Achondrogenesis is a group of severe disorders that affect the cartilage and bone development. These conditions are characterized by a small body, short limbs, and other skeletal abnormalities.
Achondrogenesis is a group of rare skeletal dysplasias characterized by extreme shortening of the arms and legs about the trunk, abnormal development of ribs, vertebra, and other skeletal abnormalities. The health problems associated with these conditions are life-threatening and most affected infants are stillborn or die shortly after birth due to respiratory failure. All types of achondrogenesis are genetic conditions; type IA and type IB, are autosomal recessive disorders, whereas achondrogenesis type II is an autosomal dominant disorder. All types of achondrogenesis are very severe skeletal dysplasias usually detected by prenatal ultrasound examination as early as week 14-17 of gestational age.
The term achondrogenesis was first used in the medical literature in 1952 by an Italian pathologist named Marco Fraccaro. Achondrogenesis is derived from Greek and means “not producing cartilage.” Achondrogenesis belongs to a group of skeletal dysplasias, (also called osteochondrodysplasias), a broad term for a group of disorders (about 450 clinical diagnoses) characterized by abnormal growth or development of cartilage and bone.
Causes
Mutations in the TRIP11, SLC26A2, and COL2A1 genes cause achondrogenesis in type 1A, type 1B, and type 2, respectively.
Each type of achondrogenesis is caused by a mutation in a specific gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Achondrogenesis type 1B is the most severe of a spectrum of skeletal disorders caused by mutations in the SLC26A2 gene. This gene provides instructions for making a protein that is essential for the normal development of cartilage and its conversion to bone. Mutations in the SLC26A2 gene cause the skeletal problems characteristic of achondrogenesis type 1B by disrupting the structure of developing cartilage, which prevents bones from forming properly.
Achondrogenesis type 2 is one of several skeletal disorders that result from mutations in the COL2A1 gene. This gene provides instructions for making a protein that forms type II collagen. This type of collagen is found mostly in cartilage and in the clear gel that fills the eyeball (the vitreous). It is essential for the normal development of bones and other connective tissues that form the body’s supportive framework. Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules, which prevents bones and other connective tissues from developing properly.
The gene mutations that cause achondrogenesis type IA and type IB are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person is a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.[rx]
All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.
Achondrogenesis type IA is caused by mutations in the TRIP11 gene. Achondrogenesis type IB is caused by mutations in the SLC26A2 gene. These two genes are required for the efficient cellular transport of certain cartilage proteins needed to build the skeleton and other tissues. Mutations of the TRIP11 gene result in deficiency of the Golgi microtubule-associated protein 210. This protein is found in most cell types of the body. The protein product of the SLC26A2 gene is a sulfate transporter that is involved in the proper development and function of cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted into bone.
The gene mutation that causes achondrogenesis type II is caused by a so-called autosomal dominant change in the COL2A1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. Most cases of achondrogenesis type II are caused by a new (de novo) mutation in the COL2A1 gene, which means that the risk for the parents of an affected infant to get another child with the same disease is not higher than 1%. This gene encodes collagen type II. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Collagen type II is most prevalent in cartilage and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.
There are very rare cases where siblings of infants with achondrogenesis type II have been affected. This is most likely due to the presence of more than one cell line in the egg or sperm from a parent (germline mosaicism). In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the COL2A1 gene mutation, while other germ cells contain normal COL2A1 genes (“mosaicism”). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene COL2A1 mutation, leading to the development of achondrogenesis II, while the parent does not have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation before pregnancy. Testing during early pregnancy may be available and is best discussed directly with a genetic specialist.
Symptoms
Achondrogenesis is characterized by premature birth, abnormal accumulation of fluid in the body (hydrops fetalis), and a head that may be abnormal in shape and less ossified. The head may look disproportionately large because the body is small. In addition, affected individuals have extremely short limbs and ribs, short neck, flat vertebrae, and many other bones of the skeleton that are not properly developed. In infants born with this disorder, the abdomen is prominent and the thoracic cage is small. Other abnormalities are incomplete closure of the roof of the mouth (cleft palate), corneal clouding, and ear deformities. The disorder is life-threatening either before birth or shortly after birth usually due to the underdeveloped thorax and small lungs.
