Cases reported as Baller-Gerold syndrome have phenotypic overlap with several other disorders, including Saethre-Chotzen syndrome (SCS; 101400). The cardinal features of the Baller-Gerold syndrome are craniosynostosis and radial aplasia (Galea and Tolmie, 1990).
Baller (1950) described ... Cases reported as Baller-Gerold syndrome have phenotypic overlap with several other disorders, including Saethre-Chotzen syndrome (SCS; 101400). The cardinal features of the Baller-Gerold syndrome are craniosynostosis and radial aplasia (Galea and Tolmie, 1990). 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 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; the Saethre-Chotzen syndrome is an autosomal dominant. 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. Santos 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.
Van Maldergem et al. (2006) pointed out the clinical overlap between the 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 ... Van Maldergem et al. (2006) pointed out the clinical overlap between the 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 2886delT frameshift mutation in exon 9 (603780.0013) 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, IVS17-2A-C, of the RECQL4 gene (603780.0014).
The diagnosis of Baller-Gerold syndrome (BGS) rests on the following findings:...
DiagnosisClinical DiagnosisThe diagnosis of Baller-Gerold syndrome (BGS) rests on the following findings:Coronal craniosynostosis, manifest clinically as abnormal shape of the skull (brachycephaly) with ocular proptosis and bulging forehead. The diagnosis needs to be confirmed by skull x-ray or preferably by 3D-CT reconstruction. When the coronal sutures are fused, the orbit is pulled back and forward. The coronal sutures cannot be discerned on the frontal view, and the same holds true for the lambdoidal sutures. Radial ray defect, manifest as oligodactyly (reduction in number of digits), aplasia or hypoplasia of the thumb, and/or aplasia or hypoplasia of the radius. Note: Radiographs may be necessary for confirmation of minor radial ray malformations.Growth retardation and poikiloderma (not in early infancy), although not diagnostic per se, may help establish the diagnosis. Molecular Genetic TestingGene. RECQL4 is the only gene currently known to be associated with BGS [Van Maldergem et al 2006]. Other loci. No other loci for BGS are known or suspected. However, some cases provisionally assigned to the BGS clinical spectrum were reassigned to other nosologic entities including Saethre-Chotzen syndrome, Roberts-SC syndrome, and Fanconi anemia [Huson et al 1990, Farrell et al 1994, Preis et al 1995, Cohen & Toriello 1996, Rossbach et al 1996, Quarrell et al 1998, Gripp et al 1999, Megarbané et al 2000, Seto et al 2001]. Clinical testing Sequence analysis of the entire gene including exons and the short introns [Wang et al 2002] detects mutations in 100% of persons with BGS. Note: This detection rate is based on results from fewer than ten families. Deletion/duplication analysis. The usefulness of deletion/duplication testing has not been demonstrated, as no deletions or duplications involving RECQL4 as causative of Baller-Gerold syndrome have been reported.Table 1. Summary of Molecular Genetic Testing Used in Baller-Gerold SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1, 2 Test AvailabilityRECQL4Sequence analysis Sequence variants 3 UnknownClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsUnknown; none reported 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Based on the fewer than ten families tested to date3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 5. No deletions or duplications involving RECQL4 as causative of Baller-Gerold syndrome have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. Confirmation of the diagnosis in a proband with clinical and radiographic evidence of coronal synostosis and radial ray defect requires molecular genetic testing to identify two disease-causing mutations in RECQL4. