# Handbook of Genetic Counseling/Achondroplasia-1

Achondroplasia

## Contracting

* Make small talk and establish rapport with the family
* Elicit the families concerns for
* Elicit Medical History
* Elicit Family History/Pedigree
* AAP Guidelines for Newborns:
* Examination-
** Confirm diagnosis
** Document all measurements on achondroplasia growth charts. Also include the following measurements: Occipital frontal circumference, body length, upper to lower segment ratio
* Guidance-
** Discuss AD inheritance
** Most individuals have normal intelligence and normal life expectancy
** Growth hormone is not an effective treatment
** Leg lengthening procedures are currently available
** Final height is approximately 4 foot for both males and females
** Discuss possible complications:
*** Kyphosis (associated with unsupported sitting)
*** Small foramen magnum-could lead to cord compression
*** Hydrocephalus- OFC size should be monitored
*** Spinal stenosis- rarely occurs in childhood; in older individuals it manifests as numbness, weakness, and altered deep tendon reflexes (individuals with severe kyphosis are at an increased risk for this)
** Psychosocial issues
*** Refer family to support group such as LPA or HGF
*** Remind parents that most individuals with achondroplasia lead productive, independent lives
*** Discuss with the family how to tell others about the diagnosis
*** Supply family with support material
** Discuss recurrence risks for future pregnancies

## Genetic Etiology

* Mode of inheritance- autosomal dominant- 75-80% arise from sporadic mutations. Correlated with advanced paternal age; virtually all new mutations arise in the father's germinal cells.
* Chromosome location- 4p16
* Molecular genetics-molecular origin arises from a mutation in one copy of the fibroblast growth factor receptor 3 gene.
** FGFR3 has an ORF of 2520 nucleotides, encoding an 840 residue protein
** >99% of cases are caused by a nucleotide change (either G to A= 98% of cases or G to C=1% of cases) at nucleotide 1138, resulting in a Gly380Arg amino acid substitution
** When FGFR3 is mutated, its normal inhibitory function is constitutively activated (turned on regardless of whether or not fibroblast growth factor is bound to it). This results in the increased inhibition of growth of cartilage cells.
** Mutations in achondroplasia can be interpreted as a gain-of-function mutation that activates the fundamentally negative growth factor exerted by the FGFR3 pathway.
* Penetrance- fully penetrant.
* Homozygosity for the mutation usually results in lethality

## Incidence

* Achondroplasia is the most commonly recognizable form of skeletal dysplasia
* Prevalence is estimated to be 1:26,000-28,000

## Clinical Features/Diagnostic Criteria

* Short stature 100%
* Rhizomelic (proximal) shortening of the limbs with redundant skin folds
* Limited elbow extension
* Short fingers held in a trident configuration
* Bowed legs
* Thoracolumbar gibbus (hump or protuberance) in infancy
* Exaggerated lumbar lordosis (swayback) develops when walking begins
* Large head with frontal bossing (prominence)
* Midface hypoplasia
* Modestly constricted chest

## Radiologic Findings

* Small skull base and foramen magnum
* Narrowing rather than widening of the interpediculate distance in the lumbar spine; short vertebral bodies
* Square iliac wings (square pelvis)
* Flat acetabulae (the cavity that provides the socket in which the head of the femur fits, narrowing of the sacrosciatic notch and characteristic radiolucency (penetrable by radiation) of the proximal femora
* Short, thick long bones
* Flared metaphyses (the growing portion of a bone)
* Short proximal and middle phalanges

## Occurrence/Recurrence Risks

* One parent with achondroplasia-
** Risk for each pregnancy is 50%
* Both parents have achondroplasia-
** 25% normal stature, 50% achondroplasia, 25% homozygous achondroplasia-lethal

## Natural History/Life Span

* Most individuals with achondroplasia have a normal lifespan
* These individuals are at an increased risk for premature death
** Usually the risk arises in infancy or childhood
** One study found a 7.5% increased risk for death in the first year.
** Usually associated with foraminal compression of the upper cervical cord or lower brain stem
** Overall, mean survival is 10% less than in the general population

## Testing

* Diagnostic-
** Clinical diagnosis is a reasonable approach, FGFR3 molecular testing is reserved for rare instances in which the clinical diagnosis is in doubt
** Molecular test is both straightforward and currently available
** The molecular PCR-based test is a direct mutation test that looks for a nucleotide change at the 1138th nucleotide.
* Prenatal-
** Can be done in a high risk pregnancy, in which one or both parents are affected
*** Uses DNA extracted from fetal cells (First, the mutation must be identified in the affected parent)
** Can also be done in a low risk pregnancy. Routine ultrasound may reveal short fetal limbs (usually not apparent until the 3rd trimester)
** Individuals with this indication may be offered amniocentesis so that a diagnosis can be confirmed/rejected.

