What is brachydactyly?

Risk Factors

The greatest risk factor for the development of brachydactyly is the inheritance of one of several disease-causing mutations. Brachydactyly can also result from embryologic disturbances and has been observed among infants exposed to drugs known to alter fetal development (teratogens); in this case, it is usually found in conjunction with other malformations.

Etiology and Genetics

Although brachydactyly was the first human trait to be ascribed an autosomal dominant Mendelian inheritance pattern, it has subsequently proven to be a genetic smorgasbord, demonstrating the concepts of incomplete penetrance (wherein carriers of causative mutations do not show evidence of disease), variable expressivity (differences in clinical presentation among individuals with the same mutation), and locus heterogeneity (multiple genes or gene combinations leading to the same phenotype). In addition, evidence suggests that certain forms of brachydactyly may be inherited as semidominant or autosomal recessive traits.

Brachydactyly can be inherited alone (isolated brachydactyly), in association with skeletal abnormalities, or as part of a syndrome. In 1951, Julia Bell developed a classification scheme for isolated brachydactyly based on the characteristic hand malformations found in family pedigrees. Categorization of brachydactyly still follows this general model of types A through E, with subtypes used to further delineate particular patterns of digit abnormalities. The majority of isolated brachydactyly types are very rare; however, brachydactyly types A3 and D are relatively common findings within certain populations.

Causative mutations have been identified for many, but not all, of the isolated brachydactyly types. Mutations in the Indian hedgehog (IHH) gene (2q35-q36) have been identified in families with brachydactyly type A1, although linkage has also been shown to a locus on 5p13.3-p13.2. Mutations in two separate genes have been associated with brachydactyly type A2: the bone morphogenetic protein receptor 1B (BMPR1B) gene (4q21-q20) and the growth and differentiation factor 5 (GDF5) gene (20q11.2). This divergence among families with a common phenotype exemplifies the genetic heterogeneity within brachydactyly.

The phenotype of patients with brachydactyly type B has been shown to correlate with the nature of the mutation in the receptor kinase-like orphan receptor 2 (ROR2) gene (9q22). Mutations in ROR2 have also been identified in patients with autosomal recessive Robinow syndrome. More recently, mutations in the noggin (NOG) gene (17q22) have been identified in patients with brachydactyly type B for whom ROR2 mutations were not detected.

The inheritance pattern of brachydactyly type C is not straightforward and has been suggested to be autosomal dominant, autosomal recessive, or semidominant. As observed for brachydactyly type A2, mutations in GDF5 have been identified in families with brachydactyly type C.

Both brachydactyly types D and E have been linked to mutations in the homeobox-containing (HOXD13) gene (2q31-q32).

Symptoms

Isolated brachydactyly is characterized by shortening of one or more digits and may affect the hands, feet, or both. Other finger abnormalities, including syndactyly (fused digits), clinodactyly (sideways deviation of the finger), or symphalangism (fused phalanges), may also be present. Syndromic forms of brachydactyly may be associated with skeletal defects (such as short stature, shortened limbs, and scoliosis), hypertension, cardiac malformations, intellectual disability, or a host of other abnormalities.

Screening and Diagnosis

Family history is a strong predictor of disease. The benign nature of isolated brachydactyly makes prenatal screening unnecessary, although it may be valuable for syndromic forms of the disease. Prenatal ultrasound performed from twelve to seventeen weeks of gestation has been used to successfully diagnose brachydactyly. Diagnosis based on analysis of DNA from the fetus is possible if the familial mutation is known.

Treatment and Therapy

Plastic surgery is an option to enhance hand function but is not applicable in most cases. If needed, hand function may also be improved through physical therapy. For those with syndromic brachydactyly, treatment of associated conditions (such as blood pressure medication for patients with hypertension) may be indicated.

Prevention and Outcomes

There is no method available for preventing brachydactyly occurrence among individuals who inherit disease-causing mutations. The prognosis for patients with isolated brachydactyly is generally favorable; the ability to achieve normal hand function is reliant on the extent and severity of the defect. In cases of syndromic brachydactyly, prognosis is influenced by the nature of the associated conditions.

Bibliography

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Firth, Helen V., Jane A. Hurst, and Judith G. Hall, eds. Oxford Desk Reference: Clinical Genetics. Oxford : Oxford UP, 2005. Print. .

Glorieux, Francis H., John M. Pettifor and Harald Jüppner. Pediatric Bone: Biology and Diseases.2nd ed. London: Academic P/ Elsevier, 2012. Print.

Goel, Ayhush, et al. "Brachydactyly." Radiopaedia.org. Radiopaedia.org, 2014. Web. 31 July 2014.

Pereda, Arrate, Intza Garin, Maria Garcis-Barcina, Blanca Gener, Elena Beristain, Ane Miren Ibañez, and Guiomar Perez de Nanclares. "Brachydactyly E: Isolated or as a Feature of a Syndrome." Orphanet Journal of Rare Diseases 8 (2013): 141. Print.

Temtamy, Samia A., and Mona S. Aglan. “Brachydactyly.” Orphanet Journal of Rare Diseases 3 (2008): 15. Print.