• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Baller-Gerold Syndrome

, MD, PhD
Centre de Génétique Humaine
Université de Franche-Comté
Besançon, France

Initial Posting: ; Last Update: June 7, 2011.


Disease characteristics. Baller-Gerold syndrome (BGS) is characterized by coronal craniosynostosis, manifest as abnormal shape of the skull (brachycephaly) with ocular proptosis and bulging forehead; 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; growth retardation and poikiloderma. Findings in individuals with BGS overlap with those of Rothmund-Thomson syndrome (RTS) and RAPADILINO syndrome, also caused by mutations in RECQL4. RTS is characterized by poikiloderma; sparse hair, eyelashes, and/or eyebrows/lashes; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer, especially osteosarcoma. 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.

Diagnosis/testing. The diagnosis of BGS is based on clinical findings. RECQL4 is the only gene currently known to be associated with BGS. Sequence analysis of the exons and the short introns of RECQL4 has detected mutations in 100% of the limited number of persons with BGS tested to date.

Management. Treatment of manifestations: Surgery before age six months to repair bilateral craniosynostosis; pollicization of the index finger as needed to create a functional grasp.

Surveillance: For persons with deleterious RECQL4 mutations that correlate with an increased risk for osteosarcoma, attention to clinical findings such as bone pain, limp, and fracture.

Agents/circumstances to avoid: Sun exposure because of risk for skin cancer.

Genetic counseling. Baller-Gerold syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing alleles in the family have been identified.


Clinical Diagnosis

The 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 Testing

Gene. 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 Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency 1, 2
RECQL4Sequence analysis Sequence variants 3 Unknown
Deletion / duplication analysis 4Exonic or whole-gene deletionsUnknown; none reported 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Based on the fewer than ten families tested to date

3. 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 Strategy

To 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.

Clinical Description

Natural History

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].

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 Correlations

Genotype-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 name Baller-Gerold syndrome was coined by Cohen [1975] based on descriptions of three affected individuals reported by Baller and Gerold from the German literature.

  • Baller [1950] described a woman with short stature, oxycephaly, hypoplasia of the left radius, and aplasia of the right radius; her parents were remotely consanguineous.
  • Gerold [1959] described male and female sibs with coronal craniosynostosis, radial and thumb aplasia, and bowing of the ulnae.

Since 1975 the designation Baller-Gerold syndrome has been used to refer to any type of craniosynostosis associated with any type of radial ray defect; this is likely an incorrect use of the term, and has led some authors to consider metopic ridging and radial ray defects observed in valproate embryopathy sufficient for a diagnosis of BGS [Santos de Oliveira et al 2006].


The prevalence of Baller-Gerold syndrome is unknown; it is probably less than 1:1,000,000.

Differential Diagnosis

The 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

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.

Treatment of Manifestations

When 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.


For 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 Avoid

Sun exposure is to be avoided because of predisposition to skin cancer.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Baller-Gerold syndrome (BGS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with BGS are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in an affected family member.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Serial ultrasound examination may identify limb shortening, radial hypo/aplasia and abnormal head shape (brachycephaly). Ultrasound examination revealing these findings at 14 weeks' gestation identified BGS in two at-risk pregnancies [Van Maldergem et al 1992, Siitonen et al 2009].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Reach: The Association for Children with Hand or Arm Deficiency
    PO Box 54
    Helston Cornwall TR13 8WD
    United Kingdom
    Phone: +44 0845 1306 225
    Fax: +44 0845 1300 262
    Email: reach@reach.org.uk

Molecular Genetics

Information 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 Databases

Data 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)


