Changing facial phenotype in Cohen syndrome: towards clues for an earlier diagnosis

Abstract

Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.

Figure 1

Facial phenotype in infancy and preschool age (<3 years); Clinical features of patients P1-F1 (19 months), P2-F2 (1 year), P3-F2 (1 year), P10-F8 (6 months), P11-F8 (15 months), P22-F17 (2 years), P23-F17 (2 years), P40-F33 (7 months), P51-F43 (9 months), P68-F58 (1 year).

Figure 2

(a): Focus on the two characteristic eyes shapes in patients with CS (infancy to school age); (1) Type 1: marked epicanthic folds, downward-slanting, high-arched palpebral fissures often with unilateral or bilateral ptosis. (2) Type 2: elongated, wave-shaped palpebral fissures with long, thick eyelashes. (b) Focus on characteristic ear shapes in patients with CS (infancy to school age); (1) long ears with an everted upper part of the auricle (2) large lobes. (c) Focus on the lower part of the face in patients with CS; (1) infancy: small, open mouth with downturned corners, a relatively short philtrum, thick lower lip and micrognathia with a marked mentolabial sulcus. (2) Adolescence and adulthood: short, upturned philtrum, thick lower lip, open mouth, prominent central incisor.

Figure 2

(a): Focus on the two characteristic eyes shapes in patients with CS (infancy to school age); (1) Type 1: marked epicanthic folds, downward-slanting, high-arched palpebral fissures often with unilateral or bilateral ptosis. (2) Type 2: elongated, wave-shaped palpebral fissures with long, thick eyelashes. (b) Focus on characteristic ear shapes in patients with CS (infancy to school age); (1) long ears with an everted upper part of the auricle (2) large lobes. (c) Focus on the lower part of the face in patients with CS; (1) infancy: small, open mouth with downturned corners, a relatively short philtrum, thick lower lip and micrognathia with a marked mentolabial sulcus. (2) Adolescence and adulthood: short, upturned philtrum, thick lower lip, open mouth, prominent central incisor.

Figure 3

Facial phenotype from early infancy to school age or adulthood (from left to right); Clinical features of patients P51-F43, P3-F2, P2-F2, P40-F33, P15-F11, P68-F58, P22-F17, P23-17, P72-F62, P10-F8, P11-F8, P7-F6, P19-F14, P18-F14.

Figure 4

Changing facial features with facial expression; (a, b) (P1-F1): atypical facial phenotype at rest (a) and typical grimacing appearance when smiling (b). (c, d) (P68-F58): less typical facial feature when smiling.

Figure 5

Less typical facial phenotype of patients with CS (patients P24-F18 and P25-18).