Achondroplasia

Disease Characteristics

• macrocephaly, broad/prominent forehead, low nasal bridge/ midface hypoplasia
• Mental development: normal intelligence; Typically, affected individuals have normal cognitive function. However, developmental delays are the norm for motor skills and sometimes speech. The children are typically hypotonic, and many have joint hypermobility.
• Visible Physical Features
  • disproprortionate short stature with short limbs (have specific growth curves; affected children who do not follow these standards should be referred for further evaluation.);
  • adult height is approximately 4 ft (120 cm) for both men and women.
  • macrocephaly with frontal bossing
  • Midface hypoplasia may cause obstructive apnea
  • fingers are short and tapered, and there is a characteristic gap between the third and fourth fingers distally, resulting in a "trident" configuration to the hand. (think star trek sign)
  • High upper-segment to lower-segment ratio:  ('long torsos'). The ratio is greater than 1 in children with shortened limbs, as it is in individuals with hypochondroplasia or achondroplasia.
  • Lumbar lordosis
  • Narrow chest: predisposition to respiratory problems (extreme in homozygous form)
  • Joint hypermobility; but Limitation of elbow extension
  • Genu varum (bow legs)
  • Thoracolumbar gibbus in infancy
  • Mild to moderate hypotonia in infancy
  • Acanthosis nigricans is seen in persons with classic achondroplasia
• Other clinical features
• abnormal foramen magnum, caudal narrowing of spinal canal (occasionally hydrocephalus) - a significant number develop pyramidal signs in their lower limbs because of abnormal foramen magnum (compression or hydrocephalus)
• Hypothyroid
• Recurring otitis media is frequently a problem.
• Skeletal dysplasias
  • Narrowed skull base
  • Rhizomelic (proximal) shortening of the long bones
  • Normal trunk length
  • Lumbar lordosis
  • Square shape to pelvis (small, square iliac wings, horizontal acetabular roofs and narrowing of the greater sciatic notch; projecting medially from the acetabular roof is a bony spike)
  • Radiolucency of the proximal ends of the femora in the neonatal period)
  • Flattened vertebral bodies with narrowing or lack of increase in interpediculate distance in the lumbar spine

Genetics

• Mnemonic: dwarf on star trek - live long and prosper sign, (4 fingers = chrom 4)
• 80% sporadic, also Autosomal dominant
• FGFR3 is the only gene known to be associated with achondroplasia.
• Send DNA testing for Fibroblast Growth Factor Receptor 3 (FGF R3). 99% of cases have a G1138A substitution in FGF R3. Substitution G1138C occurs in 1%. Also request testing for hypochondroplasia.
• Associated with advanced paternal age (i.e. age >40) ;
• Homozygous achondroplasia, caused by the presence of two mutant alleles at nucleotide 1138 of the FGFR3 gene, is a severe disorder with radiologic changes qualitatively different from those of achondroplasia. Early death results from respiratory insufficiency because of the small thoracic cage and neurologic deficit from cervicomedullary stenosis [Hall 1988].

Epidemiology

• most common form of dwarfism (disproportionate short stature): 1 in 10,000 live births
• It affects both genders equally, and there is no ethnic or geographic predisposition.

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

• monitoring of height, weight, and head circumference
• measures to avoid obesity; Hunter et al (1996) recommend that children with achondroplasia stay within one standard deviation of the mean weight on the achondroplasia growth curves [Horton et al 1978].
• MRI or CT for evaluation of severe hypotonia or signs of spinal cord compression
• Obtaining history for possible sleep apnea, with sleep studies as necessary; adenotonsillectomy, continuous positive airway pressure (CPAP) by nasal mask, and tracheostomy to correct obstructive sleep apnea
• suboccipital decompression as indicated for lower-limb hyperreflexia or clonus and central hypopnea;
• surgery to correct spinal stenosis
• Evaluation for low thoracic or high lumbar gibbus if truncal weakness is present
• Referral to a pediatric orthopedist if bowing of the legs interferes with walking
• Careful neurologic examinations, with referral to a pediatric neurologist as necessary
• management of frequent middle-ear infections
• Speech evaluation by age two years
• educational support in socialization and school adjustment.

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].

References:

http://www.geneclinics.org/profiles/achondroplasia/details.html

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