Molecular Genetic Pathogenesis

Processing 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


Literature Cited

  1. Anyane-Yeboa K, Gunning L, Bloom AD. Baller-Gerold syndrome craniosynostosis-radial aplasia syndrome. Clin Genet. 1980;17:161–6. [PubMed: 7363501]
  2. Baller F. Radiusaplasie und Inzucht. Z Menschl Vererb Konstitutionsl. 1950;29:782–90.
  3. Balraj P, Concannon P, Jamal R, Beghini A, Hoe TS, Khoo AS, Volpi L. An unusual mutation in RECQ4 gene leading to Rothmund-Thomson syndrome. Mutat Res. 2002;508:99–105. [PubMed: 12379465]
  4. Beghini A, Castorina P, Roversi G, Modiano P, Larizza L. RNA processing defects of the helicase gene RECQL4 in a compound heterozygous Rothmund-Thomson patient. Am J Med Genet A. 2003;120A:395–9. [PubMed: 12838562]
  5. Boudreaux JM, Colon MA, Lorusso GD, Parro EA, Pelias MZ. Baller-Gerold syndrome: an 11th case of craniosynostosis and radial aplasia. Am J Med Genet. 1990;37:447–50. [PubMed: 2260585]
  6. Broom MA, Wang LL, Otta SK, Knutsen AP, Siegfried E, Batanian JR, Kelly ME, Shah M. Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency. Clin Genet. 2006;69:337–43. [PubMed: 16630167]
  7. Cohen MM Jr. An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects Orig Artic Ser. 1975;11:137–89. [PubMed: 179637]
  8. Cohen MM Jr, Toriello HV. Is there a Baller-Gerold syndrome? Am J Med Genet. 1996;61:63–4. [PubMed: 8741920]
  9. Dallapiccola B, Zelante L, Mingarelli R, Pellegrino M, Bertozzi V. Baller-Gerold syndrome: case report and clinical and radiological review. Am J Med Genet. 1992;42:365–8. [PubMed: 1536180]
  10. Debeljak M, Zver A, Jazbec J. A patient with Baller-Gerold syndrome and midline NK/T lymphoma. Am J Med Genet A. 2009;149A:755–9. [PubMed: 19291770]
  11. Farrell SA, Paes BA, Lewis ME. Fanconi anemia in a child previously diagnosed as Baller-Gerold syndrome. Am J Med Genet. 1994;50:98–9. [PubMed: 8160763]
  12. Feingold M, Sklower SL, Willner JP, Desnick RH, Cohen MM. Craniosynostosis-radial aplasia: Baller-Gerold syndrome. Am J Dis Child. 1979;133:1279–80. [PubMed: 517480]
  13. Foucher G, Medina J, Lorea P, Pivato G. Principalization of pollicization of the index finger in congenital absence of the thumb. Tech Hand Up Extrem Surg. 2005;9:96–104. [PubMed: 16201251]
  14. Franceschini P, Licata D, Guala A, Di Cara G, Signorile F, Franceschini D, Genitori L, Restagno G. Long first metacarpal in monozygotic twins with probable Baller-Gerold syndrome. Am J Med Genet. 1998;80:303–8. [PubMed: 9856554]
  15. Galea P, Tolmie JL. Normal growth and development in a child with Baller-Gerold syndrome (craniosynostosis and radial aplasia). J Med Genet. 1990;27:784–7. [PMC free article: PMC1017284] [PubMed: 2074565]
  16. Gerold M. Healing of a fracture in an unusual case of congenital anomaly of the upper extremities. Zentralbl Chir. 1959;84:831–4. [PubMed: 13669699]
  17. Greitzer LJ, Jones KL, Schnall BS, Smith DW. Craniosynostosis--radial aplasia syndrome. J Pediatr. 1974;84:723–4. [PubMed: 4820706]
  18. Gripp KW, Stolle CA, Celle L, McDonald-McGinn DM, Whitaker LA, Zackai EH. TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome. Am J Med Genet. 1999;82:170–6. [PubMed: 9934984]
  19. Huson SM, Rodgers CS, Hall CM, Winter RM. The Baller-Gerold syndrome: phenotypic and cytogenetic overlap with Roberts syndrome. J Med Genet. 1990;27:371–5. [PMC free article: PMC1017134] [PubMed: 2359099]
  20. Jam K, Fox M, Crandall BF. RAPADILINO syndrome: a multiple malformation syndrome with radial and patellar aplasia. Teratology. 1999;60:37–8. [PubMed: 10413338]
  21. Kääriäinen H, Ryöppy S, Norio R. RAPADILINO syndrome with radial and patellar aplasia/hypoplasia as main manifestations. Am J Med Genet. 1989;33:346–51. [PubMed: 2801769]
  22. Kant SG, Baraitser M, Milla PJ, Winter RM. Rapadilino syndrome--a non-Finnish case. Clin Dysmorphol. 1998;7:135–8. [PubMed: 9571286]
