Meckel's syndrome: what is it, causes, symptoms, treatment, prognosis

What is Meckel Syndrome?

Meckel's syndrome Is a rare hereditary disorder characterized by abnormalities that affect multiple body systems. Patients with Meckel syndrome typically experience three classic symptoms: bulging of part of the brain and surrounding membranes (meningia) through a defect in the back of the skull (encephalocele), multiple cysts in the kidneys (cystic kidney disease), and extra fingers and toes (polydactyly). Affected children or fetuses may also have disorders that affect the head and face (craniofacial), liver, lungs, heart, and urinary tract. Lack of amniotic fluid surrounding the fetus (oligohydramnios) causes incomplete lung development (pulmonary hypoplasia).

Because of these serious health problems, babies born with Meckel syndrome do not live longer than a few days or weeks. Most affected infants die from kidney failure or respiratory disease. Parents sometimes decide to terminate the pregnancy when the fetus is diagnosed with Meckel syndrome 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 on Meckel's syndrome was published by Johann Friedrich Meckel in 1822. In 1934 G.B. Gruber published reports on people with Meckel's syndrome and called the disorder splanchnocystic dysencephaly. The disorder is also often referred to as Meckel-Gruber syndrome.

Signs and symptoms

The specific symptoms associated with Meckel syndrome vary greatly from person to person. Affected children will not have all of the symptoms described below. Disorders of the central nervous system, lungs or kidneys always lead to perinatal death.

The most common central nervous system abnormality associated with Meckel syndrome is the occipital encephalocele, a condition in which a baby is born with a tear in the skull (i.e., part of one or more of the plates that make up the skull is not sealed). The membranes that cover the brain (meninges) and brain tissue often protrude through this gap. Occipital encephalocele can cause excess cerebrospinal fluid (CSF) to build up in the skull, which causes pressure on the brain tissue (hydrocephalus). Additional central nervous system disorders that can occur in children with Meckel syndrome include the absence of most of the brain, skull, and scalp (anencephaly), absence of the midline of the hindbrain (agenesis of the cerebellar vermis), and a condition known as microcephaly, in which the head circumference is less than what would be expected for age and gender child.

Affected children may have characteristic facial features, including:

• abnormally small jaw (micrognathia);
• enlarged, low-set and ugly ears;
• cleft palate;
• cleft lip;
• sloping forehead;
• short neck.

Affected children may have eye abnormalities, including abnormally small eyes (microphthalmia) and underdeveloped eye nerves (optic nerve hypoplasia or coloboma). Multiple cysts in the kidney (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 various sizes that grow larger (10 to 20 times larger than normal) as they progress diseases. Symptoms associated with cystic kidney disease include loss of kidney function, leading to end-stage renal failure.

Those affected may also have extra fingers and toes (polydactyly). Additional skeletal malformations include bending of the long bones of the arms and legs, curvature of the fifth toe (clinodactyly), fusion of the toes / feet (syndactyly), and clubfoot.

Some people may have urinary tract abnormalities, including an inability of one or both testicles to descend into the scrotum (cryptorchidism), underdeveloped bladder and incomplete development of the genitals.

Some affected children may have disorders that affect other parts of the body, including liver, lungs or heart. Fibrous tissue may appear in the liver (liver fibrosis) and enlargement (dilation) and an excessive number of small passages that carry bile from the liver to the small intestine (bile ducts). The lungs may be underdeveloped, and the structure that covers the entrance to the larynx when swallowed may become open (cleft epiglottis). Spleen may be absent (asplenia) or present as multiple small spleens rather than one (polysplenia).

Cardiac abnormalities can include atrial and ventricular septal defects (ASD and VSD) and patent ductus arteriosus or other more complex malformations. ASD is characterized by an abnormal opening in the fibrous septum that separates the two upper chambers (atria) of the heart. VSDs are characterized by an abnormal opening in the septum that separates the two lower chambers of the heart (ventricles). The size, location and nature of the septal defect and any associated abnormalities determine the severity of the symptoms. Patent ductus arteriosus is a condition in which a channel (duct) between a blood vessel, which leads to the lungs (pulmonary artery) and the main artery of the body (aorta), cannot close after birth.

Causes

Meckel's 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's syndromeleading to the concept that Meckel's syndrome is the extreme lethal form of Joubert's syndrome.

The proteins produced by these genes are known to affect cellular structures or functions called primary cilia. Cilia are microscopic projections that protrude from the surface of the cell and help transmit information along signaling pathways. Cilia are important for many cell functions, in many types of cells, especially in the kidneys, liver, eyes, and brain. Mutations in these genes cause problems in the function of the primary cilia, resulting in various defects depending on the cell type. Early defective ciliary function can be the cause of developmental abnormalities, especially in the kidneys, brain, limbs, heart.

