Summary
Clinical characteristics.
Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. However, it exists in a continuous phenotypic spectrum with SLC26A2-related diastrophic dysplasia, and long-term survivors have been reported.
Diagnosis/testing.
The diagnosis of SLC26A2-related atelosteogenesis is established in a proband with characteristic clinical, radiologic, and histopathologic features and biallelic pathogenic variants in SLC26A2 identified by molecular genetic testing.
Management.
Treatment of manifestations: There is no specific treatment currently available, and the aim of therapy (supportive versus palliative) will depend on clinical status and respiratory prognosis of the individual patient.
Genetic counseling.
SLC26A2-related atelosteogenesis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of a proband with SLC26A2-related atelosteogenesis has at conception 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. Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible if both pathogenic variants in the family are known. Ultrasound examination early in pregnancy is a reasonable complement or alternative to molecular genetic prenatal testing.
Diagnosis
Suggestive Findings
SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia. SLC26A2-related atelosteogenesis should be 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.
Characteristic hand findings of sulfate transporter-related dysplasia:
Gap between the first and second toe (characteristic of SLC26A2-related achondrogenesis [when the phalanges are identifiable on x-ray] and SLC26A2-DTD)
Hypoplasia of the first metacarpal bone (also present in SLC26A2-related achondrogenesis and SLC26A2-DTD)
Histopathology (important when radiologic material is not available or is of poor quality)
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 SLC26A2-related achondrogenesis.
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.
Establishing the Diagnosis
The diagnosis of SLC26A2-related atelosteogenesis is established in a proband with suggestive findings and 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.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive clinical and radiographic 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 inherited disorders with perinatal-lethal skeletal dysplasia are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and radiographic findings suggest the diagnosis of SLC26A2-related atelosteogenesis, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
Single-gene testing. Sequence analysis of SLC26A2 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. Note: To date such variants have not been identified as a cause of SLC26A2-related atelosteogenesis.
A skeletal dysplasia
multigene panel that includes
SLC26A2 and other genes of interest (see
Differential Diagnosis) can be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by perinatal-lethal skeletal dysplasia, comprehensive
genomic testing, which does not require the clinician to determine which gene is likely involved, may be pursued. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in SLC26A2-Related Atelosteogenesis
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|
|
SLC26A2
| Sequence analysis 3 | >90% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
To date, only a handful of individuals with SLC26A2-related atelosteogenesis have been reported [Rossi & Superti-Furga 2001]. The following description of the phenotypic features associated with this condition is based on these reports.
The diagnosis of SLC26A2-related atelosteogenesis should be made only if specific SLC26A2 pathogenic variants that are associated with SLC26A2-related atelosteogenesis (see Genotype-Phenotype Correlations) have been identified, and/or the clinical and radiographic severity lies somewhere between SLC26A2-related achondrogenesis and SLC26A2-related diastrophic dysplasia (SLC26A2-DTD) (see Genetically Related Disorders). It follows, then, that the diagnosis of SLC26A2-related atelosteogenesis will only apply to a fetus/individual with severe prenatal-onset short stature. Almost all individuals will have club feet (adducted feet) and many will have lung hypoplasia (consequences of the generalized skeletal alterations). The dysmorphic facial features are very consistent and cleft palate is frequent.
SLC26A2-related atelosteogenesis is usually lethal in the neonatal period because of lung hypoplasia, tracheobronchomalacia, and laryngeal malformations. Pregnancy complication of polyhydramnios may occur.
Newborns with SLC26A2-related atelosteogenesis present with short limbs, adducted feet with wide space between the hallux and the second toe, hitchhiker thumb, cleft palate, and facial dysmorphism. SLC26A2-related atelosteogenesis is clinically very similar to SLC26A2-DTD [Rossi et al 1996b].
Skeletal features. 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.
Craniofacial features. 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.
Other. 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 SLC26A2-related achondrogenesis to mild SLC26A2-related multiple epiphyseal dysplasia (SLC26A2-MED).
The pathogenic variant p.Arg279Trp, the most common SLC26A2 variant outside Finland (45% of alleles), results in a mild SLC26A2-MED phenotype when homozygous and mostly the SLC26A2-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 SLC26A2-DTD phenotype or even the perinatal-lethal SLC26A2-related atelosteogenesis phenotype, particularly when combined in trans with the p.Arg279Trp variant. It has also been found in some individuals with more severe SLC26A2-MED and SLC26A2-related achondrogenesis, 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).
Another pathogenic variant specific to the Finnish population is p.Thr512Lys, which results in SLC26A2-related atelosteogenesis (de la Chapelle dysplasia) when homozygous and in SLC26A2-DTD when in compound heterozygosity with a milder allele [Bonafé et al 2008].
Most other pathogenic variants are rare.
The same pathogenic variants found in some individuals who have the SLC26A2-related atelosteogenesis phenotype can also be found in individuals with a milder phenotype (SLC26A2-MED and SLC26A2-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 – that is, in the diastrophic dysplasia-achondrogenesis group in which SLC26A2-related atelosteogenesis is considered to be a severe form of SLC26A2-DTD, and in which lethality distinguishes SLC26A2-related atelosteogenesis from SLC26A2-DTD.
