Baller-Gerold Syndrome

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 establishing the diagnosis.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

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 such as Saethre-Chotzen syndrome, Roberts-SC syndrome, or 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; however, this detection rate is based on results from fewer than ten families.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Baller-Gerold Syndrome

Test Method	Mutations Detected	Mutation Detection Frequency 1, 2	Test Availability
Sequence analysis	RECQL4 sequence variants	Unknown	Clinical

1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method
2. Based on the fewer than ten families tested to date

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

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 for at-risk pregnancies both require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

Disease-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 [Kaariainen 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.

  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 individuals with RTS. Alopecia and absence of eyelashes and brows, characteristics of RTS, are not seen in individuals with BGS.

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].

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.

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.

In a series of 34 individuals with the allelic disorder RTS, osteosarcoma developed only in those with one or two truncating RECQL4 mutations, illustrating the importance of characterizing the disease-causing mutation(s) for cancer risk assessment [Wang et al 2001].

Nomenclature

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 2005].

Prevalence

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

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 peformed 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.

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 is warranted. Currently no data are available regarding the effictiveness 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.

Agents/Circumstances to Avoid

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

Testing 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.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

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 available on a clinical basis 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 genetic 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 at risk of being carriers.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles must be identified before prenatal testing can be performed.

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 an at-risk fetus.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

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 and fewer than 100 bp, a feature predisposing to inefficient splicing [Wang et al 2002].

Pathologic allelic variants: Three mutations have been demonstrated in two 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). The missense mutation induces substitution of the hydrophilic amino acid arginine by the hydrophobic residue tryptophan.

Overall, approximately 30 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]. 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 20 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 (2007).

Abnormal gene product: Unknown

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 13 August 2007 (me) Review posted to live Web site

• 23 April 2007 (lvm) Original submission