Achondrogenesis is a group of hereditary diseases belonging to the class of severe skeletal dysplasia, often leading to antenatal death or death at an early age. The main manifestation of these pathologies is a sharp violation of the processes of ossification, which is externally manifested by shortening of the limbs, underdevelopment of the ribs, chest, spine. Diagnosis is made on the basis of X–ray data, as well as genetic studies – the search for mutations in the genes associated with achondrogenesis. There is no specific treatment, only supportive therapy and resuscitation measures are possible.
General information
Achondrogenesis is several genetic diseases characterized by underdevelopment of bone and cartilaginous elements of the skeleton. The term “achondrogenesis” was proposed in 1952 by the Italian physician Marco Fraccaro, one of the forms of this pathology is named in his honor. Based on radiological data, three types of achondrogenesis are currently distinguished (1a, 1b, 2), which are characterized by a different way of inheritance and have a difference in clinical course. By methods of genetics, it was found out that each form of achondrogenesis corresponds to a mutation of a certain gene – these genes encode proteins directly involved in the processes of ossification and formation of cartilage and bone tissue. The disease affects both boys and girls with equal probability, the incidence is determined only for achondrogenesis type 2 and is approximately 1:50,000 newborns. The mechanism of inheritance is both autosomal dominant and autosomal recessive, however, given the severity of achondrogenesis and the fact that most patients do not live to reproductive age, spontaneous somatic mutations play an important role in the development of the disease. In total, about 100 cases of pathology have been reliably described.
Causes
Violations of the formation of skeletal elements during achondrogenesis are caused by mutations of genes that encode proteins involved in the formation of connective tissues. Thus, the cause of type 1a achondrogenesis (Houston-Harris syndrome) is disorders in the structure of the TRIP1 gene localized on chromosome 17 – it encodes protein 210 associated with the Golgi complex and beta-receptors for thyroid hormones. A mutation of this type is inherited by an autosomal recessive mechanism, that is, a child with achondrogenesis can be born to healthy heterozygous parents with a probability of 25%. Defects in the structure of protein 210 caused by mutation lead to numerous disorders of the formation of not only the skeleton, but also the heart and lungs, which most often causes the death of a child shortly after birth.
Achondrogenesis type 1b (Fraccaro syndrome) is caused by a mutation of the SLC26A2 gene localized on the 5th chromosome. It encodes a sulfate ion transporter protein that is directly involved in the sulfonation of proteoglycans of connective tissues, mainly cartilage. Violations of this process due to a carrier defect lead to a slowdown in the formation of the intercellular matrix in cartilage tissue, and also stop the formation of endochondral bones, which leads to achondrogenesis. In neonatology, there are other hereditary dysplasias caused by a mutation of the SLC26A2 gene – in particular, atelosteogenesis. Mutations of this gene leading to achondrogenesis are inherited by an autosomal recessive mechanism.
Achondrogenesis type 2 (Langer-Saldino syndrome) is the most common pathology of this group. It is caused by a mutation of the COL2A1 gene located on the 12th chromosome, it encodes the type 2 collagen protein of the alpha-1 class. This protein is a structural element of cartilage and bone tissue, so defects in its structure make it impossible for the normal formation of the skeleton and lead to achondrogenesis. Mutations of the COL2A1 gene can be inherited by an autosomal dominant mechanism, but spontaneous de novo mutations play the greatest role in the occurrence of type 2 achondrogenesis. This variety is considered the mildest form of skeletal dysplasia and, according to the observations of neonatologists, is characterized by a longer life expectancy than with other variants of achondrogenesis.
Classification
Currently, there are three clinical forms of achondrogenesis, while type 1 (Parenti-Fraccaro syndrome) is divided into two varieties – 1a and 1b.
Achondrogenesis type 1a is caused by a mutation of the TRIP1 gene localized on the 17th chromosome, inherited by an autosomal recessive mechanism. This disease has such features as rib fractures, the presence of spiny processes in the proximal metaphysis of the femurs and frequent underdevelopment of internal organs, mainly the heart and lungs.
