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 mutation is currently to cause ACG1B.

Clinical testing. In individuals with radiologic and histologic features compatible with the diagnosis of sulfate transporter-related dysplasias, mutations in SLC26A2 can be found in more than 95% of alleles [Rossi & Superti-Furga 2001]. Very rarely, in individuals with typical clinical, radiologic, and histologic features of SLC26A2 dysplasia, SLC26A2 molecular testing detects no mutation or only a single heterozygous pathologic mutation; in these cases, the mutations may be present in the 5' region of the gene, which is currently not entirely covered by clinically available testing:

• Targeted mutation analysis. Testing for the four most common SLC26A2 mutations (p.Arg279Trp, p.Cys653Ser, p.Arg178X, and c.-26+2T>C ["Finnish"]) is available on a clinical basis. However, most mutations found in ACG1B are rare, private null mutations. The only recurrent mutations that may be associated with ACG1B are p.Arg178X and c.-26+2T>C.

• Sequence analysis. Sequence analysis of the whole SLC26A2 coding region is available on a clinical basis. Sequence analysis may detect rare "private" mutations in individuals in whom mutation analysis detects none or only one of the common alleles.

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

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Gene Symbol	Testing Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
SLC26A2	Targeted mutation analysis	Panel of four mutations 2	~70%	Clinical
	Sequence analysis	Private and common mutations	>95%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. p.Arg279Trp, p.Cys653Ser, p.Arg178X, and c.-26+2T>C. Mutation panel may vary by laboratory.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing 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:

  • Targeted mutation analysis for the four most common mutations is carried out at first, as it is likely to identify at least one allele in a significant percentage of probands with a SLC26A2-related dysplasia.

  • Sequence analysis of the whole coding region is carried out 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 to confirm segregation of the two alleles in both compound heterozygous and homozygous individuals. Complete sequence analysis is usually needed in patient with ACG1B as recurrent mutations are found in only a small number of affected individuals.

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

Sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is possible in the rare instances in which the diagnosis of ACG1B 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Three other phenotypes (all with an autosomal recessive mode of inheritance) are associated with mutations in SLC26A2 (DTDST):

• Atelosteogenesis type 2 (AO2) is a neonatal-lethal chondrodysplasia with clinical and histologic characteristics that resemble those of diastrophic dysplasia [Hastbacka et al 1996].

• Diastrophic dysplasia (DTD) is a skeletal dysplasia characterized by short stature, joint contractures, cleft palate, and characteristic clinical signs such as the "hitchhiker" thumb and cystic swelling of external ears. The first mutations in SLC26A2 were found in individuals with DTD [Hastbacka et al 1994].

• Recessive multiple epiphyseal dysplasia (EDM4) is characterized by joint pain (usually in the hips and knees), deformities of the hands, feet, and knees, and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, cleft palate, or cystic ear swelling. Median height in adulthood is at the tenth centile [Superti-Furga et al 1996c, Superti-Furga et al 1999, Superti-Furga et al 2001].

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) phenotype when in the compound heterozygous state.

Mutation p.Cys653Ser is the second-most common mutation (10% of alleles). It results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other mutations.

Mutation p.Arg178X is the third-most common mutation (8% of alleles) and is associated with the severe phenotypes ACG1B and AO2.

Mutation c.-26+2T>C ("Finnish" mutation), the fourth-most common mutation in non-Finnish populations (7% of alleles), is however much more frequent in Finland. It produces low levels of correctly spliced mRNA and results in DTD when homozygous. It has been found in at least one case of ACG1B in compound heterozygosity with another severe allele.

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].

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 IA and IB which are still very useful for the differential diagnosis:

• ACG1A corresponds to the former eponym Houston-Harris type.

• 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 Disorders of Bone [Superti-Furga & Unger 2007].

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

Treatment of Manifestations

Provide palliative care for viable newborns.

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

European Skeletal Dysplasia Network (ESDN) Registry
Wellcome Trust Centre for Cell-Matrix Research
Email: info@esdn.org
Web: www.esdn.org

International Skeletal Dysplasia Registry
Cedars-Sinai Medical Center
Phone: 800-233-2771 (toll-free)
Fax: 310-423-0462
Email: groupisdrinfo@cshs.org
Web: cedars-sinai.edu

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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.

• Heterozygous carriers are asymptomatic and have normal stature.

• No evidence suggests that carriers are at increased risk of developing degenerative joint disease.

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.

• To date, de novo mutations in the proband and germline mosaicism in the parents have not been reported.

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 is possible once the mutation(s) has/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.Arg178X, 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. See for a list of laboratories offering DNA banking.

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

• 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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].

Normal allelic variants. See Table 2. The coding sequence of SLC26A2 is organized in two exons separated by an intron of approximately 1.8 kb, and 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]. 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].

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 polymorphism, 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].

Pathologic allelic variants. See Table 2. Four pathogenic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, p.Cys653Ser, p.Arg178X, and c.-26+2T>C. Together they represent approximately 70% of the pathogenic mutations in SLC26A2. However, recurrent mutations are rarely found in individuals with ACG1B.

Mutation c.1751delA has been found in four out of 20 ACG1B-causing alleles and mutation p.Val341del has been found in three out of 20 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.)

Normal gene product. The sulfate transporter gene SLC26A2 encodes a transmembrane protein that 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].

The p.Arg278X and p.Val341del mutations were shown to abolish sulfate transporter activity in a Xenopus oocyte model [Karniski 2001], and in a HEK-293 cell culture model [Karniski 2004], respectively.

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. 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]
5. Dawson PA, Markovich D. Pathogenetics of the human SLC26 transporters. Curr Med Chem. 2005;12:385–96. [PubMed: 15720248]
6. 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]
7. 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]
8. Hastbacka J, de la Chapelle A, Mahtani MM, Clines G, Reeve-Daly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A. et al. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 1994;78:1073–87. [PubMed: 7923357]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. Superti-Furga A. Achondrogenesis type 1B. J Med Genet. 1996;33:957–61. [PMC free article: PMC1050792] [PubMed: 8950678]
21. 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]
22. 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]
23. 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]
24. 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]
25. 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]
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27. 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]

Revision History

• 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