Isolated Robin sequence associated with a balanced t(2;17) chromosomal translocation.

R obin sequence (RS) is a developmental malformation characterised by micrognathia, cleft palate, and glossoptosis, leading to respiratory and feeding difficulties in the majority of affected neonates. 2 These three features constitute the primary diagnostic criteria of RS, although diagnosis on the basis of any two of these three classical features has been suggested. Typically the condition occurs sporadically, but it may be familial, in which case the mode of inheritance is autosomal dominant. 5 However, the pathogenetic and phenotypic variability of RS has hampered efforts to establish a clear set of diagnostic criteria, 6 7 making the classification of this anomaly difficult and complicating the effective management and treatment. 9 Hence, the diagnosis of RS presents a challenge from both a clinical and a developmental perspective. RS has three different manifestations: (a) as part of a known syndrome; (b) in association with other abnormalities that do not constitute a recognisable syndrome (nonsyndromic), and (c) in a classical or isolated form not associated with any other significant findings. 6 10 Approximately 20–40% of reported RS cases occur in an isolated form, while between 35 and 70% of cases are syndromic. The most common syndromes associated with RS include Stickler syndrome and velocardiofacial syndrome. 16 While the underlying genetic factors in a number of the syndromes that include RS have been delineated, the genetic basis for isolated RS remains unclear. The developmental basis of RS is still contentious and it is conceivable that more than one pathogenic mechanism may be responsible for the full range of RS manifestations. One proposed theory for the origin of RS argues that mandibular hypoplasia, resulting from a developmental anomaly in either growth or placement of the mandible, is the primary defect. The cleft palate and apnoea could thus be a consequence of reduced oropharyngeal volume. This is supported by the elimination of both cleft palate and/or glossoptosis in the definition for PRS by some authors. 21–23 Further support for this hypothesis comes from an experimental paradigm of RS in which mandibular hypoplasia and relative macroglossia precede palatal closure. An alternative developmental sequence for RS centres on the hindbrain region regulating oro-oesophageal motor function. According to this theory, oral motility required for mandibular growth is disrupted in the early fetal period, and mandibular hypoplasia is a secondary consequence of these neuronal or neuromuscular deficits. This model is supported by experimental findings of cleft palate and mandibular hypoplasia in an induced model of oropharyngeal muscular degeneration. While non-genetic aetiologies for RS have been proposed, 32 there are a number of reported cases describing chromosomal abnormalities associated with the non-syndromic or isolated RS implicating an underlying genetic component (table 1). Vintiner et al reported a balanced translocation t(5;17)(q15;q23) in all affected individuals of a single family during screening for Stickler syndrome. However, together with RS, the clinical phenotype of the family included arthropathy of varying severity among the affected individuals, a feature not typical of classical RS. Additional reports have also indicated that there may be an RS locus at 17q23.3–25 36 although no gene has been isolated. Moreover, Houdayer et al reported a case of nonsyndromic RS that co-segregated with an unbalanced reciprocal translocation involving an interstitial deletion of chromosome 2 (2q32.3–q33.2), and suggested this locus as a candidate region for non-syndromic RS. This hypothesis is further strengthened by a previous report indicating involvement of the 2q32 locus in the pathogenesis of isolated cleft palate. In addition to reports of cytogenetic abnormalities, a recent study provides support for the existence of multiple genetic loci for RS with the identification of sequence variations in the COL2A1, COL11A1, and COL11A2 genes in a number of unrelated patients with non-syndromic RS. The role for these variations in the aetiology of RS has yet to be clarified, but their discovery along with evidence of distinct cytogenetic anomalies highlights the aetiological heterogeneity associated with RS. Thus, several promising loci associated with isolated RS await further characterisation.