Baller-Gerold Syndrome

Disease Overview

Baller-Gerold syndrome (BGS) is a rare genetic disorder that is apparent at birth (congenital). Common features of BGS include a distinctive misshaped appearance of the skull, facial (craniofacial) area and bones of the forearms and hands.

In infants with BGS there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Infants with BGS may also have a protruding forehead; downslanting eyelid folds (palpebral fissures), small, malformed (dysplastic), low-set ears, and/or other craniofacial abnormalities. Underdevelopment (hypoplasia) or absence (aplasia) of the bone on the thumb side of the forearms (radii) may also be present. In addition, the bone on the “pinky” side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. The term “radial ray malformations” is used in the medical literature to describe abnormal development of the arms or hands. In some people, additional physical abnormalities and/or intellectual disability may also be present. For example, certain kinds of heart defects, including ventricular septal defects and subaortic stenosis can occur in people with BGS. Treatment for BGS consists primarily of surgery to correct or repair skeletal or other defects. Other treatment is symptomatic and supportive. Baller-Gerold syndrome is thought to be inherited in an autosomal recessive pattern.

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Synonyms

• craniosynostosis with radial defects
• craniosynostosis-radial aplasia syndrome

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Signs & Symptoms

Children with BGS are born with premature closure of the joints or seams (sutures) of the skull. This causes an upward growth of the head giving it a pointed or cone-shaped appearance.

The large bone of the forearm on the “pinky” side (ulnar) is short and curved and the short bone of the forearm on the thumb side (radius) is underdeveloped or missing. These skeletal abnormalities may be present on both sides or just one (asymmetric). Sometimes, other bones in the hand called the carpal and metacarpal bones may also be missing or formed differently. Problems with fine motor skills may be present due to the deformities of the hands and arms. Underdevelopment or absence of the kneecap (patella) may also occur. In some people with BGS, other skeletal abnormalities involving the spine and pelvis are seen.

Slow growth is also a feature of BGS. Delayed growth in childhood may result in height and weight significantly below average. Heart defects can sometimes be seen in people with BGS. The more common heart defects that have been described in the medical literature on BGS are ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations. Each of these terms describes a different change to development of the structure of the heart. The severity of a heart defect depends on the type of structural issue and the individual case. Some heart defects may require surgical correction, whereas others may resolve naturally over time.

People with BGS have distinct facial features including a protruding forehead, widely-spaced eyes, short nose and small mouth. The palate, or roof of the mouth, may have a high arched appearance. The fontanelles, or the soft spots on an infant’s skull, may appear larger than would be expected. In the first few years of life, the skin may be discolored or shed easily. This is called poikiloderma.

Intellectual disability has been reported in BGS. However, most individuals have normal intelligence.

In some people with BGS, the anus may be further forward than is typical (anteriorly placed), and the opening to the anus may be missing or blocked (imperforate anus). These structural abnormalities can involve a fistula, which results in an abnormal connection between the anus and genitalia. In such cases, surgical repair may be possible.

People with BGS or carriers of a gene variant for condition may be at increased risk for certain types of cancer. These include osteosarcoma, a type of bone cancer; skin cancer; and lymphoma. The medical literature links variants in the RECQL4 gene to increased cancer risk. Signs and symptoms for these types of cancers can include bone pain, swelling and fractures for osteosarcoma, or lymph node enlargement, fever and unexplained weight loss for lymphoma.

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Causes

Baller-Gerold syndrome is caused, in most cases, by a change (variant) in a gene called RECQL4. The RECQL4 gene has an important role in maintaining the stability of DNA, the instruction manual for the body. To carry out this role, RECQL4 is involved in many activities such as the repair of damaged DNA or a cell’s response to stress. When there is a variant in the gene, RECQL4 cannot carry out these important functions. This can lead to a health condition like or similar to Baller-Gerold syndrome.

In the medical literature, variants in two other genes have been described in people with features of Baller-Gerold syndrome. These genes are TWIST and FGFR2.

BGS follows an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

The number of people with BGS is not known, but may be less than 1 in a 1,000,000. There have been less than 40 cases reported in the medical literature.

There are too few cases of BGS reported to determine, with certainty, whether it occurs more commonly in people of a particular ethnicity.

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Disorders with Similar Symptoms

Variants in the RECQL4 gene also cause Rothmund-Thomson syndrome and RAPADILINO syndrome. Some clinical features of these conditions overlap, like short stature and radial ray malformations. As such, there is ongoing discussion about whether they are separate syndromes or part of one common group.

