Baller-Gerold Syndrome
Summary
Clinical characteristics.
Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.
Diagnosis/testing.
The diagnosis of BGS is established in a proband with typical clinical findings and/or the identification of biallelic pathogenic variants in RECQL4 by molecular genetic testing.
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; sunscreen use with poikiloderma to protect against skin cancer.
Surveillance: Because individuals with allelic RECQL4 disorders are at increased risk for osteosarcoma and lymphoma, attention to clinical findings (e.g., bone pain, swelling, and/or limp) for osteosarcoma and lymph node enlargement or generalized symptoms (e.g., fever or unexplained weight loss) for lymphoma is recommended for those with BGS.
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 pathogenic variant. 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, prenatal diagnosis for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if both pathogenic variants in the family have been identified.
Diagnosis
Suggestive Findings
Baller-Gerold syndrome should be suspected in individuals with a combination of the following findings:
- Coronal craniosynostosis, manifest clinically as abnormal shape of the skull (brachycephaly) with ocular proptosis and prominent forehead and confirmed by skull x-ray or (preferably) 3D-CT reconstructionWhen the coronal sutures are fused, the orbit is pulled 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 aplasia or hypoplasia of the thumb, and/or aplasia or hypoplasia of the radiusNote: Radiographs may be necessary for confirmation of minor radial ray malformations.
- Growth restriction
- Poikiloderma consisting of hyper- and hypopigmentation of the skin with punctate atrophy and telangiectases
Establishing the Diagnosis
The diagnosis of Baller-Gerold syndrome is established in a proband with typical clinical findings and/or by identification of biallelic pathogenic variants in RECQL4 on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Baller-Gerold syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with craniosynostosis or those in whom the diagnosis of Baller-Gerold syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Baller-Gerold syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of RECQL4 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes RECQL4 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by craniosynostosis or when the diagnosis of Baller-Gerold syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Baller-Gerold Syndrome
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| RECQL4 | Sequence analysis 3 | >95% 4 |
| Gene-targeted deletion/duplication analysis 5 | Rare 6, 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Larizza et al [2013]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 7.
A large homozygous intragenic deletion was reported in a single individual of Japanese ethnicity with Baller-Gerold syndrome [Kaneko et al 2017].
Clinical Characteristics
Clinical Description
Since the original description of Baller-Gerold syndrome (BGS) by Baller [1950] and Gerold [1959], fewer than 40 individuals with BGS have been reported [Mégarbané et al 2000, Van Maldergem et al 2006, Debeljak et al 2009, Siitonen et al 2009, Piard et al 2015, Kaneko et al 2017]. BGS can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination [Van Maldergem et al 2016].
Craniofacial findings associated with craniosynostosis
- Brachycephaly
- Proptosis
- Prominent forehead
- Large fontanelles
Additional craniofacial features
- Concave nasal ridge
- Short nose
- Narrow mouth with thin vermilion of the lips
- High arched palate
Skeletal anomalies
- Upper limb anomalies. A combination of thumb hypo- or aplasia and radial hypo- or aplasia is present and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described.
- Knee abnormality. Patellar hypo- or aplasia becomes apparent in childhood.
- Late ossification of the patella may be misinterpreted as absence of the patella in infants.
- Absence of patella may result in genu recurvatum and knee instability.
Skin findings. Skin lesions may appear anytime within the first few years after birth.
- Lesions typically begin with erythema of the face and extremities.
- Findings later evolve into poikiloderma (mottled hypo-and hyper-pigmentation, atrophy, and telangiectasias).
Growth. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean.
Development/intelligence. Although intellectual deficiency has been reported [Ramos Fuentes et al 1994], most if not all patients have normal intelligence. No formal studies on intellectual development have been performed.
Other findings
- Imperforate or anterior displacement of the anus has been reported in several individuals.
- Cardiovascular defects such as ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations have been occasionally described.
