Pierre Robin Syndrome

Description

Pierre Robin sequence is a craniofacial anomaly comprising mandibular hypoplasia, cleft secondary palate, and glossoptosis leading to life-threatening obstructive apnea and feeding difficulaties during the neonatal period (summary by Tan et al., 2013).

Clinical Features

Affected brothers were reported by Smith and Stowe (1961) and pictured by McKusick et al. (1962). (It is possible that these brothers had either the Wagner syndrome (143200) or the Stickler syndrome (108300).) In the view of Opitz (1973), Stickler syndrome should come to mind first in cases of the Pierre Robin syndrome, especially familial cases.

Sachtleben (1964) also described 2 brothers who, in addition to the usual features of Pierre Robin syndrome, had bilateral syndactyly of the second and third toes and evidence of cardiac disease. The older brother had hypospadias, bipartite scrotum, and mental retardation.

Shah et al. (1970) observed Pierre Robin syndrome in 4 sibs, including a set of twins. Bixler and Christian (1971) described the full Robin syndrome in 2 sibships related to each other as second cousins. Singh et al. (1970) reported a third pair of affected brothers.

Segreti and Maumanee (1977) described Pierre Robin anomalad in 3 children, 2 females and a male, with 2 different fathers. The mother showed stigmata of the syndrome, as did her father and 2 of her other children, who had slightly high, narrow palates and micrognathia. One of the affected sibs died of a complex of cardiac malformations. The authors favored dominant inheritance.

Sheffield et al. (1987) performed a follow-up study of 64 infants. Twelve of 47 living patients (26%) were diagnosed as having an underlying syndrome, the most common of which was Stickler syndrome (in 6 cases). There was no recurrence in sibs of patients with nonsyndromic Pierre Robin complex.

The Pierre Robin syndrome qualifies as a sequence in terms of the definition laid down by David W. Smith (Jones, 1970). This does not, however, exclude the possibility of its being mendelian. The Pierre Robin sequence appears as a feature of campomelic dysplasia (114290) and a related skeletal dysplasia (602196).

Population Genetics

Tan et al. (2013) stated that the incidence of Pierre Robin sequence is estimated to be 1:8,500-14,000.

Mapping

Benko et al. (2009) performed linkage analysis in a 4-generation family (designated F1) with Pierre Robin sequence, including 12 affected individuals, and obtained a maximum lod score of 3.32 (theta = 0.0) at a 5.4-Mb interval on chromosome 17q24.3-q25.1 between markers D17S795 and D17S929.

Cytogenetics

Jakobsen et al. (2007) reported a girl with Pierre Robin sequence in whom they identified a t(2,17)(q23.3;q24.3) translocation, in which the 17q breakpoint mapped to 1.13 Mb upstream of the SOX9 gene (608160) and 800 kb downstream of the KCNJ2 gene (600681). The authors also found significantly reduced SOX9 and KCNJ2 mRNA expression in patients with Pierre Robin sequence, and suggested that nonsyndromic Pierre Robin sequence may be caused by both SOX9 and KCNJ2 dysregulation.

Benko et al. (2009) identified 3 unrelated families with autosomal dominant isolated Pierre Robin sequence segregating with different translocations, each of them sharing a breakpoint at chromosome 17q24. The other breakpoints (2q24.1, 2q32, and 5q15) did not disrupt any known genes; the 17q24 breakpoints clustered within 160 kb in the gene desert between the KCNJ2 and SOX9 genes, a region containing over 200 highly conserved noncoding elements (HCNEs).

Houdayer et al. (2001) studied a female infant with Pierre Robin sequence and an unbalanced reciprocal translation 46,XX, t(2;21) with interstitial deletion of 2q32.3-q33.2; the authors noted that the deletion was in a chromosomal region associated with cleft palate.

Ghassibe-Sabbagh et al. (2011) studied a family with Pierre Robin syndrome in which the 4-year-old proband had a cleft of the secondary palate and associated microretrognathia, microstomia, malar hypoplasia, and oligodontia; his father and paternal aunt were similarly affected. The karyotypes of the father and son were 46,XY,t(1;2)(p34;q33). The 1p breakpoint was found to interrupt the FAF1 gene (604460) within its first intron and FAF1 expression was decreased in the proband's lymphocytes compared to controls. Analysis of the 2q breakpoint showed that the region was unlikely to play a role in the phenotype, as it is not well-conserved between humans and mice, has no sites for microRNAs or regulatory elements, and contains no genes, UTRs, LINEs, SINEs, or other repetitive interspersed or tandem-repeat elements. In a study of 2,530 nonsyndromic cleft trios (see OFC13, 613857), Ghassibe-Sabbagh et al. (2011) found the FAF1 locus to be strongly associated with cleft palate.

Molecular Genetics

In a 4-generation family with Pierre Robin sequence mapping to chromosome 17q24 (designated family F1), Benko et al. (2009) sequenced 4 candidate genes, SOX9, KCNJ2, KCNJ16 (605722), and MAP2K6 (601254), but did not find any gross genomic alterations or coding-sequence mutations. However, using array comparative genomic hybridization (CGH) analysis, they identified a heterozygous 75-kb deletion located 1.38-Mb centromeric to the SOX9 gene, encompassing 10 highly conserved noncoding elements (HCNEs), that segregated with disease. Array CGH analysis in 11 additional unrelated patients with Pierre Robin sequence revealed de novo deletions in 2 sporadic cases, involving a centromeric deletion of more than 319 kb and a telomeric 36-kb deletion, respectively. DNA sequencing of the 10 HCNEs in the remaining 9 individuals with Pierre Robin sequence revealed a heterozygous T-C transition in 1 family (designated F2) within an HCNE that demonstrated features of a developmental enhancer in vitro and in vivo. The mutation abrogated the in vitro enhancer function and altered binding of the transcription factor MSX1 (142983) compared to wildtype. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions showed a regionally specific chromatin decompaction in cells expressing SOX9. Benko et al. (2009) concluded that some cases of Pierre Robin sequence may result from developmental misexpression of SOX9 due to disruption of very long range cis-regulatory elements.