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 (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. AO2 is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. However, it exists in a continuous phenotypic spectrum with diastrophic dysplasia, and long-term survivors have been reported.

Diagnosis/testing.

The diagnosis of AO2 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: 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.

AO2 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 AO2 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.

Suggestive Findings

Atelosteogenesis type 2 (AO2) is usually lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia. AO2 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.
• 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 x-ray] and DTD)
  • Hypoplasia of the first metacarpal bone (also present in ACG1B and DTD)

Histopathology (important when radiologic material is not available or is of poor quality)

• Paucity of sulfated proteoglycans in cartilage matrix [Superti-Furga et al 1996a, Rossi et al 1997] similar to that seen DTD and ACG1B
• 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.

Establishing the Diagnosis

The diagnosis of AO2 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 or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, 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).

Clinical Description

To date, only a handful of individuals with atelosteogenesis type 2 (AO2) have been reported with biallelic pathogenic variants in SLC26A2 [Rossi & Superti-Furga 2001]. The following description of the phenotypic features associated with this condition is based on these reports.

The diagnosis of AO2 should be made only if the specific SLC26A2 pathogenic variants have already been described in an individual with AO2 and/or the clinical and radiographic severity lies somewhere between achondrogenesis 1B and diastrophic dysplasia (see Genetically Related Disorders). It follows, then, that the diagnosis of AO2 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.

AO2 is usually lethal in the neonatal period because of lung hypoplasia, tracheobronchomalacia, and laryngeal malformations. Pregnancy complication of polyhydramnios may occur.

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. AO2 is clinically very similar to diastrophic dysplasia (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 ACG1B to mild recessive multiple epiphyseal dysplasia (EDM4/rMED).

• 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 1996b, 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 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 individuals with more severe MED4/rMED and 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 (EDM4/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 – that is, 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 may also be referred to as McAlister dysplasia.

AO2 is currently classified in the "sulphation disorders group" in the revised Nosology and Classification of Genetic Skeletal Disorders of Bone [Mortier et al 2019].

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 evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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.

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 (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 AO2 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. AO2 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.

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/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.

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

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 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).

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 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].

Author History

Diana Ballhausen, MD; Lausanne University Hospital (2002-2020)
Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2020)
Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2020)
Andrea Superti-Furga, MD (2002-present)
Sheila Unger, MD, FRCPC (2020-present)

Revision History

• 24 September 2020 (sw) Comprehensive update posted live
• 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

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