Meckel-Gruber Syndrome

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Meckel-Gruber Syndrome

Meckel-Gruber syndrome (MKS) is a rare, lethal, autosomal recessive disorder, characterized by occipital encephalocele, cystic dysplastic kidneys, and postaxial polydactyly. The incidence is estimated to be 1/13,250 (in USA)–1/140,000 (in Great Britain) live births. The incidence in North Africa and Finnish population is much higher at 1/3500 and 1/9000 respectively. Meckel-Gruber syndrome is considered the most frequent syndromic cause of neural tube defects.

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal recessive 2. Locus heterogeneity

a. MKS1 locus to 17q21-24 in Finnish kindreds b. MKS2 locus to 11q13 in North African-Middle

Eastern cohorts

c. MKS3 to 8q24 in Indian sub-continent cohorts

CLINICAL FEATURES

1. Major clinical features a. Clinical triad

i. Occipital encephalocele (85%)

a) Extrusion of rhombic roof elements (cerebellar vermis, caudal 3rd ventricle, distended 4th ventricle) through a widened posterior fontanelle

b) Protruding CNS structures covered by a dural sac

c) Medial occipital cortex occasionally includ- ed in the sac formed by the dilated caudal 3rd ventricle

ii. Dysplastic kidneys (100%) a) Result in oligohydramnios

b) Lead to fetal pulmonary hypoplasia iii. Postaxial polydactyly (55%)

b. Microcephaly c. Oral clefts

i. Cleft lip ii. Cleft palate d. Ambiguous genitalia 2. Other clinical features

a. CNS abnormalities i. Absent olfactory lobe

ii. Absent pituitary gland (hypopituitarism) iii. Hydrocephalus

iv. Dandy-Walker malformation b. Craniofacial features

i. Sloping forehead

ii. Microphthalmia/anophthalmia iii. Micrognathia

iv. Malformed tongue v. Abnormal ears

c. Short neck

d. Hypoplastic thyroid e. Congenital heart defect

f. Gastrointestinal abnormalities i. Omphalocele

ii. Malrotated bowel iii. Fibrotic or cystic liver g. Absent or small adrenals h. Accessory spleen

i. Urinary tract anomalies j. Short limbs

k. Abnormal palmar creases l. Club feet

m. Syndactyly 3. Lethal outcome

a. Abortions b. Stillborns c. Neonatal deaths

d. Rare survivals till 2 years of age

DIAGNOSTIC INVESTIGATIONS

1. Ultrasonography a. CNS anomalies

b. Cystic dysplastic kidneys 2. MRI of the brain for CNS anomalies

3. Echocardiography for congenital heart defect 4. Radiography

a. Microcephaly with an occipital bone defect and encephalocele or hydrocephaly

b. Short upper extremities

c. Bell-shaped thorax with abdominal distension d. Postaxial polydactyly in the hands and feet 5. Necropsy

a. Renal anomalies

i. Cystic dysplastic kidneys

ii. Hypoplastic kidneys/ureters/bladder iii. Rectovesicular fistula

b. Triad of CNS malformations i. Prosencephalic dysgenesis

a) Agenesis of olfactory bulbs and tracts (arhi- nencephaly)

b) Complete holoprosencephaly

c) Hypoplasia of optic nerves and chiasm d) Microphthalmia

e) Agenesis of the corpus callosum f) Fused thalami

g) Hypoplasia of the 3rd ventricle h) Small or absent pituitary gland

i) Microcephaly

j) Cleft/high arched palate k) Micrognathia

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MECKEL-GRUBER SYNDROME 637

637 MECKEL-GRUBER SYNDROME

ii. Occipital exencephalocele

a) Displacement of rhombic roof elements including caudal third ventricle, cerebellar vermis and fourth ventricle

b) Extruded through an enlarged posterior fontanelle rather than through an occipital cranium bifidum

c) Often associated with a variant of Dandy- Walker cyst with Chiari malformation iii. Rhombic roof dysgenesis

a) Absent brain stem tectum

b) Agenesis/dysgenesis cerebellar vermis c) Elongated brain stem

d) Aqueduct stenosis c. Histologic features of the CNS

i. Polymicrogyria ii. Heterotopias

iii. Characteristic neuroepithelial rosettes d. Hepatic dysgenesis

i. A consistent features

ii. Arrested development of the intrahepatic biliary system

a) Reactive biliary bile duct proliferation b) Bile duct dilatation

c) Portal fibrovascular proliferation e. Lung hypoplasia

f. Gastrointestinal anomalies i. Pancreatic cyst ii. Malrotated bowel iii. Anal atresia g. Genital anomalies

i. Hypoplastic genitalia ii. Bicornuate uterus

iii. Persistent urogenital sinus

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sib: 25%

b. Patient’s offspring: not surviving to reproductive age 2. Prenatal diagnosis

a. Ultrasonography: diagnosis more difficult in the 2nd trimester because of oligohydramnios secondary to poor renal output impairing visualization

i. Occipital encephalocele

ii. Renal anomalies (large cystic kidneys, renal agenesis, renal hypoplasia, and ureteral duplication) iii. Polydactyly

iv. Oligohydramnios

v. Dandy-Walker malformation vi. Cerebellar hypoplasia

b. MRI, a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios

c. Elevated serum α-fetoprotein d. Amniocentesis

i. Elevated amniotic fluid α-fetoprotein ii. Normal karyotype

3. Management

a. No specific treatment

b. Supportive care for lethal cases

c. Operative excision of a small encephalocele d. Ventriculoperitoneal shunt for hydrocephalus

REFERENCES

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638 MECKEL-GRUBER SYNDROME

Fig. 1. A neonate with Meckel-Gruber syndrome showing a large occipital encephalocele, microcephaly, sloping forehead, micro/retrognathia, low-set malformed ears, and short neck. The infant also had post-axial polydactylies. Necropsy showed unilateral renal dysgenesis. Contralateral renal cystic dysplasia was present.

Fig. 2. Another neonate with Meckel-Gruber syndrome showing a large occipital encephalocele, microcephaly, sloping forehead, micro/retrognathia, low-set malformed ears, short neck and post-axial polydactylies.