Discussion

The SRD5A3 gene, at its 4q12 locus, encodes a protein that plays a role in testosterone production. This protein is a member of the polyprenol reductase subfamily within the steroid 5-alpha reductase family. To achieve N-linked glycosylation of proteins, androgen 5-alpha dihydrotestosterone (DHT) must convert polyprenol to dolichol, with this process being hindered in the SRD5A3-CDG disease (6). Congenital defects in type Iq glycosylation are linked with mutations in the SRD5A3gene; products of this gene expressed in the hippocampus and cerebellum are essential for brain development (7).
SRD5A3-CDG (MIM 612379) is an extremely rare congenital, multisystem disease that manifests with a highly variable phenotype (8). The main disease characteristics include ocular abnormalities (optic nerve hypoplasia/atrophy, iris and optic nerve coloboma, congenital cataract, or glaucoma), intellectual disability, nystagmus, hypotonia, ataxia, and/or ichthyosiform skin lesions (9). Cerebellar or vermian hypoplasia is seen in roughly fifty percent of cases; liver enzyme and coagulation abnormalities, and microcytic anemia, kyphosis, congenital heart defects, hypertrichosis, and retinitis pigmentosa have also been reported (1, 3). Recent years have witnessed a rise in the number of detected cases considering the emergence of next-generation sequencing (2). In the literature, only 38 cases of SRD5A3-CDG have been described (3). Our patient is the first confirmed case of SRD5A3-CDG to be reported from Iran, though some familial cases have been described in nearby countries including Turkey and Pakistan (2).
Although the phenotype of SRD5A3-CDG is highly variable (9), our case fits in with the literature in terms of features such as developmental delay, hypotonia, ataxia, pigmentary retinopathy, and nystagmus. However, an unprecedented finding is telangiectasia, which is yet to be reported in cases of SRD5A3-CDG. In fact, this clinical manifestation moved our colleagues toward presuming a diagnosis of ataxia-telangiectasia. This, coupled with the gradual emergence of the manifestations and the lack of prior access to whole-exome sequencing, led to a seven-year delay in arriving at the final diagnosis. When the patient was referred to us, we suspected congenital disorders of glycosylation (CDG) due to manifestations such as pigmentary retinopathy, hypotonia, ataxia, and telangiectasia, and requested the related diagnostic tests. A diagnostic challenge was that the insulin-like growth factor (IGF)-1 level was normal, which is unexpected in CDG. The final diagnosis of SRD5A3-CDG was achieved quite late, stressing the importance of increased understanding of this disorder.
Our report highlights the significance of carefully evaluating children who present with developmental delay alongside manifestations such as ataxia and telangiectasia. Further reports are needed to improve our understanding of SRD5A3-CDG, with the hope of achieving better management strategies and patient outcomes.