When reviewing the published cases of BGS, the impression is that there is a core diagnosis consisting of lambdoid and coronal craniosynostosis in association with radial hypoplasia. The anecdotal reassignments of BGS published cases to other nosological entities were prompted by secondary haematological complications or atypical findings. Guided by clinical findings, one may therefore in specific circumstances, in addition to initial work up, require special chromosomal analysis after incubation with clastogens, or studies of DNA crosslinking sensitivity. Sequencing of FGFR1, FGFR2, FGFR3, or TWIST genes may also be required according to clinical findings.
Of note is the fact that poikiloderma is a skin manifestation that in RTS occurs after an interval of a few months. Caution should therefore be applied to BGS diagnoses made in the first few months of life and follow up evaluation is warranted.
Rothmund‐Thomson syndrome (RTS; OMIM
268400) and RAPADILINO syndrome (OMIM
266280) are two recessively inherited syndromes displaying some clinical overlap with BGS (fig 5). RTS is characterised by poikiloderma congenita (usually first manifested between 4 and 6 months of age), alopecia, skeletal defects, dystrophic nails, abnormal teeth, cataracts, and small stature. Photosensitivity is highly variable. Radial ray hypoplasia or absent thumbs occur in a minority of cases. The clinical diagnosis rests on the poikilodermatous rash. If the onset or distribution of poikiloderma is atypical, then two additional features such as bone abnormalities, cataracts, or osteosarcoma are required for a diagnosis of probable RTS.27
Analysis of 33 RTS patients suggests that approximately 60% of patients with definite or probable RTS carry mutations in RECQL428
with the remainder of RTS due to mutations in gene(s) that have not yet been identified. RAPADILINO is a rare autosomal recessive malformation syndrome.29
The acronym refers to the main clinical features (radial ray defect; patellae hypoplasia or aplasia and cleft or highly arched palate; diarrhea and dislocated joints; little size and limb malformation; nose slender and normal intelligence). Fourteen patients have been diagnosed in Finland and only three in other countries.24,29,30,31,32
One of the non‐Finnish patients was later rediagnosed as having RTS.33
It has recently been shown that RAPADILINO syndrome is caused by mutations in RECQL4
Figure 5Venn diagram of the main features of the three entities. If we hypothesise a continuum between them, then the core (overlapping) criteria would include growth deficiency, facial dysmorphia, and GI disturbance. RECQL4
encodes a member of the RecQ helicase family based on sequence conservation.34
However, few functional studies have been performed. Recently, it has been reported that the RECQL4 proteins interact in the cytoplasm with ubiquitin ligases UBR1 and UBR2 proteins of the N‐end rule pathway.35
The physiological significance of this interaction is unknown. The Fin‐major mutation24
is a splice site mutation causing in‐frame skipping of exon 7. All the Finnish patients are either homozygotes or heterozygotes for this mutation (fig 3).
Similarities between RTS and BGS have already been pointed out by one of us.12
RAPADILINO syndrome also fits into the BGS clinical spectrum since radial hypoplasia is one of the hallmarks of RAPADILINO syndrome, and one non‐Finnish case was rediagnosed as RTS after the patient developed a poikiloderma‐like rash at the age of 21 months. An intermediate phenotype with craniosynostosis, poikiloderma, and anteriorly placed anus has also been reported recently.36
The fact that the clinical course of patient 4 from family 1 and the index patient from family 2 had poikiloderma prompted us to investigate a possible continuum between these apparently distinct entities by searching for mutations in the RECQL4
gene. In both families, mutations in RECQL4
were found to be the cause of the BGS phenotype.
In conclusion, we have demonstrated in two unrelated families that RECQL4 mutations cause BGS. These results bring the number of clinical syndromes attributable to RECQL4 mutations to three: RTS, RAPADILINO, and BGS. The genotype‐phenotype correlations in these syndromes need to be studied further. It will be interesting to see whether certain mutations always lead to distinct phenotypes or if the correlation is more complex. Since a BGS phenotype has already been associated with Fanconi anaemia and Roberts SC phocomelia, and with TWIST and FGFR2 mutations, careful clinical delineation will assist in defining this nosological entity. Radial defects are a variable feature associated with otherwise classical craniosynostosis gene mutations. This feature also belongs to cytogenetically defined disorders, such as Fanconi anaemia or Roberts SC phocomelia, and to some cases of VATER Association. In these two subsets, cutaneous manifestations are found only in Fanconi anaemia patients in the form of pigmentary changes. We here provide evidence that a third subgroup of BGS patients have a RECQL4 related phenotype with eventual developmental skin lesions which are not present at birth. In this context, the consistent presence of sutural anomalies in 4/4 affected patients from family 1 may be a mutation specific manifestation perhaps related to the specific domain of the protein altered by the missense mutation. Study of intrafamilal variability and genotype‐phenotype correlations within the RECQL4 spectrum, based on a larger set of patients, will be necessary to determine whether the apparently distinctive phenotypes breed true and are linked to distinct mutations. Also, multiple malformation syndromes that include craniosynostosis and/or radial ray aplasia and/or poikiloderma should be investigated for RECQL4 mutations.