Achondroplasia

Published on 05/05/2015 by admin

Filed under Internal Medicine

Last modified 22/04/2025

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241 Achondroplasia

Instruction

Look at this patient.

Salient features

History

• Family history (autosomal dominant inheritance; however, 80% are new mutations)

• Paternal age (increases in frequency with increasing age of father at child’s birth).

Examination

• Dwarfism

• Bulging forehead

• Depression of the root of the nose

• Midface hypoplasia

• Shortened proximal extremities with hands have a ‘trident’ shape

• Trunk of normal size

• Exaggerated lumbar lordosis.

Diagnosis

This patient with short stature and normal trunk size has achondroplasia (lesion), which is caused by mutation of the gene for the fibroblast growth factor receptor (aetiology).

Questions

Is the lifespan reduced in these subjects?

No, they have a normal lifespan, although this has been disputed (Lancet 1998;352:1950).

How is the IQ affected in these patients?

IQ is normal.

Is the reproductive status affected?

Reproductive status is normal.

What are the complications of this condition?

• Hydrocephalus or compression of brainstem, spinal cord or nerve roots

• Impingement by an osteophyte or disc on the small spinal canal can cause neurological disturbance.

Advanced-level questions

What do you know about the genetics of achondroplasia?

• It is inherited as an autosomal dominant trait with complete penetrance. The gene FGFR3 on human chromosome 4, encoding fibroblast growth factor receptor 3, is mutated at location 1138, leading to replacement of guanine by adenine or cytosine (Cell 1994;78:335–42, Nature 1994;371:252). The change causes increased function of the gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in the growth plate cartilage, decreased cellular hypertrophy and decreased cartilage matrix production.

• Severe mutations in Trip11, which encodes a Golgi-associated microtubule-binding protein (thyroid receptor-interacting protein 11 or GMAP-210) causes a form of achondroplasia in mice, with defective glycosylation and cell transport of several proteins. TRIP11 mutations have now been found in humans with achondrogenesis type 1A (N Engl J Med 2010;362:206–16).

What do you know about idiopathic short stature?

Idiopathic short stature (also referred to as normal-variant short stature or short stature of undefined cause) is a diagnosis of exclusion. Growth hormone deficiency, intrauterine growth retardation, genetic or syndromic causes of short stature and other factors compromising growth, such as depression or psychosocial deprivation, should be excluded before making the diagnosis. Recombinant human growth hormone therapy was approved by the US Food and Drug Administration in 2003 for idiopathic short stature; the anticipated average height gain being 4 to 7 cm after several years of daily injections.

What do you know about Crouzon syndrome?

Crouzon syndrome is an autosomal dominant condition characterized by premature fusion of the cranial sutures (craniosynostosis); it has been shown to map to chromosome 10 and is associated with mutations of the gene for fibroblast growth factor receptor 2.

This syndrome has been depicted by aritists in several paintings, including the painter Velasquez in his portrait of Don Sebastian de Morra, a courtier of the Spanish King Phillip V.

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