Meckel-Gruber syndrome

Joseph R Siebert PhD (Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.)
Originally released July 17, 1995; last updated September 5, 2020; expires September 5, 2023


The author reviews Meckel-Gruber syndrome, the most common syndromic form of neural tube defect. Meckel-Gruber syndrome is the most severe of a number of ciliopathies. Advances in molecular genetics are helping us understand the various phenotypes and genotypes of this lethal disease.

Key points


• Meckel-Gruber syndrome is the most common syndromic condition involving a neural tube defect.


• Phenotypic changes are highly variable. Major deficits of Meckel-Gruber syndrome include renal cystic dysplasia, hepatic fibrosis with ductal plate malformation, polydactyly, and occipital encephalocele (or less commonly, Dandy-Walker malformation, holoprosencephaly, or other CNS anomaly).


• Prenatal or perinatal demise is common.


• The disorder is genetically heterogeneous and is inherited on an autosomal recessive basis, with a recurrence risk of 25%.


• Some 20 genes and additional novel variants have been linked to Meckel-Gruber syndrome; to date, these account for 50% to 60% of all cases.

Historical note and terminology

Thought to be originally described by Johann Friedrich Meckel in a pair of siblings in 1822, the syndrome was further defined by Grüber in 1934 and labeled "dysencephalia splanchnocystica" (Meckel 1822; Gruber 1934). Evidence suggests, however, that Christopher Krahe described a similar syndrome in a child born in Denmark in 1684 (Kompanje 2003). Much later reports described features of 13-15 trisomy syndrome with normal karyotype (Marshall et al 1964; Miller and Selden 1967) or a familial polydactyly with central nervous system dysplasia (Walbaum et al 1967). The identity of this syndrome was established in 1969 by Opitz and Howe, who described one case and thoroughly reviewed 43 observations reported in the literature to date (Opitz and Howe 1969). They proposed the eponym of "Meckel syndrome."

A striking combination of clinical features characterizes the syndrome, which is lethal when fully expressed. “Formes frustes” are frequent, sometimes in association with other malformation syndromes, and they are difficult to differentiate from other disorders (Mecke and Passarge 1971; Lowry 1983). Helpful diagnostic criteria were suggested by Fraser and Lytwyn and further refined by Salonen, Blankenberg and colleagues, and Ahdab-Barmada and Claassen (Fraser and Lytwyn 1981; Salonen 1984; Blankenberg et al 1987; Ahdab-Barmada and Claassen 1990). Frequently used eponyms include "Meckel syndrome," "dysencephalia splanchnocystica of Grüber," or "Meckel-Grüber's syndrome."

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