Nucleotide Excision Repair (NER) Disorders as differential diagnosis in isolated hypomyelination

Xeroderma pigmentosum (XP), Cockayne Syndrome (CS), and Trichothiodystrophy (TTD) belong to the group of Nucleotide Excision Repair (NER) disorders. Deficiencies in NER typically result in a heterogeneous phenotypic spectrum characterized by extreme sensitivity to ultraviolet radiation (XP, CS, and TTD), progressive neurological deterioration, growth failure, vision and hearing loss, premature aging (CS and TTD) and Sulfur-deficient brittle hair (TTD). CS and TTD are usually considered in the differential diagnosis of hypomyelinating disorders because brain MRI may show a pattern of white matter abnormalities consistent with hypomyelination. The presence of early brain atrophy, intracranial calcification, and significant multisystemic involvement typically guides the diagnostic process. ERCC2 (also known as XPD) is one of the genes involved in nucleotide excision repair and transcription-coupled repair pathways. However, ERCC2 is often overlooked in children with isolated leukoencephalopathy. We describe and discuss the clinical and neuroradiological features of three unreported individuals carrying biallelic mutations in ERCC2 with a primary hypomyelinating presentation. Subject 1 presented at birth with congenital cataract, and later demonstrated global developmental delay. Her MRI showed diffuse isolated hypomyelination. Subject 2 presented at age 9 months with neurodevelopmental delay and nystagmus. Their MRI showed diffuse isolated hypomyelination. Subject 3 presented at age 6 years with difficulty in school, clumsiness, tremor, myopia, delayed dentition, growth delay. Their MRI showed hypomyelination with preserved myelination in the lateral thalami and pallidum. None of them presented hair abnormalities, facial dysmorphisms, signs of progeria, brain atrophy, or cerebral calcifications. The diagnosis of NER disorder was obtained through Whole Exome Sequencing analysis, without prior clinical suspicion. This study highlights the need to consider NER disorders as a differential diagnosis in subjects presenting with isolated hypomyelination and no striking multisystemic involvement, as previously described in ERCC6 dysfunction.