Achondrogenesis type IA (Houston-Harris type) is characterized by varying facial abnormalities (flat face, protruding eyes, and protruding tongue or only minor facial anomalies), short trunk and limbs, short beaded ribs, and thin skull bones (deficient ossification of the skull). Bone formation is abnormal in the spine, pelvis, and extremities, but the degree of the severity of skeletal involvement may be variable. However, a small thorax leads to underdevelopment of the lungs and death soon after birth.
Achondrogenesis type IB (Fraccaro type) is characterized by a short trunk and limbs, a narrow chest, and a prominent abdomen. Affected infants may have a protrusion around the belly button (umbilical hernia), or near the groin (inguinal hernia), and have short fingers and toes with feet turned inward. The face may be flat, the palate may be cleft and the neck is usually short. In some cases, the soft tissue of the neck may be abnormally thickened. Achondrogenesis type IB is sub-classified as a sulfation disorder, a small group of disorders associated with mutations in the gene SLC26A2. This group includes diastrophic dysplasia and recessive multiple epiphyseal dysplasias, which are milder conditions. It is important to note that one diagnosis does not change to another while the baby is developing, even if the genetic changes are located in the same gene.
Achondrogenesis type II (Langer-Saladino type) is characterized by a narrow chest, abnormally small or short bones in the arms and/or legs, thin ribs, a flat vertebra, or deficient ossification of vertebral bodies, underdeveloped lungs, small chin, cleft palate, and club feet. Bone formation is abnormal in the spine and pelvis. Abnormal accumulation of fluid may occur (hydrops fetalis) and the abdomen may be enlarged.
Diagnosis
Achondrogenesis is diagnosed by physical features, X-ray (radiographic) findings, and examination of tissue samples under a microscope (histology). Molecular genetic tests for mutations in the SLC26A2 gene can be used to confirm the diagnosis of achondrogenesis type 1B.
Prenatal diagnosis of achondrogenesis by ultrasound is possible after 14-15 weeks of gestation. Prenatal diagnosis by chorionic villus sampling (10-12 weeks gestation) or amniocentesis (15-18 weeks gestation) is possible if the specific gene mutations have been identified in a family member.
Clinical Diagnosis
Achondrogenesis type 1B (ACG1B) is a perinatal lethal disorder with death occurring prenatally or shortly after birth. The diagnosis is usually established with the following:
Clinical features
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Extremely short limbs with short fingers and toes
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Hypoplasia of the thorax
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Protuberant abdomen
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The hydropic fetal appearance is caused by the abundance of soft tissue relative to the short skeleton
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Flat face
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Short neck
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The thickened soft tissue of the neck
Radiographic findings. While the degree of ossification generally depends on gestational age, variability can be observed between radiographs taken at similar gestational ages; thus, no single feature should be considered obligatory:
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The disproportion between the nearly normal-sized skull and very short body length. The skull may have a normal appearance or be mildly abnormal (reduced ossification for age; lateral or superior extension of the orbits; micrognathia).
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Total lack of ossification of the vertebral bodies or only rudimentary calcification of the center. The vertebral lateral pedicles are usually ossified.
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Short and slightly thin (but usually not fractured) ribs
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Iliac bone ossification is limited to the upper part, giving a crescent-shaped, “paraglider-like” appearance on x-ray. The ischium is usually not ossified.
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Shortening of the tubular bones such that no major axis can be recognized. Metaphyseal spurring gives the appearance of a “thorn apple” or (for hematologic experts) “acanthocyte.” The phalanges are poorly ossified and therefore are only rarely identified on the x-ray.