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersDisease-causing mutations in RECQL4 have also been identified in individuals with Rothmund-Thomson syndrome [Kitao et al 1999] and RAPADILINO syndrome [Siitonen et al 2003].Rothmund-Thomson syndrome (RTS) is characterized by skin changes termed poikiloderma; sparse hair, eyelashes, and/or eyebrows/lashes; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer. The skin is typically normal at birth; the skin changes of RTS begin between ages three and six months as erythema on the cheeks, which subsequently involves extremities with or without involvement of the buttocks. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectases, collectively known as poikiloderma. Skeletal abnormalities include dysplasias, osteopenia, and absent or malformed bones (including absent radii). Osteosarcoma with a median age at diagnosis of 11 years occurred in 30% of a contemporary cohort. The prevalence of skin cancers, including basal cell carcinoma and squamous cell carcinoma, is estimated to be 5% [Wang et al 2003]. The diagnosis of RTS is usually made on the basis of clinical findings. Molecular testing is confirmatory and may be useful in situations in which clinical findings are atypical. Sequence analysis of RECQL4, the only gene known to be associated with RTS, detects mutations in about 66% of affected individuals. Inheritance is autosomal recessive. RAPADILINO syndrome is an acronym for 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. It is characterized by pre- and postnatal growth retardation. Cervical spine segmentation defects have been reported. Failure to thrive results from feeding problems and juvenile diarrhea of unknown cause [Siitonen et al 2003]. Since its original description in Finland [Kääriäinen et al 1989], only 14 Finnish and two non-Finnish individuals have been reported [Vargas et al 1992, Kant et al 1998, Jam et al 1999, Siitonen et al 2003]. Osteosarcoma was reported in one of the 16 individuals. Lymphoma appears to be a frequent complication in individuals with RAPADILINO; it occurred in four patients before the age of 35 years [Siitonen et al 2009]. The Finn-specific RECQL4 splice-site mutation (IVS7+2delT) associated with RAPADILINO syndrome leads to in-frame skipping of exon 7 that is predicted to remove 44 amino acids just before the conserved helicase domain, apparently without altering transcription of the helicase domain itself. Nine of the 14 affected Finnish individuals are homozygous for IVS7+2delT and five are compound heterozygotes for IVS7+2delT and a nonsense mutation in extra-helicase exons 5, 18, and 19, thus sparing in all cases the helicase domain, which is therefore thought to play a role in poikiloderma and predisposition to osteosarcoma [Siitonen et al 2003]. RTS, RAPADILINO syndrome, and BGS share the clinical features of pre- and postnatal growth retardation, chronic diarrhea, and patellar hypo- or aplasia. Radial hypo- or aplasia is always seen in individuals with RAPADILINO syndrome and BGS and occasionally seen in those with RTS. Poikiloderma, a characteristic of both BGS and RTS, is not seen in RAPADILINO syndrome. However, the absence of poikiloderma cannot be confirmed before age one year because of its late onset. Coronal craniosynostosis, a diagnostic feature of BGS, has not been described in reported individuals with RTS. However, the author has observed coronal craniosynostosis in one of two female twins with RTS [Author, unpublished data]. Alopecia and absence of eyelashes and brows, characteristics of RTS, are not seen in individuals with BGS.
Since the original description of Baller-Gerold syndrome (BGS) by Baller [1950] and Gerold [1959], a limited number of individuals with BGS have been reported [Greitzer et al 1974, Feingold et al 1979, Anyane-Yeboa et al 1980, Pelias et al 1981, Boudreaux et al 1990, Galea & Tolmie 1990, Lewis et al 1991, Dallapiccola et al 1992, Van Maldergem et al 1992, Lin et al 1993, Ramos Fuentes et al 1994, Franceschini et al 1998, Megarbané et al 2000, Siitonen et al 2009]....
