Achondroplasia

Ryan W Y Lee MD (Dr. Lee of Shriners Hospitals for Children in Honolulu and the John A Burns School of Medicine at the University of Hawaii has no relevant financial relationships to disclose.)
Michael V Johnston MD, editor. (Dr. Johnston of Johns Hopkins University School of Medicine and Chief Medical Officer at Kennedy Krieger Institute has no relevant financial relationships to disclose.)
Originally released March 3, 2011; last updated October 28, 2016; expires October 28, 2019

Overview

Achondroplasia is an autosomal dominant disorder of bone formation caused by mutations in fibroblast growth factor receptor type 3 (FGFR3). Characteristic features include disproportionate short stature, an enlarged head with frontal bossing, midface hypoplasia, rhizomelic shortening of the limbs, and trident-shaped hands. Targeted therapeutics in the form of tyrosine kinase inhibitors show promise in animal studies for the treatment of FGFR3-related skeletal dysplasias. In this article, the author discusses the clinical neurologic aspects and molecular mechanisms involved in achondroplasia.

Key points

 

• Achondroplasia is a disorder of bone formation primarily affecting the long bones of the extremities and the base of the skull, resulting in characteristic features of short extremities, a large head, and trident-shaped hands.

 

• Achondroplasia is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor type 3 (FGFR3), with about 80% of parents unaffected.

 

• Features of achondroplasia are so distinctive that physical exam and radiographic features are often sufficient to make a diagnosis.

 

• Concerning neurologic signs include hydrocephalus and spinal stenosis secondary to either small craniocervical junction or advanced lumbar lordosis.

 

• Management involves identification and treatment of comorbidities that cause functional and social impairment. Current experimental targeted therapeutic strategies include reduction in FGFR3 signaling through tyrosine kinase inhibitors, neutralizing antibodies, soluble FGFR-3, and statins.

Historical note and terminology

The term “achondroplasia” was proposed by Jules Parrott in 1878 to describe a condition of children and adults with disproportionate short stature (Parrot 1878). In 1900, Pierre Marie further investigated the physical and intellectual features of the patient population and introduced clinical terminology such as “trident-shaped hands” (Emerson 1909). Achondroplasia is a disorder of bone formation, primarily affecting the long bones of the extremities and the base of the skull, resulting in characteristic features of short extremities, a large head, and trident-shaped hands (Emerson 1909). Achondroplasia literally translates as “without cartilage formation,” but this is a misnomer because the problem does not involve formation of cartilage, but rather lies in the conversion of cartilage to bone (ossification). The clinical spectrum of disease ranges from hypochondroplasia (mild) to achondroplasia (severe).

Although Parrott and Marie are credited as the first modern scientists to clinically describe achondroplasia, archeological evidence in artisan and fossil records substantiate recognition of the condition in ancient Egyptian, Greek, and Roman civilizations (Kozma 2006). Additionally, a Korean study reported dwarfism-related skeletal dysplasias from the Joseon Dynasty (Woo et al 2015). Egypt was the most important source of information about achondroplasia in the Old World. Individuals with achondroplasia, or “dwarfs” as termed by archeological scholars, were assimilated into the daily life of ancient Egypt, and their disorder was not recognized as a physical disability. Artisan sculptures, paintings, and skeletal remains dating as early as 4500 BCE depict dwarfs employed as animal tenders, personal attendants, entertainers, and jewelers (Filer 1995). Several dwarfs attained high-ranking positions in the Old Kingdom (2700 to 2190 BCE) society and, as a result, were buried in extravagant tombs in royal cemeteries close to the Egyptian pyramids (Emery 1954; Ghalioungui and El Dawakhly 1965; Weeks 1970). There were at least 2 dwarf gods, Ptah and Bes, which represented regeneration and protection during childbirth, respectively (Kozma 2008). Furthermore, Egyptian moral teachings and wisdom writings commanded respect for dwarfs and other individuals with disabilities (Kozma 2006). Ancient Egyptian representations of achondroplasia continue to receive appreciation in contemporary art galleries such as the Walters Art Museum in Baltimore, Maryland (Kozma 2010). Techniques for appropriate methodology for identifying achondroplasia from the cranial skeleton alone have been proposed by archaeologists studying historic remains (Hefner and Warren 2016).

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