Sc Phocomelia Syndrome

A number sign (#) is used with this entry because the SC phocomelia syndrome is caused by mutation in the ESCO2 gene (609353), the protein product of which is required for the establishment of sister chromatid cohesion during S phase. Mutations in the same gene cause Roberts syndrome (268300).

Clinical Features

In a family with surname beginning with S and another with surname beginning with C, Herrmann et al. (1969) described a syndrome consisting of the following features: (1) nearly symmetrical reductive malformations of the limbs, resembling phocomelia; (2) flexion contractures of various joints; (3) multiple minor anomalies, including capillary hemangioma of the face, forehead and ears, hypoplastic cartilages of the ears and nose, micrognathia, scanty, silvery-blond hair, and cloudy corneas; (4) intrauterine and extrauterine growth retardation; (5) possibly mental retardation, and (6) autosomal recessive inheritance. Feingold (1992) provided follow-up on the 'C-patient' reported by Herrmann et al. (1969). At age 14 the patient developed moyamoya disease (252350) causing left hemiparesis. Chromosome studies showed premature centromere separation characteristic of this syndrome, i.e., splaying of the heterochromatin, repulsion of the short arms of the acrocentric chromosomes, and splaying of Y chromosome heterochromatin. At the age of 23 the patient developed chest pain and electrocardiographic changes indicative of anterior myocardial infarction. Subsequently he was found to have an apical aneurysm of the left ventricle with apical thrombosis and died of congestive heart failure. He remained short throughout his life; his final height was 139 cm. Although his facial characteristics remained constant, his scanty silvery blond hair became brown and less sparse. Mild valvular aortic stenosis was diagnosed at one time. The same syndrome was probably described by O'Brien and Mustard (1921) in 3 of 8 children of normal parents who were related as double first cousins.

Hall and Greenberg (1972) described an affected 8-year-old girl who was mentally normal. They were impressed with hypotrichosis and midfacial hemangioma, for which reason they proposed the designation hypomelia-hypotrichosis-facial hemangioma syndrome. They emphasized a characteristic appearance of the face. Although the SC syndrome is sometimes referred to as the pseudothalidomide syndrome, some cases of the Holt-Oram syndrome (142900) may be more deserving of that name (Lenz et al., 1974). Humeroradial synostosis was also a feature; see 143050 and 236400.

Grosse et al. (1975) described a case of what they termed the tetraphocomelia-cleft palate syndrome. Capillary hemangioma of the glabella and lids and fine silvery-blond hair were described. The authors questioned the separateness of Roberts syndrome (268300) and this syndrome. By an analysis of phenotype, Herrmann and Opitz (1977) could not tell whether the SC phocomelia syndrome and the Roberts syndrome were 'due to different recessive genes, different alleles, or the same recessive gene.' Tomkins et al. (1979) noted the uncertainty as to whether Roberts syndrome and the SC syndrome are distinct entities. They found a consistent centromeric abnormality of the chromosomes, namely, puffing and splitting, in 4 patients who had certain clinical features in common: bilateral corneal opacities, microcephaly, absence of radii, limitation of extension at the elbow and knees, enlargement of the phallus, and survival beyond the neonatal period. The usual absence of cleft palate in the SC syndrome may be a difference. Qazi et al. (1979) described chromosomal abnormalities like those of Roberts syndrome. Opitz and Lowry (1987) stated that early on they had the impression that the Roberts syndrome and the SC pseudothalidomide syndrome may occur in different members of the same sibship and that the identification of identical cytological markers complements the conclusion of nosologic identity (as well as effective prenatal diagnosis).

In a Christian Lebanese family, BenEzra et al. (1982) observed 2 brothers with radial aplasia and abnormality of anterior chamber cleavage in the eye. Both showed a normal XY karyotype except for unusual sister chromatid disjunction at the centromeric region during prophase and metaphase. In the first brother, the radius and thumbs were absent and the tibia and fibula were relatively short; bilateral microphthalmia with central corneal leukoma was described, as well as moderate micrognathia and aplasia of the alae nasi. The second brother had extensive facial hemangioma, total cleft palate, total aplasia of the radius and ulna, marked shortening of the humerus, absent thumbs, absent fibula, and deformed tibia. Comment concerning parental consanguinity was not made. Presumably, this disorder falls into the same group as Roberts syndrome and SC phocomelia syndrome.

Parry et al. (1986) reported the cases of 2 middle-aged sisters with most of the manifestations of the SC phocomelia syndrome including postnatal growth retardation, symmetric limb deficiencies with radial aplasia and absent thumbs, facial anomalies with microcephaly, microphthalmia, hypoplastic nasal alae, and borderline to mild mental retardation. Unusual findings included congenital paralysis of some cranial nerves in both and malignant melanoma in 1. Tumor cells and cultured lymphocytes and fibroblasts of both patients showed premature separation of centromeric heterochromatin (PCS).

Holmes-Siedle et al. (1990) described what they called the Roberts/SC phocomelia syndrome in 3 sibs of second-cousin parents. One child survived to age 9. A somewhat unusual feature was craniosynostosis; overlap with the Baller-Gerold syndrome (218600), which has craniosynostosis as a feature, was discussed.

Goh et al. (2010) studied a 31-year-old man who was referred for short stature and subaortic stenosis; the latter had been repaired at 8 years of age but recurred in adulthood, requiring reoperation. Upon examination he had short stature and dysmorphic features, including hypertelorism, downslanting palpebral fissures, prominent nasal bridge, and hypoplastic alae nasi with prominent columella. His ears were simple and slightly posteriorly angulated; he had a high palate and mild retrognathia. His extremities displayed no obvious defects, but careful measurement showed limb lengths ranging from less than the 50th centile to less than the 5th centile for adult males. Karyotype showed premature centromere separation in all metaphases. Skeletal survey showed no limb reduction defects, but there was evidence of hypertelorism, mild brachymetacarpalia, brachyphalangy, and short femoral necks. Analysis of the ESCO2 gene revealed homozygosity for a truncating mutation. Goh et al. (2010) reviewed previously reported adult cases of Roberts syndrome/SC phocomelia, and noted that this case highlighted the variability in the RBS/SC phocomelia spectrum and demonstrated that clinically apparent limb anomaly might not be an obligate feature for diagnosis of the condition.

Molecular Genetics

In one of the original families described by Herrmann et al. (1969) and in the sisters described by Parry et al. (1986), Schule et al. (2005) found compound heterozygosity for mutations in the ESCO2 gene (see 609353.0004 and 609353.0006). Altogether Schule et al. (2005) found 7 novel mutations in exons 3 through 8 of the ESCO2 gene in 6 individuals with SC phocomelia from 5 families.

Gordillo et al. (2008) stated that Roberts syndrome and SC phocomelia were considered to be the same syndrome with varying phenotypic expression, and that they would henceforth designate all such cases of Roberts syndrome/SC phocomelia as 'RBS.' The authors analyzed the ESCO2 gene in 16 Roberts syndrome/SC phocomelia pedigrees with 17 affected individuals and identified 15 different mutations; 13 individuals were homozygous, and 4 were compound heterozygous for the mutations.