Clinical characteristics.

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

Diagnosis/testing.

The diagnosis of ACG1B is established in a proband with characteristic clinical, radiologic, and histopathologic features. Identification of biallelic pathogenic variants in SLC26A2 on molecular genetic testing can confirm the diagnosis.

Management.

Treatment of manifestations: Palliative care for live-born neonates.

Genetic counseling.

ACG1B is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC26A2 pathogenic variants. Once the SLC26A2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

ACG1B should be suspected in individuals with the following clinical and radiographic findings.

Clinical findings

• Extremely short limbs with short fingers and toes and clubfeet
• Hypoplasia of the thorax
• Protuberant abdomen
• Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton
• Flat face with micrognathia
• 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).
• 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 in hematologic terms, acanthocyte). The phalanges are poorly ossified and thus 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]

Establishing the Diagnosis

The diagnosis of ACG1B can be established in a proband with the characteristic clinical and radiographic findings described in Suggestive Findings and/or biallelic pathogenic (or likely pathogenic) variants in SLC26A2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SLC26A2 variants of uncertain significance (or of one known SLC26A2 pathogenic variant and one SLC26A2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype and/or clinical context.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other skeletal dysplasias are more likely to be diagnosed using genomic testing (see Option 2).

Other 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 1996a].

Note: It is often difficult to distinguish between the three different forms of achondrogenesis: ACG1A, ACG1B, and ACG2 (see Differential Diagnosis).

Clinical Description

Achondrogenesis type 1B (ACG1B), one of the most severe chondrodysplasias, is a perinatal-lethal disorder with death occurring prenatally or shortly after birth. The mechanism of the prenatal death is unknown. In the live-born neonate, 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 (e.g., maternal breathing difficulties, preterm labor).

Infants with ACG1B appear hydropic with an abundance of soft tissue relative to the short skeleton. The face is flat and the neck is short with thickened soft tissue.

The limbs are extremely shortened, with 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 hernias 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 SLC26A2-related multiple epiphyseal dysplasia (SLC26A2-MED). Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with ACG1B, while pathogenic variants located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996b, Karniski 2001].

Pathogenic variant p.Arg279Trp is the most common SLC26A2 variant outside Finland (45% of alleles); it results in the mild SLC26A2-MED phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) and SLC26A2-related atelosteogenesis phenotypes when in the compound heterozygous state [Barbosa et al 2011].

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

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

• Variant p.Cys653Ser results in SLC26A2-MED when homozygous and in SLC26A2-MED or DTD when present in trans with other pathogenic variants.
• Variant c.-26+2T>C is sometimes referred to as the "Finnish" variant, because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous. c.-26+2T>C is the only other pathogenic variant that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (SLC26A2-MED and DTD) or severe (SLC26A2-related atelosteogenesis and ACG1B) alleles [Dwyer et al 2010].

The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (SLC26A2-related atelosteogenesis and DTD) if the second allele is a relatively mild pathogenic variant. Indeed, missense variants located outside the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of a null allele [Rossi & Superti-Furga 2001].

Nomenclature

The term "achondrogenesis" (Greek for "not producing cartilage") was used by the pathologist Marco Fraccaro in 1952 to denote the condition observed in a stillborn with severe micromelia and marked histologic changes in cartilage. Subsequently, "achondrogenesis" was used to characterize the most severe forms of human chondrodysplasia, invariably lethal before or shortly after birth.

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. Currently, three types of achondrogenesis are recognized and are distinguishable by molecular genetic testing and radiographic findings: ACG1A (an autosomal recessive disorder associated with pathogenic variants in TRIP11), ACG1B (the topic of this GeneReview), and ACG2 (an autosomal dominant disorder associated with pathogenic variants in COL2A1).

In the 2023 revised Nosology of Genetic Skeletal Disorders [Unger et al 2023], ACG1B is referred to as SLC26A2-related achondrogenesis and included in the sulfation disorders group.

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 evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Provide palliative care for live-born neonate.

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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 presumed to be heterozygous for an SLC26A2 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC26A2 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (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

• If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial SLC26A2 pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease.

Offspring of a proband. ACG1B is a perinatal-lethal condition; affected individuals do not reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC26A2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC26A2 pathogenic variants in the family. (See also Family planning.)

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic 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.
• Carrier detection for the reproductive partner of a heterozygous individual is possible using SLC26A2 molecular genetic testing (see Table 1).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular Pathogenesis

SLC26A2 encodes a sulfate transporter protein [Hästbacka 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. SLC26A2 is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues [Haila 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 1996]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper endochondral bone formation [Corsi et al 2001, Forlino et al 2005].

Loss of SLC26A2 sulfate transporter activity is associated with several skeletal disorders (see Genetically Related Disorders) [Rossi & Superti-Furga 2001].

Mechanism of disease causation. Loss of function. The predicted residual activity of the sulfate transporter correlates with phenotypic severity [Rossi et al 1997, Cai et al 1998, Rossi & Superti-Furga 2001, Karniski 2004, Maeda et al 2006].

Author History

Diana Ballhausen, MD; Lausanne University Hospital (2002-2022)
Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2022)
Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2022)
Andrea Superti-Furga, MD (2002-present)
Sheila Unger, MD (2022-present)

Revision History

• 16 March 2023 (sw) Revision: "SLC26A2-Related Achondrogenesis" added as synonym; Nomenclature updated
• 9 June 2022 (sw) Comprehensive update posted live
• 14 November 2013 (me) Comprehensive update posted live
• 22 September 2009 (me) Comprehensive update posted live
• 27 December 2006 (me) Comprehensive update posted live
• 21 July 2004 (me) Comprehensive update posted live
• 30 August 2002 (me) Review posted live
• 21 February 2002 (lb) Original submission

Literature Cited

• Barbosa M, Sousa AB, Medeira A, Lourenço T, Saraiva J, Pinto-Basto J, Soares G, Fortuna AM, Superti-Furga A, Mittaz L, Reis-Lima M, Bonafé L. Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population. Clin Genet. 2011;80:550–7. [PubMed: 21155763]
• 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. [PMC free article: PMC4361899] [PubMed: 18708426]
• 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]
• 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]
• 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]
• Forlino A, Piazza R, Tiveron C, Della Torre S, Tatangelo L, Bonafé 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]
• Haila S, Hästbacka 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]
• Hästbacka 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 E. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell. 1994;78:1073–87. [PubMed: 7923357]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• 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]
• 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]
• 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]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• 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. 1996;271:18456–64. [PubMed: 8702490]
• 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]
• 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]
• 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]
• 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]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• 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]
• Superti-Furga A. Achondrogenesis type 1B. J Med Genet. 1996;33:957–61. [PMC free article: PMC1050792] [PubMed: 8950678]
• Superti-Furga A, Hästbacka 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. 1996a;12:100–2. [PubMed: 8528239]
• 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. 1996b;63:144–7. [PubMed: 8723100]
• Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M, Sutton VR, Warman ML, Superti-Furga A. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023. Epub ahead of print. [PMC free article: PMC10081954] [PubMed: 36779427]