A novel variant in the AGPS gene causes the rare rhizomelic chondrodysplasia punctata type 3: A case report.

Figure 1: The skeletal survey shows bilateral rhizomelic and shortening of the humeri and the femurs (A, B, C). Punctate ossification is identified at the proximal femur and distal femur and around the knees (C). Punctate ossification is noted at the proximal humeri bilaterally around the shoulder joint and along the upper spine (A, B, D, F). The vertebral bodies are not remarkable (F). The pelvis is within the normal limit (C). The head is within the normal limit (G, H). The nasogastric tube tip is seen just beyond the gastroesophageal junction (D, E). The stomach is distended (D, E). Normal cardio-mediastinal outline (E).

Shawli AM, Nazer AT, Khayyat Y, Alqurashi MG, and Hakami F. (2022) A novel variant in the AGPS gene causes the rare rhizomelic chondrodysplasia punctata type 3: A case report. Cureus, 13(12)

Plasmalogens are a class of lipid that contain a vinyl-ether bond, which provides these lipids with unique characteristics including roles in membrane structure and organization, vesicular fusion, lipid raft formation, and preventing oxidative stress. Rhizomelic chondrodysplasia punctata (RCDP) is a rare class of recessive genetic disorders that is caused by an inability to synthesize plasmalogens due to mutations in genes that encode the enzymes in the biosynthetic pathway. The common symptoms seen in people with RCDP include congenital cataracts, skeletal dysplasia, chondrodysplasia punctata in the cartilage of large joints, cardiac malformations, recurrent respiratory infections, and seizure disorders. RCDP can be separated into 5 types which are dependent on the mutation causing the plasmalogen deficiency. Mutations in alkylglycerone phosphate synthase (AGPS), a gene that encodes an enzyme in the biosynthetic pathway, causes RCDP type 3. Shawli et al have discovered another AGPS variant causing RCDP type 3 in a patient and discusses this rare case of RCDP.

The RCDP presentation of a 16-day-old girl was described. Although she had a good APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) score, the patient was below the 3rd centile in length, weight, and head circumference at 44 cm, 4.85 lbs, and 29 cm, respectively. During a physical examination, the patient was found to have facial dysmorphisms including low set ears, long philtrum, and upslanting palpebral fissures of both eyes. They also found shortened proximal bones in upper limb and contracture in both elbows and talipes equinovarus, rhizomelia, shortening of the humeri and femurs. As well, she had punctate ossification at proximal and distal femur, around the knees, around the shoulder joint, and along the upper spine. She also had a pansystolic murmur and was hypotonic.

At the time of publishing, the authors state that there have been 9 cases of RCDP type 3 reported in the literature, each caused by a different variant. Genetic testing confirmed the RCDP diagnosis and narrowed it down to RCDP type 3 due to a 4-base pair deletion at (c.1639_1642del p.) in the AGPS gene, which caused a frameshift leading to a premature stop codon. The patient’s parents were both found to be heterozygous for RCDP type 3. The mutation found in this individual is a novel mutation leading to RCDP type 3.

Shawli et al discovered a novel AGPS mutation variant leading to RCDP type 3 and of the types of RCDP, type 3 is one of the rarest forms. As there are so few cases of type 3, it cannot be determined if there is a relationship between the mutation variant and the severity of disease. The case described above is similar to the condition of a four-year-old patient described by Itzkovitz et al* where the patient was also found to be below the 3rd centile in weight, length, and head circumference. Some of the developmental differences seen in the young patient in this paper have been seen in other patients with RCDP type 3, but some have also experienced other symptoms, which suggests that the mutation variants alter the presentation. Increased awareness of RCDP and how it manifests will lead to earlier diagnosis, as seen in this patient, and improved clinical management.

*Itzkovitz B, Jiralerspong S, Nimmo G, Loscalzo M, Horovitz DDG, Snowden A, Moser A, Steinberg S, and Braverman N. (2011) Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia puncata (RCDP) types 2 and 3. Human Mutation