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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Achondrogenesis Type 1B

Synonym: ACG1B

, MD, PhD, , PhD, , MD, and , MD.

Author Information
, MD, PhD
Associate Professor; Head, Division of Molecular Pediatrics
Lausanne University Hospital
Lausanne, Switzerland
, PhD
Laboratory of Molecular Pediatrics
Lausanne University Hospital
Lausanne, Switzerland
, MD
Senior Lecturer, Division of Molecular Pediatrics
Lausanne University Hospital
Lausanne, Switzerland
, MD
Professor of Pediatrics, Department of Pediatrics
Lausanne University Hospital
Lausanne, Switzerland

Initial Posting: ; Last Update: November 14, 2013.

Summary

Disease 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 mutations are 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 disease-causing 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.

Diagnosis

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].

Molecular Genetic Testing

Gene. SLC26A2 (known previously as DTDST) is the only gene in which mutations are known to cause ACG1B [Superti-Furga 1996b].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Achondrogenesis Type 1B

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SLC26A2Targeted mutation analysisPanel of selected mutations 4 See footnote 5
Sequence analysis Sequence variants 6>90% 7
Deletion/duplication analysis 8(Multi)exonic and whole-gene deletion/duplicationUnknown, none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. % of disease alleles detected in individuals with typical clinical, radiologic, and histologic features of ACG1B

4. Mutation panel may vary by laboratory.

5. Dependent on mutation panel and population tested. The four most common SLC26A2 mutations (p.Arg279Trp, c.-26+2T>C (IVS1+2T>C), p.Arg178Ter, and p.Cys653Ser) account for approximately 70% of disease alleles in all SLC26A2-related dysplasias, but only 10% of disease alleles in ACG1B.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. 90% of alleles in individuals with radiologic and histologic features compatible with the diagnosis of sulfate transporter-related dysplasias [Rossi & Superti-Furga 2001]

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

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 mutation analysis is available, recurrent mutations 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 mutations 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 disease-causing mutations 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 disease-causing mutations in the family.

Clinical Description

Natural History

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 mutations predicting stop codons or structural mutations in transmembrane domains of the sulfate transporter are associated with ACG1B, while mutations 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].

Mutation p.Arg279Trp is the most common SLC26A2 mutation 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.

The mutation p.Arg178Ter is the second-most common mutation (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 mutation. This mutation has also been found in some cases of more severe recessive multiple epiphyseal dysplasia (rMED) and of ACG1B, making it one of two mutations identified in all four SLC26A2-related dysplasias.

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

Mutation p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when present in trans with other mutations.

Mutation c.-26+2T>C is sometimes referred to as the "Finnish" mutation, 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. Mutation c.-26+2T>C is the only other mutation that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Bonafe, unpublished results; Dwyer et al 2010].

The same mutations found in the ACG1B phenotype can also be found in the milder phenotypes (AO2 and DTD) if the second allele is a relatively mild mutation. Indeed, missense mutations 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 mutations 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 mutations in 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 mutations in 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 mutations 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.

Differential Diagnosis

Achondrogenesis type 1B (ACG1B) should be distinguished from other lethal chondrodysplasias. As this is a large group of disorders, differentiation may be problematic.

Making the correct diagnosis in fetuses with severe short-limbed chondrodysplasia by clinical and ultrasonographic findings alone is difficult. It is therefore important to obtain good radiographs, tissue for DNA extraction, skin biopsy for fibroblast culture, and bone and cartilage tissues for histology and biochemistry. The combination of radiologic and histologic findings gives a provisional diagnosis, which can then be confirmed by selected biochemical and/or molecular genetic investigations [Unger et al 2001].

Achondrogenesis is subtyped according to radiologic and histopathologic characteristics [Borochowitz et al 1988, Superti-Furga et al 2001]:

  • Achondrogenesis type 1A (ACG1A; Houston-Harris type)
  • ACG1B (Fraccaro type)
  • Achondrogenesis type 2 (ACG2; Langer-Saldino type)

Within the achondrogenesis group, clinical and radiologic distinction between ACG1A, ACG1B, and ACG2 is not always possible. The presence of rib fractures and the absence of ossification of vertebral pedicles may suggest ACG1A. The hands and fingers are markedly shortened in ACG1B and less so in ACG1A; they can be almost normal in ACG2. ACG2 shows more severe underossification of the vertebral bodies compared to ACG1B, in addition to quite typical configuration of the iliac bones with concave medial and inferior borders, and nonossification of the ischial and pubic bones.

Histology of the cartilage is very useful in distinguishing the three different forms of achondrogenesis:

  • ACG1A. The cartilage matrix is normal and inclusions are present in the chondrocytes.
  • ACG1B. The matrix is clearly abnormal (presence of "demasked," coarse collagen fibers, sometimes giving a wavy, sponge-like appearance) and has abnormal staining properties because of the reduced proteoglycans.
  • ACG2. The cartilage is hypervascular and hypercellular with reduced matrix and vacuoles ("Swiss cheese-like"), but has roughly normal staining properties.

