Case of the Week #553
*Belveder Centre: Centre de Médecine et d’Echographie Materno-Fœtales, Tunis, TUNISIE; **St Mary's Medical Center, San Francisco, California, United States
Posting Dates: February 15 - February 28, 2022
28-year-old G5P0 woman in a consanguineous relationship was referred to our center at 12 weeks, 5 days of gestation for ultrasound evaluation due to history of prior fetal anomalies. The patient previously had 4 fetal losses, two terminations and two pregnancies affected with fetal anomalies.
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Answer
Ultrasound findings in the first trimester demonstrate elevated nuchal translucency, an anomaly of the posterior fossa, occipital encephalocele, polycystic kidneys and polydactyly (unilateral hexadactyly in one hand and polydactyly of the foot) consistent with Meckel Gruber Syndrome. The patient requested a termination of pregnancy. Pathologic exam and karyotype of the current case was not performed.
The patient had a history of 2 prior pregnancies with fetal hydrocephalus. The pathology of the previous case was obtained and revealed a male fetus of approximately 26 weeks gestation with microcephaly, encephalocele, polycystic kidneys, hexadactyly, liver fibrosis, and pulmonary hypoplasia. The heart was normal.
Discussion
Meckel-Gruber syndrome is a lethal autosomal recessive disease characterized by a triad of brain malformation, polycystic kidneys, and polydactyly [1]. It was first described by Johann Friedrich Meckel in 1822 [2]. It occurs in approximately 1 in 135,000 live births in Europe [3], but may be more frequent in certain populations in Finland (1in 9,000) [4], Kuwaiti Bedouin populations (1in 3,500) [5], and Gujarati Indians (1 in 1,300) [6]. It is caused by mutations in cilia-related genes and often occurs in the context of consanguineous unions. Mutations in 14 genes encoding proteins that are structural or functional components of the primary cilium have been identified to cause Meckel-Gruber syndrome. Several other genes have been implicated on the basis of pathogenic private mutations in individual families with either Meckel-Gruber syndrome or Meckel-Gruber-like phenotypes [7]. In total, these genes explain only 50-60% of Meck Gruber cases [7].
The primary cilium is a microtubule-based organelle that projects from the apical surface of vertebrate cells. It acts as an “antenna,” receiving and transducing chemosensory and mechanosensory signals that regulate pathways such as Wnt and Shh which have essential roles during embryonic development [7].
Clinical manifestations include central nervous system anomalies such as occipital encephalocele, hydrocephalus, anencephaly, holoprosencephaly, as well as Dandy-Walker [8,9]. Polydactyly may affect all four extremities and is typically postaxial (80%) [7,9]. Other anomalies may include cleft lip/palate, cardiac and genital anomalies, liver fibrosis, and bone dysplasia [8,9]. Affected individuals have oligohydramnios due to renal dysfunction resulting in pulmonary hypoplasia [7].
The diagnosis can be made on prenatal ultrasonography and is often detected before the 14th gestational week [10]. The fetal bladder can also be visualized by ultrasonography from 11 weeks, and the absence of a visible fetal bladder is often indicative of renal dysfunction [7]. Molecular genetic testing can be used to confirm the diagnosis or to guide genetic counseling. At-risk couples, in which both individuals are carriers of a disease-causing mutation, have a 25% risk of having an affected child with each pregnancy [7].
Differential diagnoses include trisomy 13, Bardet-Biedl syndrome, Hydrolethalus, and Smith-Lemli-Opitz Syndrome [1, 7].
References
[1] Attie-Bitach, T. “Meckel syndrome.” Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=564, Last update 2/2021.
[2] Meckel J. Beschreibung zweier, durch sehr ähnliche Bildungsabweichungen entstellter Geschwister. Dtsch Arch Physiol (1882) 7:99–172.
[3] Auber B, Burfeind P, Herold S, et al. A disease causing deletion of 29 base pairs in intron 15 in the MKS1 gene is highly associated with the campomelic variant of the Meckel-Gruber syndrome. Clin Genet (2007) 72:454–9.
[4] Salonen R, Norio R. The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet (1984) 18:691–8.
[5] Teebi AS, Alsaleh QA, Odeh H. Meckel syndrome and neural-tube defects in Kuwait. J Med Genet (1992) 29:140.
