Pierre Robin Malformation 

Robin sequence (RS), previously known as Pierre Robin syndrome and Pierre Robin anomalad, consists of the following 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.

Examples are shown in the images below.

Robin sequence is a series of anomalies all initiated by one developmental problem. Other definitions have been suggested based on a combination of mandibular deficiency, presence of U-shaped or V-shaped cleft palate (see the image below), and airway obstruction.

This condition is not only causally heterogenous but also pathogenetically and phenotypically varies.^[1] Each of the 3 symptoms can occur in wide scale of severity. Based on the combination of symptoms, newborn babies and infants suffer from airway obstruction and feeding problems. Three grades of severity have been recomended.^[2]

Robin sequence occurs as an isolated defect, as part of a recognized syndrome, or as part of a complex of multiple congenital anomalies. Diagnosis of a possible syndrome is very often critically important for correct management of a newborn affected with Robin sequence.^{[3, 4]}

The condition is named after the French dental surgeon Pierre Robin (1867-1950). His first paper described only micrognathia, glossoptosis, and respiratory distress.^[5] One decade later, he included cleft palate in the list of symptoms.^[6] His main interest was glossoptosis; over a 30-year period, he published more than 20 articles and monographs on embryology, anatomy, complications, and management of this disorder.^[7]

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 Robin sequence is part of a recognized syndrome, part of a complex of multiple anomalies, or part of an unrecognized syndrome.

Isolated Robin sequence 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 Robin sequence 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 Robin sequence caused by deformation. Therefore, catch-up growth is unlikely.

In patients with Robin sequence, 13-27.7% of other family members are affected with cleft lip with or without cleft palate.^{[8, 9]} Jakobsen et al compared data in several databases and proposed genes that might participate in etiology of Robin sequence, including GAD67 on 2q31, PVRL1 on 11q23-q24, and SOX9 on 17q24.3-q25.1.^[10] Melkoniemi et al detected disease-associated mutations in COL11A1 and COL11A2 genes in some patients with nonsyndromic Robin sequence.^[11]

More recently, Jacobsen et al screened 10 unrelated patients affected with Robin syndrome for SOX9 and KCNJ2 mutations and suggested that nonsyndromic Robin sequence may be caused by both SOX9 and KCNJ2 dysregulation.^[12] Several lines of evidence for the existence of a 17q24 locus underlying Robin sequence, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9, have been reported by Benko et al.^[13]

The proportion of cases that are isolated Robin sequence varies in different studies. Hanson and Smith found that 25% of Robin sequence cases had specific syndromes, another 35% had multiple anomalies without a specific recognized syndrome, and only 40% had isolated Robin sequence.^[14] Another study found that 74% of cases were isolated Robin sequence.^[15]

Among syndromic cases, the most common is Stickler syndrome, which comprises 20-25% of all cases (see the images below).

The second most common Robin sequence syndrome is velocardiofacial syndrome, which comprises about 15% of all Robin sequence cases.^[16]Treacher Collins syndrome (mandibulofacial dysostosis), Nager syndrome, spondyloepiphyseal dysplasia congenita, and other recognized syndromes comprise the rest of the syndromic Robin sequence cases.

Cohen listed 46 conditions associated with Robin sequence (see the image below).^[17]

Although this list is representative, it is not complete. Robin sequence may be present with other conditions and various other anomalies, especially those involving the eye, ear, heart, and limb.^[18] When Robin sequence is diagnosed, a full genetic evaluation (including fluorescent in situ hybridization [FISH] for 22q deletion and testing for mutation in the Treacle [TCOF1] gene) is appropriate, together with diagnostic tests for other suspected syndromes (eg, bone radiographs, ophthalmology examination).

Among 47 patients with Robin sequence who were monitored by Sheffield et al, 12 patients were diagnosed as syndromic.^[19] Out of 52 cases reported by Sher, 15 patients had Stickler syndrome and only 5 had nonsyndromic Robin sequence.^[20]

Distinguishing between micrognathia (ie, a small mandible) and retrognathia (ie, an essentially normal-sized mandible) is important. In micrognathia, the mandible is small; in 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.^[21]

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. Retrognathia rarely produces 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. Cleft palate or Robin sequence 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 spondyloepiphyseal dysplasia congenita is caused by multiple mechanisms, including 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.^[22] Furthermore, the upper respiratory obstruction of the Robin sequence may worsen the respiratory condition of the patient with spondyloepiphyseal dysplasia congenita (see the image below).

The mandible in Robin sequence is often compared with the mandible in Treacher Collins syndrome (see the image below).

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 widely varies in both conditions, the defects in Robin sequence may initially seem much greater than in Treacher Collins syndrome; however, a significant difference between these conditions becomes very apparent as the infant develops. In deformational Robin sequence, so-called "catch-up growth" occurs, although it may be incomplete.^[23] In Treacher Collins syndrome, mandibular growth remains severely affected.

Frequency

United States

The reported birth prevalence of Robin sequence varies from 1 in 2000 to 1 in 30,000.^[24] Bush and Williams suggested 1 in 8500.^[25] The case definition of Robin sequence still varies, and differences in definition lead to differences in the reported birth prevalence.^[26] In studies with the highest birth prevalence of Robin sequence, 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 cases per 1000 births).^[27]

Most nonsyndromic Robin sequence cases are sporadic. In the older literature, several authors reported a familial occurrence.^{[28, 29, 30]} Some of these cases were probably 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 Robin sequence cases, and Robin sequence is the most constant feature of Stickler syndrome. When correctly diagnosed, myopia is detected early; this can prevent retinal detachment and possibly blindness.