ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:2598–2603 (2007) Clinical Report Mandibuloacral Dysplasia and a Novel LMNA Mutation in a Woman With Severe Progressive Skeletal Changes Tomoki Kosho, 1 * Jun Takahashi, 2 Takashige Momose, 2 Akinori Nakamura, 1 Akihiro Sakurai, 1 Takahito Wada, 1 Kunihiro Yoshida, 1 Keiko Wakui, 1 Takefumi Suzuki, 3 Kazuo Kasuga, 4 Gen Nishimura, 5 Hiroyuki Kato, 2 and Yoshimitsu Fukushima 1 1 Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan 2 Department of Orthopedics, Shinshu University School of Medicine, Matsumoto, Japan 3 Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan 4 Department of Orthopedics, Okaya Municipal Hospital, Okaya, Japan 5 Department of Radiology, Tokyo Metropolitan Kiyose Children’s Hospital, Kiyose, Japan Received 5 February 2007; Accepted 7 June 2007 A 56-year-old Japanese woman with mandibuloacral dys- plasia and type A lipodystrophy is described. Mutation analysis identified a homozygous missense mutation (1585G > A) in exon 9 of the LMNA gene that replaces well-conserved residue alanine at position 529 to threonine (A529T). The woman showed, in addition to the usual clinical manifestations of the disorder, severe progressive skeletal changes: osteoporotic changes with multiple frac- tures; osteolysis of the right radius; and destructive changes of the vertebrae, leading to compression of the cervical spinal cord and paraplegia. Laboratory findings included markedly reduced bone mineral density; significantly increased urine N-telopeptide of collagen type I, an osteoclast marker; and normal serum bone specific alkaline phosphatase, an osteoblast marker. Regular follow up of adult patients with the disorder is desirable, including skeletal radiography, estimates of bone mineral density, and biochemical markers of bone turnover. Treatment with bisphosphonates to inhibit osteoclast activity is likely to be beneficial. ß 2007 Wiley-Liss, Inc. Key words: mandibuloacral dysplasia; LMNA; osteolysis; destructive vertebral changes; paraplegia; bone mineral density; biochemical markers of bone turnover How to cite this article: Kosho T, Takahashi J, Momose T, Nakamura A, Sakurai A, Wada T, Yoshida K, Wakui K, Suzuki T, Kasuga K, Nishimura G, Kato H, Fukushima Y. 2007. Mandibuloacral dysplasia and a novel LMNA mutation in a woman with severe progressive skeletal changes. Am J Med Genet Part A 143A:2598 –2603. INTRODUCTION Mandibuloacral dysplasia (MAD) is a rare autoso- mal recessive disorder characterized by postnatal growth retardation, craniofacial features (prominent eyes, beaked nose), skeletal manifestations (man- dibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, and joint contrac- tures), cutaneous changes (atrophic skin, partial alopecia, mottled hyperpigmentation), and partial (type A) or generalized (type B) lipodystrophy [Simha et al., 2003; Afifi and El-Bassyouni, 2005]. A total of 15 patients with MAD and type A lipodys- trophy (MADA) from 10 families have been found to have homozygous R527H or A529V missense muta- tions in the lamin A/C (LMNA) gene [Novelli et al., 2002; Shen et al., 2003; Simha et al., 2003; Garg et al., 2005]. The proteins lamin A/C are major components of nuclear lamina, a fibrous network underlying the inner surface of the nuclear envelope that determines nuclear shape and size [Lin and Worman, 1993]. Another patient with MAD and type B lipodystrophy (MADB) has been reported to have compound heterozygous mutations in the zinc metalloprotei- nase (ZMPSTE24) gene, involved in post-transla- tional processing of prelamin A [Agarwal et al., 2003]. Additionally, Garg et al. [2005] reconfirmed other six patients from two families with LMNA mutations as having MAD, who were originally reported as Grant sponsor: The Ministry of Health, Welfare, and Labor; Grant sponsor: The Ministry of Education, Culture, Sports, Science, and Technology. *Correspondence to: Tomoki Kosho, M.D., Department of Medical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail: ktomoki@hsp.md.shinshu-u.ac.jp DOI 10.1002/ajmg.a.31983