Clinical 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 pathogenic variants 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 pathogenic alleles in the family are known. Ultrasound examination early in pregnancy is a reasonable complement or alternative to molecular genetic prenatal 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].

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 analysis for the four most common SLC26A2 pathogenic variants 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 analysis for pathogenic variants. Parental DNA analysis for the variants found in the proband is recommended, as most probands are compound heterozygotes.
• Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having AO2 is use of a multigene 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 pathogenic variants.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants 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 pathogenic variants in the family.

Clinical Description

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.

• Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of ACG1B.
• The combination of a severe pathogenic variant (predicting stop codons or structural variants in transmembrane domains) with a pathogenic variant located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5’-flanking region of the gene results in the less severe phenotypes, i.e., AO2 and DTD [Hästbacka et al 1996, Superti-Furga et al 1996c, Rossi et al 1997, Karniski 2001, Rossi & Superti-Furga 2001, Karniski 2004].

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

The pathogenic variant p.Arg178Ter is the second-most common variant (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 variant. It has also been found in some cases of more severe MED4/rMED and of ACG1B, making it one of two pathogenic variants identified in all four SLC26A2 related dysplasias.

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

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.

Together with p.Arg178Ter, c.-26+2T>C is the only pathogenic variant 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].

The pathogenic variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other pathogenic variants. It is not found in AO2 or ACG1B.

Another pathogenic variant 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 pathogenic variants are rare.

The same pathogenic variants 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 variant. Indeed, pathogenic 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 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 sibs with a novel condition very similar to AO2, with very hypoplastic ulna and fibula; one additional sib and one more person 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 pathogenic variants 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.

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
• Consultation with a clinical geneticist and/or genetic counselor

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 in the US and www.ClinicalTrialsRegister.eu in Europe 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.

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 pathogenic variant in SLC26A2. Note: Parental testing is always recommended when pathogenic variants are identified in a proband, in order to confirm the segregation of pathogenic variants 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 pathogenic variants 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 (Heterozygote) Detection

Carrier testing for at-risk family members is possible once the pathogenic variants 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 pathogenic variant 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, allelic variants, 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. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk is a possible option.
• 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 pathogenic variants. 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 pathogenic variants have been identified.

Molecular Genetic Pathogenesis

Pathogenic variants 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) [Hästbacka 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 pathogenic variant, 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 pathogenic variant c.-26+2T>C (the "Finnish" allele) located in this region was shown to lead to reduced mRNA transcription [Hästbacka et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene.

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 pathogenic variant is combined with a severe, structural pathogenic variant (e.g., p.Arg178Ter, p.Leu131CysfsTer41 [Rossi et al 1996b], p.Asn425Asp [Rossi et al 1997] or c.1724delA) [Hästbacka et al 1996] The same pathogenic variants associated in some individuals with the AO2 phenotype can be found in individuals with DTD if the second allele is a relatively mild pathogenic variant, or in individuals with ACG1B if the second pathogenic variant 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].

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 [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. 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 [Hästbacka et al 1994, Hästbacka et al 1999].

Abnormal gene product. Most of the SLC26A2 pathogenic variants 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" pathogenic variant c.-26+2T>C have reduced levels of mRNA with intact coding sequence [Rossi et al 1996b]. Thus, the variant presumably interferes with splicing and/or further mRNA processing and transport [Hästbacka et al 1994, Hästbacka et al 1999]. The other Finnish variant 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 pathogenic variant 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.

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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 live
• 21 July 2004 (me) Comprehensive update posted live
• 30 August 2002 (me) Review posted live
• 1 March 2002 (lb) Original submission