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.