DiagnosisClinical DiagnosisAchondrogenesis 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 featuresExtremely short limbs with short fingers and toesHypoplasia of the thoraxProtuberant abdomenHydropic fetal appearance caused by the abundance of soft tissue relative to the short skeletonFlat faceShort neckThickened soft tissue of the neckRadiographic 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) ribsIliac 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]TestingHistopathologic 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 TestingGene. 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:Targeted mutation analysis identifies the four most common SLC26A2 mutations (p.Arg279Trp, p.Cys653Ser, p.Arg178X, and c.-26+2T>C ["Finnish"]). 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 of the entire SLC26A2 coding region 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 1BView in own windowGene SymbolTesting MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilitySLC26A2Targeted mutation analysisPanel of four mutations 2~70%ClinicalSequence analysisPrivate and common mutations>95%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 StrategyConfirming/establishing the diagnosis in a probandThe 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.Genetically Related (Allelic) DisordersThree 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 HistoryAchondrogenesis 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 CorrelationsGenotype-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].

Differential DiagnosisAchondrogenesis 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)Achondrogenesis type 1B (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.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.

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with achondrogenesis type 1B (ACG1B), the following evaluations are recommended:Complete skeletal surveyRespiratory statusTreatment of ManifestationsProvide palliative care for viable newborns.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC26A25q32Sulfate transporterFinnish Disease DatabaseSLC26A2Data 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) View in own window 600972ACHONDROGENESIS, TYPE IB; ACG1B 606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2Molecular Genetic PathogenesisMutations 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.)Table 2. Selected SLC26A2 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change Reference SequencesNormalc.835C>Tp.Arg492TrpNM_000112​.3
NP_000103​.2c.2065A>Tp.Thr689SerPathologicc.-26+2T>C
(IVS1+2T>C)--c.532C>Tp.Arg178Xc.835C>Tp.Arg279Trpc.1957T>Ap.Cys653SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal 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.