Achondrogenesis Type 1b

Clinical characteristics.

Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. Death occurs prenatally or shortly after birth.

Diagnosis/testing.

The diagnosis of ACG1B rests on a combination of clinical, radiologic, and histopathologic features. SLC26A2 (DTDST) is the only gene in which mutation is known to cause ACG1B.

Management.

Treatment of manifestations: Palliative care for liveborn neonates.

Genetic counseling.

ACG1B is inherited in an autosomal recessive manner. 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both pathogenic alleles in the family are known and the carrier status of the parents has been confirmed. Ultrasound examination after 14-15 weeks’ gestation can be diagnostic.

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

• Extremely short limbs with short fingers and toes
• Hypoplasia of the thorax
• Protuberant abdomen
• Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton
• Flat face
• Short neck
• 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:

• 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).
• Total lack of ossification of the vertebral bodies or only rudimentary calcification of the center. The vertebral lateral pedicles are usually ossified.
• Short and slightly thin (but usually not fractured) ribs
• Iliac bone ossification limited to the upper part, giving a crescent-shaped, "paraglider-like" appearance on x-ray. The ischium is usually not ossified.
• 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 x-ray.
• 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].

Testing Strategy

To confirm/establish the diagnosis in a proband

• The diagnosis is first suspected on the basis of clinical and radiologic findings.
  Note: It is often difficult to distinguish between the three different forms of achondrogenesis: ACG1A, ACG1B, and ACG2 (see Differential Diagnosis).
• Histopathology of cartilage is recommended as the second diagnostic step.
• Molecular genetic testing is the preferred diagnostic test in probands with a clinical, radiologic, and/or histopathologic diagnosis of ACG1B: it allows precise diagnosis in the great majority of cases:
  • Although targeted analysis for pathogenic variants is available, recurrent pathogenic variants are found in only a small number of individuals with ACG1B; therefore, sequence analysis of the entire coding region may be considered a first-line molecular genetic test.
  • Parental DNA analysis for the pathogenic variants found in the proband is recommended to confirm segregation of the two alleles in both compound heterozygous and homozygous individuals.

Note: A biochemical test is usually not needed before molecular genetic testing.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Description

Achondrogenesis type 1B (ACG1B), one of the most severe chondrodysplasias, is a perinatal lethal disorder with death occurring prenatally or shortly after birth. The mechanism of the prenatal death is unknown. In the viable newborn, death is secondary to respiratory failure and occurs shortly after birth.

Fetuses with ACG1B often present in breech position. Pregnancy complications as a result of polyhydramnios may occur.

Clinical features of ACG1B include extremely shortened limbs, inturning of the feet and toes (talipes equinovarus), and brachydactyly (short stubby fingers and toes). The thorax is narrow and the abdomen protuberant. Frequently, umbilical or inguinal herniae are present.

Genotype-Phenotype Correlations

Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders that extends from lethal ACG1B to mild recessive multiple epiphyseal dysplasia (EDM4). Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with ACG1B, while pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996c, Karniski 2001].

Variant p.Arg279Trp is the most common SLC26A2 pathogenic variant outside Finland (45% of alleles); it results in the mild EDM4 phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) and atelosteogenesis type 2 (AO2) phenotypes when in the compound heterozygous state.

Variant p.Arg178Ter is the second-most common pathogenic variant (9% of alleles) and is associated with a more severe DTD phenotype or even the perinatal-lethal AO2 phenotype, particularly when combined in trans with the p.Arg279Trp pathogenic variant. This variant has also been found in some cases of more severe recessive multiple epiphyseal dysplasia (rMED) and of ACG1B, making it one of two pathogenic variants identified in all four SLC26A2-related dysplasias.

Variants p.Cys653Ser and c.-26+2T>C are the third most common pathogenic variants (8% of alleles for each).

Variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when present in trans with other pathogenic variants.

Variant c.-26+2T>C is sometimes referred to as the "Finnish" variant, because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous. c.-26+2T>C is the only other pathogenic variant that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Bonafé, unpublished results; Dwyer et al 2010].

The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (AO2 and DTD) if the second allele is a relatively mild pathogenic variant. Indeed, missense variants located outside the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of a null allele [Rossi & Superti-Furga 2001].

Penetrance

For pathogenic variants in SLC26A2, penetrance is complete.

Nomenclature

The term achondrogenesis (Greek for "not producing cartilage") was given by the pathologist Marco Fraccaro in 1952 to the condition observed in a stillborn with severe micromelia and marked histologic changes in cartilage. In 1939, Hans Grebe attributed the same name to the condition observed in two sisters with markedly short limbs and digits but normal trunk; this condition, although superficially similar to Fraccaro's achondrogenesis, became later known as Grebe chondrodysplasia or Grebe syndrome.

Subsequently, the name achondrogenesis was used to characterize the most severe forms of human chondrodysplasia, invariably lethal before or shortly after birth. In the 1970s, the heterogeneity of achondrogenesis was recognized. Using a combination of radiologic and histologic criteria, achondrogenesis type I (also called Fraccaro-Houston-Harris type) and type II (called Langer-Saldino type) were distinguished.

In the 1980s, a new classification of achondrogenesis (types I to IV) based on radiologic criteria was proposed; the classification did not prove helpful and was later abandoned.

In the late 1980s it was shown that achondrogenesis type II was caused by mutation of the gene encoding collagen II.

Borochowitz et al [1988] provided convincing histologic criteria for the further subdivision of achondrogenesis type I into types IA and IB, which is still very useful for the differential diagnosis:

• ACG1A corresponds to the former eponym Houston-Harris type, and is caused by mutation of TRIP11 [Smits et al 2010].
• ACG1B corresponds to the Fraccaro type. The confirmation of ACG1B as a separate entity came with the demonstration of sulfate transporter pathogenic variants in this histologic type.
• ACG2 corresponds to the Langer-Saldino type.

ACG1B is currently classified in the "sulfation disorders group" in the revised Nosology and Classification of Genetic Skeletal Disorders [Warman et al 2011].

Prevalence

No data on the prevalence of ACG1B are available.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with achondrogenesis type 1B (ACG1B), the following evaluations are recommended:

• Complete skeletal survey
• Respiratory status
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Provide palliative care for viable newborns.

Evaluation of Relatives at Risk

See Related Genetic Counseling Issues for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.