A case of hereditary novel mutation in SLC26A2 gene (c.1796 A.> C) identified in a couple with a fetus affected with atelosteogenesis type 2 phenotype in an antecedent pregnancy

Introduction

Atelosteogenesis type 2 or AO II (Greek ateles=incomplete, osteogenesis=bone formation) is a rare lethal osteochondrodysplasia, characterized by severe limb shortening, facial dysmorphism, cleft palate, abducted thumbs and toes [1]. It is an autosomal recessive condition, caused by a homozygous or compound heterozygous mutation in the SLC26A2 gene. Only 25 cases have been reported in the literature [2].

We present a case with a novel mutation in SLC26A2 gene, identified in an Indian family, with details of the prenatal diagnosis (PND).

Case presentation

A 23-year-old Indian primigravidae, with second degree consanguinity, was referred to our fetal medicine center in view of suspected fetal skeletal dysplasia. Target scan revealed a singleton pregnancy corresponding to a gestational age (GA) of 21+1 weeks, with appropriate biometry of head and abdomen. Limb survey revealed severe quadrimelic shortening (less than first centile). Additional findings were polyhydramnios, small thorax, short stubby fingers and bilateral extreme plantar flexion of feet (Figure 1).

Figure 1:

Prenatal ultrasound images from a fetus of 21+1 weeks with AO II (inferred retrospectively) showing, (A) dumb bell shaped short curved femur (B) narrow thorax (C) Cleft hard palate, (D) plantar flexed foot and (E) hitch hiker thumb.

A diagnosis of lethal osteochondrodysplasia was made. Counseling emphasized on fetal karyotype, termination of pregnancy and fetal autopsy. Amniocentesis was performed and karyotype was normal (46, XY). After termination of pregnancy, the fetus was sent for autopsy.

Autopsy report revealed a male fetus of 21–22 weeks GA with dysmorphic facies and rhizomesoacromelic shortening of all four limbs, bilateral brachydactyly with hitch-hiker thumbs, bilateral talipes eqinovarus with wide sandal gap and proximally placed big toes, short and narrow thoracic cavity, and hypoplastic thymus. A provisional diagnosis of AO II was made.

Fetogram and bone histopathology was consistent with AO II. Further genetic workup was refused by the couple at this point.

Six months later she presented with a new pregnancy. Scan done at 13 weeks revealed fetal hydrops. The couple opted for termination of pregnancy. Parental carrier screening for AO II was advised.

Molecular genetic test revealed a heterozygous status for non synonymous (p.L 599F/eu599 phe) novel mutation (c.1796 A.> C) in exon 2 of SLC26A2 gene in both parents. A 25% recurrence risk for an affected fetus in each pregnancy was explained with the options for PND.

In her next pregnancy, a chorionic villus sampling (CVS) was done at 12 weeks. The report came as heterozygous for the previously mentioned mutation. The antenatal care was managed routinely. She delivered a healthy female baby weighing 3000 g at term. The baby was normal at 2 years follow-up.

Discussion

The main clinical and imaging features of AO II are enumerated in Table 1, along with those detected in the index fetus of our case. Molecular diagnosis could not be done in the index pregnancy, however it is inferred that a homozygous SLC26A2 gene mutation lead to development of AO II in it, based on the ultrasound and autopsy features, and identification of the heterozygous mutation in the parents, and demonstration of inheritance of the same mutation in the subsequent normal fetus via PND.

The SLC26A2 gene located on chromosome 5q32 encodes the transmembrane diastrophic dysplasia sulfate transporter (DTDST). A mutation in the gene disrupts the ability of cartilage cells to take up adequate sulfate ions, resulting in inability to produce normal proteoglycans, which affects the structure of cartilage and osteogenesis [3], causing a spectrum of autosomal recessive chondrodysplasias. In decreasing order of severity, they include achondrogenesis type IB (ACG-1B), AO II, diastrophic dysplasia (DTD), diastrophic dysplasia variant (DTDv), and recessively inherited multiple epiphyseal dysplasia (rMED) [4]. ACG-1B is the most severe form of chondrodysplasia within this spectrum, with extreme limb shortening. The DTD and DTDv can be differentiated from AO II by normal trunk, cystic swelling of ears and may be non lethal. Recessive MED has mild phenotypic features such as short stature, joint deformities and pain, gait disorders, irregular epiphyses of tubular bones, multilayered patella and early-onset osteoarthritis, and may even escape medical attention.

Other types of AO (I and III) are now reported. AO I or boomerang dysplasia, is a rare lethal osteochondrodysplasia with autosomal dominant inheritance, caused by mutations in the filamin B (FLNB) gene. It characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows [5] and is distinguished from AO II by better development of the distal humerus and femur, better ossification in vertebral bodies and pubic bones, absence of Hitch-hiker thumbs and toes, rarity of cleft palate and presence of coronal clefts of the vertebrae. In AO II, the Femur and Humerus have a dumb bell shape with bifid distal ends and less marked vertebral anomalies. The fibula is usually hypoplastic in AO I, whereas in AO II it is often absent. AO III is also an autosomal dominant lethal skeletal dysplasia caused by mutation in the FLNB gene, and is characterized by overlapping clinical findings, that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations [6].

AO II needs to be distinguished from other lethal dwarfing conditions. Thanatophoric dysplasia (the commonest lethal skeletal dysplasia) is characterized by telephone receiver shaped Femur, unlike the dumb bell ones in AO II. In Campomelic dysplasia, the long bones are bowed and additional abnormalities include hydrocephalus, cardiac and renal defects.

The mutation described in our case report is a novel one, not yet described in any other population. An unknown consanguinity in this family or a probable founder effect is a likely possibility. The mutation was elucidated by amplification of the genomic DNA with Polymerase chain reaction followed by bidirectional sequencing [7]. The resultant sequence was analyzed and compared with published gene sequence [8]. Being a novel mutation, it is difficult to comment on ethnicity.

PND was done through CVS in our case. Preimplantation genetic diagnosis (PGD) is also an option for PND, once the mutation specific probes are developed. Though expensive, it has an obvious advantage of absolute certainty of conceiving an unaffected pregnancy.

Conclusion

A novel hereditary mutation in SLC26A2 gene was identified, and by inference, was associated with a phenotype of AO II. The multimodality work up of all cases of skeletal dysplasia was thus emphasized.