Cancer risk. One case of lymphoma was reported in an individual with Baller-Gerold syndrome [Debeljak et al 2009]. However, an increased risk for osteosarcoma, lymphoma, and skin cancer in other disorders associated with pathogenic variants in RECQL4 (see Genetically Related Disorders) has been reported. Therefore, individuals with Baller-Gerold syndrome with symptoms suggestive of cancer should have prompt evaluation.
Genotype-Phenotype Correlations
No formal genotype-phenotype correlations have been made owing to the small number of patients reported to date.
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 2006].
Prevalence
The prevalence of Baller-Gerold syndrome is unknown; it is probably less than 1:1,000,000 [Mo et al 2018].
Differential Diagnosis
The major differential diagnosis for Baller-Gerold syndrome (BGS) comprises the allelic disorders Rothmund-Thomson syndrome and RAPADILINO syndrome (OMIM 266280). (See Genetically Related Disorders.) See Figure 1.
Figure 1.
Diagram showing overlapping and unique clinical features of the RECQL4-associated disorders. Note: "Mutated cases" refers to cases with a molecular diagnosis. From Van Maldergem et al [2016]
Additional conditions to consider are included in Table 2.
Table 2.
Disorders to Consider in the Differential Diagnosis of BGS
| Disorder | Gene(s) | MOI | Clinical Features of This Disorder | |
|---|---|---|---|---|
| Overlapping with BGS | Distinguishing from BGS | |||
| Fanconi anemia (FA) | Various 1 | AR AD XL |
|
|
| Fetal valproate syndrome (OMIM 609442) | N/A | N/A |
|
|
| VACTERL (OMIM 192350) | Unknown | Sporadic | Thumb hypo- or aplasia |
|
| SALL4-related disorders | SALL4 | AD | Radial ray malformations |
|
| Holt-Oram syndrome | TBX5 | AD | Upper-extremity malformations may involve radial bones. |
|
| Thrombocytopenia-absent radius (TAR) syndrome | See footnote 2 | See footnote 2 | Shortening of upper limbs, sometimes severe |
|
| Saethre-Chotzen syndrome | TWIST | AD |
|
|
| Roberts syndrome | ESCO2 | AR |
|
|
| CDAGS syndrome (OMIM 603116) | Unknown | AR |
|
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
CDAGS = craniosynostosis and clavicular hypoplasia; delayed fontanelle closure, cranial defects and deafness; anal anomalies; genitourinary malformations; and skin eruption [Mendoza-Londono et al 2005]
- 1.
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). Approximately 20 genes have been associated with FA.
- 2.
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].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with Baller-Gerold syndrome (BGS), the following are recommended if they have not already been completed:
- Consultation with a clinical geneticist and/or genetic counselor
- Neurosurgery or craniofacial specialist consultation for evaluation of craniosynostosis
- Orthopedic surgery and occupational therapy assessment to evaluate hand and arm function and need for surgery
- Dermatology evaluation if poikiloderma develops
Treatment of Manifestations
Craniosynostosis should be managed by neurosurgical/craniofacial specialists. 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 are able to function without orthopedic surgical intervention.
If poikiloderma is present, sensible use of sunscreens may protect against potential risk for skin cancer due to UV exposure.
If cancer arises, medical care should be sought from an oncologist familiar with the type of cancer.
Surveillance
Although lymphoma has only been described in one individual with BGS to date [Debeljak et al 2009], it is known that individuals with RECQL4 pathogenic variants associated with both Rothmund-Thomson syndrome and RAPADILINO syndrome are at increased risk for developing osteosarcoma and lymphoma. Given the potential risk, it would be reasonable for affected individuals with BGS and RECQL4 pathogenic variants (or their guardians) to be aware of the signs and symptoms associated with these malignancies. These signs and symptoms may include bone pain, swelling, and/or limp for osteosarcoma, and lymph node enlargement or generalized symptoms such as fever or unexplained weight loss for lymphoma.
Agents/Circumstances to Avoid
Excessive sun exposure should be avoided because of the theoretic increased risk for 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 in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.