Natural HistorySince the original description of Baller-Gerold syndrome (BGS) by Baller [1950] and Gerold [1959], a limited number of individuals with BGS have been reported [Greitzer et al 1974, Feingold et al 1979, Anyane-Yeboa et al 1980, Pelias et al 1981, Boudreaux et al 1990, Galea & Tolmie 1990, Lewis et al 1991, Dallapiccola et al 1992, Van Maldergem et al 1992, Lin et al 1993, Ramos Fuentes et al 1994, Franceschini et al 1998, Megarbané et al 2000, Siitonen et al 2009].At birth. Brachycephaly, shallow orbits, bulging forehead and megafontanelles, all manifestations of coronal synostosis, are always present at birth in individuals with BGS. Additional features such as saddle nose, nose hypoplasia, small mouth with thin vermilion border, and high arched palate, are part of the craniofacial phenotype. A combination of oligodactyly, thumb hypo- or aplasia, and radial hypo- or aplasia is present and may be asymmetrical.Patellar hypo- or aplasia is observed in childhood. Note: Late ossification of the patella may be misinterpreted as absence of the patella in infants.Anterior displacement of the anus has been reported in several individuals.Skin is normal.In infancy. A few months after birth skin lesions may appear. Swelling of the extremities is seen first, followed by a peculiar mottled hypopigmentation (poikiloderma) on the arms, forearms, and legs. Blistering can develop on the face and then spread to the buttocks and extremities. After years, it becomes reticulated with hypo- and hyperpigmentation, punctate atrophy, and telangiectasias. A hallmark is failure to thrive, with length decelerating to stabilize around -4 SD.In childhood. Failure to thrive is the rule, with height and weight under 4 SD below the mean. Absence of patella may result in genu recurvatum and knee instability. In adulthood. Osteosarcoma, lymphoma, and skin cancer usually develop during the second and third decades. A high frequency of lymphoma was observed: four cases in the RAPADILINO cohort evaluated in Finland [Siitonen et al 2009] and one case of Baller-Gerold syndrome [Debeljak et al 2009]. Intelligence is normal.
Genotype-phenotype information is provisional, owing to the limited number of individuals meeting the suggested diagnostic criteria for BGS. ...
Genotype-Phenotype CorrelationsGenotype-phenotype information is provisional, owing to the limited number of individuals meeting the suggested diagnostic criteria for BGS. Fourteen of 34 individuals with the allelic disorder RTS developed osteosarcoma. Of note, only those with one or two truncating RECQL4 mutations developed osteosarcoma, illustrating the importance of characterizing the disease-causing mutation(s) for cancer risk assessment [Wang et al 2001].
The major differential diagnosis for Baller-Gerold syndrome (BGS) comprises the allelic disorders Rothmund-Thomson syndrome and RAPADILINO syndrome. (See Allelic Disorders.) ...
Differential DiagnosisThe major differential diagnosis for Baller-Gerold syndrome (BGS) comprises the allelic disorders Rothmund-Thomson syndrome and RAPADILINO syndrome. (See Allelic Disorders.) The second group of conditions to consider are those in which radial ray hypoplasia is a major component and craniosynostosis is occasionally described. This group includes the following:Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Craniosynostosis may occur. Progressive bone marrow failure with pancytopenia typically presents in the first decade. By age 40 to 48 years, the estimated cumulative incidence of bone marrow failure is 90%; of hematologic malignancies (primarily acute myeloid leukemia), 10%-33%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract), 28%-29%. The diagnosis of FA rests on the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of at least 13 complementation groups A, B, C, D1 (BRCA2), D2, E, F, G, I, J, L, M, N, for which all genes have been identified. Inheritance is autosomal recessive for all except FANCB, which is X-linked.Fetal valproate syndrome is the well-recognized association of reduction limb defects, radial hypo- or aplasia, trigonocephaly (resulting from metopic craniosynostosis), spina bifida, and other malformations (eye, palate, heart). The metopic ridging and radial ray defects observed in valproate embryopathy have been confused with BGS [Santos de Oliveira et al 2006]. VACTERL association includes vertebral anomalies, anal atresia, cardiac anomalies, tracheo-esophageal fistula, renal anomalies, and limb anomalies. The latter often comprises thumb hypo- or aplasia and in this respect may resemble BGS. SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome) and acro-renal-ocular syndrome (AROS), two phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypo- or aplasia of the thumbs; hypo- or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesico-ureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Additional