Alternative titles; symbols
SNOMEDCT: 77608001; ORPHA: 1225; DO: 0050654;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.3 | Baller-Gerold syndrome | 218600 | Autosomal recessive | 3 | RECQL4 | 603780 |
A number sign (#) is used with this entry because of evidence that Baller-Gerold syndrome (BGS) is caused by homozygous or compound heterozygous mutation in the RECQL4 gene (603780) on chromosome 8p24.
Rothmund-Thomson syndrome type 2 (268400), which shows phenotypic overlap with BGS, is also caused by biallelic mutation in the RECQL4 gene.
The cardinal features of the Baller-Gerold syndrome are craniosynostosis and radial aplasia (Galea and Tolmie, 1990). Cases reported as Baller-Gerold syndrome have phenotypic overlap with several other disorders, including Saethre-Chotzen syndrome (SCS; 101400).
Baller (1950) described a female with oxycephaly and absent radius. The parents were third cousins. Gerold (1959) described a brother and sister, aged 16 years and 2 days, with tower skull, radial aplasia, and slight ulnar hypoplasia. Pelias et al. (1981) observed parental consanguinity. Their patient also had bilateral conductive hearing loss; auditory deficit was not observed in earlier reported cases. The radial deficiency is not necessarily symmetric. In all cases the ulna is short and curved. Malformation or absence of some carpals and metacarpals, and absent or hypoplastic thumbs have been observed in some cases. The patients are almost always short. Skeletal anomalies of the spine and pelvis are frequent. Anteriorly placed anus and imperforate anus with either perineal fistula or rectovaginal fistula have been observed. Anomalies of the heart and urogenital system and mental and/or motor retardation have been noted in some patients.
Boudreaux et al. (1990) reported the alleged eleventh case of Baller-Gerold syndrome; probable parental consanguinity supported autosomal recessive inheritance. Galea and Tolmie (1990) described a sporadic case. They pointed out that the published cases, still few in number, can be divided into those with craniosynostosis and radial defects alone and those with additional malformations. Their case was of the former type. They stated: 'Although the Baller-Gerold syndrome is allocated an asterisk in the autosomal recessive section of McKusick's catalogue, we are at present uncomfortable with the prospect of reassuring our proband that his own children have a negligible risk of being affected.' Because of possible genetic heterogeneity, their caution may be appropriate.
The patient reported by Dallapiccola et al. (1992) had, in addition to the cranial and radial features, imperforate anus, rectovaginal fistula, prenatal growth deficiency, and mental retardation. Van Maldergem et al. (1992) described a newborn who lived only 2 hours and had extensive agenesis of the frontal and parietal bones resulting in a very large fontanel in addition to coronal bilateral craniosynostosis. Anterior placement of the anus and pancreatic islet cell hypertrophy were also noted. Lin et al. (1993) described 3 new cases, bringing the total number of reported cases to 20. Two of their patients were sibs. Ramos Fuentes et al. (1994) described unusually mild involvement in a 3-year-old boy with trigonocephaly and bilateral absent radii and thumbs. His growth and psychomotor development had been normal. No visceral anomalies were found. Ramos Fuentes et al. (1994) found reports of 21 cases in the 'Western literature.'
In the 2 families studied by Van Maldergem et al. (2006) with mutations in the RECQL4 gene, affected individuals had craniosynostosis, radial defects, and growth retardation, and 2 patients developed poikiloderma.
Phenotypic Overlap
Huson et al. (1990) described a patient with craniostenosis and radial aplasia which led to an initial diagnosis of Baller-Gerold syndrome. Mild fibular hypoplasia on skeletal survey led to review of the diagnosis, and similarity of the facial phenotype to that of Roberts syndrome (268300) was noted. Chromosome analysis showed the premature centromere separation characteristic of that condition. The case raised the question as to whether the Baller-Gerold syndrome should be considered a distinct entity. Huson et al. (1990) suggested that cases diagnosed as having Baller-Gerold syndrome should have cytogenetic analysis and, conversely, that known Roberts syndrome survivors should be reviewed for signs of craniostenosis.
Lewis et al. (1991) observed association with congenital hydrocephalus which was detected along with the other abnormalities by ultrasound at 26 weeks' gestation. However, the diagnosis of Baller-Gerold syndrome was later changed by Farrell et al. (1994): when the patient was reviewed at age 3 years, chronic thrombocytopenia was noted. This new finding, combined with the pattern of anomalies (bilateral radial ray defects, right renal dysplasia, ventricular septal defect, anteriorly placed anus, and persistent cloaca), led to consideration of the diagnosis of Fanconi anemia (227650). Diepoxybutane (DEB) chromosome testing in 2 laboratories showed an elevated rate of mean chromosome breaks per cell consistent with that diagnosis. Farrell et al. (1994) pointed out that VACTERL with hydrocephalus (276950) has also been shown to represent Fanconi anemia on the basis of chromosome breakage studies.
