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Sections Meckel-Gruber Syndrome
Overview
Presentation
- History
- Physical
- Causes
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DDx
Workup
Treatment
Medication
Follow-up
Tables
References

Workup

Laboratory Studies

Alpha-fetoprotein (AFP) level from either maternal blood or amniotic fluid may help to detect an encephalocele in patients with Meckel-Gruber syndrome (MGS) (although most encephaloceles are closed and do not elevate AFP levels). AFP can be measured in amniotic fluid after about 12 weeks' gestation and in maternal blood after about 15 weeks' gestation.

Chromosome analysis

Chromosome analysis is essential to exclude trisomy 13, which Meckel-Gruber syndrome mimics. Trisomy 13 carries a 1% recurrence risk, as opposed to the 25% recurrence rate for Meckel-Gruber syndrome. Linkage or mutation analysis is not yet available.

If anomalies are detected early in the first trimester, chorionic villus sampling (CVS) can be performed at 10-12 weeks' gestation or later in pregnancy if oligohydramnios does not permit amniocentesis.

Amniocentesis is performed after 14 weeks’ gestation if an adequate fluid pocket is present.

Tests can be done to assess prenatal diagnosis, linkage, as well as carrier testing.

Table. Chromosomal Markers for Meckel Gruber Syndrome (Open Table in a new window)

Protein Name	Locus Name	Gene	Chromosomal Locus
Meckel syndrome type 1 protein	MKS1	MKS1	17q23
...	MKS2	TMEM216	11q13
Meckelin	MKS3	TMEM67	8q21.1-q22.1
...	MKS4	CEP290	12q21.3
Protein fantom	MKS5	RPGRIP1L	16q12.2
Coiled-coil and C2 domain-containing protein 2A	MKS6	CC2D2a	4p15.3
...	MKS7	NPHP3	3q22.1
...	MKS8	TCTN2	12q24.31
...	MKS9	B9D1	17p11.2
...	MKS10	B9D2	19q13.2
...	MKS11	TMEM231	16q23.1
...	MKS12	KIF14	1q32.1

Prenatal ultrasonography

Prenatal ultrasonography is currently the best method available to diagnose Meckel-Gruber syndrome and is available in 2-dimensional (2D), 3-dimensional (3D), and 4-dimensional (4D) modalities; 4D is particularly useful in assessing facial features and deformities, musculoskeletal malformations, and limitation of movement.^{[30, 31]}

The second trimester is the usual time of diagnosis; however, with a skilled operator, first-trimester diagnosis may be possible for both high-risk and low-risk families.

Color Doppler can be used to assess for lung perfusion in the last trimester, to search for the presence of renal arteries in cases of oligohydramnios, (suspected renal agenesis or hypoplasia), and also to assess flow in the umbilical arteries.

Diagnosis in the second trimester becomes more difficult when oligohydramnios secondary to poor renal output impairs visualization.

Occipital encephalocele is easily visualized beginning in late first trimester. Part of the brain and meninges protrude through the skull defect.

Large, cystic, echogenic kidneys are a consistent ultrasonographic finding, although oligohydramnios can obscure detection of renal dysplasia. Experienced ultrasonographers may be able to detect polydactyly in the second trimester if oligohydramnios is not present.

MRI

Magnetic resonance imaging (MRI) is a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios. It is mainly used when ultrasonography findings are inconclusive or are insufficient to guide treatment choices.

Atlhough MRI is useful in detecting the origin and extent of an abnormality, it must be performed after 18 weeks' gestation. Moreover, while the modality is superior to ultrasonography in detecting CNS abnormalities that are commonly found in Meckel-Gruber syndrome, it is limited in that it cannot be used to assess fetal movement.

MRI can reveal renal size and occipital defects, such as encephaloceles.

Histologic Findings

The primary renal abnormality appears to be failed interaction of the metanephric duct and renal blastema. The kidneys, therefore, show little corticomedullary differentiation, and the nephrons are severely deficient, causing enlargement of the kidneys. Thin-walled cysts appear throughout the parenchyma.

