What is Baller-Gerold Syndrome?

By Emily Henderson, B.Sc.

Baller-Gerold syndrome (BGS) is a rare, unusual complication of the skull and limb bones. It is a congenital genetic disorder affecting the growth of the skull and limb bones. It is also referred to as craniosynostosis-radial aplasia syndrome and craniosynostosis with radial defects.

The skull, facial (craniofacial) area and bones of the forearms and wrists have a unique distorted appearance in BGS. Premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull occurs in infants with BGS (craniosynostosis). As a result, the infant may develop turribrachycephaly (head appears short, wide, and pointed at the top portion) or trigonocephaly (head appears triangular).

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Causes and Symptoms

In most cases, a non-working (mutated) gene called RECQL4 is the cause of Baller-Gerold syndrome. The RECQL4 gene plays a vital role in the stability of DNA, the body's instruction handbook. RECQL4 is involved in a variety of actions to fulfill this duty, including the repair of damaged DNA and the cell's reaction to stress. When the gene is mutated, RECQL4 is unable to perform these critical activities, resulting in BGS. TWIST and FGFR2 are the two other genes also found to have some association in the development of BGS.

The joints or seams (sutures) of the skull close prematurely in children with Baller-Gerold syndrome. This causes the head to grow upward, resulting in a pointed or cone-shaped look. The forearm's broad bone on the pinky side (ulnar) is short and bent, while the forearm's short bone on the thumb side (radius) is undeveloped or missing. These skeletal anomalies might affect both sides of the body or just one (asymmetric).

The carpal and metacarpal bones of the hand may be missing or have a distinct shape. Fine motor skills issues may be evident as a result of hand and arm abnormalities. The patella (kneecap) bone may also be underdeveloped or absent. Other skeletal deformities involving the spine and pelvis are present in some persons with BGS.

Another distinctive feature of patients with BGS is slow/delayed growth. Delayed growth in childhood can lead to a significantly lower height and weight than usual. In people with BGS, heart defects can also occur. Ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations are the most common heart defects that have been described in the medical literature to date on BGS.

Each of these terms refers to a specific change in the heart's structure. The severity of a heart defect is determined by the type of structural deformity and the unique circumstances of each case. Some heart defects may require surgery, while others may heal naturally over time.

Malformation of the lower limb (club feet and genu valgum), distinct facial features (widely-spaced eyes, cleft palate, and protruding forehead), rectovaginal fistula, anteriorly placed anus, malformations of the kidney are included in the wide spectrum of Baller-Gerold syndrome symptoms. Occasional intellectual disability, skin complications (hemangioma, poikiloderma, and hyperpigmentation) are also some important characteristic features observed in patients with BGS.

Pattern of Inheritance

BGS follows the inheritance pattern in an autosomal recessive form. When a child receives a mutated gene from both parents, the child develops recessive genetic disorders. Close blood relatives (consanguineous) have a higher likelihood of carrying the same faulty gene than unrelated parents, increasing the risk of having children with a recessive genetic condition.

F. Baller in 1950 reported a female patient with oxycephaly and a missing radius whose parents were third cousins. While reporting cases of Baller-Gerold Syndrome, Pelias et al. also detected parental consanguinity in 1981.

Epidemiology

The exact number of persons who have BGS is unknown, but it is thought to be less than one in a million. So far, less than 40 cases have been described in the medical literature. BGS has been recorded in limited quantities to identify whether it is more common in people of a certain ethnicity.

Diagnosis and Treatment

The diagnosis of Baller-Gerold syndrome includes clinical and genetic diagnosis. Clinical diagnosis is based upon the examination of the clinical findings present in the patients. The skeletal abnormalities may be diagnosed and further analyzed based on reports through X-ray and 3D-CT scan. Genetic diagnosis involves testing for the RECQL4 gene in the patients.

Baller-Gerold syndrome is treated by focusing on symptom management. It may include surgery to correct skeletal deformities such as broken skull bones. In addition, surgery to repair the hand may be required in some cases. Craniosynostosis can be evaluated by a neurosurgeon or a craniofacial specialist. Occupational therapy and orthopedic surgery may also be used to examine hand and arm function.

Patients with evidence of poikiloderma, or changes in the texture of the skin, may be referred to a dermatologist. The medical research on BGS suggests that it may increase the risk of some cancers of the skin, bones, and blood. Additional methods to manage or lower the risk of cancer for a person with BGS may be recommended by the healthcare professional.

In babies with an early fusion of a specific cranial suture and deformity of the upper limb extremities at birth, BGS should be investigated. To distinguish BGS from other genetic disorders with similar symptoms or indications, a thorough physical examination is required to discover crucial symptoms or signs, and a proper genetic test that includes the RECQL4 gene is required to confirm BGS.

References:

• (2021). BALLER-GEROLD SYNDROME; BGS (#218600). [Online] OMIM. Available at: https://www.omim.org/entry/218600#creationDate
• (2020). Baller-Gerold syndrome. [Online] NIH-National Center for Advancing Translational Sciences. Available at: https://rarediseases.info.nih.gov/diseases/1602/baller-gerold-syndrome
• (2019). Baller-Gerold Syndrome. [Online]National Organization for Rare Disorders. Available at: https://rarediseases.org/
• Kim, S, J. (2019). Baller-Gerold Syndrome in a Premature Infant with a Mutation in the RECQL4 Gene. Neonatal Med, 26(4):240-245. https://doi.org/10.5385/nm.2019.26.4.240
• 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; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1204/

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