Achondroplasia

Authors:
Ravi Savarirayan, Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne
Valerie Cormier-Daire, Department of Genetics, Hopital Neckar Enfants Malades, Paris, France
David L. Rimon, Medical Genetics Birth Defects Center, Steven Spielberg Pediatrics Research Center, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California

Achondroplasia is the most common form of disproportionate short stature (dwarfism) with an estimated incidence of 1 per 20,000-30,000 live births. This type of dwarfism has been recognised for more than 4000 years, and can be seen depicted in many ancient statues and drawings. Achondroplasia is inherited as an autosomal dominant trait with approximately 75% of cases re[resenting new dominant mutations. The molecular defects underlying achondroplasia have recently been elucidated and comprise heterozygous mutations in the fibroblast growth factor receptor 3 (FGFR3) gene located on the short arm of chromosome 4. This gene encodes a tyrosine kinase cell surface receptor, and one specific gain-of-function mutation (G1138A), resulting in a glycine to arginine substitution in the transmembrane domain of FGGR3, is responsible for the vast majority (approx. 98%) of cases, and is the most common known mutation in humans.

Diagnosis of achondroplasia is usually made at or around birth, based on the typical appearance of these infants comprising; disproportionate short stature with short limbs, especially the most proximal (rhizomelic) segments, redundant folds of skin overlying the shortened limbs, short and broad hands and feet with a "trident" configuration of the digits, a shortened thorax with relatively long abdomen, limitation of elbow extension, and a characteristic facial appearance with a disproportionately large head, prominent forehead, depressed nasal bridge, flat midface, and a short, upturned nose. The clinical diagnosis is confirmed by the specific radiographic features of the condition, which include a large skull with relatively small cranial base, narrow foramen magnum, short, flat vertebral bodies, lack of normal increase in interpediculate distance from upper lumbar vertebrae caudally, short pedicles with narrow vertebral canal, square-shaped lilac wings, short narrow sciatic notches, flat acetabular roof, short limbs with short thick tubular bones, broad and short metacarpals and phalanges, fibular overgrowth, and short ribs.

The diagnosis of achondroplasia can now be made before birth by molecular testing for the specific FGFR3 mutation in families with a prior history of the condition. Like many other skeletal dysplasias, the diagnosis of achondroplasia can be suspected by the use of prenatal ultrasonography, although it cannot be made until relatively late in pregnancy because shortening of the long bones becomes manifest only after 24 weeks of gestation.

Hypochondroplasia and thanatophoric dysplasia are related conditions, also due to mutations in the FGFR3 gene. However, achondroplasia can be readily distinguished from these, as the changes in hypochondroplasia are milder and those in thanatophoric dysplasia much more severe and almost invariably lethal.

The majority of individuals with achondroplasia are of normal intelligence, have a normal lifespan, and lead independent and productive lives. These individuals, however, face many potential medical, psychosocial and architectural challenges, secondary to their abnormal skeletal development and subsequent disproportionate short stature. The mean final adult height in achondroplasia is 130 cm for men and 125 cm for women and specific growth charts have been developed to document and track linear growth, head circumference and weight in these individuals. Human growth hormone and other drug therapies have not been effective in significantly increasing final adult stature in achondroplasia. Recently surgical limb lengthening procedures have been employed successfully to increase leg length by up to 12 inches.

There are many potential medical problems that a person with achondroplasia may experience during his or her life. In early infancy, the most potentially serious of these is compression of the cervico-medullary spinal cord secondary to a narrow foramen magnum, cervical spinal canal, or both. This complication may be manifest clinically by symptoms and signs of high cervical myelopathy, central apnea or profound hypotonia and motor delay and may, in some instances, require decompressive neurosurgery. Other potential complications in infancy include significant nasal obstruction that may lead to sleep apnea in a minority (3%) of cases, development of a thoraco-lumbar kyphosis, which usually resolves upon weight bearing and hydrocephalus in a small proportion of cases (1%) during the first 2 years of life, which may require shunting, From early childhood, and as the child begins to walk, several orthopedic manifestations may evolve including progressive bowing of the legs due to fibular overgrowth, development of lumbar lordosis and hip flexion contractures. Recurrent ear infections with ensuing chronic serious otitis media are common complications at this time and may lead to conductive hearing loss with consequent delayed speech and language development. The older child with achondroplasia commonly develops malocclusion secondary to a disproportionate cranial base with a subsequent crowding of teeth and crossbite.

The main potential medical complication of the adult with achondroplasia is lumbar spinal canal stenosis, with impingement on the spinal cord roots. This complication may be manifested by lower limb pain and parasthesiae, bladder or bowel dysfunction and neurological signs and may require decompressive surgery.

Throughout their lives, some people with achondroplasia may experience a variety of psychosocial challenges. These can be addressed by specialised medical and social support of the individual and family, appropriate anticipatory guidance and by interaction with patient support groups such as the "Little People of America".

(Reproduced from the SSPA Journal, no. 163, March-April 2001).

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