  23. Kellermayer R, Siitonen HA, Hadzsiev K, Kestila M, Kosztolanyi G. A patient with Rothmund-Thomson syndrome and all features of RAPADILINO. Arch Dermatol. 2005;141:617–20. [PubMed: 15897384]
  24. Khakhar RR, Cobb JA, Bjergbaek L, Hickson ID, Gasser SM. RecQ helicases: multiple roles in genome maintenance. Trends Cell Biol. 2003;13:493–501. [PubMed: 12946629]
  25. Kitao S, Ohsugi I, Ichikawa K, Goto M, Furuichi Y, Shimamoto A. Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics. 1998;54:443–52. [PubMed: 9878247]
  26. Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, Lindor NM, Furuichi Y. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet. 1999;22:82–4. [PubMed: 10319867]
  27. Klopocki E, Schulze H, Strauss G, Ott CE, Hall J, Trotier F, Fleischhauer S, Greenhalgh L, Newbury-Ecob RA, Neumann LM, Habenicht R, Konig R, Seemanova E, Megarbane A, Ropers HH, Ullmann R, Horn D, Mundlos S. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet. 2007;80:232–40. [PMC free article: PMC1785342] [PubMed: 17236129]
  28. Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, Newbury-Ecob R, Reardon W. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J Med Genet. 2003;40:473–8. [PMC free article: PMC1735528] [PubMed: 12843316]
  29. Lewis ME, Rosenbaum PL, Paes BA. Baller-Gerold syndrome associated with congenital hydrocephalus. Am J Med Genet. 1991;40:307–10. [PubMed: 1951434]
  30. Lin AE, McPherson E, Nwokoro NA, Clemens M, Losken HW, Mulvihill JJ. Further delineation of the Baller-Gerold syndrome. Am J Med Genet. 1993;45:519–24. [PubMed: 8465861]
  31. Lindor NM, Furuichi Y, Kitao S, Shimamoto A, Arndt C, Jalal S. Rothmund-Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am J Med Genet. 2000;90:223–8. [PubMed: 10678659]
  32. Megarbané A, Melki I, Souraty N, Gerbaka J, El Ghouzzi V, Bonaventure J, Mornand A, Loiselet J. Overlap between Baller-Gerold and Rothmund-Thomson syndrome. Clin Dysmorphol. 2000;9:303–5. [PubMed: 11045594]
  33. Morozov V, Mushegian AR, Koonin EV, Bork P. A putative nucleic acid-binding domain in Bloom's and Werner's syndrome helicases. Trends Biochem Sci. 1997;22:417–8. [PubMed: 9397680]
  34. Nakayama H. RecQ family helicases: roles as tumor suppressor proteins. Oncogene. 2002;21:9008–21. [PubMed: 12483516]
  35. Nakayama H, Nakayama K, Nakayama R, Irino N, Nakayama Y, Hanawalt PC. Isolation and genetic characterization of a thymineless death-resistant mutant of Escherichia coli K12: identification of a new mutation (recQ1) that blocks the RecF recombination pathway. Mol Gen Genet. 1984;195:474–80. [PubMed: 6381965]
  36. Paznekas WA, Cunningham ML, Howard TD, Korf BR, Lipson MH, Grix AW, Feingold M, Goldberg R, Borochowitz Z, Aleck K, Mulliken J, Yin M, Jabs EW. Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet. 1998;62:1370–80. [PMC free article: PMC1377134] [PubMed: 9585583]
  37. Pelias MZ, Superneau DW, Thurmon TF. Brief clinical report: a sixth report (eighth case) of craniosynostosis-radial aplasia (Baller-Gerold) syndrome. Am J Med Genet. 1981;10:133–9. [PubMed: 7315870]
  38. Preis S, Majewski F, Korholz D, Gobel U. Osteosarcoma in a 16-year-old boy with Baller-Gerold syndrome. Clin Dysmorphol. 1995;4:161–8. [PubMed: 7606324]
  39. Quarrell OW, Maltby EL, Harrison CJ. Baller Gerold syndrome and Fanconi anaemia. Am J Med Genet. 1998;75:228–9. [PubMed: 9450894]
  40. Ramos Fuentes FJ, Nicholson L, Scott CI. Phenotypic variability in the Baller-Gerold syndrome: report of a mildly affected patient and review of the literature. Eur J Pediatr. 1994;153:483–7. [PubMed: 7957363]
  41. Rossbach HC, Sutcliffe MJ, Haag MM, Grana NH, Rossi AR, Barbosa JL. Fanconi anemia in brothers initially diagnosed with VACTERL association with hydrocephalus, and subsequently with Baller-Gerold syndrome. Am J Med Genet. 1996;61:65–7. [PubMed: 8741921]