Rothmund-Thomson syndrome (RTS) is a rare genetic disorder that can affect many parts of the body. The disorder is characterized by distinctive abnormalities of the skin, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities, and an increased risk of cancer, especially bone cancer (osteosarcoma). People typically begin having signs of RTS during infancy and the first feature to appear is a rash that starts on the cheeks and later spreads to other parts of the body. The rash gradually becomes chronic and persists for life and is called poikiloderma. Other features may appear that involve other areas of the body such as the eyes, bones, teeth and hair, and patients may often be small in size compared to their peers. People with RTS are at an increased risk for developing cancer, particularly certain types of skin and bone cancer. RTS is inherited as an autosomal recessive genetic condition. Two-thirds of cases are due to variants in the RECQL4 gene. For the other one-third of patients, the gene(s) involved has not yet been identified. Alopecia, or hair loss, and a lack of eyelashes and eyebrows, are unique features of RTS in contrast to BGS and RAPADILINO syndrome.

RAPADILINO syndrome is a very rare, autosomal recessive disorder, the acronym of which stands 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. The condition involves skeletal defects, including cervical spine segmentation defects as well as feeding difficulties and juvenile diarrhea. There is also an increased risk for certain types of cancer, including osteosarcoma and lymphoma. These cancers may occur early in life, as four patients were diagnosed before age 35. About 17 cases of RAPADILINO syndrome have been reported in the medical literature. Of these, 14 came from families in Finland. RAPADILINO syndrome is thought to be caused by to one or more variants in the RECQL4 gene.

Symptoms of the following disorders can be similar to those of Baller-Gerold Syndrome. Comparisons may be useful for a differential diagnosis:

Crouzon syndrome is a rare genetic disorder. It is a form of craniosynostosis, a condition in which there is premature fusion of the fibrous joints (sutures) between certain bones of the skull. The sutures allow an infant’s head to grow and expand. Eventually, these bones fuse together to form the skull. In Crouzon syndrome, the sutures fuse prematurely affecting the proper growth of the skull and head and potentially altering the shape and development of the skull. Certain bones in the face may be affected as well. The severity of craniosynostosis can be different in one infant when compared to another. Symptoms primarily include differences of the face and head. Intelligence is usually not affected. Crouzon syndrome is caused by variants in one of the FGFR genes, usually FGFR2, and is inherited in an autosomal dominant manner.

Fanconi anemia (FA) is a rare genetic disorder, in the category of inherited bone marrow failure syndromes. Half the patients are diagnosed prior to age 10, while about 10% are diagnosed as adults. Early diagnoses are facilitated in people with birth defects, such as small size, abnormal thumbs and/or radial bones, skin pigmentation, small head, small eyes, abnormal kidney structures, and cardiac and skeletal anomalies. The disorder is often associated with a progressive deficiency of all bone marrow production of blood cells, red blood cells, white blood cells and platelets. Affected individuals have an increased risk of developing a cancer of blood-forming cells in the bone marrow called acute myeloid leukemia (AML), or tumors of the head, neck, skin, gastrointestinal system, or genital tract. FA occurs equally in males and females, and is found in all ethnic groups. It is usually inherited as an autosomal recessive genetic disorder, but X-linked inheritance has also been reported.

Fetal valproate syndrome (FVS) is a rare condition that is caused by exposure of the unborn baby to valproic acid or sodium valproate (dalpro, depakene, depakote, depakote sprinkle, divalproex, epival, myproic acid) during the first three months of pregnancy (the first trimester). Valproic acid is a medication used to treat certain types of seizures (epilepsy), bipolar disorder and migraines. Although many babies exposed to valproic acid are born healthy, a small percentage of pregnant women who take this medication can have a baby born with FVS. The exact prevalence of this condition is not known. Symptoms of this condition may include neural tube defects such as spina bifida, distinctive facial features, congenital heart defects and other musculoskeletal abnormalities.

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Diagnosis

Primary features of BGS that may be part of the clinical diagnosis include coronal craniosynostosis, delayed or restricted growth, radial ray malformations and poikiloderma. These medical findings are described in more detail under the sections “General Discussion” and “Signs & Symptoms”. Skeletal abnormalities of the skull, forearms and thumbs may be apparent at birth. These features may be seen with imaging such as a skull X-Ray or 3D-CT scan.

Diagnostic evaluation for BGS may also include genetic testing to determine if there are gene variants that may explain the clinical signs and symptoms. If a genetic cause is identified, this information can also sometimes be used to learn about what other medical risks may be present. Sequencing of the RECQL4 gene detects most cases of BGS. However, recent medical literature shows that not all people who have signs and symptoms of BGS have identifiable variants in the RECQL4 gene. This may be the case for most people with a clinical diagnosis of BGS who do not have poikiloderma, or changes in skin appearance. There may be a different genetic cause in these situations.