features include sensorineural and/or conductive deafness. Diagnosis is based on clinical findings and detection of a SALL4 mutation. Inheritance is autosomal dominant [Kohlhase et al 2003]. Holt-Oram syndrome (HOS) is characterized by upper-extremity malformations involving radial, thenar, or carpal bones; congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum; and/or cardiac conduction disease. Seventy-five percent of individuals with HOS have a congenital heart malformation. The diagnosis of HOS is based on established clinical criteria and can be confirmed through molecular genetic testing. More than 70% of individuals who meet strict diagnostic criteria have an identifiable mutation in TBX5. Inheritance is autosomal dominant. Thrombocytopenia-absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and presence of the thumbs despite more or less severe shortening of the upper limbs. TAR syndrome can be differentiated from BGS by the presence of craniosynostosis in individuals with BGS and the presence of thumbs in those with TAR syndrome. In contrast, the thumbs can be absent in individuals with Fanconi anemia or Roberts SC-phocomelia syndrome. Previously thought to be autosomal recessive, the mode of inheritance of TAR syndrome is complex, with a microdeletion in 1q21.1 being necessary but not sufficient to determine the phenotype [Klopocki et al 2007].The third group of conditions to consider are those in which craniosynostosis is the major finding, but other features may suggest BGS.Saethre-Chotzen syndrome is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), ptosis, and characteristic appearance of the ear (small pinna with a prominent crus). Syndactyly of digits two and three of the hand is variably present. Although mild-to-moderate developmental delay and intellectual disability have been reported, normal intelligence is more common. Less common manifestations of Saethre-Chotzen syndrome include short stature, parietal foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated distal hallucal phalanx, and congenital heart malformations. Mutations in TWIST are causative [Paznekas et al 1998]. On rare occasion the radius is hypoplastic. Inheritance is autosomal dominant. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Baller-Gerold syndrome, occupational therapy assessment to evaluate hand and arm function is recommended. ...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Baller-Gerold syndrome, occupational therapy assessment to evaluate hand and arm function is recommended. Treatment of ManifestationsWhen craniosynostosis is bilateral, surgery is usually performed before age six months. Pollicization of the index finger to restore a functional grasp has had satisfactory results in a number of persons with absence of the thumb [Foucher et al 2005]. However, many children with aplasia of the thumb can use their first and second digits for grasping without pollicization.SurveillanceFor persons with deleterious RECQL4 mutations that correlate with an increased risk for osteosarcoma, attention to clinical findings such as bone pain, limp, and fracture is warranted. Currently no data are available regarding the effectiveness of routine screening such as x-rays, MRI, and bone scan. Furthermore, the risk of added radiation exposure from diagnostic studies and the benefit of "early" detection of osteosarcoma are unknown. Because lymphoma has been observed in individuals with BGS [Debeljak et al 2009] and its allelic disorders RAPADILINO syndrome (4/14 cases) [Siitonen et al 2009] and Rothmund-Thomson syndrome [Simon et al 2010], it seems reasonable to monitor individuals for lymph node swelling and /or mediastinal enlargement on chest radiographs.Agents/Circumstances to AvoidSun exposure is to be avoided because of predisposition to skin cancer.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Baller-Gerold Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRECQL48q24.3ATP-dependent DNA helicase Q4Finnish Disease Database RECQL4 homepage - Mendelian genesRECQL4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Baller-Gerold Syndrome (View All in OMIM) View in own window 218600BALLER-GEROLD SYNDROME; BGS 603780RECQ PROTEIN-LIKE 4; RECQL4Molecular Genetic PathogenesisProcessing of aberrant DNA structures that arise during DNA replication and repair is a major role of ATP-dependent DNA helicase Q4, the protein encoded by RECQL4 (see Normal gene product). Disruption of DNA replication fork progression by stable secondary structures (e.g., forked structures that mimic replication forks, synthetic 4-way junctions and D-loops, gapped DNA, RNA-DNA hybrids, triplex DNA and G-quadruplex DNA) is likely to impede replication fork progression resulting in arrest or collapse of the fork. This can have potentially mutagenic or even lethal consequences