2 Clinical presentationThe patient was a 4 yr-old boy referred to Myelin Disorders Clinic at Children's Medical Center, Tehran, Iran in 2017 due to macrocephaly and abnormal facies. He was the second child born to a consanguineous marriage. He was born after a full-term, uneventful pregnancy with a birth weight, length and head circumference (HC) of 4200 g, 47 cm and 39 cm, respectively. Within the first months of life, macrocephaly and puffy eyelids were noted, but motor, cognitive and speech developmental milestones were compatible with chronological age at age one yr-old. HC at age of 1 year was 49 cm (>+2 Z-score). By the age of 2 yr, he developed umbilical hernia, which later underwent surgical operation, but it was not completely disappeared, so that it was visible at the time of our examination at 4 yr old in spite of previous corrective surgery. From age of 3 yr-old up to now, half a tablet per day of levothyroxine has been prescribed for him due to clinical suspicion of hypothyroidism, but review of his medical documents did not reveal abnormal thyroid function tests. By the age of 4 yr, when he referred to Myelin Disorders Clinic, his head circumference and height were 54.5 cm (>+3 Z-score) and 106 cm (>-2 Z-score), respectively ( Fig. 1 .A). Developmental milestones regarding Denver Developmental Screening Test (DDST) were normal. Neurologic examinations were normal but systemic exams showed abnormal facial characteristics including sparse eyebrows, high forehead, broad nasal bridge, epicanthic folds, downward slanted palpebral fissures, long philtrum, retro-micrognathia, full lips, coarsening appearance, gingival hyperplasia and premature teeth. Clinical examination also showed flat feet, hyperextensible skin, joints hyperlaxity and easy bruising. No symptom of ichthyosis or scoliosis were noticed. A large hypopigmented skin lesion under anterior abdominal region around umbilicus was observed ( Fig. 1 .B-E). His parents claimed that the skin lesion was the remaining of an old burn. Open full size image Fig. 1 Diagram of head circumference of index case over time is shown by black dots. Standard deviation (SD) lines with the corresponding Z-score are presented (A). Clinical features of the proband: coarse facies with downward slanted palpebral fissures, high forehead, broad nasal bridge, epicanthic folds, retro-micrognathia, Puffy droopy eyelids, full everted lips and sparse eyebrows (B), gum hypertrophy, irregular dentition long philtrum (C), flat feet (D) and umbilical hernia (E). First brain MRI of patient at age 4 years. Axial and coronal planes at the level of basal ganglia and centrum semiovale, in T2 weighted spin echo and FLAIR sequences images reveals diffuse abnormal white matter signal more pronounced at superficial subcortical and deep peritrigonal regions (F, G, H). Bilateral anterior temporal small subcortical cysts formation (I, J-black arrows) and increased perivascular spaces in posterior deep white matter are noticed clearly visible in FlAIR sequence images (K-black arrow). Sequence chromatogram showing homozygote and heterozygote state of NM_001242581.1: c.2251dup mutation in the parents and affected boy (L).For more detailed evaluations brain MRI and complementary metabolic studies using gas chromatography–mass spectrometry (GC-MS) were performed. Eventually whole exome sequencing (WES) was performed to look for a probable genetic factor involved in leukoencephalopathy and abnormal facies.