Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-13 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Definition: Meckel syndrome is a rare and lethal syndrome characterized by occipital cephalocele, post-axial polydactyly and dysplastic cystic kidneys. It can be associated with many other conditions, and fibrotic lesion of the liver is one of the most common associations.

Synonyms: Dysencephalia splanchnocystica, Meckel syndrome (used in English literature). This is the preferred appellation and is used by both Medline's Medical Subject Heading and the Birth Defect Encyclopedia, Gruber syndrome (used in the European literature)[2], Meckel—Gruber syndrome.

Incidence: Not precisely known, but authors agree that this is a very rare condition. According to Bergsma, the incidence of Meckel syndrome is 0.2: 10,000 live births[3]. Salonen stated that the incidence of Meckel syndrome at birth varies from 0.07-0.7: 10,000 births. In Finland, the disorder is unusually frequent and reaches 1.1:10,000 births.  It is also estimated that this syndrome corresponds to 5% of all neural tube defects .

Etiology: Autosomal recessive inheritance.

Recurrence risk: A 25% recurrence risk is involved.

Genetic anomaly: The locus for Meckel syndrome is on chromosome 17, long arm, region 2, bands 1-4. Phenotype variability and cases that did not have confirmed linkage to 17q suggests that there is some degree of locus heterogeneity.

Diagnosis: In 1981, Fraser and Lytwyin suggested that the cystic dysplastic kidneys are a constant anomaly in Meckel syndrome and therefore must be present in addition to at least two minor defects to make the diagnosis[7]. This concept is still discussed, and the reported incidence of renal disorder in this syndrome varies from 95% to 100%. The kidneys have initially microscopic cysts that develop destroying the parenchyma and enlarging the organ up to 10 or 20 times5 (fig. 1). The first sonographic finding in most cases is oligohydramnios, due to the renal dysfunction, and it develops early in the second trimester when the kidneys replace extracellular diffusion as the main source of amniotic fluid. However, some cases of Meckel syndrome have normal amniotic fluid (fig. 1) and thus the presence of normal fluid does not exclude the diagnosis. Sometimes absence of the bladder can also be recognized. An early sonogram, with normal aspect, in a family at risk for recurrence, does not exclude Meckel syndrome, and a follow-up at 20 weeks of gestation is recommended5.

Occipital cephalocele is present in 60% to 80% (figs. 2-3). Maternal serum or amniotic fluid a-fetoprotein level may be normal, as a membrane may cover the cephalocele. Post-axial polydactyly is present in 55% to 75%5,[8] (fig. 4). Other limb anomalies such a bowing and shortening may also be present.

Finding at least two of the three features of the classical triad, in the presence of normal karyotype makes the diagnosis (fig. 5).

Figure 1: Large bilateral cystic kidneys that resemble multicystic kidneys. Note that the amniotic fluid level is normal, which is atypical.

Figure 2: 8 mm posterior cephalocele in axial and sagittal views.

Figure 3: 8 mm posterior cephalocele in axial and sagittal views.

Figure 4: Postaxial polydactyly.

Figure 5: Note the small posterior cephalocele, the large abdominal distention due to the bilateral cystic kidneys and the postaxial polydactyly.

Differential diagnosis: The differential diagnosis will depend on the type of the associated anomalies. Due to several sonographic similarities between these conditions, trisomy 13 must be excluded by karyotype. Another possible differential diagnosis is autosomal dominant polycystic kidney disease.

Associated anomalies: The constellation of possible anomalies associated with this syndrome is extensive (Table 1). In some situations, such a wide phenotypic variation makes the recognition of the disease more difficult.

Prognosis: Meckel syndrome is a lethal disorder. Most infants are stillborn or die hours or days after birth. A few sometimes survive a few months with poor quality of life. According to Ramadani, there is one report of a long survivor who died at the age of 28 months9. In 1997, Paavola reported another atypical case of a long survivor who died at 18 months of life6.

Management: A karyotype study should be obtained when Meckel syndrome is suspected, to exclude chromosomal disorders. If the diagnosis is made before viability, termination can be offered. When the family decides to continue the pregnancy, or if the diagnosis is made after viability, the standard obstetrical management is not altered.

