NORD gratefully acknowledges Chelsea Leonard, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
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 patients, 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.
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 congential 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 the 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 mutations in the RECQL4 gene to increased cancer risk. Signs and symptoms for these types of cancer can include bone pain, swelling and fractures for osteosarcoma, or lymph node enlargement, fever and unexplained weight loss for lymphoma.
Baller-Gerold syndrome is caused, in most cases, by a non-working (mutated) 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 mutation 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, two other genes have been described in people with features of Baller-Gerold syndrome. These genes are TWIST and FGFR2.
BGS is transmitted by an autosomal recessive inheritance pattern. Recessive genetic disorders occur when an individual inherits a gene mutation from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass on the gene mutation and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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.
Parents who are close blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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.
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. A healthcare provider may confirm these features through imaging such as a skull X-Ray or 3D-CT scan.
Diagnostic evaluation for BGS may also include genetic testing. A healthcare provider may order genetic testing to determine if there is a genetic mutation 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 an identifiable mutation 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 cases, the provider may recommend surgery. Some patients may show signs of poikiloderma, or changes in appearance of the skin. In these cases, 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. The healthcare provider may recommend additional steps to manage or reduce the risk for 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. Managing the risk for bone and blood cancer can be a joint effort of the healthcare provider and patient or family. There are certain signs and symptoms that indicate a cancer could be present. However, because the presence of 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 mutations in the gene linked to BGS, REQL4, it is important to watch for bone pain, swelling or limp. For lymphoma, the type of blood cancer linked to mutations in REQL4, it may be important to follow up with a healthcare provider in the event of fever or unexplained weight loss.
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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