Clinical Testing and Work-Up

Before or after a diagnosis of BGS, it is recommended to meet with several different types of healthcare providers. Consultation with a clinical geneticist or genetic counselor may include genetic testing, if not already performed, and discussion about how BGS may impact the person and their family. A neurosurgeon or craniofacial specialist can offer evaluation of craniosynostosis. Additionally, occupational therapy and orthopedic surgery may manage assessment of hand and arm function. In some people, surgery may be recommended. Some patients may show signs of poikiloderma, or changes in appearance of the skin. In these people, referral to a dermatologist may be helpful.

The medical literature on BGS describes a possible risk for certain types of cancer. This includes skin, bone and blood cancer. Additional steps may be recommended to manage or reduce the risk of cancer for a person with BGS. Sunscreen use and limits on sun exposure may help to reduce the risk for skin cancer. These measures may be especially important in people with poikiloderma. There are certain signs and symptoms that indicate a cancer could be present. However, these signs and symptoms could be due to reasons other than a cancer. For osteosarcoma, or the bone cancer that could occur more commonly in people with variants in the REQL4 gene, it is important to watch for bone pain, swelling or limp. For lymphoma, the type of blood cancer linked to variants in REQL4, it may be important to follow up with a healthcare provider in the event of fever or unexplained weight loss.

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Standard Therapies

Treatment

Treatment of BGS involves surgery to relieve pressure inside the skull due to the craniosynostosis. This can be done by separating the bony sections and lining the seams between them with materials to prevent fusion. The younger the patient is at the time of the surgery, the better the results.

Some people with BGS may need surgery to correct other skeletal deformities such as thumb reconstruction from the index finger. However, there are many children with BGS that do not need this type of surgery. Physical and occupational therapy may help in the development of fine motor skills.

If a heart defect is present, cardiac surgery may also be required.

Healthcare providers from multiple specialties, including neurosurgery, orthopedics, genetics and dermatology may be involved in the care of a person with BGS.

Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Stevenson RE, Hall JG. Human Malformations and Related Anomalies. 3rd ed. Oxford University Press, New York, NY. 2015:224.

Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 7th ed. W. B. Saunders Co., Philadelphia, PA; 2013:430-31.

Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 5th ed. Oxford University Press, New York, NY; 2010:674.

Castriota-Scanderberg A, Dallapiccola B. Abnormal Skeletal Phenotypes. Springer Verlag. Berlin, Germany. 2005:28, 381.

Temple IK. Baller-Gerold Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:157-58.

JOURNAL ARTICLES
Mo D, Zhao Y, Balajee AS. Human RecQL4 helicase plays multifaceted roles in the genomic stability of normal and cancer cells. Cancer Lett. 2018;413:1–10.

Mojumdar A, De March M, Marino F, Onesti S. The human RecQ4 helicase contains a functional RecQ C-terminal region (RQC) that is essential for activity. J Biol Chem. 2017;292:4176–84.

Piard J, Aral B, Vabres P, Holder-Espinasse M, et al. Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes. Clin Genet. 2015;87:244–51.

Gupta MD, Mukhopadhyay S, Yusuf J, Tyagi S. Baller-gerold syndrome a rare cause of heart-hand syndrome.ISRN Cardiol. 2011:962084.

Masai H. RecQL4: a helicase linking formation and maintenance of a replication fork. J Biochem, 2011;149:629-631.

Debeljak M, Zver A, Jazbec J. A patient with Baller-Gerold syndrome and midline NK/T lymphoma. Am J Med Gen A. 2009;149(A):755-9.

Siitonen HA, Sotkasiira J, Biervliet M, Benmansour A, et al. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 2009;17:151-58.

Van Maldergem L. Siitonen HA, Jalkh N, Chouery E, et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. 2006;43:148-52.

INTERNET
Baller-Gerold syndrome. Genetics Home Reference. U.S. National Library of Medicine, Bethesda, MD. 2013 Aug [Updated 2019 Jan 2]. Available at: https://ghr.nlm.nih.gov/condition/baller-gerold-syndrome. Accessed May 8, 2019.

Kohlhase J. Townes-Brocks Syndrome. 2007 Jan 24 [Updated 2016 Jan 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1445/ Accessed May 8, 2019.

McKusick VA, Ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Baller-Gerold Syndrome. Entry Number; 218600: Last Edit Date; 10/26/2017. https://www.omim.org/entry/218600 Accessed May 8, 2019.

Olivier-Faivre, Laurence. Baller-Gerold syndrome. 2009 Apr. Orphanet [Internet]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1225 Accessed May 8, 2019.

Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-Related Craniosynostosis Syndromes. 1998 Oct 20 [Updated 2011 Jun 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1455/ Accessed May 8, 2019.

Van Maldergem L, Piard J, Larizza L, et al. Baller-Gerold Syndrome. 2007 Aug 13 [Updated 2018 Apr 19]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1204/ Accessed May 8, 2019.

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Patient Organizations

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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