Excerpt from Pierre Robin Malformation

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Background

Robin sequence (RS) (see Images 1-2), previously known as Pierre Robin syndrome and Pierre Robin anomalad, consists of 3 essential components:

• Micrognathia or retrognathia
• Cleft palate (usually U-shaped, but V-shape also possible)
• Glossoptosis, often accompanied by airway obstruction. (The tongue is not actually larger than normal, but because of the small mandible, the tongue is large for the airway and therefore causes obstruction. Rarely, the tongue is smaller than normal.)

A sequence is a series of anomalies all initiated by one malformation.

Other definitions have been suggested based on a combination of mandibular deficiency, presence of U-shaped or V-shaped cleft palate (see Image 5), and airway obstruction. This condition is not only causally heterogenous but also pathogenetically and phenotypically variable (Pruzansky, 1969).

Robin sequence occurs as an isolated defect, as part of a recognized syndrome, or as part of a complex of multiple congenital anomalies.

The condition is named after the French dental surgeon Pierre Robin (1867-1950). His main interest was glossoptosis, and over a 30-year period, he published more than 20 articles and monographs on embryology, anatomy, complications, and management of this disorder (Beighton, 1986).

Pathophysiology

Etiology and pathogenesis

Robin sequence is etiologically heterogenous. Etiologic heterogeneity suggests pathogenetic heterogeneity and phenotypic variability. These include various causes of malformations and deformations and connective tissue dysplasia (see Clinical). A major distinction should be made between isolated occurrences of Robin sequence and cases in which RS is part of a recognized syndrome, part of a complex of multiple anomalies, or part of an unrecognized syndrome.

Isolated RS is often a deformation resulting from intrauterine forces acting on the mandible, which restrict its growth and impact the tongue between the palatal shelves. Some deformational cases of RS have been associated with oligohydramnios. Because micrognathia results from intrauterine molding, mandibular catch-up growth is expected after birth once intrauterine forces are removed. The most severe cases of micrognathia are unlikely to be isolated RS caused by deformation. Therefore, catch-up growth is unlikely.

In patients with RS, 13-27.7% of other family members are affected with cleft lip and/or palate (Marques, 1998; Holder-Espinasse, 2001). Jakobsen et al (2006) compared data in several databases and proposed genes that might participate in etiology of RS, including GAD67 on 2q31, PVRL1 on 11q23-q24, and SOX9 on 17q24.3-q25.1. Melkoniemi et al (2003) detected disease-associated mutations in COL11A1 and COL11A2 genes in some patients with nonsyndromic RS. Further research is required to confirm that they are candidate genes for RS.

The proportion of cases that are isolated RS varies in different studies. Hanson and Smith (1975) found that 25% of RS cases had specific syndromes, another 35% had multiple anomalies without a specific recognized syndrome, and only 40% had isolated RS. Another study (Williams et al, 1981) found that 74% of cases were isolated RS.

Among syndromic cases, the most common is Stickler syndrome, which makes up 20-25 % of all RS cases (see Images 6-8). The second most common RS syndrome is velocardiofacial syndrome, which makes up about 15% of all RS cases (Shprintzen, 1981). Treacher Collins syndrome (mandibulofacial dysostosis), Nager syndrome, spondyloepiphyseal dysplasia congenita, and other recognized syndromes make up the rest of the syndromic RS cases.

Cohen (1997) listed 46 conditions associated with RS (see Image 9). Although this list is representative, it is not complete. RS may be present with other conditions and various other anomalies, especially those involving the eye, ear, heart, and limb (Gorlin, 2001). When RS is diagnosed, a full genetic evaluation (including fluorescent in situ hybridization [FISH] for 22q deletion, test for mutation in Treacle (TCOF1) gene) is appropriate, together with diagnostic tests for other suspected syndromes (eg, bone radiographs, ophthalmology examination).

Among 47 patients with RS who were monitored by Sheffield et al (1987), 12 patients were diagnosed as syndromic. Out of 52 cases reported by Sher (1992), 15 patients had Stickler syndrome and only 5 had nonsyndromic Robin sequence.

Distinguishing between micrognathia (ie, a small mandible) and retrognathia (ie, an essentially normal-sized mandible) is important. With micrognathia the mandible is small; with retrognathia, the mandible size is essentially normal but the mandible is retrognathic in position because the cranial base angle is larger than normal. Most Robin conditions are either micrognathic or retrognathic (Cohen, 1990).

In velocardiofacial syndrome, the mandible is retrognathic. Because the cranial base is altered, the mandible grows downward instead of forward. This gives the appearance of a small mandible, but the bone mass is normal. It is unusual for retrognathia to produce severe airway distress.

In the vast majority of other syndromes, the mandible is micrognathic. The bone mass is decreased, and the mandible is disproportionately small. Severe airway obstruction is more common with these syndromes.

One of the most severe problems with airway obstruction may occur in patients affected with spondyloepiphyseal dysplasia congenita (SED). Cleft palate (CP) or RS is often present in this autosomal dominant condition that has a mutation in the COL2A1 gene, located on chromosome 12 (12q13.11-q13.2), the same as found in Stickler syndrome type I (hereditary progressive arthroophthalmopathy). The respiratory compromise in SED is caused by multiple mechanisms: a small abnormal chest, a tracheobronchomalacia, and/or a central apnea caused by compression of cervical spinal cord or medulla oblongata caused by cervical instability (Harding, 1990). Furthermore, the upper respiratory obstruction of the RS may worsen the respiratory condition of the patient with SED (see Image 10).

The mandible in Robin sequence is often compared with the mandible in Treacher Collins syndrome (see Image 11). When comparing two newborn babies with these conditions, one can see that the mandible in both conditions is short. Because the severity of the defects varies widely in both conditions, the defects in Robin sequence may initially seem much greater than in Treacher Collins syndrome; however, a significant difference between these two conditions becomes very apparent as the infant develops. In deformational Robin sequence, so-called "catch-up growth" occurs, although it may be incomplete (Kreiborg, 1996). In Treacher Collins syndrome, mandibular growth remains severely affected.

Frequency

United States

The reported birth prevalence of Robin sequence varies from 1 in 2000 (Poswillo, 1968) to 1 in 30,000. Bush and Williams (1963) suggested 1 in 8500. The case definition of Robin sequence still varies, and it is obvious that differences in definition lead to differences in the reported birth prevalence (Shprintzen, 1988). In studies with the highest birth prevalence of RS, syndromic cases are most likely included.

The study of a population-based sample of 4433 patients with orofacial cleft (ascertained from 2,509,881 California births) reported a birth prevalence of nonsyndromic Robin sequence as 1 in 18,730 (0.05/1000 births) (Tolarova, 1998).

The majority of nonsyndromic RS cases are sporadic. In the older literature, several authors reported a familial occurrence (Smith, 1961; Bixler, 1971; Shah, 1970). Very probably, some of these cases were syndromic. The authors' recommendation is to consider Stickler syndrome first when a familial occurrence of Robin sequence is found. Stickler syndrome is the most common syndrome among RS cases, and RS is the most constant feature of Stickler syndrome. When diagnosed correctly, myopia will be detected early; this can prevent retinal detachment and possibly blindness.

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