Features observed on histologic examination after staining with cationic dyes distinguish ACG1B from ACG1A, in which the matrix appears close to normal and chondrocytes show intracytoplasmic inclusions, and from ACG2, in which the matrix is rarified and vacuolated but stains normally and there are no "collagen rings." ACG2 also has inclusions.

See Achondrogenesis: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Other osteochondrodysplasias that are often in the differential diagnosis of ACG1B:

  • Osteogenesis imperfecta types 2 and 3. Typical signs are soft undermineralized skull and blue sclerae; the bones are bowed but not as short as in achondrogenesis. Multiple fractures are present.
  • Thanatophoric dysplasia. The limbs are longer than in ACG and the thorax is narrow but elongated. In thanatophoric dysplasia type II, cloverleaf skull is common.
  • Short rib-polydactyly syndromes. Polydactyly is usually present; when absent, the short rib-polydactyly syndromes may be confused with thanatophoric dysplasia.
  • Roberts syndrome. Severe limb shortening with only mildly affected axial skeleton may suggest Roberts syndrome. In Roberts syndrome standard cytogenetic preparations stained with Giemsa or C-banding techniques show in most chromosomes during metaphase the characteristic chromosomal abnormality of premature centromere separation (PCS) and separation of the heterochromatic regions [also called heterochromatin repulsion (HR)]. Mutations in ESCO2 are causative.
  • Fibrochondrogenesis. Distinguishing radiographic features of fibrochondrogenesis are marked metaphyseal flaring of the long bones and clefts of the vertebral bodies.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Genetics consultation

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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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 genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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

  • The parents of an affected child are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in SLC26A2. Note: Parental testing is always recommended when mutations are identified in a proband, in order to confirm the segregation of mutations 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.
  • Heterozygous carriers are asymptomatic and have normal stature.
  • No evidence suggests that carriers are at increased risk of developing degenerative joint disease.
  • To date, de novo mutations in the proband and germline mosaicism in the parents have not been reported.

Sibs of a proband

  • 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.

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 Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations 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 mutation is reduced from the general population risk of 1:100 to approximately 1:330.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal testing is before pregnancy.
  • 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies

  • Molecular genetic testing. Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

    Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
  • 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 week 14-15, and reliability is highly operator dependent.
  • Biochemical testing. No data on prenatal functional biochemical testing (sulfate incorporation test on chorionic villus or fibroblasts) are available.

Low-risk pregnancies

  • One parent is heterozygous and the other parent does not have one of the four common mutations. Follow up of pregnancies by ultrasound is recommended [Canto et al 2007, Schramm et al 2009].
  • 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 a skeletal dysplasia is usually not made until the second trimester.
  • 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 (see Differential Diagnosis).

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Compassionate Friends
    Supporting Family After a Child Dies
    PO Box 3696
    Oak Brook IL 60522
    Phone: 877-969-0010 (toll free); 630-990-0010
    Fax: 630-990-0246
    Email: nationaloffice@compassionatefriends.org
  • Helping After Neonatal Death (HAND) - Support Groups
    PO Box 341
    Los Gatos CA 95031
    Phone: 888-908-4263
    Email: info@handonline.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Achondrogenesis Type 1B: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC26A25q32Sulfate transporterFinnish Disease Database (SLC26A2)SLC26A2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Achondrogenesis Type 1B (View All in OMIM)

600972ACHONDROGENESIS, TYPE IB; ACG1B
606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2

Molecular Genetic Pathogenesis

Mutations in SLC26A2 [Dawson & Markovich 2005] are responsible for the family of chondrodysplasias including achondrogenesis 1B (ACG1B), diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and recessive multiple epiphyseal dysplasia (EDM4) (see Genetically Related Disorders) [Hastbacka et al 1996, Superti-Furga et al 1996a, Superti-Furga et al 1999]. Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans that are not sulfated or are insufficiently sulfated [Rossi et al 1996a, Rossi et al 1998, Satoh et al 1998], most likely because of intracellular sulfate depletion [Rossi et al 1996a]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper enchondral bone formation [Corsi et al 2001, Forlino et al 2005]. A correlation exists between the mutation, the predicted residual activity of the sulfate transporter, and the severity of the phenotype [Cai et al 1998, Rossi & Superti-Furga 2001, Karniski 2004, Maeda et al 2006].

Gene structure. The coding sequence of SLC26A2 is organized in two coding exons separated by an intron of approximately 1.8 kb. A further untranslated exon is located 5' relative to the two coding exons; it has probable regulatory functions, as the mutation c.-26+2T>C (the "Finnish" allele) located in this region was shown to lead to reduced mRNA transcription [Hastbacka et al 1999].

Benign allelic variants. See Table 2. The p.Thr689Ser allele has been frequently observed at the heterozygous or homozygous state in several controls of different ethnicities and is very likely to be a normal allelic variant [Cai et al 1998, Rossi & Superti-Furga 2001].