for the cell as it results in chromosome instability and, ultimately, cell death or cancer. Mutations in RECQL4 impair the processing of these aberrant structures. In this respect, ATP-dependent DNA helicase Q4 can be considered a caretaker of the genome [Wu & Hickson 2006].Normal allelic variants. RECQL4 has 21 exons, spanning over 6.5 kb. The gene has a coding sequence consisting of 3,627 bases based on the open reading frame of the initial cDNA clone. RECQL4 is unique for having 13 introns composed of fewer than 100 bp, a feature predisposing to inefficient splicing Wang et al [2002]. Pathologic allelic variants. Six mutations have been demonstrated in four families with Baller-Gerold syndrome (BGS): a homozygous splice site mutation (IVS17-2A>C) and compound heterozygosity for a missense mutation (p.Arg1021Trp) and a classic RTS frameshift mutation (g.2886delT) were observed in the two families initially reported [Van Maldergem et al 2006]. The missense mutation induces substitution of the hydrophilic amino acid arginine by the hydrophobic residue tryptophan. An individual with a homozygous c.2335del22 mutation determining a p.Asp779Lysfs*57 truncation and two terminated pregnancies with compound heterozygosity for c.496C>T and c.3151A>G determining p.Gln166X and p.Ile1051Val, respectively, were subsequently described [Siitonen et al 2009]. The latter missense mutation is of unknown significance since predictive modeling (PolyPhen and SIFT) is inconclusive, although it affects a conserved interspecies residue and is not found in the single nucleotide polymorphisms databases. Overall, approximately 50 different RECQL4 mutations resulting in absent or truncated protein have been published [Kitao et al 1999, Lindor et al 2000, Balraj et al 2002, Wang et al 2002, Beghini et al 2003, Siitonen et al 2003, Wang et al 2003, Kellermayer et al 2005, Broom et al 2006, Van Maldergem et al 2006, Sznajer et al 2007, Siitonen et al 2009]. The helicase domain, located in exons 8-14, is frequently the site of truncating mutations, but mutations in the N-terminus have also been described. Normal gene product. RECQL4 encodes ATP-dependent DNA helicase Q4, a protein of 1,208 amino acids that bears homology to a family of proteins known as RecQ helicases [Kitao et al 1998]. Helicases are enzymes involved in unwinding and remodeling of double-stranded nucleic acids into single strands. They are ATP-dependent enzymes. They have essential functions at various stages of DNA processing (replication, recombination, repair, transcription), but also translation, RNA processing, and chromosome segregation. Helicases therefore contribute to maintaining genomic integrity. They are classified into families according to their direction of translocation along nucleic acid substrates and by the presence and conservation of characteristic helicase domains and motifs [Singleton & Wigley 2002]. The RecQ helicases belong to superfamily 2 of helicases. The first RecQ helicase was identified more than 25 years ago in Escherichia coli [Nakayama et al 1984]. RecQ helicases have a role in the processing of aberrant DNA structure that arises during DNA replication and repair [Khakhar et al 2003]. Members of the RecQ family can be distinguished from other helicases by a conserved domain varying from 320 to 390 amino acids in length in the middle of the protein. This region contains seven helicase motifs characteristic of the DExH-box superfamily that are involved in the binding and hydrolysis of NTP and the separation of nucleic acid duplexes [van Brabant et al 2000, Nakayama 2002]. At the C-terminal region, two other conserved sequence elements are commonly found in RecQ helicases: the RecQ-C-terminal (RQC; also known as RecQ-Ct) and the helicase-and-RNase D C-terminal (HRDC) domains [Morozov et al 1997]. Although the RQC and HRDC domains are found in most RecQs, some family members miss one or both domains. This is the case with the protein encoded by human RECQL4, which lacks the RQC and HRDC domains. The RQC domain seems to be unique to RecQ helicases and probably has a role in mediating specific protein-protein interactions. At least five RECQL human orthologs are known: RECQL, RECQL4, RECQL5, BLM, and WRN. Mutations in BLM are associated with Bloom syndrome; mutations in WRN are associated with Werner syndrome; both are chromosome instability conditions inherited in an autosomal recessive manner. RECQL4 has been associated with Rothmund-Thomson syndrome, RAPADILINO syndrome, and Baller-Gerold syndrome. To date, no human disease is known to be associated with RECQL or RECQL5 protein deficiency. Despite its sequence structure, ATP-dependent DNA helicase Q4 does not actually demonstrate helicase activity, unlike the proteins encoded by related genes BLM and WRN. For a review see Van Maldergem et al [2008].Abnormal gene product. Unknown