February 18, 2020
Years published: 1989, 1996, 2003, 2016, 2020
NORD gratefully acknowledges Pr. Tania Attie-Bitach, Hôpital Necker-Enfants Malades et Institut Imagine (INSERM), Paris, France, for assistance in the preparation of this report.
Meckel syndrome is a rare inherited disorder characterized by abnormalities affecting several organ systems of the body. Three classic symptoms are normally associated with Meckel syndrome: protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back of the skull (occipital encephalocele), multiple cysts on the kidneys (cystic kidneys), and extra fingers and/or toes (polydactyly). Affected children or fetuses may also have abnormalities affecting the head and face (craniofacial area), liver, lungs, heart, and genitourinary tract. The lack of amniotic fluid surrounding the fetus (oligohydramnios) induces incomplete development of the lungs (pulmonary hypoplasia).
Because of these serious health problems, infants born with Meckel syndrome do not survive longer than a few days or weeks. Most affected infants die of kidney failure or respiratory problems. Parents sometimes choose to terminate a pregnancy when a fetus with Meckle syndrome is diagnosed during pregnancy.
Meckel syndrome is inherited as an autosomal recessive condition through thirteen genes: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237.
The first report of Meckel syndrome was published by Johann Friedrich Meckel in 1822. In 1934, G.B. Gruber published reports on individuals with Meckel syndrome and named the disorder dysencephalia splanchnocystica.
The specific symptoms associated with Meckel syndrome vary greatly from one individual to another. Affected children will not have all of the symptoms detailed below. Central nervous system, pulmonary or kidney abnormalities always result in perinatal death.
The most common central nervous system abnormality associated with Meckel syndrome is occipital encephalocele, a condition in which an infant is born with a gap in the skull (i.e., a part of one or more of the plates that form the skull does not seal). The membranes that cover the brain (meninges) and brain tissue often protrude through this gap. Occipital encephalocele may result in accumulation of excessive cerebrospinal fluid (CSF) in the skull, which causes pressure on the tissues of the brain (hydrocephaly). Additional central nervous system abnormalities that may occur in infants with Meckel syndrome include the absence of a major portion of the brain, skull, and scalp (anencephaly), absence of the median part of the posterior brain (cerebellar vermis agenesisi), and a condition known as microcephaly, in which the head circumference is smaller than would be expected for age and sex.
Affected infants may have distinctive facial features including an abnormally small jaw (micrognathia); enlarged, low-set and malformed ears; cleft palate; cleft lip; sloping forehead; and short neck. Affected children may have eye (ocular) abnormalities including abnormally small eyes (microphthalmia), and underdevelopment of the nerves of the eyes (optic nerve hypoplasia or coloboma). Multiple cysts on the kidneys (multicystic kidney dysplasia) are the most common symptom associated with Meckel syndrome. The condition is characterized by normal kidney tissue that is replaced by fluid-filled sacs or cysts of varying sizes that become larger (10-20 times greater than normal) as the disease progresses. Findings associated with cystic kidneys include loss of kidney function, leading to end-stage renal failure. Improper kidney function also results in a reduction in the amount of amniotic fluid surrounding the developing fetus (oligohydramnios).
Affected individuals may also have extra fingers and toes, most often extra fingers on the “pinky” side of the hands (postaxial polydactyly). Additional skeletal malformations include bowing of the long bones of the arms and legs, curvature of the fifth fingers (clinodactyly), webbing of the fingers and toes (syndactyly), and club foot where the foot are rotated internally (talipes equinovarus).
In some individuals, abnormalities of the genitourinary tract may be present including failure of the one or both testes to descend into the scrotum (cryptorchidism), underdeveloped (hypoplastic) bladder, and incomplete development of genitalia.
Some affected infants may have abnormalities affecting other organs of the body including the liver, lungs or heart. The liver can show excessive fibrous tissue (fibrosis) and widening (dilatation) and excessive number (proliferation) of the small passages that carry bile from the liver to the small intestines (bile ducts). The lungs may be underdeveloped (hypoplastic) and the structure that covers the entrance of the larynx when swallowing may be clefted (cleft epiglottis). The spleen may be missing (asplenia), or be present as multiple small spleens, rather than a single (polyspenia).
Heart abnormalities may include atrial and ventricular septal defects (ASDs and VSDs) and patent ductus arteriosus or other more complex malformations. ASDs are characterized by an abnormal opening in the fibrous partition (septum) that separates the two upper chambers (atria) of the heart. VSDs are characterized by an abnormal opening in the septum that divides the heart’s two lower chambers (ventricles). The size, location, and nature of a septal defect and any associated abnormalities determine the severity of symptoms. Patent ductus arteriosus is a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth.
Genital abnormalities include external or internal genitalia in both male or female.
Meckel syndrome can be caused by changes (mutations) in thirteen genes: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237. Mutations in these 13 genes account for 75 percent of all cases; the remaining 25 percent have unknown genetic causes. Most of these genes are also responsible for a neurological disorder called Joubert syndrome, leading to the concept that Meckel syndrome is the extreme lethal form of Joubert syndrome.
The proteins produced by these genes are known to influence cell structures or function called primary cilia. Cilia are microscopic projections that stick out on the surface of the cell and help transmit information in signaling pathways. Cilia are important for many cell functions, in many cell types especially in the kidney, liver, eye and brain. Mutations in these gene cause problems in the function of the primary cilia, resulting in various defects dependent of the cell type. Early defective ciliary function can be responsible for developmental abnormalities, specifically in the kidneys, brain, limbs, heart.
Meckel syndrome is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits the same altered gene for the same trait from each parent. If an individual receives one normal gene and one altered gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Meckel syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The incidence of Meckel syndrome is estimated in various areas around the world to be 1 in 13,250 to 1 in 140,000 live births. The disorder is more common in the Finnish population due to a founder effect, with an incidence of 1 in 9000 and 1 in 3,000 people of Belgian ancestry. However, Gujarati Indians have a prevalence of 1 in 1,300. It occurs more frequently in the context of consanguineous unions.
A diagnosis of Meckel syndrome is often made on ultrasound during pregnancy or at birth thorough clinical evaluation. Molecular genetic testing can be used to confirm the diagnosis and guide genetic counseling. Prenatal diagnosis is available through ultrasonography as early as 14 weeks, which can detect certain abnormalities (e.g., encephalocele, polydactyly, cystic kidneys and oligohydramnios). Chromosomal analysis may be performed to rule out trisomy 13. Smith Lemli- Opitz syndrome may be excluded by biochemical testing.
No curative treatment is currently available for Meckel syndrome which has a constantly fatal outcome due to renal failure and lung hypoplasia. Treatment is symptomatic and supportive.
Genetic counseling is recommended for the families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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