Robin Sequence With Cleft Mandible And Limb Anomalies

A number sign (#) is used with this entry because of evidence that Robin sequence with cleft mandible and limb anomalies is caused by homozygous or compound heterozygous mutation in the EIF4A3 gene (608546) on chromosome 17q25.

Description

Patients with Richieri-Costa-Pereira syndrome display a pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of the mandible, cleft palate/Robin sequence, absence of lower central incisors, minor ear anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability is also a common finding (summary by Favaro et al., 2011).

Clinical Features

Richieri-Costa and Pereira (1992) described a seemingly distinct entity in 5 unrelated Brazilian patients. The features were short stature, Robin sequence, cleft mandible, and limb defects. The ears were low set and prominent. Retromicrognathia, microstomia, highly arched palate, and cleft lower alveolar ridge was accompanied by hypoplastic mandible and cleft through the midline with absence of the lower incisors by x-ray. The thumbs were hypoplastic, as was the distal part of the tibias with proximal and lateral displacement of the fibulas and clubfoot. Females had apparently normal intellect; the oldest was 6 years at the time of the report. Affected males were either stillborn or died within 1 week of birth; more severe defects, including apodia, were noted in 1. Richieri-Costa and Pereira (1993) reported 2 male patients, aged 1 year and 13 years, from 2 unrelated Brazilian families, who were no more severely affected than previously reported females. Since 6 of the 7 reported families came from the same area of Sao Paulo, Richieri-Costa and Pereira (1993) thought it likely that they had a common ancestor.

Tabith and Bento-Goncalves (1996) examined 5 patients with the Richieri-Costa-Pereira syndrome, 3 of whom had previously been reported by Richieri-Costa and Pereira (1992, 1993). All patients had the same laryngeal anomalies with variable severity: small, round larynx, absent or hypoplastic epiglottis, hypertrophic aryepiglottic folds, and a fold in the posterior part of the larynx above the level of the glottis. During emission of sounds there was a medialization of the aryepiglottic folds, probably a protection mechanism of the inferior airways upon swallowing. Tabith and Bento-Goncalves (1996) concluded that these anatomic and functional abnormalities cause the voice disorder (marked hoarseness and breathiness) characteristic of the syndrome. Tabith and Bento-Goncalves (2003) examined 2 additional patients with this syndrome and found the same laryngeal alterations and voice characteristics.

Walter-Nicolet et al. (1999) described this syndrome in a newborn French boy who probably represented the first non-Brazilian case. Born to consanguineous parents, he showed cleft mandible, pre/postaxial hand anomalies, and clubfoot.

Ferreira de Lima et al. (2003) studied 15 families using identity by descent as a hypothesis to attempt gene localization. Fourteen families were Brazilian, suggesting a founder effect. They examined through linkage analysis 497 polymorphic markers and also performed direct sequencing of exons for 10 candidate genes selected on the basis of their expression in the developing mandible and limb. No evidence for allele sharing at any locus tested or mutations in candidate genes were found.

Golbert et al. (2007) reported another Brazilian female with this disorder, the offspring of second-degree cousins of Portuguese ancestry. In addition to previously reported features, she had pseudarthrosis of the clavicle, hip subluxation with bilateral acetabular dysplasia, and mesomelic shortening of the limbs (hypoplasia of tibia and fibula).

Graziadio et al. (2009) reported a 19-year-old Brazilian woman, born of consanguineous parents, who had short stature, microstomia, micrognathia, pre- and postaxial hand anomalies, and clubfeet, as well as mesomelic shortening of the lower limbs. The authors noted that although the patient did not have an overt mandibular cleft, she lacked the lower central incisors, indicative of an anomaly. Graziadio et al. (2009) stated that this was the first report of an adult with this condition.

Favaro et al. (2011) reported a 20-year follow-up of 28 patients from 25 apparently unrelated Brazilian families, including 12 previously reported patients (Richieri-Costa and Pereira, 1992; Richieri-Costa and Pereira, 1993; Tabith and Bento-Goncalves, 1996; Guion-Almeida and Richieri-Costa, 1998; Tabith and Bento-Goncalves, 2003). The female-to-male ratio of the sample was 1.8:1; however, taking into consideration all affected individuals, including those who had died, the ratio decreased to 1.3:1. The unique pattern of anomalies was observed in all cases, although there was variable severity. The main clinical characteristic was severe and atypical midline mandibular involvement, which was invariably present and ranged from abnormal fusion seen on X-ray to complete lack of fusion resulting in a wide gap.

