Adult Phenotypes in Angelman- and Rett-Like Syndromes

Abstract

BACKGROUND: Angelman- and Rett-like syndromes share a range of clinical characteristics, including intellectual disability (ID) with or without regression, epilepsy, infantile encephalopathy, postnatal microcephaly, features of autism spectrum disorder, and variable other neurological symptoms. The phenotypic spectrum generally has been well studied in children; however, evolution of the phenotypic spectrum into adulthood has been documented less extensively. To obtain more insight into natural course and prognosis of these syndromes with respect to developmental, medical, and socio-behavioral outcomes, we studied the phenotypes of 9 adult patients who were recently diagnosed with 6 different Angelman- and Rett-like syndromes. METHODS: All these patients were ascertained during an ongoing cohort study involving a systematic clinical genetic diagnostic evaluation of over 250, mainly adult patients with ID of unknown etiology. RESULTS: We describe the evolution of the phenotype in adults with EHMT1, TCF4, MECP2, CDKL5, and SCN1A mutations and 22qter deletions and also provide an overview of previously published adult cases with similar diagnoses. CONCLUSION: These data are highly valuable in adequate management and follow-up of patients with Angelman- and Rett-like syndromes and accurate counseling of their family members. Furthermore, they will contribute to recognition of these syndromes in previously undiagnosed adult patients.

Fig. 1

Clinical pictures. A, B Typical facial features of Kleefstra syndrome in patient 1. Note the midface hypoplasia, arched eyebrows and prognathism. C, D Typical facial appearance of Pitt Hopkins syndrome in patient 2. Note the coarse face with prognathism, broad mouth with down-turned corners and large nose. E, F Patient 3 with a mutation in MECP2 and his carrier sister (G, H). I, J Patient 4 with a mutation in CDKL5. Note her coarse face. K, L Patient 5 and 6 (M, N) with Dravet syndrome. O, P Patient 7 with Phelan-McDermid syndrome. Note the long face and full lips. Q–T Brother pair with Phelan-McDermid syndrome. Note the long face, prominent chin, and large ears in both brothers.

Fig. 2

Clinical pictures. A, B Clubbing of toe- and fingernails in patient 2 with a mutation in TCF4. C, D 2–3 toe syndactyly in patient 7 who was diagnosed with Phelan-McDermid syndrome.