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Atelosteogenesis Type 2

Synonyms: McAlister Dysplasia, de la Chapelle Dysplasia

, 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,
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: January 23, 2014.

Summary

Disease characteristics. Clinical features of atelosteogenesis type 2 (AO2) include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midfaceretrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. AO2 is lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia.

Diagnosis/testing. The diagnosis of AO2 rests on a combination of clinical, radiologic, and histopathologic features. SLC26A2 (DTDST) is the only gene in which mutations are known to cause AO2. The diagnosis can be confirmed by molecular genetic testing of SLC26A2.

Management. Treatment of manifestations: Palliative care for liveborns.

Genetic counseling. AO2 is inherited in an autosomal recessive manner. At conception, each sib of a proband with AO2 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. Ultrasound examination early in pregnancy is a reasonable complement or alternative to molecular genetic prenatal diagnosis.

Diagnosis

Clinical Diagnosis

Atelosteogenesis type 2 (AO2) is usually lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia. The diagnosis is suspected when the following are present:

Clinical features

  • Rhizomelic limb shortening with normal-sized skull
  • Hitchhiker thumbs
  • Small chest
  • Protuberant abdomen
  • Cleft palate
  • Distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)

Other usual findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot.

Radiographic findings

  • Normal-sized skull with disproportionately short skeleton
  • Platyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete.
  • Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified.
  • Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed.

    Note: (1) A distally pointed, triangular humerus had led Slaney et al [1999] to the suggestion of a new condition, but this finding is a typical feature of achondrogenesis 1B (ACG1B) bordering on AO2 [Unger et al 2001]. (2) The first individuals with de la Chapelle dysplasia described by De la Chapelle et al [1972] and Whitley et al [1986] showed a triangular remnant of ulna and fibula. Those individuals were subsequently classified as having AO2 [Bonafé et al 2008].
  • Characteristic hand findings of sulfate transporter-related dysplasia:
    • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of diastrophic dysplasia [DTD])
    • Gap between the first and second toe (characteristic of ACG1B [when the phalanges are identifiable on the x-rays] and DTD)
    • Hypoplasia of the first metacarpal bone (also present in ACG1B and DTD)

Testing

Histopathologic testing. The histopathology of cartilage is essentially similar to that seen in diastrophic dysplasia (DTD) and achondrogenesis 1B (ACG1B), as it reflects the paucity of sulfated proteoglycans in cartilage matrix [Superti-Furga et al 1996a, Rossi et al 1997]. It shows an abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity. Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of ACG1B. The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities.

Biochemical testing. The incorporation of sulfate in 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, Rossi et al 1997] which can be observed even in total macromolecules. The determination of sulfate uptake is possible but very cumbersome and is not used for diagnostic purposes [Superti-Furga et al 1996b].

Molecular Genetic Testing

Gene. SLC26A2 (previously known as DTDST) is the only gene in which mutations are known to cause atelosteogenesis type 2 (AO2).

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Atelosteogenesis Type 2

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SLC26A2Targeted mutation analysisPanel of selected mutations 4 See footnote 5
Sequence analysis 6Sequence variants>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 ~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.
  • Histopathology of cartilage is recommended as a second diagnostic step. It is particularly important when radiologic material is not available or is of poor quality.
  • Molecular genetic testing is the preferred diagnostic test in probands with a clinical, radiologic, and/or histopathologic diagnosis of AO2. It allows precise diagnosis in the great majority of cases.
  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having AO2 is molecular genetic testing of SLC26A2.
    • Targeted mutation analysis for the four most common SLC26A2 mutations is performed first, as it is likely to identify at least one pathogenic allele in nearly 100% of AO2 cases (one pathogenic allele in ~60% and both pathogenic alleles in ~35%).
    • Sequence analysis of the entire coding region is performed when neither or only one allele has been identified by targeted mutation analysis. Parental DNA analysis for the mutations found in the proband is recommended, as most probands are compound heterozygotes.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having AO2 is use of a multi-gene panel.

Sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is possible in the rare cases in which the diagnosis of AO2 is strongly suspected but molecular genetic testing fails to detect SLC26A2 mutations.