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Only mildly abnormal clavicles (somewhat shortened but normally shaped and ossified) and scapulae (small with irregular contours) [Superti-Furga 1996]
Testing
Histopathologic testing. In ACG1B, the histology of the cartilage shows a rarified cartilage matrix partially replaced by a larger number of cells. After hematoxylin-eosin staining, the matrix appears non-homogeneous with coarse collagen fibers. The fibers are denser around the chondrocytes, where they can form “collagen rings.” After staining with cationic dyes (toluidine blue, alcian blue), which bind to the abundant polyanionic sulfated proteoglycans, normal cartilage matrix appears as a homogeneous deep blue or violet; in ACG1B, cartilage staining with these dyes is much less intense because of the defective sulfation of the proteoglycans.
Biochemical testing. The incorporation of sulfate into macromolecules can be studied in cultured chondrocytes and/or skin fibroblasts through double labeling with 3H-glycine and 35S-sodium sulfate. After incubation with these compounds and purification, the electrophoretic analysis of medium proteoglycans reveals a lack of sulfate incorporation [Superti-Furga 1994] which can be observed even in total macromolecules. The determination of sulfate uptake is possible but cumbersome and is not used for diagnostic purposes [Superti-Furga et al 1996b].
Molecular Genetic Testing
Gene. SLC26A2 (known previously as DTDST) is the only gene in which mutation is known to cause ACG1B [Superti-Furga et al 1996b].
Treatment
Treatment of achondrogenesis is symptomatic and supportive and involves palliative care, in which physicians attempt to reduce or minimize pain, stress, and specific symptoms associated with the disorder. Genetic counseling is recommended for families with an affected child. Psychosocial support for the entire family is essential as well.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify the genetic status of family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Achondrogenesis type 1B (ACG1B) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
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The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a pathogenic variant in SLC26A2. Note: Parental testing is always recommended when pathogenic variants are identified in a proband to confirm the segregation of pathogenic variants in the family and confirm the carrier status of both parents. Results should always be discussed with the family in the context of a genetic counseling consultation.
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Heterozygous carriers are asymptomatic and have normal stature.
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No evidence suggests that carriers are at increased risk of developing the degenerative joint disease.
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To date, de novo pathogenic variants in the proband and germline mosaicism in the parents have not been reported.
Sibs of a proband
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At conception, each sib of a proband with ACG1B has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
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Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Offspring of a proband. ACG1B is a perinatal lethal condition; affected individuals do not reproduce.
Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.
Carrier (Heterozygote) Detection
Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.
Carrier detection in reproductive partners of a heterozygous individual is possible. The partners can be screened for the four most common pathogenic alleles: p.Arg279Trp, p.Cys653Ser, p.Arg178Ter, and c.-26+2T>C. When these four alleles are excluded, the risk of carrying a SLC26A2 pathogenic variant is reduced from the general population risk of 1:100 to approximately 1:330.
Related Genetic Counseling Issues
Family planning
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The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
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It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
DNA banking. Because likely, testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).
Prenatal Testing and Preimplantation Genetic Testing
High-risk pregnancies
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Molecular genetic testing. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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Ultrasound examination. Transvaginal ultrasound examination early in pregnancy is a reasonable alternative to molecular prenatal diagnosis because the testing is not invasive. However, the diagnosis can be made with confidence only at weeks 14-15, and reliability is highly operator-dependent.
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Biochemical testing. No data on prenatal functional biochemical testing (sulfate incorporation test on chorionic villus or fibroblasts) are available.
Low-risk pregnancies
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One parent is heterozygous and the other parent does not have one of the four common pathogenic variants. Follow-up of pregnancies by ultrasound is recommended [Canto et al 2007, Schramm et al 2009].
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Routine ultrasound examination. Routine prenatal ultrasound examination may identify very short fetal limbs ± polyhydramnios ± small thorax and raise the possibility of achondrogenesis in a fetus not known to be at risk. Subtle ultrasound findings may be recognizable in the first trimester, but in low-risk pregnancies, the diagnosis of skeletal dysplasia is usually not made until the second trimester.
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Molecular genetic testing. DNA extracted from cells obtained by amniocentesis can be theoretically analyzed to try to make a molecular diagnosis prenatally. However, the differential diagnosis in such a setting is very broad.
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