Hepatic lesions can be considered one of the hidden abnormalities of Meckel-Gruber syndrome because they are visible only during postmortem examination. Development arrests at the stage of bilaminar plates, which become atrophic during normal development. In Meckel-Gruber syndrome, the plates do not atrophy and prevent reorganization by the remaining biliary cells to form tubular ducts. The resultant fibrosis can be severe enough to occlude portal veins. Bile canaliculi are smaller and less well developed and have inspissated bile within the abnormal ductules.

Treatment & Management

Hartill V, Szymanska K, Sharif SM, Wheway G, Johnson CA. Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances. Front Pediatr. 2017. 5:244. [QxMD MEDLINE Link]. [Full Text].
Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet. 2006 Feb. 38(2):191-6. [QxMD MEDLINE Link].
Lu Y, Peng H, Jin Z, Cheng J, Wang S, Ma M, et al. Preimplantation Genetic Diagnosis for a Chinese Family with Autosomal Recessive Meckel-Gruber Syndrome Type 3 (MKS3). PLoS One. 2013 Sep 5. 8(9):e73245. [QxMD MEDLINE Link]. [Full Text].
Baala L, Audollent S, Martinovic J, Ozilou C, Babron MC, Sivanandamoorthy S. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet. 2007 Jul. 81(1):170-9. [QxMD MEDLINE Link].
Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007 Jul. 39(7):875-81. [QxMD MEDLINE Link].
Tallila J, Jakkula E, Peltonen L, Salonen R, Kestila M. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet. 2008 Jun. 82(6):1361-7. [QxMD MEDLINE Link]. [Full Text].
Online Mendelian Inheritance in Man. Meckel syndrome, type 7; MKS7. OMIM. Available at http://www.omim.org/entry/267010?search=mks7&highlight=mks7. Accessed: Aug 19, 2015.
Online Mendelian Inheritance in Man. Meckel syndrome, type 8; MKS8. OMIM. Available at http://www.omim.org/entry/613885?search=mks8&highlight=mks8. Accessed: Aug 19, 2015.
Online Mendelian Inheritance in Man. Meckel syndrome, type 9; MKS9. OMIM. Available at http://www.omim.org/entry/614209?search=mks9&highlight=mks9. Accessed: Aug 19, 2015.
Online Mendelian Inheritance in Man. Meckel syndrome, type 10; MKS10. OMIM. Available at http://www.omim.org/entry/614175?search=mks10&highlight=mks10. Accessed: Aug 19, 2015.
Online Mendelian Inheritance in Man. Meckel syndrome, type 11; MKS11. OMIM. Available at http://www.omim.org/entry/615397?search=mks11&highlight=mks11. Accessed: Aug 19, 2015.
Online Mendelian Inheritance in Man. Meckel syndrome 12; MKS12. OMIM. Available at http://www.omim.org/entry/616258?search=mks12&highlight=mks12. Accessed: Aug 19, 2015.
Barisic I, Boban L, Loane M, et al. Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe. Eur J Hum Genet. 2015 Jun. 23 (6):746-52. [QxMD MEDLINE Link].
Abdelhamed ZA, Wheway G, Szymanska K, Natarajan S, Toomes C, Inglehearn C, et al. Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum Mol Genet. 2013 Apr 1. 22(7):1358-72. [QxMD MEDLINE Link]. [Full Text].
Dowdle WE, Robinson JF, Kneist A, et al. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet. 2011 Jul 15. 89(1):94-110. [QxMD MEDLINE Link]. [Full Text].
Weng RR, Yang TT, Huang CE, Chang CW, Wang WJ, Liao JC. Super-Resolution Imaging Reveals TCTN2 Depletion-Induced IFT88 Lumen Leakage and Ciliary Weakening. Biophys J. 2018 Jul 17. 115 (2):263-75. [QxMD MEDLINE Link].
Parelkar SV, Kapadnis SP, Sanghvi BV, Joshi PB, Mundada D, Oak SN. Meckel-Gruber syndrome: A rare and lethal anomaly with review of literature. J Pediatr Neurosci. 2013 May. 8(2):154-7. [QxMD MEDLINE Link]. [Full Text].
Shetty BP, Alva N, Patil S, Shetty R. Meckel-Gruber syndrome (dysencephalia splanchnocystica). J Contemp Dent Pract. 2012 Sep 1. 13(5):713-5. [QxMD MEDLINE Link].