## Explanation of Findings + Management/Treatment Options

* Growth and Feeding-
** Height/length should be monitored at each visit and plotted on achondroplasia specific growth charts.
** Measures should be taken during adolescence to monitor/prevent obesity
** No treatment will reverse the growth deficiency
** Growth hormone therapy has not significantly affected growth
** Extended limb lengthening techniques has been shown to increase height by up to 12 inches. Procedure involves cutting through the bone, and stretching it as the fractured region heals
* Development and Behavior-
** Overall individuals have normal cognitive development and function but they also have delayed and unusual motor development
** Some have language related problems-may be due to high frequency of chronic ear infections/hearing loss
** A very small amount will have severe learning problems or MR
** Hypotonia may be indicative of problems at the craniocervical junction
** Assessment for special needs is crucial
** Various adaptive devices such as stools and furniture modifications can be used to assist in short stature/hypotonia needs.
* Neurological-
** Hydrocephalus-
*** Assessment of ventricular size and volume of extra-axial fluid by ultrasound, MRI, or computerized tomography at diagnosis
*** All children should have serial HC measurements plotted on achondroplasia specific growth charts every 1-2 months until 1 year of age and then at each visit thereafter.
*** Signs of increased intracranial pressure include, accelerated head growth, bulging fontanel, lethargy or irritability, unexplained vomiting and headaches.
*** If any of these signs occur, MRI should be done and compared to the one obtained at diagnosis
*** If hydrocephalus has developed, shunting should be performed- prognosis is usually favorable
** Cervicomedullary Junction Constriction-
*** Every infant with Achondroplasia has a small and often misplaced foramen magnum due to abnormal growth of the endochondral cranial base
*** Causes risk for apnea-associated death or paralysis
*** These apnea related deaths often arise due to compression at the craniocervical junction, resulting in damage to the respiratory control centers in the lower medulla.
*** Compression can also result in high cervical myelopathy, which leads to hypotonia, weakness, hyperreflexia, asymmetric reflexes and ankle clonus.
*** Doctors should carefully examine the patient
*** Neuroimaging- tomography or MRI of the brain
*** Overnight sleep study in a sleep center should be performed
*** Parents and care providers should be counseled concerning careful neck support and handling. All strollers, jumpers, baby seats etc. should support the head, and limit movement.
*** If evidence of cord compression is present (from MRI) surgical decompression should be done immediately. Approximately 8% of individuals with achondroplasia undergo this type of surgery.
* Respiratory-
** Individuals with achondroplasia have small thoraces. This may result in decreased effective lung volumes, decreased respiratory reserve, and increased hypoxemia.
** Snoring is a uniform feature and should not be reflective of an obstruction of the airway
** Obstruction of the airway is common in individuals (#'s vary according to study)
*** May be due to hypoplasia of the cranial base and midface (resulting in diminution of the airway size) as well as hypertrophy of the lymphatic ring
** In some, appropriate positive airway pressure at night is used to maintain appropriate oxygen saturations.
** Sleep studies are recommended
** Surgical removal of the tonsils and adenoids may be necessary
** Tracheostomy may be needed in rare occasions (2% or less)
* Ears and Hearing-
** Middle ear dysfunction is a frequent complication, >50% have it severe enough to require myringotomy and ventilation tube placement
** ENT evaluation should be done at 6months of age and then every 6-9 months throughout preschool.
** Hearing loss may result in speech and language delays. In these cases, a referral should be made for speech and language therapy.
* Musculoskeletal-
** Kyphosis-
*** Present in 90-95% of infants
*** Usually spontaneously resolves
*** Clinical evaluation of the spine every 6 months through 3 years of age
*** If kyphosis is moderate or marked, radiographic assessment should be obtained
*** Parents should be counseled against allowing unsupported sitting during the first year of life
*** Bracing may be needed if the radiograph shows and irreversible curve of >30°
*** Surgical intervention may be necessary
** Lumbosacral Spinal Stenosis-
*** Stenosis of the entire spinal canal is uniformly present; more problematic in adults
*** Symptoms include: numbness, dysesthesias, radicular pain, leg weakness, clumsiness, gait changes, problems associated with bowel and bladder dribbling
*** MRI will assess the severity and level of the stenosis
*** Intervention methods include: neurosurgical laminectomy,
*** Decompression laminectomy usually results in some improvement of symptoms and function. Only 50% of patients show long-term benefits, additional surgery is often needed.

## Knee instability

* Nearly all young individuals with achondroplasia have knee instability.
* Hyperextension of between 20-70°
* Contributes to the motor delays seen in these individuals
* Bracing may be needed for severe knee instability (rare)
** Varus deformity-
*** Bowleg deformity
*** Assessment should be made while child is standing
*** Three weight bearing joints should be "in plumb"
*** Surgery may be needed for those with severe misalignment
** Other-
*** Most develop lordosis- swayback
**** May exacerbate risk for spinal stenosis in the lumbosacral region (in adults)
**** May be associated with pain at the apex resulting in chronic coccydynia
**** Coccydynia can be treated by sewing padding into the underwear
*** Hypermobility of the shoulders
*** Limitation of elbow movement
**** Surgical intervention for elbow limitation is not indicated, rather adaptive devices should be used
*** Hypermobile wrists
**** Discomfort and fatique of wrists from doing fine motor tasks may be relieved by a stabilizing brace
*** Orthodontics
**** Crowding of the teeth
**** Palatal expansion or braces

## Differential Diagnosis

* Thanatophoric dysplasia- nearly always a lethal condition; more severe findings than achondroplasia
* Homozygous achondroplasia
* Hypochondroplasia- milder findings than achondroplasia

## Common Psychosocial Issues

* Anxiety concerning the diagnosis
* Fear of the associated complications
* Adjusting and adaptation worries for the family
* Family support- support groups

## Support Groups

* The Little people of America (LPA)
    P.O. Box 745
    Lubbock, Texas 79408
    Phone: 888-LPA-2001
    [Website http://www.lpaonline.org]
* MAGIC Foundation for Children's Growth
    [www.magicfoundation.org http://www.magicfoundation.org]
* Human Growth Foundation
    [www.hgfound.org http://www.hgfound.org]

## Resources

* Pauli RM, Chapter 2. (2001). Management of Genetic Syndromes. Ed. Allanson JE, Cassidy SB. New York: Wiley-Liss, Inc.
* [www.geneclinics.org http://www.geneclinics.org]
* Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company.
* American Academy of Pediatrics Committee on Genetics (1995) Health supervision for children with achondroplasia. Pediatrics 95: 443-451.

## Notes

The information in this outline was last updated in 2002.