Meckel syndrome

Overview

Meckel syndrome (also known as Meckel–Gruber syndrome) is a rare, lethal autosomal recessive disorder characterized by a combination of congenital anomalies that primarily affect the central nervous system, kidneys, and liver. It is considered a type of ciliopathy—a group of genetic conditions caused by defects in the function or structure of cellular cilia. Meckel syndrome was first described by Johann Friedrich Meckel in the 19th century and later characterized in more detail by George B. Gruber.

The classic triad of features includes occipital encephalocele (a protrusion of brain tissue through a skull defect), cystic dysplasia of the kidneys, and polydactyly (extra fingers or toes). Other anomalies such as hepatic fibrosis, cleft lip/palate, and genital malformations may also be present. Meckel syndrome is typically diagnosed prenatally or at birth, and it is incompatible with life in most cases, with affected infants usually dying in the perinatal period.

Causes

Meckel syndrome is caused by mutations in one of several genes that affect primary cilia structure and function. These genes include:

• MKS1

• TMEM67 (also known as MKS3)

• CEP290

• RPGRIP1L

• CC2D2A

• TMEM216

These genes encode proteins involved in the function of primary cilia—small hair-like structures found on nearly all human cells that are essential for signaling pathways during embryonic development. Mutations impair cellular signaling, leading to the multi-organ malformations seen in Meckel syndrome.

Meckel syndrome follows an autosomal recessive inheritance pattern, meaning both copies of a specific gene must be mutated for a child to be affected. Parents of an affected child are typically asymptomatic carriers.

Symptoms

The clinical presentation of Meckel syndrome is severe and involves multiple organ systems. Symptoms are typically evident on prenatal imaging or at birth. The most common features include:

Neurological Abnormalities

• Occipital encephalocele: Protrusion of brain tissue through a defect in the back of the skull

• Hydrocephalus: Accumulation of cerebrospinal fluid in the brain

• Microcephaly or brain hypoplasia

Renal Anomalies

• Cystic dysplasia of the kidneys: Enlarged, multicystic kidneys with disrupted architecture

• Renal insufficiency or failure in utero

Hepatic and Gastrointestinal Abnormalities

• Congenital hepatic fibrosis: Fibrous tissue in the liver disrupting normal function

• Biliary ductal plate malformations

Limb and Craniofacial Abnormalities

• Polydactyly: Typically postaxial (extra fingers/toes on the outer side of limbs)

• Cleft lip and/or cleft palate

• Micrognathia: Small jaw

Other Features

• Genital anomalies: Including ambiguous genitalia

• Pulmonary hypoplasia: Underdeveloped lungs due to oligohydramnios from kidney dysfunction

• Oligohydramnios: Reduced amniotic fluid, often due to impaired fetal urine production

Due to the severity of the anomalies, most affected fetuses are stillborn or die shortly after birth.

Diagnosis

Diagnosis of Meckel syndrome can be made prenatally or postnatally through a combination of imaging, clinical examination, and genetic testing.

Prenatal Diagnosis

• Ultrasound (second trimester):

  • Encephalocele

  • Large, cystic kidneys

  • Polydactyly

  • Oligohydramnios

• Fetal MRI: May provide additional anatomical detail

• Amniocentesis or chorionic villus sampling: For genetic testing and identification of known mutations

Postnatal Diagnosis

• Physical examination: Confirmation of craniofacial and limb abnormalities

• Imaging: Brain and abdominal ultrasound, CT, or MRI

• Histopathology: Biopsy of kidney or liver (if indicated postmortem)

• Genetic testing: Confirms mutations in known MKS-associated genes

Differential diagnosis includes other ciliopathies such as Joubert syndrome, Bardet–Biedl syndrome, and autosomal recessive polycystic kidney disease (ARPKD).

Treatment

There is currently no cure for Meckel syndrome. Due to its severity and poor prognosis, treatment is typically supportive and palliative. Management strategies include:

• Prenatal counseling: Genetic counseling for at-risk couples and informed decision-making about the pregnancy

• Palliative care: Comfort care after birth for infants who survive delivery

• Postnatal support: If an infant survives birth, interventions may include respiratory support, feeding assistance, and symptom management

In rare milder cases with less severe organ involvement, limited supportive treatments may be pursued, but survival beyond the neonatal period is exceedingly rare.

Prognosis

The prognosis for Meckel syndrome is extremely poor. Most affected fetuses are stillborn or die shortly after birth due to respiratory failure, severe brain anomalies, or renal dysfunction. Factors contributing to poor outcomes include:

• Severe kidney dysfunction leading to oligohydramnios and pulmonary hypoplasia

• Large encephaloceles and brain malformations incompatible with life

• Inability to sustain basic physiological functions postnatally

Genetic counseling is essential for families, as the recurrence risk in subsequent pregnancies is 25% due to autosomal recessive inheritance. Carrier testing and prenatal genetic testing can assist in early diagnosis for future pregnancies.