Pierre Robin Sequence With Pectus Excavatum And Rib And Scapular Anomalies

Clinical Features

In a 5-generation family with multiple musculoskeletal anomalies, Stalker and Zori (1997) described an apparently new malformation syndrome with autosomal dominant inheritance. The features included the Pierre Robin-type cleft palate (261800), pectus excavatum, rib anomalies, and hypoplasia of the distal segments of the scapulae. The propositus at birth was mildly hypotonic with a Robin-type cleft involving the soft and hard palate with micrognathia, and with moderately severe pectus excavatum. Radiographs showed 11 pairs of ribs and hypoplasia of the inferior subscapular area, more pronounced on the left than on the right. The mother at birth had a U-shaped cleft of the soft palate and micrognathia, a grade II/VI systolic murmur that resolved neonatally, moderate pectus excavatum, low-set hairline, and hyperextensibility of joints. The maternal grandmother of the propositus had micrognathia with intact palate, webbed neck with low-set hairline, hypoplastic scapulae, severe pectus excavatum, and no joint hyperextensibility. Radiographs showed 11 pairs of ribs, hypoplasia of the subscapular areas, and a dysplastic right third rib. Among the other members of the family, there was one instance of male-to-male transmission. Stalker and Zori (1997) considered the syndrome in this family to be distinct from other reported syndromes, including the disorder reported by Chitayat et al. (1991) in 2 half brothers (see 311895).

Stalker et al. (2001) reported that after the birth of an infant with multiple congenital anomalies and an unbalanced karyotype of 46,XX, der(13)t(13;17)(q22.1;q23.3) in the family reported by Stalker and Zori (1997), the mother was identified as having a balanced 13/17 translocation, 46,XX, t(13;17)(q22.1;q23.3). The translocation segregated with the skeletal phenotype in all family members studied. The authors noted that chromosome analysis should be considered when a previously unrecognized collection of physical or developmental problems is segregating in a kindred.

Unger (2005) suggested that the disorder in the patients reported by Stalker and Zori (1997) was in fact the mildest end of the spectrum of campomelic dysplasia (114290). In a reply to the letter of Unger (2005), Stalker et al. (2005) agreed that the abnormalities in their family might be caused by disruption of SOX9 (608160) expression, but argued that it was also possible that they were caused by disruption of an as yet unknown gene distinct from SOX9.

Hill-Harfe et al. (2005) mapped the chromosome 17 breakpoint in the family studied by Stalker and Zori (1997) and Stalker et al. (2001), which they called 'family F,' at a site 931.8 kb upstream of the transcriptional start of the SOX9 gene. They concluded that the disorder in this family might be a mild form of campomelic dysplasia. Pierre Robin sequence, hypoplastic scapulae, and 11 pairs of ribs were the primary features in family F and are also nearly universal in both mild and severe forms of CMPD. Family F also had minor facial dysmorphism consisting of flat face, broad nasal bridge, micrognathia, and hypertelorism, consistent with CMPD. However, many of the other features of CMPD were not present in this family: stature and life span were normal; there was no bowing of the long bones and no clubbing of the feet; pelvic bones, spine, and epiphyses were normal; there was no evidence of sex reversal. Hill-Harfe et al. (2005) noted that the scoliosis and hearing loss that are nearly ubiquitous in long-term survivors of CMPD (Mansour et al., 2002) were not seen in family F.

Velagaleti et al. (2005) presented a balanced translocation, t(4;17) (q28.3;q24.3), segregating in a family with mild CMPD with Pierre Robin sequence. They found that the 17q24.3 breakpoint mapped approximately 900 kb upstream of SOX9, which was within the same BAC clone as the breakpoints of 2 other reported patients with mild CMPD. The authors identified a candidate upstream cis-regulatory element, SOX9cre1 (SOX9 conserved regulatory element-1). They suggested that the mild CMPD phenotype found in their patient and others (Stalker and Zori, 1997; Stalker et al., 2001; Hill-Harfe et al., 2005) may be the result of slightly modified expression of chondrocyte-specific genes, secondary to altered SOX9 regulation as a result of spatial dissociation from the distal SOX9cre1.