Paula and Bobby
Parents of Lillie
What is Achondroplasia; ACH?
Achondroplasia is characterized by dwarfism. The syndrome makes it difficult for the body to convert cartilage into bone, which leads to restricted bone growth. It is the most common cause of dwarfism. Affected individuals usually have short limbs, including the arms and legs, but a normal sized torso.
It is a congenital syndrome that is usually identified at birth. The majority of cases of the syndrome are not inherited, but are the first case in a family.
This syndrome is also known as:
What gene change causes Achondroplasia; ACH?
Mutations to the FGFR3 gene are responsible for the syndrome.
80% of cases are de novo, as in the first mutation in a family. The remaining cases are inherited.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
what are the main symptoms of Achondroplasia; ACH?
Short-limbed dwarfism is the most common symptom with adults rarely growing taller than 4-4.5 feet tall. A large head and forehead are also common.
Other physical characteristics of the syndrome include underdeveloped parts of the face, inward facing and bow legged knees, short fingers and toes, a curve of the lower back and overcrowding of the teeth.
Individuals may also experience weight control issues as well as health conditions related to issues with their respiratory and nervous systems.
Possible clinical traits/features:
Autosomal dominant inheritance, Obesity, Recurrent otitis media, Motor delay, Flared metaphysis, Neonatal short-limb short stature, Conductive hearing impairment, Ventriculomegaly, Brachydactyly, Malar flattening, Elbow dislocation, Spinal stenosis with reduced interpedicular distance, Skeletal dysplasia, Upper airway obstruction, Spinal canal stenosis, Trident hand, Macrocephaly, Sudden cardiac death, Frontal bossing, Midface retrusion, Small foramen magnum, Acanthosis nigricans, Genu varum, Generalized joint laxity, Depressed nasal bridge, Short femoral neck, Limb undergrowth, Hyperhidrosis, Hydrocephalus, Hyperlordosis, Kyphosis, Apnea, Brain stem compression, Abnormality of the metaphysis, Abnormality of the dentition, Abnormality of the ribs, Megalencephaly, Muscular hypotonia, Rhizomelia, Abnormal form of the vertebral bodies, Infantile muscular hypotonia, Anteverted nares, Narrow chest, Neurological speech impairment, Joint hypermobility, Limited hip extension, Limited elbow extension, Lumbar hyperlord
How does someone get tested for Achondroplasia; ACH?
The initial testing for Achondroplasia can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical Information on Achondroplasia; ACH
Achondroplasia is an autosomal dominant metaphyseal chondrodysplasia resulting in the most common type of short limbed dwarfism. The phenotype includes rhizomelic limb shortening, midface hypoplasia, frontal bossing, macrocephaly, narrow chest, hypotonia and joint laxity. Craniocervical junction stenosis is uniformly present, and if severe, can result in cervical myelopathy and sudden death in infancy. Achondroplasia is caused by a recurrent mutation in FGFR3.
CLINICAL DESCRIPTION (GENERAL):
Achondroplasia is the most common cause of dwarfism and results in disproportionate short stature, with average male heights of 131 cm and female heights of 124 cm (Horton et al., 1978). Short limbs with rhizomelic shortening are universal, as is brachydactyly with a usual trident configuration of the hands. Ligamentous laxity, joint hypermobility and hypotonia are almost uniformly seen in infancy and can result in delayed development (Fowler et al., 1997; Ireland et al., 2012). Intelligence is unaffected. Typical facial features include macrocephaly, midface retrusion with depressed nasal bridge and frontal bossing. Middle ear dysfunction resulting in recurrent otitis is common. Obstructive sleep apnea is seen due to midface retrusion, and a small chest exacerbates desaturations. Craniocervical junction stenosis is uniformly present (Hecht et al., 1989), and spinal stenosis presents later in life and is the most common medical issue in adults.