Achondrogenesis type 1b – caused by a mutation of the SLC26A2 gene located on the 5th chromosome, is also inherited by autosomal recessive principle. In this form of pathology, the integrity of the chest is usually preserved, thorny processes are found in the distal metaphyses of the femurs during X-ray examination. Histological examination of cartilage reveals a decrease in the volume of the intercellular matrix with an abundance of collagen fibers.
Achondrogenesis type 2 is caused by a mutation of the COL2A1 gene located on the 12th chromosome, the mechanism of inheritance is autosomal dominant, but spontaneous somatic mutations play an important role. The radiological features of this form of the disease is a sharp decrease in ossification of the spine and sacrum.
Data on the detection of the 3rd and 4th types of achondrogenesis are currently the subject of scientific controversy. Currently, geneticists have not confirmed the discovery of mutations of new genes that would cause such disorders.
Symptoms
The main manifestations of achondrogenesis are severe skeletal disorders having the character of dysplasia, often accompanied by other developmental anomalies. There are shortening of the limbs relative to the body up to their almost complete underdevelopment. The size of the head in patients with achondrogenesis is increased, hydrocephalus is often observed, the face is flat, the bridge of the nose is sunken. The abdomen is often swollen, the chest is reduced.
A fairly common phenomenon in achondrogenesis is micrognathia – underdevelopment of the lower jaw. Due to violations of the structure of the chest, as well as due to abnormalities in the development of the lungs and heart (especially in type 1a), respiratory and heart failure occurs, which in many cases causes the death of the patient.
Among other malformations in achondrogenesis, cleft of the soft and hard palate, deformities of the ear cartilages, corneal opacity are often detected. If a child is born alive, then the duration of his life ranges from several hours to several months, after which a fatal outcome occurs due to numerous developmental anomalies.
Diagnostics
The diagnosis of “achondrogenesis” is based on the assessment of the patient’s current status, X-ray data, genetic studies and the study of hereditary anamnesis and histological structure of cartilage. On bones x-ray, shortening of long tubular bones, ossification disorders of the vertebral column, ribs are detected, pathological fractures of the latter are often detected (especially with achondrogenesis type 1a). A decrease in ossification is also observed in the pelvic bones and on the sacrum. Thorny processes are found on the metaphyses of the femoral bones during achondrogenesis.
In the case of achondrogenesis type 1a, histological examination of cartilage reveals the preservation of the intercellular matrix, chondrocytes have a large number of inclusions in the form of vacuoles. In type 1b, on the contrary, there is a sharp decrease in the volume of intercellular matter, while a large number of collagen fibers are observed, which often surround chondrocytes in the form of a dense cocoon. The histological picture in type 2 achondrogenesis can be quite diverse – from the complete absence of fibers in the matrix to a picture similar to type 1b disease.
The genetic diagnosis of achondrogenesis is performed by sequencing the COL2A1 and SLC26A2 genes in order to detect mutations. With respect to the SLC26A2 gene, it is also possible to diagnose carriage in healthy heterozygotes. The study of hereditary anamnesis is justified only in relation to achondrogenesis of types 1a and 1b, which have an autosomal recessive inheritance mechanism. Type 2 in the vast majority of cases occurs due to a de novo mutation, so the search for similar disorders in relatives does not make sense. Prenatal diagnosis of achondrogenesis using ultrasound and genetic analysis is also possible – the material is taken by amniocentesis.
Treatment and prognosis
There is currently no specific treatment for achondrogenesis, only supportive therapy is possible. It comes down to resuscitation measures, support of breathing and blood circulation of the patient. The prognosis is extremely unfavorable, if the child was born alive, then his life time ranges from several hours to several months. Death in most cases occurs due to respiratory failure caused by an anomaly of the structure of the chest and defects of internal organs associated with achondrogenesis.