Atelosteogenesis is a group of genetic pathologies–chondrodysplasia, which often lead to death at an early age or at the stage of intrauterine development. The main manifestations of the diseases are hypoplasia of the femoral and humerus bones in their distal parts, shortening of the ribs and narrowing of the chest, dislocations of the joints and curvature of the tubular bones. Diagnosis of atelosteogenesis is made on the basis of an X-ray picture of bone structures, the present status of the patient, the results of genetic studies. There is currently no treatment for any form of atelosteogenesis.
Q74.8 Other specified congenital abnormalities of the limb(s)
Atelosteogenesis (dysplasia de la Chapelle, neonatal bone dysplasia) is a form of lethal chondrodysplasia, which is characterized by high mortality at an early age. The most common form of pathology (type 2 atelosteogenesis) is inherited by an autosomal recessive mechanism. Types of diseases of the 1st and 3rd types are caused by mutations inherited by the autosomal dominant type, but the most common cause of such atelosteogenesis is de novo genetic damage.
The incidence is quite low – no more than 1:1,000,000, with the same probability the disease occurs in both boys and girls. There are isolated cases when patients lived to adulthood or old age, the vast majority of them suffered from type 2 atelosteogenesis and only one – type 3 disease. In practical pediatrics, it is considered one of the most severe forms of congenital chondrodysplasia.
The cause of atelosteogenesis is mutations in the genes FLNB (1st and 3rd types) and SLC26A2 (2nd type). The FLNB gene, located on the 3rd chromosome, encodes a protein called filamin B, which is involved in the construction of the intracellular framework, is part of numerous connective tissue structures. Forms of atelosteogenesis caused by damage to this gene are characterized by an autosomal dominant type of inheritance, but, given the high lethality of such mutations, spontaneous varieties are more common. Due to the violation of the structure of the protein filamin B, numerous anomalies of the skeleton, connective tissues, and internal organs occur, which often lead to stillbirth or death at an early age.
Type 2 atelosteogenesis caused by a mutation of the SLC26A2 gene is characterized by an autosomal recessive type of inheritance. This gene, located on the 5th chromosome, encodes the structure of the sulfate ion transporter protein, which plays a key role in the formation of cartilage proteoglycans. It is also involved in the formation of endochondral types of bones, therefore, when the structure of this protein is disrupted, anomalies of the development of the musculoskeletal system, characteristic of atelosteogenesis, occur. In addition, various disorders in the formation of internal organs are possible – hypoplasia of the lungs, congenital heart defects. All this leads to the fact that patients with type 2 atelosteogenesis quite often die at an early age.
Currently , there are three main types of the disease:
- Type 1 atelosteogenesis is caused by a lethal mutation of the FLNB gene, which occurs de novo in most cases. It is the most severe developmental anomaly, in many cases leading to antenatal fetal death.
- Type 2 atelosteogenesis (de la Chapelle dysplasia) is caused by a mutation of the SLC26A2 gene transmitted by an autosomal recessive mechanism. Antenatal or perinatal death in this form is rare, in most cases patients die in the first months or years of life from dysfunction of internal organs.
- Type 3 atelosteogenesis is also caused by a mutation in the FLNB gene, transmitted by an autosomal dominant mechanism or occurring spontaneously. Death usually occurs in the first weeks of life from severe underdevelopment of some organs.
In most cases, a neonatologist, relying only on the patient’s examination data and the X-ray picture, is not able to differentiate individual types of atelosteogenesis. Only a geneticist can do this by sequencing sequences of genes associated with the disease and determining the type of mutation.
The symptoms of the disease are characterized by a certain variability. In most cases, shortening of the upper and lower extremities, reduction of the size of the chest, withdrawal of the thumbs on the hands and feet are observed in sick newborns. The face is often flat, it shows pronounced hypertelorism, sinking of the bridge of the nose and the back of the nose.
In newborns, hypoplasia of the lung tissue is also detected, heart defects and laryngeal stenosis often occur, which are often the cause of death. If patients with atelosteogenesis do not die in the first days and weeks of life, then later they are diagnosed with severe scoliosis, equinovarus deformity of the foot, clubfoot. Death at an older age also occurs from concomitant disorders of the internal organs.
Diagnosis of atelosteogenesis is made on the basis of an assessment of the patient’s current status, data from X-ray studies and using methods of modern genetics. At the same time, the radiographs show the curvature of long tubular bones, the absence of foci of ossification in their distal areas. X-rays of the chest organs reveal shortening and ossification of the ribs, changes in the shape of the thoracic vertebrae, the presence of crevices in their bodies. During the examination, dislocations of the knee, hip and shoulder joints are often found. Ossification of the bones of the hand is disturbed.
Genetic methods for the diagnosis of atelosteogenesis are reduced to sequencing the sequence of the FLNB and SLC26A2 genes in order to identify and determine the type of mutations. Differential diagnosis should be performed with other forms of hereditary neonatal dysplasia (diastrophic dysplasia, Larsen syndrome). Prenatal diagnosis of atelosteogenesis using echographic or genetic (amniocentesis) methods is also possible.
There is no specific etiotropic treatment of any form of atelosteogenesis at the moment. Supportive treatment is reduced to resuscitation postpartum measures, in some cases – surgical interventions to correct heart defects or other internal disorders. The prognosis is extremely unfavorable, only a few percent of patients with atelosteogenesis survive to the age of one year, isolated cases have been described when patients lived to adulthood.