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

Atelosteogenesis type 2 (AO2) is usually lethal in the neonatal period because of lung hypoplasia, tracheobronchomalacia, and laryngeal malformations. Pregnancy complications of polyhydramnios may occur.

AO2 is clinically very similar to diastrophic dysplasia (DTD) [Rossi et al 1996b].

Newborns with AO2 present with short limbs, adducted feet with wide space between the hallux and the second toe, hitchhiker thumb, cleft palate, and facial dysmorphism. Disproportion between the short skeleton and normal-sized skull is immediately evident; the limb shortening is mainly rhizomelic; the gap between the toes, ulnar deviation of the fingers, and adducted thumbs are typical of sulfate transporter-related dysplasias [Newbury-Ecob 1998, Superti-Furga et al 2001]. The neck is short, the thorax narrow, and the abdomen protuberant.

Cleft palate is a constant feature, whereas the degree of facial dysmorphism is variable. Midface retrusion is usually present, together with a flat nasal bridge and micrognathia. Epicanthal folds, widely spaced eyes, and low-set ears can also be present.

Spinal scoliosis and dislocation of the elbows are reported [Newbury-Ecob 1998].

Genotype-Phenotype Correlations

Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype [Rossi et al 1997] in a spectrum from lethal ACG1B to mild EDM4.

Mutation p.Arg279Trp, the most common SLC26A2 mutation outside Finland (45% of alleles) is a mild mutation resulting in the EDM4 phenotype when homozygous and mostly in the DTD phenotype when in the compound heterozygous state.

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. It has also been found in some cases of more severe MED4/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).

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.

Together with p.Arg178Ter, c.-26+2T>C is the only mutation that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (MED4/rMED and DTD) or severe (AO2 and ACG1B) alleles [Bonafe, unpublished results; Dwyer et al 2010].

Mutation p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other mutations. It is not found in AO2 or ACG1B.

Another mutation specific to the Finnish population is p.Thr512Lys, which results in AO2 (de la Chapelle dysplasia) when homozygous and in DTD when in compound heterozygosity with a milder allele [Bonafé et al 2008].

Most other mutations are rare.

The same mutations associated in some individuals who have the ACG1B phenotype can be found in individuals with a milder phenotype (EDM4 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].

Nomenclature

The name "atelosteogenesis" was coined by Maroteaux et al [1982] for a different condition.

Sillence et al [1987] created the term "atelosteogenesis type 2" for a group of fetuses or stillborns who had all previously been diagnosed as having "severe diastrophic dysplasia." The reason was an apparent hypoplasia of the distal humerus and variable fibular hypoplasia (but not aplasia) that was slightly reminiscent of atelosteogenesis type 1 (AO1). The redefinition of this severe DTD variant as atelosteogenesis type 2 was unfortunate because it suggested a relationship with AO1 and at the same time denied the relationship with diastrophic dysplasia. Later biochemical and molecular studies brought this entity back to its origin; i.e., in the diastrophic dysplasia-achondrogenesis group in which AO2 is considered to be a severe form of DTD, and in which lethality distinguishes AO2 from DTD.

De la Chapelle et al [1972] described two siblings with a novel condition very similar to AO2, with very hypoplastic ulna and fibula; one additional sibling and one more case with this condition (de la Chapelle dysplasia) were reported by Whitley et al [1986]. The histopathologic similarities with ACG1B suggested a relationship with the sulfate transporter-related dysplasias. The identity of de la Chapelle dysplasia with AO2 was subsequently confirmed by molecular testing, which revealed mutations in SLC26A2 [Bonafé et al 2008].

AO2 is currently classified in the "sulfation disorders group" in the revised Nosology and Classification of Genetic Skeletal Disorders of Bone [Warman et al 2011].

Prevalence

No data on the prevalence of AO2 are available. Among the sulfate transporter-related dysplasias, AO2 is the rarest phenotype.

Differential Diagnosis

Atelosteogenesis type 2 (AO2), rather than DTD, must be considered when distinct hypoplasia of one or more long bones (humerus, ulna, radius, or fibula) is present. Histopathology is very similar in the two conditions, although the cartilage growth plate shows fewer disorganized hypertrophic and proliferative zones and columnar zones in DTD than in AO2.