Al-Belushi M, Al Ibrahim A, Ahmed M, Ahmed B, Khenyab N, Konje JC. A review of Meckel-Gruber syndrome--incidence and outcome in the state of Qatar. J Matern Fetal Neonatal Med. 2016. 29 (12):2013-6. [QxMD MEDLINE Link].
Wright C, Healicon R, English C, Burn J. Meckel syndrome: what are the minimum diagnostic criteria?. J Med Genet. 1994 Jun. 31(6):482-5. [QxMD MEDLINE Link].
Salonen R, Norio R. The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet. 1984 Aug. 18(4):691-8. [QxMD MEDLINE Link].
Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet. 1984 Aug. 18(4):671-89. [QxMD MEDLINE Link].
Shaheen R, Szymanska K, Basu B, et al. Characterizing the morbid genome of ciliopathies. Genome Biol. 2016 Nov 28. 17 (1):242. [QxMD MEDLINE Link]. [Full Text].
Barker AR, Thomas R, Dawe HR. Meckel-Gruber syndrome and the role of primary cilia in kidney, skeleton, and central nervous system development. Organogenesis. 2014 Jan 1. 10 (1):96-107. [QxMD MEDLINE Link]. [Full Text].
Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006. 7:125-48. [QxMD MEDLINE Link].
Paavola P, Salonen R, Weissenbach J. The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet. 1995 Oct. 11(2):213-5. [QxMD MEDLINE Link].
Morgan NV, Gissen P, Sharif SM, Baumber L, Sutherland J, Kelly DA. A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24. Hum Genet. 2002 Oct. 111(4-5):456-61. [QxMD MEDLINE Link].
Consugar MB, Kubly VJ, Lager DJ, Hommerding CJ, Wong WC, Bakker E. Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet. 2007 Jun. 121(5):591-9. [QxMD MEDLINE Link].
Frank V, den Hollander AI, Bruchle NO, Zonneveld MN, Nurnberg G, Becker C. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Hum Mutat. 2008 Jan. 29(1):45-52. [QxMD MEDLINE Link].
Behairy NH, Talaat S, Saleem SN, El-Raouf MA. Magnetic resonance imaging in fetal anomalies: What does it add to 3D and 4D US?. Eur J Radiol. 2009 Mar 24. [QxMD MEDLINE Link].
Eckmann-Scholz C, Jonat W, Zerres K, Ortiz-Brüchle N. Earliest ultrasound findings and description of splicing mutations in Meckel-Gruber syndrome. Arch Gynecol Obstet. 2012 Oct. 286(4):917-21. [QxMD MEDLINE Link].

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Author

Parul Bhagwati Jayakar, MD, MS, FACMG Director of Neurogenetics/Metabolic Program, Director of Cytogenetics Laboratory, Consultant in Clinical Genetics, Division of Genetics and Metabolism, Miami Children's Hospital; Assistant Professor, Genetics Residency Program Director, University of Miami, Leonard M Miller School of Medicine

Parul Bhagwati Jayakar, MD, MS, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Coauthor(s)

Michail Spiliopoulos, MD Clinical Assistant Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, Temple University Hospital

Michail Spiliopoulos, MD is a member of the following medical societies: American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Anuj Jayakar Georgetown University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Suzanne M Carter, MS, and Susan J Gross, MD, FRCS(C), FACOG, FACMG, to the original writing and development of this article.

Sections Meckel-Gruber Syndrome
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
Follow-up
Tables
References

Meckel-Gruber Syndrome Workup

Laboratory Studies

Chromosome analysis

Imaging Studies

Prenatal ultrasonography

MRI

Histologic Findings

Meckel-Gruber Syndrome Workup

Laboratory Studies

Chromosome analysis

Imaging Studies

Prenatal ultrasonography

MRI

Histologic Findings

References

Tables

Contributor Information and Disclosures

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