Patient with macrocephaly and hypopigmented skin was diagnosed with Smith-Kingsmore syndrome after skin biopsy.

Case description A 1-year-old girl was seen at the genetics department because of macrocephaly and pigmentation abnormalities. After birth, hypopigmented skin patches, following the lines of Blaschko, were noted. She has a depressed nasal bridge, light-coloured eyes and a thick lower lip vermillion. At 4 months, she was seen by a paediatric neurologist because of macrocephaly. A developmental delay was noted: she started crawling at 18 months and at 21 months, she could not yet walk or talk. She showed little interest in toys and had stereotypic movements. A MRI of the brain showed macrocephaly with accelerated subcortical myelinisation. Genetic testing Gene panel testing for neurodevelopmental disorders on DNA extracted from biopsied affected skin, detected a novel heterozygous pathogenic MTOR variant: GRCh37 (hg19): NM_004958.3: c.5930C>T; p.(Thr1977Ile) in 20% of the reads. Discussion Pathogenic variants in the MTOR gene are associated with Smith-Kingsmore syndrome, characterized by aberrant skin pigmentation, macrocephaly and intellectual disability. Patients can show facial dysmorphic features: a large forehead, midfacial hypoplasia and micrognathia, hypertelorism with downslanted palpebral fissures, and a short nose with a depressed nasal bridge. Patients can have a narrow thorax, short extremities, and deep palmar creases of the hands and the feet. Hypomelanosis of Ito, a typical pattern of skin hypopigmentation, is typical for these patients. Patients can have abnormal brain imaging. With an enlargement of the whole brain (megalencephaly) or of only one hemisphere (hemimegalencephaly). Global developmental delay and intellectual disability, and autistic features are frequent. Some patients have seizures and feeding problems. There is variable expression and the pathogenic MTOR variants can be identified in the germline, as well as in a mosaic state. Conclusion Our patient shows the typical phenotype of Smith-Kingsmore syndrome, caused by a pathogenic variant in the MTOR gene in a mosaic state.