The differentiation of AO2 from other subtypes of atelosteogenesis ("incomplete bone formation"), and even from other lethal skeletal dysplasias, should be based on clinical examination as well as radiographic imaging.

The radiologic differentiation of AO2 from the achondrogenesis syndromes (including ACG1B) is based on the more severe underossification of the skeleton and extreme limb shortening seen in ACG1B. Histopathology, which is similar in AO2 and ACG1B because of their common pathogenesis, is helpful in distinguishing between AO1 and AO2.

Compared to AO2, atelosteogenesis type 1 shows better development of the long bones and better ossification of the spine and pelvis. Hitchhiker thumb and gap between the toes are not present in AO1 and cleft palate is rare. Absence of the fibula may suggest AO1, whereas dysplasia of the fibula is more typical of AO2. The humerus may be completely absent in AO1.

Other disorders in the differential diagnosis with AO2 are the lethal short-rib polydactyly syndromes (when polydactyly is absent) and thanatophoric dysplasia, in which the typical "telephone receiver" femur is visible on x-ray. In thanatophoric dysplasia type II, cloverleaf skull is common.

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 atelosteogenesis type 2 (AO2), the following evaluations are recommended:

  • Complete skeletal survey
  • Respiratory status
  • Medical genetics consultation

Treatment of Manifestations

Provide palliative care for the viable newborn.

Evaluation of Relatives at Risk

See Genetic Counseling 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

Atelosteogenesis type 2 (AO2) 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 thus 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 a proband and germline mosaicism in the parents have not been reported.

Sibs of a proband

  • At conception, each sib of a proband with AO2 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 chance of his/her being a carrier is 2/3.

Offspring of a proband. AO2 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 once the disease-causing mutations have been identified in the family.

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. The risk of carrying an SLC26A2 mutation is reduced from the general population risk of 1:100 to approximately 1:330 when these four alleles are excluded.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the 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. If the disease-causing mutations have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.
  • 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. There are no data on prenatal functional biochemical testing (sulfate incorporation test on chorionic villus or fibroblasts).

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, raising the possibility of AO2 in a fetus not known to be at risk. Subtle findings on ultrasound examination 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.
  • Molecular genetic testing. DNA extracted from cells obtained by amniocentesis can theoretically be 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 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. Atelosteogenesis Type 2: 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 Atelosteogenesis Type 2 (View All in OMIM)

256050ATELOSTEOGENESIS, TYPE II; AO2
606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2

Molecular Genetic Pathogenesis

Mutations in SLC26A2 (formerly DTDST) [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, Rossi et al 1997, Superti-Furga et al 1999, Superti-Furga 2001, Superti-Furga et al 2001]. Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [Rossi et al 1998, Satoh et al 1998], most probably 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 predicted severity of the phenotype [Rossi et al 1997, 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]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The p.Thr689Ser allele has been frequently observed at the heterozygous or homozygous state in several controls of different ethnicities and is thus a common benign variant (Table 2) [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]. See Table 2.

Pathogenic allelic variants. 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 variants in SLC26A2. See Table 2.

Of the four, the p.Arg279Trp, p.Arg178Ter, and c.-26+2T>C variants are associated with the AO2 phenotype [Superti-Furga et al 1996c, Rossi & Superti-Furga 2001]. In individuals with AO2, the p.Arg279Trp mutation is combined with a severe, structural mutation (e.g., p.Arg178Ter, p.Leu131CysfsTer41 [Rossi et al 1996b], p.Asn425Asp [Rossi et al 1997] or c.1724delA) [Hastbacka et al 1996] The same mutations associated in some individuals with the AO2 phenotype can be found in individuals with DTD if the second allele is a relatively mild mutation, or in individuals with ACG1B if the second mutation is a structural, severe one [Rossi & Superti-Furga 2001].

AO2 variant de la Chapelle dysplasia results from homozygosity of the Finnish-specific p.Thr512Lys pathogenic variant [Bonafé et al 2008].

