Meckel-Gruber syndrome (MGS) is a rare autosomal recessive disorder that is the product of a number of different gene mutations and often occurs in consanguinity [1] [2]. There is no male or female preponderance. The features associated with MGS are severe and often not compatible with life resulting in intrauterine fetal death, usually due to renal failure. Also, there is an impaired amniotic fluid production and lung maturation. A minority of pregnancies are carried to term and the babies who are born with MGS rarely survive past the neonatal period, while the longest surviving case documented died at 28 months [3].

MGS chiefly affects the nervous system, kidneys, and limbs, which is mediated by defective ciliary function. The main central nervous system (CNS) manifestation is the presence of a meningoencephalocele, usually located in the occiput. Renal pathology in the form of polycystic kidneys is often the case and occurs bilaterally. Postaxial polydactyly can affect both upper and lower extremities. Individuals with MGS may also exhibit microphthalmia, cleft lip, micrognathia, liver fibrosis, gonadal dysgenesis, and congenital cardiovascular malformations such as aortic septal defect (ASD) and coarctation of the aorta [4] [5]. Moreover, there are several other congenital defects that can arise, giving MGS a more variable clinical picture. These include hydrocephalus, anencephaly, and holoprosencephaly. MGS has many genotypic features of Joubert syndrome.

• Coarctation of the Aorta

  Individuals with MGS may also exhibit microphthalmia, cleft lip, micrognathia, liver fibrosis, gonadal dysgenesis, and congenital cardiovascular malformations such as aortic septal defect (ASD) and coarctation of the aorta. [symptoma.com]

  Other anomalies include microcephaly, microphthalmia or anophthalmia, cleft lip and/or palate, genital anomalies, lung hypoplasia, and congenital heart disease such as atrial septal defect (ASD), ventricular septal defect (VSD), coarctation of the aorta [accessanesthesiology.mhmedical.com]

  Cardiac lesions like atrial septal defect, coarctation of the aorta and pulmonary stenosis may be present [ 7, 8 ]. Worldwide, the incidence of Meckel-Gruber syndrome is 1 per 13,250–140,000 live births. [ncbi.nlm.nih.gov]

• Splenomegaly

  […] reactive biliary neoductules proliferation (reactive bile duct proliferation) bile duct dilatation arrested development of the intrahepatic biliary system (biliary cylinders) reactive portal fibrosis portal fibrous vascular obliteration splenic anomalies splenomegaly [humpath.com]

• Macrostomia

  Synopsis variable prenatal growth deficiency craniofacial anomalies microcephaly sloping forehead micrognathia low-set ears microphthalmia hypotelorism hypertelorism iris coloboma cleft palate cleft lip lobulated tongue natal teeth macrostomia short neck [humpath.com]

• Low Set Ears

  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones. [disorders.eyes.arizona.edu]

  Patients also present a typical “Meckel appearance” with micrognathia, flat nose, hypertelorism, a sloping forehead, wide mouth with full lips, low-set ears, and short neck. Precautions before ... [accessanesthesiology.mhmedical.com]

  The new-born was examined by our neonatologist, and the external examination revealed anencephaly (Fig. 2) with head circumference 25.5 cm, occipital encephalocele (Fig. 3), cleft lip and cleft palate (Fig. 2), upper slanting of eyes (Fig. 2), low set [academic.oup.com]

• Short Neck

  Patients also present a typical “Meckel appearance” with micrognathia, flat nose, hypertelorism, a sloping forehead, wide mouth with full lips, low-set ears, and short neck. A complete medical history must be obtained. [accessanesthesiology.mhmedical.com]

  Short Neck: This syndrome shows distinctive features related to an abnormality of the bones, such as a short neck. Clinodactyly: It is a congenital defect affecting smaller bones, such as the little finger, that causes the bone to curve to one side. [icliniq.com]

  On examination the fetus showed occipital meningoencephalocele [Figure 2]a, along with low set ears, microcephaly, absence of forehead, hypertelorism, large protruding eyes, a large nose, and a short neck. [jfmpc.com]

  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones. [disorders.eyes.arizona.edu]

• Kidney Failure

  Prognosis MKS is lethal in utero or in the very early neonatal period with pulmonary hypoplasia and kidney failure as the main causes of early demise. * European Reference Network A summary on this disease is available in Italiano (2015) Deutsch (2006 [orpha.net]

  Most often, affected infants die of respiratory problems or kidney failure. 2. Frequency Meckel syndrome affects 1 in 13,250 to 1 in 140,000 people worldwide. [encyclopedia.pub]