Table: Associated anomalies with Meckel syndrome

Central nervous system

·         occipital cephalocele

·         microcephaly

·         holoprosencephaly

·         cerebral & cerebellar hypoplasia

·         hypoplasia of pituitary gland

·         Dandy – Walker malformation[10]

Face

·         cleft lip / palate

·         micrognathia

·         ear anomalies

·         microphthalmia 9 [11]

·         epicanthal folds11

·         nasal anomalies11

·         hypotelorism or hypertelorism14

Mouth

·         lobulated tongue14

·         cleft epiglottis14

·         neonatal teeth14

Skeletal

·         polydactyly

·         short limbs

·         talipes

·         bell-shaped thorax

·         syndactyly11

·         club foot5

·         clinodactyly5

Renal

·         polycystic kidneys

·         renal agenesis

·         renal hypoplasia

·         horseshoe kidneys

·         double ureter

Hepatic

·         hepatic fibrosis[12]

·         ductal agenesis

·         portal fibrosis

Genitalia

·         hypoplasia

·         ambiguous genitalia9

·         hermaphrodites4

·         cryptorchidism14

Cardiac

·         ventricular or atrial defects5

·         aortic hypoplasia or coarctation5

·         aortic valvular stenosis5

·         rotational anomalies5

·         pulmonary stenosis14

Lungs

·         hypoplasia of the lungs14

Others

·         growth restriction

·         short webbed neck

·         malrotation of the guts

·         accessory spleen

·         adrenal agenesis

·         omphalocele

·         hypoplasia or absent bladder

·         imperforate anus14

·         enlarged placenta14

·         single umbilical artery14

Modified and adapted from Jaffe[13], Casamassima11, Nyberg5, Radamani9 and Gallimore10, Salonen4, Jones[14]

References

[1] Buyse ML (Ed.) (1990) Birth Defects Encyclopedia. Blackwell Scientific Publication

[2] Altmann P, Wagenbichler P, Schaller A (1977). A casuistic report on the Gruber or Meckel syndrome, Hum Genet 38, 357-362

[3] Bergsma, D., (1979). Birth Defects. In Atlas and Compendium. National Foundation – March of Dimes. The Macmillan Press Ltd.( London )

[4] Salonen, R., Norio, R.(1984).The Meckel syndrome: clinicopathological findings in 67 patients, Am. J. Med. Genet., 18: 671 - 689

[5] Nyberg, D.A., Hallesy, D., Mahony, B. S., Hirsch, J. H., Luthy, D. A., Hickok, D. (1990). Meckel – Gruber syndrome; importance of prenatal diagnosis. J Ultrasound Med., 9, 691 - 696

[6] Paavola, P., Salonen, R., Weissenbach, J., Peltonen, L.(1995). The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat. Genet., 11, 213-215

[7] Farag TI, Usha R, Mady SA, Al-Nagdy K, El-Badramany M (1990). Phenotypic variation in Meckel-Gruber syndrome. Clin. Genet. 38, 176-179

[8] Weinstein BJ, Benacerraf BR. (1994). Meckel syndrome, first trimester diagnosis. Fetus, 4:5: 4-5

[9] Ramadani HM, Nasrat HA. (1992). Prenatal diagnosis of recurrent Meckel syndrome. Int. J. Gynecol. Obstet. 39, 327-332

[10] Gallimore, A. P., Davies, P. F.(1992). Meckel syndrome: prenatal ultrasonographic diagnosis in two cases showing marked differences in phenotypic expression. Australas Radiology, 36(1), 62 - 64

[11] Casamassima AC, Mamunes P, Gladstone Jr. IM, Solomon S, Moncure C. (1987). Anew syndrome with features of the Smith-Lemli-Optiz and Meckel-Gruber syndrome in a sibship with cerebellar defects. Am. J. Ed Genet, 26, 321-336

[12] Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. (1997)Clinical and genetic heterogeneity in Meckel syndrome. Hum. Genet., 101, 88-92

[13] Jaffe R. (1991). Meckel-Gruber syndrome. Fetus 1:5, 1-3

[14] Jones, K. L.(1997) Meckel-Gruber syndrome. Smith’s Recognizable patterns of human malformation. (5^th Edition) W. B. Saunders Company