Annals of Medicine and Surgery · 2 authors, 2 centres
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This case report describes a 4-year-old Syrian boy with 4H leukodystrophy caused by a homozygous variant of uncertain significance in the POLR3B gene. The diagnosis was confirmed through whole-exome sequencing after clinical and MRI findings suggested hypomyelination. This is the first reported case of POLR3B-related leukodystrophy in Syria, highlighting the importance of genetic testing for rare leukodystrophies.
**Background:** 4H leukodystrophy is a rare autosomal recessive disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, with onset from neonatal to late childhood. It is caused by mutations in POLR3A, POLR3B, or POLR1C genes. This case report presents the first diagnosed 4H leukodystrophy in Syria, caused by a homozygous variant of uncertain significance in POLR3B.
**Methods:** A 4-year-old Syrian boy presented with psychomotor delay and shivering starting at age 20 months. Clinical history included cesarean delivery due to abnormal labor and cord coiling, birth weight 2.9 kg, delayed walking, and progressive neurologic symptoms. Physical examination revealed delayed speech and language, delayed dentition, difficulty running, gait imbalance, dysarthria, short attention span, and medial strabismus in the left eye. MRI without contrast showed T2 bilateral hyperintense areas symmetrically in periventricular white matter, centrum semiovale, and cerebellum white matter. Laboratory analysis showed elevated lactic acid (28.7 mg/dl; normal 5.4–20.7), pyruvate (1.12 mg/dl; normal 0.2–0.9), 4-Hydroxy-Phenylactic acid, 3-Hydroxy propionic acid, and decreased PCO2 (31.5 mmHg; normal 35–45), HCO3 (20.3 mmol/l; normal 22–26), total CO2 (21.3 mmol/l; normal 22–29), and 25-Hydroxyvitamin D (20.45 ng/ml; normal 32–150). Whole-exome sequencing identified a homozygous missense variant of uncertain significance in POLR3B (NM_018082.5:c.3005T>C; p.Ile1002Thr).
**Key Results:** The patient's clinical and MRI findings were consistent with hypomyelinating leukodystrophy. Genetic testing revealed a homozygous variant in POLR3B, confirming the diagnosis of 4H leukodystrophy. The patient had an 11-year-old brother with Noonan syndrome and a sister who died at 4 days from pulmonary infection. A vitamin cocktail (B1, B2, CoQ10, carnitine) provided slight improvement but was stopped after genetic results showed no benefit. Future treatment options include stem cell therapy.
**Clinical Implications:** This case underscores the importance of considering POLR3-related leukodystrophy in children with hypomyelination on MRI and progressive neurologic symptoms. Genetic testing is essential for definitive diagnosis, as biochemical findings are often nonspecific. Early diagnosis enables appropriate genetic counseling for families and avoids ineffective treatments. The variant reported (p.Ile1002Thr) is classified as a variant of uncertain significance, but its homozygosity and clinical correlation support its pathogenicity. This is the first reported case in Syria, expanding the geographic and ethnic spectrum of POLR3B mutations.