Souza et al. (2011) reported a Brazilian sister and brother with RCPS. The 5-year-old girl had unusually severe limb defects, including tibiofibular hypoplasia with bowing and bilateral clubfoot, and underwent several leg-lengthening procedures without good results. Her 1-year-old brother, who presented serious respiratory distress and feeding problems in the neonatal period, had similar but milder limb defects. Laryngoscopy showed typical findings of RCPS in both sibs, with hypertrophic aryepiglottic folds and a rudimentary or absent epiglottis.

Raskin et al. (2013) described a severely affected 7-month-old Brazilian boy who presented at birth with craniofacial pansynostosis, micrognathia, webbed neck with fatty hyperplasia of the anterior and posterior surfaces, thoracic deformity with severe bilateral sternoclavicular chondral dysfunction, and short limbs with radial dysgenesis and finger and toe anomalies. The infant required ventilatory support during the first several months of life, as well as gastrostomy for feeding due to airway anomalies. Nasofibroscopy revealed prolapse of the base of the tongue over the larynx and agenesis of the epiglottis, and facial CT scan showed mandibular agenesis. Radiography showed radial agenesis, ulnar hypoplasia, malformations of hands and fingers, tibial hypoplasia, fibular agenesis, and toe deformities. At 7 months of age, the patient was fed by gastrostomy and received supplemental oxygen via tracheostomy. The authors stated that this was the most severe RCPS phenotype reported to that time.

Inheritance

Normal parents, parental consanguinity in 3 instances, recurrence in sibs, and normal karyotype in the patients reported by Richieri-Costa and Pereira (1992) suggested autosomal recessive inheritance.

In a review of 28 patients from 25 apparently unrelated Brazilian families, Favaro et al. (2011) observed high rates of recurrence in sibs and cousins (36%) and parental consanguinity (44%), supporting the hypothesis of autosomal recessive inheritance.

Mapping

Favaro et al. (2014) performed homozygosity mapping in 7 patients with RCPS from 4 unrelated consanguineous Brazilian families and found the only extended region of homozygosity unique to affected individuals at chromosome 17q25.3. Microsatellite-marker and SNP genotyping in 20 affected family members from 17 apparently unrelated Brazilian families and 46 unaffected relatives confirmed linkage to 17q25.3, with a maximum lod score of 9.533 for marker rs2289534 (theta = 0). Recombinants at rs2289534 and rs3829612 narrowed the disease locus to a 122-kb region at chr17:78,039,369-78,161,152 (GRCh37).

Molecular Genetics

In 20 affected individuals with RCPS mapping to chromosome 17q25.3 from 17 previously studied Brazilian families (Richieri-Costa and Pereira, 1992; Richieri-Costa and Pereira, 1993; Tabith and Bento-Goncalves, 1996; Guion-Almeida and Richieri-Costa, 1998; Tabith and Bento-Goncalves, 2003; Favaro et al., 2011), Favaro et al. (2014) analyzed the candidate gene EIF4A3 (608546) and identified homozygosity for an expanded 16-repeat allele (608546.0001) in 17 of the patients and compound heterozygosity for the 16-repeat allele and a 15-repeat allele (608546.0002) in 3 of them. Analysis of an additional 5 Brazilian RCPS patients identified homozygosity for the 16-repeat allele in 4 of them, including the sibs reported by Souza et al. (2011) and the severely affected boy originally described by Raskin et al. (2013); the fifth patient was a compound heterozygote for a 14-repeat expanded allele (608546.0003) and a missense mutation (D270G; 608546.0004). Unaffected family members either lacked the expanded allele or were heterozygous for the 16-repeat allele; the expanded allele was not found in 520 Brazilian controls, who had only 3 to 12 repeats. Favaro et al. (2014) noted that although the RCPS phenotype varies in expressivity, even within families, the main clinical craniofacial characteristic of midline mandibular involvement was fully penetrant in all 16-repeat allele homozygotes and 16/15-repeat allele compound heterozygotes, and that the latter compound heterozygotes presented a phenotype very similar to that of the homozygous patients. In contrast, the Brazilian man who was compound heterozygous for a 14-repeat allele and a missense mutation in the EIF4A3 gene had a milder phenotype with mandibular fusion.