[6] Young ID, Rickett AB, Clarke M. High-incidence of Meckels syndrome in Gujarati Indians. J Med Genet (1985) 22:301–4.
[7] Hartill V, Szymanska K, Sharif S et al. Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances. Front Pediatr. 2017 Nov 20;5:244.
[8] Fraser FC, Lytwyn A. Spectrum of anomalies in the Meckel syndrome, or maybe there is a malformation syndrome with at least one constant anomaly. Am J Med Genet (1981) 9:67–73.
[9] Salonen R. The Meckel syndrome – clinicopathological findings in 67 patients. Am J Med Genet (1984) 18:671–89.
[10] Sepulveda W, Sebire NJ, Souka A, et al. Diagnosis of the Meckel-Gruber syndrome at eleven to fourteen weeks’ gestation. Am J Obstet Gynecol (1997) 176:316–9.
Discussion Board
Winners
Albert Buwono Indonesia Physician
ahmed gohar United States Physician
Emad Abdelrahim Elshorbagy Egypt Physician
Dianna Heidinger United States Sonographer
Javier Cortejoso Spain Physician
Danilo Feitosa Brazil Physician
Seadet Zeynalova Azerbaijan Physician
Fatih ULUC Turkey Physician
Margarita Alvarez de la Rosa Rodríguez Spain Physician
Umber Agarwal United Kingdom Physician
Igor Yarchuk Ukraine Physician
Dmitry Abelov Russian Federation Physician
Cem Sanhal Turkey Physician
Dr.Neel Vaghasia India Physician
Claudette Schekorra United States Sonographer
Andrii Averianov Ukraine Physician
Ana Ferrero Spain Physician
Alexandr Krasnov Ukraine Physician
Mayank Chowdhury India Physician
filiz halici öztürk Turkey Physician
Omayyah Dar Odeh Jordan Physician
silvio tartaglia Italy Physician
Rachel Schmidbauer United States Sonographer
aline mansour Lebanon Physician
Vladimir Lemaire United States Physician
Shilpen Gondalia India Physician
DAVID BEAUMONT United Kingdom Physician
Ivan Ivanov Russian Federation Physician
Sara Abdallah Salem Egypt Physician
Amal Badi United Arab Emirates Physician
Halil Mesut Turkey Physician
Miğraci Tosun Turkey Physician
Anita Silber Israel Physician
Tudor Iacovache Romania Physician
Vicente Patiño Oleaque Spain Physician
Crismaru Iulia Romania Physician
Suat İnce Turkey Physician
Chala Yevgeniya Ukraine Physician
Rime NSEIR France Physician
Liem Dang Le Viet Nam Physician
Amparo Gimeno Spain Physician
Elena Andreeva Russian Federation Physician
Samantha Wheaton United States Sonographer
Yasemin Dogan Turkey Physician
Ta Son Vo Viet Nam Physician
ALBANA CEREKJA Italy Physician
Selvanandhini Gopalasundaram India Physician
Eda Özden Tokalıoğlu Turkey Physician
SAMUEL GELVEZ TELLEZ Colombia Physician
Murat Cagan Turkey Physician
rahous karim United States
Mame-Diarra Ndiaye United States
Sonio Sonio France AI
Siddhesh Rajiwade India Maternal fetal medicine specialist
Karin Tinnemeier Germany Physician
GOYAL MANISH United States
Büşra Cambaztepe Turkey Physician
Henri Brown United States Student
Lynn Davis United States Sonographer
gholamreza azizi Iran, Islamic Republic of Physician
Maria Roberta Spina United States
Rasha Abo Almagd Egypt Physician
Julia Kyyashko United States
Inass Osman United Kingdom Physician
Leah Guzman United States
JOSE MARIA RAMOS MAESO United States
Michaela Černá Krpcová Czech Republic Physician
Karolina Gruca-Stryjak United States
Megumi Akiyama United States
hayal şerefhanov United States
Alan Buchbinder United States
Fatih AKKUŞ Turkey Physician
Gayane Begjanyan Armenia Physician
Segolene Trastour United States
B Gourmelen United States
DIMITRIOS SPILIOPOULOS United States
Sonia Roohollahi Iran, Islamic Republic of Radiologist