Let’s look at the condition that is the leading cause for dwarfism, Achondroplasia. I wanted to focus more on the genetics of the disorder to understand what is the mechanism that triggers the process. From PubMed Health at National Institute Of Health HERE
Causes, incidence, and risk factors
Achondroplasia is one of a group of disorders called chondrodystrophies or osteochondrodysplasias.
Achondroplasia may be inherited as an autosomal dominant trait, which means that if a child gets the defective gene from one parent, the child will have the disorder. If one parent has achondroplasia, the infant has a 50% chance of inheriting the disorder. If both parents have the condition, the infant’s chances of being affected increase to 75%.
However, most cases appear as spontaneous mutations. This means that two parents without achondroplasia may give birth to a baby with the condition.
Signs and tests
During pregnancy, a prenatal ultrasound may show excessive amniotic fluid surrounding the unborn infant.
Examination of the infant after birth shows increased front-to-back head size. There may be signs of hydrocephalus (“water on the brain”).
X-rays of the long bones can reveal achondroplasia in the newborn.
From the Wikipedia Article on Achondroplasia HERE
Achondroplasia is a common cause of dwarfism. It occurs as a sporadic mutation in approximately 75% of cases (associated with advanced paternal age) or may be inherited as an autosomal dominant genetic disorder.
Achondroplastic dwarfs have short stature, with an average adult height of 131 centimeters (51.5 inches) for males and 123 centimeters (48.4 inches) for females. Achondroplastic adults are known to be as short as 62.8 cm (24.7 inches). The disorder itself is caused by a change in the DNA for fibroblast growth factor receptor 3 (FGFR3), which causes an abnormality of cartilage formation. If both parents of a child have achondroplasia, and both parents pass on the mutant gene, then it is very unlikely that the homozygous child will live past a few months of its life. The prevalence is approximately 1 in 25,000.
In normal figures, FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones.
Causes
People with achondroplasia have one normal copy of the FGFR3 gene and one mutant copy. Two copies of the mutant gene are invariably fatal before or shortly after birth. Only one copy of the gene has to be present for the disorder to occur. Therefore, a person with achondroplasia has a 50% chance of passing on the gene to his or her offspring, meaning that there will be a 50% chance that each child will have achondroplasia. Since it is fatal to have two copies (homozygous), if two people with achondroplasia have a child, there is a 25% chance of the child dying shortly after birth, a 50% chance the child will have achondroplasia, and a 25% chance the child will have an average phenotype. People with achondroplasia can be born to parents that do not have the condition. This is the result of a new mutation.[2]
New gene mutations leading to achondroplasia are associated with increasing paternal age[3] (over 35 years old). Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during spermatogenesis; it is theorized that oogenesis has some regulatory mechanism that hinders the mutation from originally occurring in females (although females are still readily able to inherit and pass on the mutant allele). More than 99% of achondroplasia is caused by two different mutations in the FGFR3. In about 98% of cases, a G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine substitution (Bellus et al. 1995, Shiang et al. 1994, Rousseau et al. 1996). About 1% of cases are caused by a G to C point mutation at nucleotide 1138. The mutant gene was discovered by John Wasmuth and his colleagues in 1994.
In early 1994, linkage studies placed the achondroplasia gene on the short arm of human chromosome 4, distal to an anonymous marker, D4S43.
This region on chromosome 4 had been scrutinized for more than 10 years by scientists searching for the Huntington’s disease gene, and among the genes already known to reside in this area was fibroblast growth factor receptor 3 (FGFR3).
Proteins in the family of fibroblast growth factor receptors have a highly conserved structure. The protein spans the cell membrane and consists of three extracellular immunoglobulin-like domains, a lipophilic transmembrane domain, and intracellular tyrosine kinase domains. FGFR3 is expressed in cartilage and brain, and the mouse homologue is known to mediate the effect of fibroblast growth factor on chondrocytes.
By virtue of its known function and chromosomal localization, therefore, the gene encoding FGFR3 was a strong candidate for the achondroplasia gene.