There is evidence that p.Arg492Trp is a rare benign variant, found in seven out of 200 Finnish controls and in five out of 150 non-Finnish controls; in vitro expression of this variant showed normal sulfate transport activity [Bonafé et al 2008]. This allele was erroneously considered pathogenic in previous reports [Rossi & Superti-Furga 2001].

Pathogenic allelic variants. See Table 2. Four pathogenic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, p.Cys653Ser, p.Arg178Ter, and c.-26+2T>C. Together they represent approximately 70% of the pathogenic allelic variants in SLC26A2, however, most of these alleles are found in individuals with allelic disorders (see Genetically Related Disorders). These recurrent mutations are rarely found in individuals with ACG1B.

Two mutations, c.1751delA and p.Val341del, seem to be recurrent in ACG1B. Mutation c.1751delA has been found in seven out of 40 ACG1B-causing alleles and mutation p.Val341del has been found in nine out of 40 ACG1B-causing alleles; their frequency is however very low in other SLC26A2-related skeletal phenotypes.

In compound heterozygotes, the phenotype associated with each pathogenic allele depends on the combination with the second mutation. Distinct phenotypes known to be allelic to ACG1B are atelosteogenesis type 2 (AO2), diastrophic dysplasia (DTD), and recessive multiple epiphyseal dysplasia (rMED). (For more information, see Table A.)

Table 2. SLC26A2 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Benignc.835C>Tp.Arg492TrpNM_000112​.3
NP_000103​.2
c.2065A>Tp.Thr689Ser
Pathogenicc.-26+2T>C 2
(IVS1+2T>C)
--
c.532C>Tp.Arg178Ter
c.835C>Tp.Arg279Trp
c.1724delA 3
(1751delA)
p.Lys575SerfsTer10
c.1020_1022del 3p.Val341del
c.1957T>Ap.Cys653Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Ter = termination codon

1. Variant designation that does not conform to current naming conventions

2. Frequent in the Finnish population, but also accounts for 7% of alleles in non-Finnish populations. See Genotype/Phenotype Correlations.

3. Recurrent mutations in individuals with ACG1B

Normal gene product. The sulfate transporter gene SLC26A2 encodes a protein of 739 amino acids that is predicted to have 12 transmembrane domains and a carboxy-terminal, cytoplasmic, moderately hydrophobic domain [Hastbacka et al 1994]. This protein transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. The sulfate transporter protein belongs to the family of sulfate permeases. The overall structure with 12 membrane-spanning domains is shared with two other human anion exchangers: PDS (OMIM 274600), a chloride-iodide transporter involved in Pendred syndrome; and CLD, which is responsible for congenital chloride diarrhea. The function of the carboxy-terminal hydrophobic domain of SLC26A2 is not yet known. SLC26A2 is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues [Haila et al 2001]. The size of the predominant mRNA species is larger than 8 kb, indicating the existence of significant untranslated sequences [Hastbacka et al 1999].

Abnormal gene product. Most of the SLC26A2 mutations either predict a truncated polypeptide chain or change amino acids that are located in transmembrane domains or conserved in man, mouse, and rat. Individuals homozygous for the "Finnish" mutation c.-26+2T>C have reduced levels of mRNA with intact coding sequence [Rossi et al 1996b]. Thus, the mutation presumably interferes with splicing and/or further mRNA processing and transport [Hastbacka et al 1996, Hastbacka et al 1999].

ACG1B-associated mutations p.Arg178Ter, c.1724delA, and p.Val341del were shown to abolish or to drastically reduce sulfate transporter activity in a Xenopus oocyte model [Karniski 2001], and in a HEK-293 cell culture model [Karniski 2004], respectively.

References

Literature Cited

  1. Bonafé L, Hästbacka J, de la Chapelle A, Campos-Xavier AB, Chiesa C, Forlino A, Superti-Furga A, Rossi A. A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. J Med Genet. 2008;45:827–31. [PubMed: 18708426]
  2. Borochowitz Z, Lachman R, Adomian GE, Spear G, Jones K, Rimoin DL. Achondrogenesis type I: delineation of further heterogeneity and identification of two distinct subgroups. J Pediatr. 1988;112:23–31. [PubMed: 3275766]
  3. Cai G, Nakayama M, Hiraki Y, Ozono K. Mutational analysis of the DTDST gene in a fetus with achondrogenesis type 1B. Am J Med Genet. 1998;78:58–60. [PubMed: 9637425]
  4. Canto MJ, Buixeda M, Palau J, Ojeda F. Early ultrasonographic diagnosis of diastrophic dysplasia at 12 weeks of gestation in a fetus without previous family history. Prenat Diagn. 2007;27:976–8. [PubMed: 17602446]
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Chapter Notes

Revision History

  • 14 November 2013 (me) Comprehensive update posted live
  • 22 September 2009 (me) Comprehensive update posted live
  • 27 December 2006 (me) Comprehensive update posted to live Web site
  • 21 July 2004 (me) Comprehensive update posted to live Web site
  • 30 August 2002 (me) Review posted to live Web site
  • 21 February 2002 (lb) Original submission
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