Disease Characteristics



Clinical course

Most individuals who have achondroplasia have a normal life span, but approximately 7% die suddenly in the first year. (due to central or obstructive apneas) Most of these deaths result from cervicomedullary junction compression due to abnormal shape or size of the foramen magnum. Affected children should be monitored carefully for signs of apnea, respiratory problems, exaggerated hypotonia, hyperreflexia, weakness, asymmetric reflexes, and ankle clonus. If cervicomedullary junction compression is suspected, magnetic resonance imaging of the area with cerebrospinal fluid flow studies may confirm the diagnosis. Surgical decompression of the foramen magnum has been highly successful if severe compression has not already occurred.

Although children who have achondroplasia are at increased risk for hydrocephalus, this is not typically life-threatening, and with appropriate intervention, the prognosis is favorable. As mentioned, respiratory difficulties may be a sign of cord compression, and occasionally there is restrictive lung disease, but lung disease is not a likely cause of death. Gastroesophageal reflux and cardiac arrhythmia are seen in children who have achondroplasia at about the same rate as in the general population, and these conditions are not associated with sudden death in affected individuals.

Obesity is a major problem in achondroplasia. Excessive weight gain is manifest in early childhood. Until a height of about 75 cm is reached, the mean weight-to-height ratio for children with average stature and children with achondroplasia is virtually identical. Above a height of 75 cm, the weight-to-height ratio for individuals with achondroplasia exceeds that of the general population [Hunter et al 1996]. In adults, obesity can aggravate the morbidity associated with lumbar stenosis and contribute to nonspecific joint problems and possibly to early mortality from cardiovascular complications [Hecht et al 1988].

The most common medical complaint in adulthood is symptomatic spinal stenosis involving L1-L4 [Thomeer & van Dijk 2002]. Lower lumbar levels are usually not involved. Aside from the spinal stenosis, adults with achondroplasia do not experience other specific medical complications. An increased risk of sudden death in the fourth and fifth decades has been reported [Hecht et al 1987]. The cause of this increased mortality is not known.

Recommendations for management of children with achondroplasia include

Genetic counseling.

Achondroplasia is inherited in an autosomal dominant manner. Over 80% of individuals with achondroplasia have parents with normal stature and have achondroplasia as the result of a de novo gene mutation. Such parents have a low risk of having another child with achondroplasia. An individual with achondroplasia who has a reproductive partner with normal stature has a 50% risk in each pregnancy of having a child with achondroplasia. When both parents have achondroplasia, the risk to their offspring of having normal stature is 25%; of having achondroplasia, 50%; and of having homozygous achondroplasia (a lethal condition), 25%. Prenatal molecular genetic testing is available.

Genetically Related (Allelic) Disorders

Other phenotypes associated with mutations in FGFR3 include:

* Hypochondroplasia
* FGFR-related craniosynostosis
* Thanatophoric dysplasia
* SADDAN dysplasia [Vajo et al 2000]. Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN dysplasia) is a rare disorder characterized by extremely short stature, severe tibial bowing, profound developmental delay, and acanthosis nigricans. Unlike individuals with thanatophoric dysplasia, those with SADDAN dysplasia survive past infancy. The three unrelated individuals with this phenotype who have been observed to date have had obstructive apnea, but have not required prolonged mechanical ventilation. An FGFR3 K650M mutation has been identified in all three individuals [Francomano et al 1996 , Bellus et al 1999]. Note that acanthosis nigricans may also be seen in persons with classic achondroplasia [Van Esch & Fryns 2004].


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