Extending the spectrum of AKT1 mosaicism: not just the Proteus syndrome

DEAR EDITOR, A 5-year-old girl was referred to us for evaluation of a pigmented birthmark, unchanged since birth, on her right cheek. There was no other previous medical history of note and no family history of relevant problems. Cutaneous examination revealed a pigmented keratinocytic epidermal naevus following fine Blaschko lines on the right cheek and neck (Fig. 1), and a solitary, 1-cm caf e-au-lait macule on the lower leg. Subtle hemihypertrophy of the right cheek was noted, including the tragus of the ear, which had appeared to progress over time. In conjunction, she was noted to have rightsided hemihypertrophy of the tongue with intraoral pigmentation of the mucosal surfaces, linear naevoid-looking change on the right side of the tongue and right-sided misalignment of the teeth. Her parents also gave a history of frequent malodorous right ear discharge. The patient was referred to otorhinolaryngology, who diagnosed a severe right-sided conductive hearing loss. The remainder of her physical examination was unremarkable. Magnetic resonance imaging confirmed soft tissue hemihypertrophy of the cheek, with extensive soft tissue overgrowth within the right external auditory canal and middle-ear cleft, and a sclerotic bony spur in the posterior inferior aspect of the external auditory canal (Fig. 1g). Mosaicism for a growth-promoting mutation was suspected. With appropriate consent for genetic investigations a punch skin biopsy was obtained from the epidermal naevus, and DNA extracted directly by standard methods. DNA was also extracted from a venous blood sample. Histology confirmed a keratinocytic epidermal naevus (Fig. 2). Initial sequencing of HRAS and KRAS hotspot mutations, as described in epidermal naevus syndromes, was negative. However, Sanger sequencing for hotspot mutations in AKT1 revealed a heterozygous missense mutation, c.49G>A, p.Glu17Lys, present in the epidermal naevus but not the blood (Fig. 2). Although we only have a single biopsy from this patient, given existing knowledge of this particular mutation, postzygotic mosaicism is highly likely to be the cause of her entire clinical phenotype and not just the epidermal naevus. In mosaic form, this is the characteristic causal mutation in the first cohort of patients with clinically delineated Proteus syndrome, as defined by strict diagnostic criteria. Proteus syndrome is a rare overgrowth syndrome characterized by a normal phenotype or limited features at birth followed by