. JS'nin en yaygın karakteristik beyin görüntüsü eksenel düzlemdeki molar diş işareti (MTS), serebellar vermis (CV) hipoplazisi ve derinleşmiş interpedunküler fossadır. MTS, bu hastalık için anahtar tanısal özelliktir. Şimdiye kadar, JSRD'nin çeşitli alt tipleri için 30'dan fazla nedensel gen bulundu.Bunlardan biri INPP5E. Ekstra sinir sistemi kusurları arasında polikistik böbrek hastalığı, retina dejenerasyonu, iskelet kusurları (polidaktili gibi) ve karaciğer bozukluğu yer alır. Joubert Sendromu prenatal dönemde teşhis edilebilir. MTS prenatal dönemde ultrasonografi ile rahatlıkla görülebilir. Vermian hipoplazisi ve ek organ anomalileri olması akıla JS getirmeli ve molar diş bulgusu araştırılmalıdır.

Anahtar Kelimeler:

joubert sendromu, molar diş bulgusu, vermian hipoplazi, polikistik böbrek, INPP5E geni

Prenatal Diagnosis of Joubert Syndrome With Whole Exome Sequencing

Joubert syndrome(JS), was first discovered by Marie Joubert, which is a rare autosomal recessive inherited disease belonging to ciliopathy with the causative mutation of genes. A 27-years-old woman was referred to our clinic for advanced research over the detection of fetal renal cyst.We observed policycstic kidney in detailed examination.INPP5E mutation was detected on chorion villus sampling.We were thought may be this findings will be associated with the syndrome, primarily joubert syndorme (JS),upon detection the vermis hypoplasia, policyctic kidney and molar teeth sign was observed on USG in the 23rd week of pregnancy.The vermis hypoplasia, posterior fossa expansion and bilateral polycystic kidney was seen on MRI and radiologist was reported as Dandy-Walker depend on this findings.They did not pay attention to the molar tooth finding.We were explanied prognosis and suggeted termination to the family.The family was accepted and fetus was terminated. The most common characteristic brain image of JS is the molar tooth sign(MTS) on the axial plane, cerebellar vermis (CV) hypoplasia, and a deepened interpeduncular fossa.The MTS is the key diagnostic feature for this disease. So far, more than 30 causative genes have been found for the various subtypes of JSRD.One of them is INPP5E. Defects of additional extra-nervous systems involve polycystic kidney disease, retinal degeneration, skeletal defects (such as polydactyly), and liver disorder. Joubert Syndrome can be diagnosed in prenatally period.MTS can be seen easily with usg during prenatal period.The vermian hypoplasia and additional organ anomalies must be brought to mind JS and MTS should be searched.

Keywords:

joubert syndrome, mollar teeth sign, vermian hypoplasia, INPP5E gene, polycystic kidney,

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1. JoubertM, Eisenring JJ, Robb JP, et al. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969;19:813–25.
2. Maria BL, Quisling RG, Rosainz LCet al: Molar tooth sign in Joubert syndrome: clinical,radiologic, and pathologic significance.J Child Neurol 1999;14:368–376.
3. Parisi M, Glass I: Joubert Syndrome and related disorders.Gene Rev1993, rev. 2013.
4. Doherty D: Joubert syndrome: insights into brain development, cilium biology, and complex disease.Semin Pediatr Neurol2009;16:143–154
5. B. L.Maria, A. Bozorgmanesh, K.N. Kimmel,D.Teriaque, and R. G. Quisling, “Quantitative assessment of brainstem devel-opment in Joubert syndrome and Dandy- Walker syndrome,” Journal of Child Neurology,vol. 16, no.10, pp. 751–758, 2001.
6. Louie CM, Gleeson JG. Genetic basis of Joubert syndrome and related disorders of cerebellar development. Hum Mol Genet 2005;2(14 SpecNo):R235–42.
7. Gleeson JG, Keeler LC, Parisi MA, Marsh SE, Chance PF, Glass IA, Graham JM Jr, Maria BL, Barkovich AJ, Dobyns WB: Molar tooth sign of the midbrainhindbrain junction: occurrence in multiple distinct syndromes. Am J Med Genet A 2004, 125:125-134.
8. Brancati F, Dallapiccola B, Valente EM. Joubert Syndrome and related disorders. Orphanet J Rare Dis 2010;5:20
9. Siyuan Linpeng, Jing Liu, Jianyan Pan, Yingxi Cao, Yanling Teng, Desheng Liang , et. All. Diagnosis of Joubert Syndrome 10 in a Fetus with Suspected Dandy-Walker Variant by WES: A Novel Splicing Mutation in OFD1. BioMed Research International Volume 2018, Article ID 4032543, 7 pages https://doi.org/10.1155/2018/4032543
10. Kroes HY, Monroe GR, van der Zwaag B, et al. Joubert syndrome: genotyping a Northern European patient cohort. Eur J Hum Genet 2016;24:214–20
11. Elhassanien AF, Alghaiaty HAA. Joubert syndrome: clinical and radiological characteristics of nine patients. Ann Indian Acad Neurol 2013;16:239–44
12. Parisi MA, Doherty D, Chance PF, Glass IA: Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet2007, 15:511-521.
13. Kroes HY, van Zon PH, van de Putte DF, Nelen MR, Nievelstein RJ, Wittebol-Post D, van NO, Mancini GM, van der Knaap MS, Kwee ML, Maas SM, Cobben JM, De Nef JE, Lindhout D, Sinke RJ: DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands. Eur J Med Genet2008, 51:24-34
14. Vilboux T, Doherty DA, Glass IA, et al. Molecular geneticfindings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center. Genet Med 2017;19:875–82
15. Bielas, S. L., Silhavy, J. L., Brancati, F., Kisseleva, M. V., Al-Gazali, L.,et al: Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet2009;41:1032–1036.
16. Doherty D. Joubert syndrome: insights into brain development, cilium biology, and complex disease. Semin Pediatr Neurol 2009;16:143–54.
17. Travaglini L, Brancati F, Silhavy Jet al: Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders.Eur J Hum Genet2013; 21:1074–1078