Rapadilino Syndrome

A number sign (#) is used with this entry because of evidence that RAPADILINO syndrome is caused by homozygous or compound heterozygous mutation in the DNA helicase gene RECQL4 (603780) on chromosome 8q24.

Clinical Features

In a brother and sister and in 3 sporadic patients, Kaariainen et al. (1989) described a syndrome with radial and patellar aplasia or hypoplasia as main features. Additional findings were absence of thumbs, dislocation of joints, unusual facies (long face with narrow palpebral fissures, long slender nose, small chin, and unusual ears), cleft or highly arched palate, diarrhea in infancy, small stature, and normal intelligence. There was no parental consanguinity and the parents in all cases were healthy, although the father of 1 sporadic case had had habitual dislocations of 1 knee. The families originated from different parts of Finland. The unusual acronym was derived as follows: RA for radial, PA for both absent/hypoplastic patellas and cleft/highly arched palate, DI for diarrhea, as well as dislocated joints, LI for little size and limb malformations, and NO for long, slender nose and normal intelligence.

Among 62 patients with radial aplasia/hypoplasia in Finland, Kaariainen (1993) found a total of 11 cases of RAPADILINO syndrome. Stiff interphalangeal joints were present in at least 5 of the 11, mottled or stippled pigmentation in at least 4, and hearing defect in at least 2. The 11 cases were distributed in 8 families; there were 3 males and 8 females. In 3 families with brother/sister pairs, the sister was always more severely affected than the brother. The parents in all 8 families were healthy; in 2 of the families, they were consanguineous.

Vargas et al. (1992) reported an isolated case in a boy who had severe radial hypoplasia, absent thumbs and patellas, short stature, persistent diarrhea, slender nose, and normal intelligence.

Molecular Genetics

Siitonen et al. (2003) noted clinical similarities between RAPADILINO syndrome and Rothmund-Thomson syndrome (268400), which can be caused by mutation in the RECQL4 gene. In a screening for mutations in the RECQL4 gene in 10 Finnish families with RAPADILINO syndrome, they identified 4 different mutations, a splice site mutation in intron 7 (603780.0009) and 3 nonsense mutations. Nine of 13 patients were homozygous and another 4 heterozygous for the splice site mutation.

Siitonen et al. (2009) identified homozygosity or compound heterozygosity for RECQL4 mutations in 16 (46%) of 35 Finnish patients with a suspected clinical diagnosis of RTS, RAPADILINO, or BGS. The authors stated that the most common RECQL4 mutation, 1390+2delT in intron 7 (603780.0009), is enriched in the isolated Finnish population and that all Finnish RAPADILINO patients carry at least 1 copy of the mutation. Reviewing the 15 reported Finnish RAPADILINO patients for cancer status, Siitonen et al. (2009) found that 2 patients had osteosarcoma and 4 had lymphoma, indicating a high cancer incidence of 40%.