CLINICAL DESCRIPTION (BODY SYSTEMS):
Skeletal: Short-limbed short stature with brachydactyly, ligamentous laxity, rhizomelia, genu varum, limited elbow extension, thoraco-lumbar kyphosis in infancy changing to lumbar lordosis with assumption of orthograde posture, spinal stenosis
Neurologic: Hypotonia is universally seen and contributes to aberrant motor development, craniocervical junction stenosis can cause upper cervical myelopathy, benign increased extra-axial cerebrospinal fluid is present in the majority of patients but true hydrocephalus is seen in <5% (Pauli and Botto, 2018). Hydrocephalus is felt to arise secondary to increase venous pressure from small jugular foraminae.
Head, eyes, ears, nose and throat: Middle ear dysfunction, recurrent otitis (either serous or infectious), conductive hearing loss (Tunkel et al., 2012), obstructive sleep apnea, relatively narrow palate and mandibular overgrowth are almost universal and frequently require orthodontia.
Respiratory: Narrow rib cage with increased compliance of ribs in neonatal period can result in restrictive lung disease, central and obstructive sleep apnea are seen (Tasker et al., 1998)
Skin: Possible acanthosis nigricans (Smid et al., 2018)
Radiographic findings: Short robust tubular bones with generalized mild metaphyseal changes, narrow sacrosciatic notch combined with square ilia in the pelvis, horizontal acetabulae and proximal femoral radiolucency, narrowing of the interpedicular distance of the caudal spine may be seen (Langer et al., 1967)
MODE(S) OF INHERITANCE: Autosomal dominant
PREVALENCE: Approximately 1:25,000
LIFE EXPECTANCY: Risk of death in infancy has decreased due to screening tools for craniocervical junction stenosis (Hashmi et al., 2018). There seems to be an increased risk of cardiovascular disease and mortality in young adults (Wynn et al., 2007). Life expectancy may approach the same as average stature individuals with good management.
AGE OF ONSET: Birth
PRENATAL PRESENTATION: Short limbs, increased occipital frontal circumference and polyhydramnios seen on ultrasound. Most evident in third trimester.
ASSOCIATED GENE: FGFR3
RECURRENT MUTATIONS: Greater than 95-99% of mutations occur at nucleotide c.1138 and change a glycine to arginine at position 380. Most are G>A, but G>C is also found.
TYPE OF MUTATIONS: c.1138G>A (p.Gly380Arg); c.1138G>C (p.Gly380Arg) is seen in approximately 99%. Based on the mechanism of action, gene deletions and duplications do not result in achondroplasia.
GENOTYPE/PHENOTYPE CORRELATION: The same amino acid substitution affects almost all patients, therefore no genotype/phenotype correlation exists.
The term achondroplasia was coined by Parrot in 1878, although examples of people with achondroplasia go back millennia.
Dr. Leonard Langer described the radiological findings of achondroplasia in 1967. His descriptions of square ilia, narrow sacrosciatic notch, horizontal inferior edge of ilia (acetabular roof), lucent proximal femora, increased angulation at L-S junction, short broad tubular bones and slight cupping at the ends of the ribs would serve as the diagnostic gold standard for years. Mutations in FGFR3, which encodes the transmembrane receptor FGFR3, were found to be causative of achondroplasia in 1994 (Shiang et al., 1994). Shiang et al., (1994) and Bellus et al., (1995) showed the large majority of mutations occur at the same nucleotide (c.1138) and cause a glycine to be replaced by an arginine at position 308 of the mature protein. This homogeneity is virtually universal among patients. The mutation increases the activity of FGFR3, which subsequently suppresses enchondral bone growth via chondrocyte growth plate suppression (Deng et al., 1996).
Increased mortality was documented in a study by Hecht et al., (1987) and they hypothesized that foramen magnum stenosis contributed. In 1989, Hecht et al. documented smaller growth of the foramen magnum. Pauli et al., (1995) assessed foramen magnum size combined with data from polysomnograms and neurological exams to determine when craniocervical decompression may be needed. Danielpour et al., (2007) subsequently described changes in cerebrospinal fluid dynamics in patients with achondroplasia in flexion and extension using cine MRI. Cerebrospinal fluid flow stopped in flexion, and posterior medullary compression occurred in extension. Decompression benefitted these patients. Current recommendations include neuroimaging of the craniocervical junction at time of diagnosis along with polysomnography (Trotter et al., 2005). These recommendations and subsequent interventions have decreased the mortality in the first year of life (Hashmi et al., 2018).