  42. Santos de Oliveira R, Lajeunie E, Arnaud E, Renier D. Fetal exposure to sodium valproate associated with Baller-Gerold syndrome: case report and review of the literature. Childs Nerv Syst. 2006;22:90–4. [PubMed: 15789214]
  43. Seto ML, Lee SJ, Sze RW, Cunningham ML. Another TWIST on Baller-Gerold syndrome. Am J Med Genet. 2001;104:323–30. [PubMed: 11754069]
  44. Siitonen HA, Kopra O, Kaariainen H, Haravuori H, Winter RM, Saamanen AM, Peltonen L, Kestila M. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum Mol Genet. 2003;12:2837–44. [PubMed: 12952869]
  45. Siitonen HA, Sotkasiira J, Biervliet M, Benmansour A, Capri Y, Cormier-Daire V, Crandall B, Hannula-Jouppi K, Hennekam R, Herzog D, Keymolen K, Lipsanen-Nyman M, Miny P, Plon SE, Riedl S, Sarkar A, Vargas FR, Verloes A, Wang LL, Kääriäinen H, Kestilä M. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 2009;17:151–8. [PMC free article: PMC2986053] [PubMed: 18716613]
  46. Simon T, Kohlhase J, Wilhelm C, Kochanek M, De Carolis B, Berthold F. Multiple malignant diseases in a patient with Rothmund-Thomson syndrome with RECQL4 mutations: Case report and literature review. Am J Med Genet A. 2010;152A:1575–9. [PubMed: 20503338]
  47. Singleton MR, Wigley DB. Modularity and specialization in superfamily 1 and 2 helicases. J Bacteriol. 2002;184:1819–26. [PMC free article: PMC134918] [PubMed: 11889086]
  48. Sznajer Y, Siitonen HA, Roversi G, Dangoisse C, Scaillon M, Ziereisen M, Tenoutasse S, Kestila M, Larizza L. Atypical Rothmund-Thomson syndrome in a patient with coumpound heterozygous mutations in RECQL4 gene and phenotypic features of RECQL4 syndromes. Eur J Pediatr. 2007;167:175–81. [PubMed: 17372760]
  49. van Brabant AJ, Stan R, Ellis NA. DNA helicases, genomic instability, and human genetic disease. Annu Rev Genomics Hum Genet. 2000;1:409–59. [PubMed: 11701636]
  50. Van Maldergem L, Siitonen HA, Jabs EW, Gordillo M. RECQL4 and the Baller-Gerold, RAPADILINO and Rothmund-Thomson syndromes. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2 ed. New York, NY: Oxford University Press; 2008.
  51. Van Maldergem L, Siitonen HA, Jalkh N, Chouery E, De Roy M, Delague V, Muenke M, Jabs EW, Cai J, Wang LL, Plon SE, Fourneau C, Kestila M, Gillerot Y, Megarbane A, Verloes A. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. 2006;43:148–52. [PMC free article: PMC2564634] [PubMed: 15964893]
  52. Van Maldergem L, Verloes A, Lejeune L, Gillerot Y. The Baller-Gerold syndrome. J Med Genet. 1992;29:266–8. [PMC free article: PMC1015930] [PubMed: 1583650]
  53. Vargas FR, de Almeida JC, Llerena Junior JC, Reis DF. RAPADILINO syndrome. Am J Med Genet. 1992;44:716–9. [PubMed: 1481838]
  54. Wang LL, Gannavarapu A, Kozinetz CA, Levy ML, Lewis RA, Chintagumpala MM, Ruiz-Maldanado R, Contreras-Ruiz J, Cunniff C, Erickson RP, Lev D, Rogers M, Zackai EH, Plon SE. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003;95:669–74. [PubMed: 12734318]
  55. Wang LL, Levy ML, Lewis RA, Chintagumpala MM, Lev D, Rogers M, Plon SE. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001;102:11–7. [PubMed: 11471165]
  56. Wang LL, Worley K, Gannavarapu A, Chintagumpala MM, Levy ML, Plon SE. Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome. Am J Hum Genet. 2002;71:165–7. [PMC free article: PMC384974] [PubMed: 12016592]
  57. Wu L, Hickson ID. DNA helicases required for homologous recombination and repair of damaged replication forks. Annu Rev Genet. 2006;40:279–306. [PubMed: 16856806]

Chapter Notes

Author Notes

Electronic resources

Revision History

  • 7 June 2011 (me) Comprehensive update posted live
  • 13 August 2007 (me) Review posted to live Web site
  • 23 April 2007 (lvm) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1204PMID: 20301383
PubReader format: click here to try


Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...