Two groups of investigators have recently reported analyses of the FGFR3 gene in people with achondroplasia. Both groups found FGFR3 mutations in the DNA from affected persons and found no such mutations in the DNA from unaffected persons. In families with multiple affected members the identified mutations were inherited with the disorder. Amazingly, both groups found that every mutation was at exactly the same nucleotide in the transmembrane domain of the FGFR3 gene. In all but a very few other genetic disorders studied thus far, different affected families have different mutations in the disease gene. Shiang et al. found that 15 of the 16 achondroplasia mutations they analyzed had a guanine-to-adenine (G-to-A) transition at nucleotide 1138; the 16th mutation was a guanine-to-cytosine (G-to-C) transversion at the same nucleotide. (A point mutation is called a “transition” when a purine replaces a purine or a pyrimidine replaces a pyrimidine; it is called a “transversion” when a purine replaces a pyrimidine or vice versa.) Both mutations resulted in the substitution of arginine for glycine at amino acid 380 of the protein. Similarly, Rousseau et al. found that all 23 achondroplasia mutations in their series resulted in the same substitution at the same amino acid of the transmembrane domain of the FGFR3 protein. This high proportion of identical mutations (100 percent for the amino acid change), which is unprecedented for an autosomal dominant disorder in which more than 80 percent of cases represent new mutations, may explain the consistency of the phenotype in achondroplasia.
The achondroplasia mutations occur in a cytidine phosphate guanosine (CpG) dinucleotide in the FGFR3 gene sequence. CpG dinucleotides are known to be mutational “hot spots”; the cytosine residues adjacent to a guanine have a tendency to be methylated and then deaminated, resulting in the substitution of thymine for cytosine. This event will change a guanine to an adenine on the opposite (sense) strand which was the observed event in 37 of the 39 FGFR3 mutations reported to date. The mutation rate at nucleotide 1138 of the FGFR3 gene is therefore two to three orders of magnitude higher than the mutation rates calculated for CpG-mutation hot spots in the factor IX gene, making nucleotide 1138 the most highly mutable nucleotide currently known in the human genome. The reason for the exceptionally high mutation rate at this nucleotide, as well as the phenotypic effects of other mutations in the FGFR3 gene, remains to be explored.
Both the G-to-A transition and the G-to-C transversion at FGFR3 nucleotide 1138 create new recognition sites for restriction enzymes, making it exceptionally easy to test for the presence or absence of the mutations in genomic DNA. As a result, prenatal diagnosis of heterozygous achondroplasia, homozygous achondroplasia, and the homozygous unaffected state is now possible. The availability of prenatal diagnosis raises complex ethical issues concerning reproductive options for couples with achondroplasia. Since adults with achondroplasia are always heterozygous for the abnormal gene, it is possible for two affected parents to have children who are homozygous affected, heterozygous, or homozygous unaffected (i.e., of average stature). If only one parent is affected, the children will be either heterozygous or homozygous unaffected.
Other important advances have recently been made in our understanding of skeletal dysplasias. Hypochondroplasia, a skeletal disorder similar to but distinct from achondroplasia, seems to be linked to the same region on chromosome 4 as is achondroplasia, but no FGFR3 mutations have yet been identified in DNA from people with this condition. Reardon et al. recently reported FGFR2 mutations in patients with the Crouzon syndrome, the most common form of craniosynostosis. Through the use of positional cloning techniques, the gene for diastrophic dysplasia, an autosomal recessive skeletal dysplasia, was recently found to encode a sulfate transporter. Diastrophic dysplasia, like achondroplasia, is characterized by dwarfism, and it is especially common in Finland. Headway is being made in the identification of the genes causing several other skeletal dysplasias, including pseudoachondroplasia, multiple epiphyseal dysplasia, and cartilage hair hypoplasia. Thus, we appear to be on the threshold of a revolution in our understanding of the role of specific genes in normal and pathologic skeletal growth and development.
From MedScape Reference HERE…
Background
Achondroplasia, a nonlethal form of chondrodysplasia, is the most common form of short-limb dwarfism. It is inherited as a mendelian autosomal dominant trait with complete penetrance. Approximately 80% of cases are due to new or de novo dominant mutations with a mutation rate estimated to be 0.000014 per gamete per generation. Salient phenotypic features include disproportionate short stature, megalencephaly, a prominent forehead (frontal bossing), midface hypoplasia, rhizomelic shortening of the arms and legs, a normal trunk length, prominent lumbar lordosis, genu varum, and a trident hand configuration.
Pathophysiology
Achondroplasia is caused by mutations in the fibroblast growth factor receptor-3 (FGFR3) gene. At present, FGFR3 is the only gene known to cause achondroplasia.[1] This gene has been mapped to chromosome 4, band p16.3 (4p16.3). All causal mutations occur at the exact same location within the gene; hence molecular testing by targeted mutational analysis is easily done and interpreted. The mutations (G1138A, G1138C) cause an increased function of theFGFR3 gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage, decreased cellular hypertrophy, and decreased cartilage matrix production.