Table 2. SLC26A2 Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Benignc.1474C>Tp.Arg492TrpNM_000112​.3
NP_000103​.2
c.2065A>Tp.Thr689Ser
Pathogenic for AO2 phenotypec.-26+2T>C
(IVS1+2T>C)
See footnote 2
c.391delC
(delC418)
p.Leu131CysfsTer41 2
c.532C>Tp.Arg178Ter 2
c.835C>Tp.Arg279Trp 2
c.1535C>Ap.Thr512Lys 2
c.1273A>Gp.Asn425Asp 2
c.1724delA (c.1751delA)p.Lys575SerfsTer10
Pathogenic for other SLC26A2-related phenotypes 2c.1957T>Ap.Cys653Ser 2

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.

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

2. See Genotype-Phenotype Correlations

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: (1) PDS, a chloride-iodide transporter involved in Pendred syndrome and (2) 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 greater than 8 kb, indicating the existence of significant untranslated sequences [Hastbacka et al 1994, 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 are evolutionarily conserved in SLC26A2 orthologous genes of 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 1994, Hastbacka et al 1999]. The other Finnish mutation specifically found in individuals with Finnish AO2 (de la Chapelle dysplasia) and DTD, p.Thr512Lys, has been proven to abolish the sulfate transporter activity in vitro [Bonafé et al 2008].