Meckel syndrome is inherited as an autosomal recessive genetic disorder. Recessive genetic disorders occur when a person inherits the same altered gene for one trait from each parent. If a person receives one working gene and one non-working gene for a disease, then the person will be a carrier of the disease, but usually asymptomatic. The risk of both carrier parents passing on a non-working gene and therefore having a sick child is 25% in every pregnancy. The risk of having a carrier child, like the parents, is 50% with each pregnancy. The probability for a child to receive normal genes from both parents is 25%. The risk is the same for men and women.

Parents who are close relatives (siblings) are more likely than unrelated parents parents who have the same abnormal gene, which increases the risk of having a child with a recessive genetic disorder.

Affected populations

Meckel's syndrome affects men and women in equal numbers. More than 200 cases have been reported in the medical literature. The estimated incidence of Meckel syndrome in various regions of the world ranges from 1 in 13,250 to 1 in 140,000 live births. The disorder is more common in the Finnish population due to the founder effect, with a frequency of 1 in 9000 and 1 in 3000 of Belgian descent. However, in Gujarati people, the disease has a prevalence of 1 in 1,300. The disorder occurs more often in the context of kinship unions.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of Meckel's syndrome. Comparisons can be useful for differential diagnosis:

• Smith-Lemli-Opitz Syndrome (7-dehydrocholesterol reductase deficiency) is a rare inherited developmental disorder characterized by multiple congenital disorders. Symptoms may include characteristic facial features, microcephaly, short stature, mental retardation, extra fingers or toes (polydactyly), loss of vision, incomplete development of the male genitals, short nose with displaced nostrils, and stenosis gatekeeper. Some patients may have brain or heart abnormalities. The specific symptoms associated with each person vary greatly. Smith-Lemli-Opitz syndrome is inherited in an autosomal recessive manner.
• Trisomy 13 (Patau syndrome) is a chromosomal disorder in which all or part of chromosome 13 is duplicated three times (trisomy), rather than twice in the cells of the body. In some affected individuals, only a percentage of cells may contain an extra chromosome 13 (mosaicism), while other cells contain a normal chromosome pair. In people with trisomy 13, the range and severity of associated symptoms and signs may depend on the specific location of the duplicated (trisomic) part of chromosome 13, as well as the percentage of cells containing anomalies. However, in many affected infants and children, these abnormalities may include developmental delays, profound mental retardation, unusually small eyes (microphthalmia), an abnormal depression in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), undescended testes (cryptorchidism) in men, and extra fingers and toes (polydactyly). Additional craniofacial malformations may also be present, such as a relatively small head (microcephaly); wide flat nose; wide-set eyes; vertical skin folds that cover the eyes; inner corners (epicantal folds); defects of the scalp; and ugly, low-set ears. Affected children may also have incomplete development of certain areas of the brain (eg, the forebrain); renal abnormalities; congenital heart defects. Life-threatening complications can develop during infancy or early childhood.
• Short rib syndrome — polydactyly are a group of rare skeletal disorders characterized by growth deficits leading to short stature, narrow chest and abnormally short ribs, as well as extra fingers and legs. There is significant overlap in symptoms associated with short rib syndrome, polydactyly. Additional signs may include polycystic kidney disease, underdevelopment (hypoplasia) of the lungs, anomalies of the genitourinary system, anomalies of the central nervous system, developmental delays, cleft lip and cleft palate. Severe forms of short rib syndrome - polydactyly include Saldino-Noonan, Mayevsky, Verma-Naumov, and Beamer-Langer syndrome. These disorders are inherited in an autosomal recessive manner.

Diagnostics

The diagnosis of Meckel syndrome is often made by ultrasound during pregnancy or childbirth, with careful clinical examination. Molecular genetic testing can be used to confirm the diagnosis and conduct genetic counseling. Prenatal diagnosis is available with ultrasonography as early as 14 weeks gestation, which can detect certain abnormalities (for example, encephalocele, polydactyly, cystic kidney damage and oligohydramnios). Chromosomal analysis can be done to rule out trisomy 13. To exclude Smith Lemli-Opitz syndrome, a biochemical study can be performed.

Standard treatments

There is currently no cure for Meckel syndrome. The disorder is permanently fatal due to renal failure and hypoplasia of the lungs. Treatment is symptomatic and supportive. Genetic counseling is recommended for families.

Forecast

The disorder is fatal in the womb or in the very early neonatal period with pulmonary hypoplasia and renal failure as major causes of early death.