Kohji Kato1, Seiji Mizuno2, Mie Inaba2, Shinobu Fukumura3, Naoko Kurahashi4, Koichi Maruyama4, Daisuke Ieda5, Kei Ohashi5, Ikumi Hori5, Yutaka Negishi5, Ayako Hattori5, Shinji Saitoh6. 1. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya 467-8601, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. 2. Department of Pediatrics, Central Hospital, Aichi Human Service Center, 713-8 Kagiya-cho, Kasugai 480-0392, Japan. 3. Department of Pediatrics, Sapporo Medical University School of Medicine, S1 W17, Chuo-ku, Sapporo 060-8556, Japan. 4. Department of Pediatric Neurology, Central Hospital, Aichi Human Service Center, 713-8 Kamiya, Kasugai 480-0392, Japan. 5. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya 467-8601, Japan. 6. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Mizuho-Ku, Nagoya 467-8601, Japan. Electronic address: ss11@med.nagoya-cu.ac.jp.
Abstract
BACKGROUND: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. METHODS: PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. RESULTS: We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (-0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. CONCLUSION: The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.
BACKGROUND: Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. METHODS:PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. RESULTS: We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (-0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. CONCLUSION: The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.