The nucleotide G1138A and G1138C mutations of FGFR3 account for 99% of the mutations resulting in a specific point mutation, hence an amino acid substitution.[2] About 98% of cases have the G1138A mutation resulting from a G-to-A point change. One percent of cases have a G-to-C point change at nucleotide 1138, causing the G1138C mutation. A rare missense mutation (Lys650Met) in the tyrosine kinase region of FGFR3 causes a disorder termed severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) . See Differentials.
Genetics of Achondroplasia
- Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Bruce Buehler, MD
Epidemiology
Frequency
United States
Frequency has not been documented in the United States.
International
Frequency is believed to be 1 case per 15,000-40,000 births worldwide. In 1986, Orioli et al reported on the frequency of all skeletal dysplasias in a study population of 349,470 live births and stillbirths. Based on their study, the prevalence rate for achondroplasia was estimated to be 0.5-1.5 cases per 10,000 births and the mutation rate to be 1.72-5.57 x 10-5 per gamete per generation.
Mortality/Morbidity
Sudden death within the first year of life is attributed to abnormalities at the craniocervical junction causing spinal cord compression. Central apnea occurs due arterial compression at the cervical level of the foramen magnum. The small foramen magnum present in these patients may also cause a high cervical myelopathy.
The risk of sudden death for infants with achondroplasia is 2-5%. This risk can be minimized with appropriate assessment of the craniocervical junction, which includes a thorough neurological history and examination, neuroimaging (either CT scanning or MRI), and polysomnography. If neurological abnormalities are detected, referral to medical center with neurosurgical consultation services is indicated.
Caregivers should use an infant carrier with a firm back that gives good neck support and to use a rear-facing car seat for travel as long as possible. Use of mechanical swings and carrying slings should be avoided to limit the potential for uncontrolled head movement.
Thoracolumbar kyphosis occurs in most infants with achondroplasia. Severe kyphosis is related to unsupported sitting of the infant before adequate trunk muscle strength has developed. Angular deformities of the extremities, premature degenerative joint disease, and spinal disorders are common clinical features.
Cervical instability is present in a large number of patients. Great care must be taken with manipulation of the neck, as would occur for preparation of intubation in general anesthesia. Uncontrolled neck movements could cause significant neurological compromise with spinal cord compression.
Obesity, when present, aggravates the morbidity related to lumbar stenosis, nonspecific joint problems, and cardiovascular risks. Based on the weight/height (W/H) curves developed by Hunter et al for boys and girls with achondroplasia, the mean W/H curve in children with achondroplasia matches the control curve until the children reach 75 cm in height. Beyond 75 cm, the weight in children with achondroplasia increases disproportionately to height. The Quetelet index or body mass index (BMI=W/H2) can be used to estimate weight excess in children ages 3-6 years; after that, the Rohrer index (RI=W/H3) should be used for children and adolescents ages 6-18 years.
Respiratory disorders are seen frequently, including apnea and abnormalities of gas exchange. Studies report that as many as 75% of children with achondroplasia have a pathologic apnea index (>30 episodes). Brainstem compression may contribute to central apnea whereas obstructive apnea may be due to midface structural abnormalities such as hypoplasia.
Severe upper airway obstruction occurs in less than 5% in children with achondroplasia. Tonsillectomy and adenoidectomy do not help resolve this obstruction very well in children with achondroplasia. Hypotonicity, a narrow trunk with a small thoracic cage and adenotonsillar hypertrophy all contribute to confining the airway and causing upper airway obstruction.
Children with achondroplasia who have respiratory dysfunction and obstructive sleep apnea (OSA) detected by polysomnography have associated cognitive deficits, as evident in children with OSA within the general population. Restrictive pulmonary disease, with or without restrictive airway disease, occurs in less than 5% of children younger than 3 years old. This risk is greater for those who live at higher elevations.
A study of school-aged children with achondroplasia reported CT findings, including kinking of the medulla and neuroanatomic abnormalities consistent with arrested hydrocephalus, including enlarged ventricles and hypoplasia of the corpus callosum. These CT findings are similar to those seen in children with compensated, unshunted hydrocephalus. The hydrocephalus may be due to increased intracranial venous pressure secondary to stenosis of the sigmoid sinus at the level of the narrowed jugular foramina.
Although their overall cognitive scores are within normal, children with achondroplasia may show mild deficits in visual-spatial tasks. This deficit has been identified in children with arrested hydrocephalus.
Motor milestones are usually delayed for the first year of life due to a large cranium and poor overall muscle tone (hypotonia). Language development is normal, if no conductive hearing loss is present.
Me: Overall I felt that the studying of the genetics and the mechanism that causes the disorder was something that I and the readers needed to do to understand.
Pingback: Complete List Of Posts - |