The surgical burden is high for patients with achondroplasia. Most undergo surgery, most commonly ENT and orthopedic procedures (Hoover-Fong, 2017). The majority of children require long-lasting pressure equalizing tubes in addition to adenotonsillectomy (Legare et al., 2018). Guided growth procedures may decrease the need for derotational osteotomities in the future.
Prior to the 1980s, early diagnosis of achondroplasia occurred at birth or shortly thereafter. With the advent of routine prenatal ultrasound, prenatal diagnosis could occur, although it would become much more accurate and common after the discovery of the molecular etiology in 1994. Since 2010, approximately 32% of diagnoses are made prenatally, 60% within the first day of life and 76% by one month (Legare et al., 2018).
At Birth or Diagnosis:
• Plot weight, length and occipital frontal circumference on achondroplasia-specific growth curves (Horton et al., 1978; Hoover-Fong et al., 2007)
• Neuroradiologic imaging of craniocervical junction via MRI or CT. Thorough neurologic history and examination. Baseline neuroimaging of the brain to assess for hydrocephalus (Pauli and Botto, 2018)
• Baseline sleep study to look for sleep apnea associated with craniocervical junction stenosis (Pauli and Botto, 2018)
• Hearing screen at birth and again by 1 year of age
• Yearly growth measurements, including occipital frontal circumference, plotted on the appropriate achondroplasia growth chart (Horton et al., 1978; Hoover-Fong et al., 2007). The anterior fontanelle can close as late as age 6 years, therefore ongoing OFC measurements are important
• Monitoring for obstructive sleep apnea yearly by asking about snoring, glottal stops, daytime somnolence, difficult morning waking, bed wetting, irritability and depression. Obtain sleep study if concerns arise
• Yearly hearing screen until late elementary school years
• At least yearly evaluations with bone dysplasia specialist to monitor for kyphosis, lordosis and genu varum
• Complete neurological exam every year to monitor for spinal stenosis and cervical myelopathy due to craniocervical junction stenosis
• Ear, nose and throat evaluation if recurrent ear fluid or infections are present
• Inquire about adjustment to school and social situations
MANAGEMENT AND TREATMENT:
Craniocervical junction constriction: Intervention is likely needed if the following are seen: central hypopnea or apnea on sleep study; spinal cord compression or T2 abnormality on MRI or decreased size on computed tomography compared to documented achondroplasia standards; hyper-reflexia; or profound hypotonia (Pauli and Botto, 2018). Referral to pediatric neurosurgeon experienced in skeletal dysplasias for a likely decompression is warranted (Bagley et al., 2006). Approximately 20% of patients with achondroplasia may require craniocervical decompression (Hoover-Fong et al., 2017). Avoidance of activities that put stress on the craniocervical junction is recommended (trampolines, collision sports, gymnastics, etc.). Encourage rear-facing car seats as long as possible.
Little People of America, Inc. (LPA) https://www.lpaonline.org/
Restricted Growth Association UK https://rgauk.org/
Little People of Ireland (LPI): www.lpi.ie/
Little People of Canada https://comdir.bfree.on.ca/lpc/
Dwarfism Awareness Australia Inc. https://dwarfismawarenessaustralia.com/faqs/
Short Statured People of Australia (SSPA) https://www.sspa.org.au/
Little People of New Zealand https://lpnz.org.nz/
Short Statured people of Iraq: https://www.beyondachondroplasia.org/en/resources/patient-groups/associations/28-asia
Glory to Achondroplasia (GTA in Japan): http://glory-to-achondroplasia.com/
Little People of Pakistan: http://lppakistan.blogspot.pt/
Little People Association of the Philippines: https://www.facebook.com/LPAP2016/
Think Genetic: https://www.thinkgenetic.com/diseases/achondroplasia/organizations/106
(1) University of Wisconsin School of Medicine and Public Health
DATE OF UPDATE:
December 20, 2018
* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]
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