The p.Arg178Ter mutation was shown to abolish 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. 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]
  3. Corsi A, Riminucci M, Fisher LW, Bianco P. Achondrogenesis type IB: agenesis of cartilage interterritorial matrix as the link between gene defect and pathological skeletal phenotype. Arch Pathol Lab Med. 2001;125:1375–8. [PubMed: 11570921]
  4. Dawson PA, Markovich D. Pathogenetics of the human SLC26 transporters. Curr Med Chem. 2005;12:385–96. [PubMed: 15720248]
  5. De la Chapelle A, Maroteaux P, Havu N, Granroth G. A rare lethal bone dysplasia with recessive autosomic transmission. Arch Fr Pediatr. 1972;29:759–70. [PubMed: 4644462]
  6. Dwyer E, Hyland J, Modaff P, Pauli RM. Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family. Am J Med Genet A. 2010;152A:3043–50. [PubMed: 21077202]
  7. Forlino A, Piazza R, Tiveron C, Della Torre S, Tatangelo L, Bonafe L, Gualeni B, Romano A, Pecora F, Superti-Furga A, Cetta G, Rossi A. A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype. Hum Mol Genet. 2005;14:859–71. [PubMed: 15703192]
  8. Haila S, Hastbacka J, Bohling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U. SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types. J Histochem Cytochem. 2001;49:973–82. [PubMed: 11457925]
  9. Hastbacka J, de la Chapelle A, Mahtani MM, Clines G, Reeve-Daly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A, Coloma A, Lovett M, Buckler A, Kaitila I, Lander ES. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 1994;78:1073–87. [PubMed: 7923357]
  10. Hastbacka J, Kerrebrock A, Mokkala K, Clines G, Lovett M, Kaitila I, de la Chapelle A, Lander ES. Identification of the Finnish founder mutation for diastrophic dysplasia (DTD). Eur J Hum Genet. 1999;7:664–70. [PubMed: 10482955]
  11. Hastbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES. Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet. 1996;58:255–62. [PMC free article: PMC1914552] [PubMed: 8571951]
  12. Karniski LP. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. Hum Mol Genet. 2001;10:1485–90. [PubMed: 11448940]
  13. Karniski LP. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet. 2004;13:2165–71. [PubMed: 15294877]
  14. Maeda K, Miyamoto Y, Sawai H, Karniski LP, Nakashima E, Nishimura G, Ikegawa S. A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia. Am J Med Genet A. 2006;140:1143–7. [PubMed: 16642506]
  15. Maroteaux P, Spranger J, Stanescu V, Le Marec B, Pfeiffer RA, Beighton P, Mattei JF. Atelosteogenesis. Am J Med Genet. 1982;13:15–25. [PubMed: 7137218]
  16. Newbury-Ecob R. Atelosteogenesis type 2. J Med Genet. 1998;35:49–53. [PMC free article: PMC1051187] [PubMed: 9475095]
  17. Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001;17:159–71. [PubMed: 11241838]
  18. Rossi A, Bonaventure J, Delezoide AL, Cetta G, Superti-Furga A. Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution in the diastrophic dysplasia sulfate transporter. J Biol Chem. 1996a;271:18456–64. [PubMed: 8702490]
  19. Rossi A, Bonaventure J, Delezoide AL, Superti-Furga A, Cetta G. Undersulfation of cartilage proteoglycans ex vivo and increased contribution of amino acid sulfur to sulfation in vitro in McAlister dysplasia/atelosteogenesis type 2. Eur J Biochem. 1997;248:741–7. [PubMed: 9342225]
  20. Rossi A, Kaitila I, Wilcox WR, Rimoin DL, Steinmann B, Cetta G, Superti-Furga A. Proteoglycan sulfation in cartilage and cell cultures from patients with sulfate transporter chondrodysplasias: relationship to clinical severity and indications on the role of intracellular sulfate production. Matrix Biol. 1998;17:361–9. [PubMed: 9822202]
  21. Rossi A, van der Harten HJ, Beemer FA, Kleijer WJ, Gitzelmann R, Steinmann B, Superti-Furga A. Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia. Hum Genet. 1996b;98:657–61. [PubMed: 8931695]
  22. Satoh H, Susaki M, Shukunami C, Iyama K, Negoro T, Hiraki Y. Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfated proteoglycans. J Biol Chem. 1998;273:12307–15. [PubMed: 9575183]
  23. Sillence DO, Kozlowski K, Rogers JG, Sprague PL, Cullity GJ, Osborn RA. Atelosteogenesis: evidence for heterogeneity. Pediatr Radiol. 1987;17:112–8. [PubMed: 3562108]
  24. Slaney SF, Sprigg A, Davies NP, Hall CM. Lethal micromelic short-rib skeletal dysplasia with triangular-shaped humerus. Pediatr Radiol. 1999;29:835–7. [PubMed: 10552063]
  25. Superti-Furga A. A defect in the metabolic activation of sulfate in a patient with achondrogenesis type IB. Am J Hum Genet. 1994;55:1137–45. [PMC free article: PMC1918434] [PubMed: 7977372]
  26. Superti-Furga A. Defects in sulfate metabolism and skeletal dysplasias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill. 2001:5189-201.
  27. Superti-Furga A, Bonafe L, Rimoin DL. Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet. 2001;106:282–93. [PubMed: 11891680]
  28. Superti-Furga A, Hastbacka J, Rossi A, van der Harten JJ, Wilcox WR, Cohn DH, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R. A family of chondrodysplasias caused by mutations in the diastrophic dysplasia sulfate transporter gene and associated with impaired sulfation of proteoglycans. Ann N Y Acad Sci. 1996a;785:195–201. [PubMed: 8702127]
  29. Superti-Furga A, Hastbacka J, Wilcox WR, Cohn DH, van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet. 1996b;12:100–2. [PubMed: 8528239]
  30. Superti-Furga A, Neumann L, Riebel T, Eich G, Steinmann B, Spranger J, Kunze J. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. J Med Genet. 1999;36:621–4. [PMC free article: PMC1762965] [PubMed: 10465113]
  31. Superti-Furga A, Rossi A, Steinmann B, Gitzelmann R. A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: genotype/phenotype correlations. Am J Med Genet. 1996c;63:144–7. [PubMed: 8723100]
  32. Unger S, Le Merrer M, Meinecke P, Chitayat D, Rossi A, Superti-Furga A. New dysplasia or achondrogenesis type 1B? The importance of histology and molecular biology in delineating skeletal dysplasias. Pediatr Radiol. 2001;31:893–4. [PubMed: 11727031]
  33. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155A:943–68. [PMC free article: PMC3166781] [PubMed: 21438135]
  34. Whitley CB, Burke BA, Granroth G, Gorlin RJ. de la Chapelle dysplasia. Am J Med Genet. 1986;25:29–39. [PubMed: 3799721]

Chapter Notes

Revision History

  • 23 January 2014 (me) Comprehensive update posted live
  • 1 October 2009 (me) Comprehensive update posted live
  • 28 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
  • 1 March 2002 (lb) Original submission
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