Rossbach et al. (1996) described 2 brothers with presumed Baller-Gerold syndrome, one of whom had previously been diagnosed with the association of vertebral, cardiac, renal and limb anomalies, anal atresia, and tracheoesophageal fistula (VACTERL) with hydrocephalus, who were evaluated for chromosome breakage because of severe thrombocytopenia in one of them. Spontaneous and clastogen-induced breakage was markedly increased in both patients as compared to controls. Clinical manifestations and chromosome breakage consistent with Fanconi anemia had been reported earlier in patients with a prior diagnosis of Baller-Gerold syndrome by Farrell et al. (1994) and in 3 patients with the VACTERL association with hydrocephalus by Toriello et al. (1991) and Porteous et al. (1992). The authors commented that the observations underscore the clinical heterogeneity of Fanconi anemia and raise the question of whether these syndromes are distinct disorders or phenotypic variants of the same disorder. Cohen and Toriello (1996) likewise raised the question 'Is there a Baller-Gerold syndrome?'
As outlined earlier, phenotypic overlap of Baller-Gerold syndrome with several other syndromes required narrowing the definition of Baller-Gerold syndrome. The finding of premature centromere separation pointed to Roberts syndrome rather than BGS as indicated by Huson et al. (1990). Other cases of presumed Baller-Gerold syndrome were rediagnosed as Fanconi pancytopenia or VACTERL association (Rossbach et al., 1996). Such reports led to a narrowed redefinition of BGS based on the exclusion of cytogenetic and hematopoietic abnormalities and the absence of additional malformations in patients with craniosynostosis and preaxial upper limb abnormalities. Gripp et al. (1999) reported on a patient with unilateral radial aplasia and bicoronal synostosis without additional malformations and without chromosome breakage, who fitted this narrow definition of Baller-Gerold syndrome. They identified a novel mutation in the TWIST gene (601622.0008), which is characteristic of Saethre-Chotzen syndrome. Because the TWIST mutation pointed to the diagnosis of SCS, the whole family was investigated. Facial asymmetry, prominent nose, high palate, and hallux valgus observed in the father and older sister were consistent with mild presentation of SCS and these 2 individuals were found also to carry the TWIST mutation. This experience further points to the question raised by Cohen and Toriello (1996) of whether there is a Baller-Gerold syndrome. The patient of Gripp et al. (1999) illustrated the practical significance of the distinction. BGS has been thought to be an autosomal recessive disorder; the Saethre-Chotzen syndrome is an autosomal dominant disorder.
Seto et al. (2001) reported a patient with characteristic features of Baller-Gerold syndrome, including metopic, sagittal, and coronal synostosis and bilateral radial ray hypoplasia, with a novel mutation in the TWIST gene (601622.0010). Other features included small, round ears with prominent crus helices and cervical anomalies. The father, who also carried the mutation, had very mild features of Saethre-Chotzen syndrome. Since mutations in the TWIST gene are typically associated with SCS, the authors suggested that some cases of Baller-Gerold syndrome should be reclassified as a heterogeneous form of Saethre-Chotzen syndrome.
De Oliveira et al. (2005) reported 3 patients with a history of fetal exposure to sodium valproate who were born with metopic synostosis and upper limb malformations similar to Baller-Gerold syndrome.
The transmission pattern of BGS in the families reported by Van Maldergem et al. (2006) was consistent with autosomal recessive inheritance.
Baller-Gerold syndrome is caused by mutations in the RECQL4 gene (603780) and therefore maps to chromosome 8q24.3 (Van Maldergem et al., 2006).
Van Maldergem et al. (2006) pointed out the clinical overlap between BGS and Rothmund-Thomson syndrome (RTS; 268400) and RAPADILINO syndrome (266280). Because patients with RAPADILINO syndrome and a subset of patients with RTS have mutations in the RECQL4 gene (603780), they reassessed 2 previously reported BGS families and found causal mutations in RECQL4 in both. In the first family, reported by Van Maldergem et al. (1992), 4 affected offspring had craniosynostosis and radial defect and 1 of them developed poikiloderma. In this family, compound heterozygosity for an R1021W missense mutation (603780.0012) and a frameshift mutation in exon 9 (603780.0005) was found. The second family had been reported by Megarbane et al. (2000). The one affected member was the son of first-cousin parents. He had craniosynostosis, radial ray defect, poikiloderma, and short stature. He had a homozygous splice site mutation of the RECQL4 gene (IVS17-2A-C; 603780.0014).
Van Maldergem et al. (2006) republished a clinical photograph of Baller's original patient. They pointed out that the first patient appeared to have changes in the skin of the forearm compatible with poikiloderma.
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