  […] fatalities are due to respiratory problems or kidney failure. [verywellhealth.com]

  Most often, affected infants die of respiratory problems or kidney failure. Meckel syndrome affects 1 in 13,250 to 1 in 140,000 people worldwide. [ghr.nlm.nih.gov]

  Most often, affected infants die of respiratory problems or kidney failure. Frequency Meckel syndrome affects 1 in 13,250 to 1 in 140,000 people worldwide. [medlineplus.gov]

The diagnosis of Meckel-Gruber syndrome relies on the clinical presentation. It is generally accepted that patients are diagnosed with MGS if they display a minimum of two of the most commonly occurring manifestations, that is, multicystic kidneys, occipital encephalocele, and postaxial polydactyly [6]. Other defects may also be taken into consideration during the diagnostic process, such as liver fibrosis. The characteristic features of MGS can be visualized via antenatal ultrasonography and most cases are recognized at this stage [7] [8] [9]. Early ultrasound examination is preferred (usually in the first or early second trimester), as late ultrasound scans pose a diagnostic challenge due to additional features such as oligohydramnios [8]. Neural tube defects may be revealed by abnormal alpha-fetoprotein levels [10].

Clinical diagnosis can be complicated by the presence of other disorders such as Joubert syndrome. Molecular genetic testing and karyotyping are especially useful in cases of clinical uncertainty, where the signs are atypical or masked by comorbidities. Late ultrasound findings include oligohydramnios and no visible bladder [4] [7]. Magnetic resonance imaging (MRI), also done prenatally, can aid diagnosis if ultrasound findings are unclear [11]. Although it cannot record fetal movements, MRI is effective in the detection of CNS pathology.

Karyotyping is useful in ruling out trisomy 13. Additional possible prenatal procedures include chorionic villus sampling (CVS) and amniocentesis.

• Occipital Encephalocele

  In addition, an occipital encephalocele was seen. This constellation of findings is consistent with the Meckel-Gruber syndrome. [fetalsono.com]

  Meckel Gruber syndrome is the most common syndromic form of neural tube defect and the classic triad of clinical features is characterized by occipital encephalocele, cystic kidneys and fibrotic changes to the liver. [dnatesting.uchicago.edu]

  Keywords: Encephalocele, Meckel-Gruber syndrome, polycystic kidney, polydactyly Introduction Meckel-Gruber syndrome (MGS) is a triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. [ncbi.nlm.nih.gov]

  Definition / general Meckel-Gruber syndrome (Meckel syndrome or MKS) is a rare, lethal ciliopathic genetic disorder characterized by abnormalities affecting several organ systems Three classic symptoms are normally associated with MKS: occipital encephalocele [pathologyoutlines.com]

  The first child was a girl having occipital encephalocele and died at the age of one year. The second child was a boy with occipital encephalocele and died two hours after birth. [jiom.com.np]

Appropriate treatment instituted in our case led to a good early outcome. [ncbi.nlm.nih.gov]

No treatment is currently available; the outcome is always fatal Gross description Occipital encephalocele is characterized by extrusion of rhombic roof elements, cerebellar vermis, caudal third ventricle and distended fourth ventricle through a widened [pathologyoutlines.com]

Management and treatment No treatment is currently available for Meckel syndrome which has a constantly fatal outcome. [orpha.net]

Treatment Treatment Options: There is no treatment for this syndrome. The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system. [disorders.eyes.arizona.edu]

The parents should be counseled about prognosis of the fetus and the outcome. Counselers should strictly give information about the recurrence risk for the next pregnancies. [ncbi.nlm.nih.gov]

Prognosis can vary if the baby has atypical signs of MGS or if the baby has a different syndrome. Elective termination of affected pregnancies may be an option for some couples. Prognosis The prognosis for MGS is quite poor. [encyclopedia.com]

Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. [disorders.eyes.arizona.edu]

TMEM67 mutation (MKS3) is a major cause of MKS and the related ciliopathy Joubert syndrome, although the complete etiology of the disease is not well understood. [mayoclinic.pure.elsevier.com]

In recent years, the molecular etiology of the diseases in the ciliopathic group has been elucidated owing to the widespread use of next-generation sequencing technology. [liebertpub.com]

[…] category of diseases thought to be caused by dysfunction of cilia and flagella; polycystic liver and kidney disease, Bardet-Biedl syndrome, Alstrom syndrome and Joubert syndrome also belong to the same group (Annu Rev Genomics Hum Genet 2006;7:125) Etiology [pathologyoutlines.com]