De la Chapelle et al [1972] described two sibs with a novel condition very similar to SLC26A2-related atelosteogenesis, 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 SLC26A2-related achondrogenesis suggested a relationship with the sulfate transporter-related dysplasias. The identity of de la Chapelle dysplasia with SLC26A2-related atelosteogenesis was subsequently confirmed by molecular testing, which revealed pathogenic variants in SLC26A2 [Bonafé et al 2008].
SLC26A2-related atelosteogenesis may also be referred to as McAlister dysplasia.
SLC26A2-related atelosteogenesis is classified in the sulfation disorders group in the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023].
Prevalence
No data on the prevalence of SLC26A2-related atelosteogenesis are available. Among the sulfate transporter-related dysplasias, SLC26A2-related atelosteogenesis is the rarest phenotype.
Differential Diagnosis
SLC26A2-related achondrogenesis and SLC26A2-related diastrophic dysplasia have phenotypic overlap with SLC26A2-related atelosteogenesis (and should be considered in the differential diagnosis (see Table 2).
The differentiation of SLC26A2-related atelosteogenesis from other subtypes of atelosteogenesis ("incomplete bone formation"), and even from other lethal skeletal dysplasias, should be based on clinical examination as well as radiographic imaging.
Table 3.
Genes of Interest in the Differential Diagnosis of SLC26A2-Related Atelosteogenesis
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| Gene(s) | Differential Disorder | MOI | Differentiating Clinical & Radiographic Features |
|---|
|
FLNB
| FLNB-related AO1 (FLNB-AOI) (See FLNB Disorders.) | AD | Hitchhiker thumb & gap between toes are not present in FLNB-AO1 & cleft palate is rare. FLNB-AO1 shows better development of long bones & better ossification of spine & pelvis. Absence of fibula may suggest FLNB-AO1; dysplasia of fibula is more typical of SLC26A2-related atelosteogenesis. Humerus may be completely absent in FLNB-AO1.
|
Multiple
genes 1 incl:
DYNC2H1
IFT80
TTC21B | Lethal short-rib polydactyly
syndromes (w/o polydactyly)
(OMIM 613091, 611263, 613819) | AR |
|
|
FGFR3
| Thanatophoric dysplasia (TD) | AD |
|
AD = autosomal dominant; AO1 = atelosteogenesis type 1; AR = autosomal recessive; MOI = mode of inheritance
- 1.
Management
There is no specific treatment available. Decisions regarding supportive therapy versus palliative treatment depend on the degree of respiratory compromise at birth.
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with SLC26A2-related atelosteogenesis, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with SLC26A2-Related Atelosteogenesis
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| System/Concern | Evaluation | Comment |
|---|
|
Musculoskeletal
| Complete skeletal survey in viable newborn | |
|
Pulmonary
| Eval of respiratory status in viable newborn | |
Genetic
counseling
| By genetics professionals 1 | To inform affected persons & their families re nature, MOI, & implications of SLC26A2-related atelosteogenesis to facilitate medical & personal decision making |
MOI = mode of inheritance
- 1.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
For long-term survivors, care should include surgical repair of cleft palate.
Utility of surgery for club feet is unclear as this is quite complicated and the results limited.
Physiotherapy is useful for retaining range of motion.
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. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
SLC26A2-related atelosteogenesis is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one SLC26A2 pathogenic variant based on family history).
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. (Although a
de novo pathogenic variant has not been reported in
SLC26A2-related atelosteogenesis to date,
de novo variants are known occur at a low but appreciable rate in autosomal recessive disorders [
Jónsson et al 2017].)
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 being unaffected and not a carrier.
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.
SLC26A2-related atelosteogenesis is usually perinatal lethal; 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
At-risk relatives. Carrier testing for at-risk relatives requires prior identification of the SLC26A2 pathogenic variants in the family.
Reproductive partners of known carriers. Sequence analysis of SLC26A2. Caution should be used when interpreting the phenotypic outcome of various pathogenic variant combinations.
Prenatal Testing and Preimplantation Genetic Testing
High-risk pregnancies
Molecular genetic testing. Once the SLC26A2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Ultrasound examination. Transvaginal ultrasound examination early in pregnancy is a reasonable alternative to molecular prenatal testing because the testing is not invasive. However, the diagnosis can be made with confidence only at weeks 14-15, and reliability is highly operator dependent.
Low-risk pregnancies
If one parent is known to be heterozygous for an SLC26A2 pathogenic variant and the other parent does not have an SLC26A2 pathogenic variant, routine prenatal care is recommended.
Routine ultrasound examination. Routine prenatal ultrasound examination may identify very short fetal limbs ± polyhydramnios ± small thorax, raising the possibility of SLC26A2-related atelosteogenesis 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).
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Atelosteogenesis Type 2: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
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 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].
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].
Table 5.
Notable SLC26A2 Pathogenic Variants
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| Reference Sequences | DNA Nucleotide Change | Predicted
Protein Change | Comment [Reference] |
|---|
|
NM_000112.4
| c.-26+2T>C
(IVS1+2T>C 1) | -- | Founder variant in Finnish population 2 |
NM_000112.4
NP_000103.2
| c.532C>T | p.Arg178Ter | Common pathogenic variant 2 |
| c.835C>T | p.Arg279Trp | Most common pathogenic variant outside of Finland 2 |
| c.1535C>A | p.Thr512Lys | Second-most common pathogenic variant in the Finnish population [Bonafé et al 2008] |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
- 2.