Etiology Defective ciliary biology underlies MKS. Mutations in many different cilia-related genes have been associated with this disorder, often in the context of consanguineous unions. [orpha.net]

A common molecular etiology appears to be disruption of ciliary TZ structure and function, affecting essential developmental signaling and the regulation of secondary messengers. [eprints.uwe.ac.uk]

Trends databases, including Google Trends database, can be used to estimate the digital epidemiology of these diseases. [nepjol.info]

We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. [ncbi.nlm.nih.gov]

There is a shortage of epidemiological studies surveying the region of the Middle East and Arabic countries. [ccsenet.org]

Pathophysiology It has been suggested that a failure of mesodermal induction causes MKS. The induction cascades of early morphogenesis involve numerous growth factors, homeobox genes, and paired domain genes. [accessanesthesiology.mhmedical.com]

140,000 live births; the live birth prevalence is significantly higher in the Finnish population (1/9,000); therefore this syndrome is suggested to be a Finnish heritage disease (J Pediatr Neurosci 2013;8:154) No gender or ethnic predilection is reported Pathophysiology [pathologyoutlines.com]

Meckel–Gruber syndrome is named for Johann Meckel and Georg Gruber. [1] [2] [3] Pathophysiology [ edit ] Meckel–Gruber syndrome (MKS) is an autosomal recessive lethal malformation. Recently, two MKS genes, MKS1 and MKS3, have been identified. [en.wikipedia.org]

Etiology and Pathophysiology Several genetic loci have been identified in individuals with Meckel-Gruber syndrome. The disorder is caused by dysfunction of primary cilia during embryogenesis. [radiologykey.com]

Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions. © 2015. Published by The Company of Biologists Ltd. [ncbi.nlm.nih.gov]

Prevention How Is Meckel Syndrome Prevented? There is no known way to prevent Meckel syndrome. [unitedbrainassociation.org]

Early diagnosis and proper management can prevent death at an early age. Parents should be given proper advise and genetic counselling for future management of the infants. References 1. [jiom.com.np]

[…] severely deficient, causing enlargement of the kidneys; thin walled cysts appear throughout the parenchyma Hepatic dysgenesis and liver fibrosis are identified only at postmortem examination; in Meckel-Gruber syndrome, the plates do not atrophy and prevent [pathologyoutlines.com]

[…] for up to one month Engineers have developed a Jell-O-like pill that quickly expands on reaching the stomach and uses an embedded sensor to monitor health status over an extended period of time. ‹ › New understanding could help improve prediction and prevention [news-medical.net]

1. Su SL, Liu CM, Lee JN. Prenatal diagnosis of Meckel-Gruber syndrome case reports. Gaoxiong Yi Xue Ke Xue Za Zhi. 1995;11(2):127–132.
2. Smith UM, Consugar M, Tee LJ, et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet. 2006;38(2):191–196.
3. Parelkar SV, Kapadnis SP, Sanghvi BV, Joshi PB, Mundada D, Oak SN. Meckel-Gruber Syndrome: a are and lethal anomaly with review of literature. J Pediatr Neurosci. 2013;8(2):154–157.
4. Alexiev BA, Lin X, Sun CC, Brenner DS. Meckel-Gruber Syndrome: pathologic manifestations, minimal diagnostic criteria, and differential diagnosis. Arch Pathol Lab Med. 2006;130(8):1236–1238.
5. Paavola P, Salonen R, Baumer A, et al. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997;101(1):88–92.
6. Paavola P, Salonen R, Weissenbach J, Peltonen L. The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet. 1995;11(2):213–215.
7. Ickowicz V, Eurin D, Maugey-Laulom B, et al. Meckel-Gruber Syndrome: sonography and pathology. Ultrasound Obstet Gynecol. 2006;27(3):296–300.
8. 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;286(4):917–921.
9. de Silva MV, Senanayake H, Siriwardana KD. Meckel Gruber Syndrome: Occurrence in non-consanguineous marriages. Ceylon Med J. 2004;49(1):30–31.
10. Sepulveda W, Sebire NJ, Souka A, Snijders RJ, Nicolaides KH. Diagnosis of Meckel Gruber syndrome at eleven to fourteen weeks’ gestation. Am J Obstet Gynecol. 1997;176(2):316–319.
11. 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 Radio. 2010;74(1):250–255.