2018, 65 (2), 227-238 Note Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene Haruka Sasaki1), 2), Kumiko Yanagi3) *, Satoshi Ugi4), Kunihisa Kobayashi1), Kumiko Ohkubo5), Yuji Tajiri6), Hiroshi Maegawa4), Atsunori Kashiwagi7) and Tadashi Kaname3) * 1) Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka 818-8502, Japan 2) Division of Diabetic Medicine, Bunyukai Hara Hospital, Ohnojo, Fukuoka 816-0943, Japan 3) Department of Genome Medicine, National Research Institute for Child Health, Setagaya, Tokyo 157-8535, Japan 4) Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan 5) Department of Laboratory Medicine, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan 6) Division of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Fukuoka 830-0111, Japan 7) Diabetes Center, Seikokai Kusatsu General Hospital, Kusatsu, Shiga 525-8585, Japan Abstract. Segmental progeroid syndromes with lipodystrophy are extremely rare, heterogeneous, and complex multi-system disorders that are characterized by phenotypic features of premature aging affecting various tissues and organs. In this study, we present a “sporadic/isolated” Japanese woman who was ultimately diagnosed with mandibular hypoplasia, deafness, progeroid features, and progressive lipodystrophy (MDPL) syndrome (MIM #615381) using whole exome sequencing analysis. She had been suspected as having atypical Werner syndrome and/or progeroid syndrome based on observations spanning a 30-year period; however, repeated genetic testing by Sanger sequencing did not identify any causative mutation related to various subtypes of congenital partial lipodystrophy (CPLD) and/or mandibular dysplasia with lipodystrophy (MAD). Recently, MDPL syndrome has been described as a new entity showing progressive lipodystrophy. Furthermore, polymerase delta 1 (POLD1) gene mutations on chromosome 19 have been identified in patients with MDPL syndrome. To date, 21 cases with POLD1-related MDPL syndrome have been reported worldwide, albeit almost entirely of European origin. Here, we identified a de novo mutation in exon 15 (p.Ser605del) of the POLD1 gene in a Japanese case by whole exome sequencing. To the best of our knowledge, this is the first identified case of MDPL syndrome in Japan. Our results provide further evidence that mutations in POLD1 are responsible for MDPL syndrome and serve as a common genetic determinant across different ethnicities. Key words: Lipodystrophy, Mandibular hypoplasia, Progeroid features, POLD1 mutation, Japanese case CONGENITAL LIPODYSTROPHIES comprise a severe insulin resistance, glucose intolerance, diabetes, very rare group of heterogeneous disorders that affect dyslipidemia, and fatty liver disease [1-6]. Recently, the adipose tissue distributions and are characterized by genetic origins of some cases have been clarified. A pro‐ varying degrees of body fat loss (complete and/or partial) totypic example is Werner syndrome, which is a rare and various profound metabolic derangements such as autosomal recessive syndrome (MIM #277700) charac‐ terized by a variety of clinical signs of premature aging Submitted Jul. 12, 2017; Accepted Oct. 23, 2017 as EJ17-0287 that has been shown to be caused by biallelic germline Released online in J-STAGE as advance publication Dec. 2, 2017 mutations in the Werner helicase gene (WRN: encoding a Correspondence to: Haruka Sasaki, MD, PhD., Fukuoka Univer‐ RecQ DNA helicase/exonuclease) [7]. Mandibular dys‐ sity, 1-2-6-1202, Momochihama, Sawara-ku, Fukuoka 814-0001, Japan. plasia associated with lipodystrophy (MAD) type A E-mail: [email protected] (MIM #248370) and type B (MIM #608612) comprise *These authors equally contributed to this work. another type of rare autosomal recessive syndrome, ©The Japan Endocrine Society 228 Sasaki et al. Table 1 Classification of genetic subtypes of lipodystrophy Clinical subtype/Eponym Gene Chromosome Locus Inheritance transmission OMIM Generalized CGLD1 AGPAT2 11q13 AR #608594 CGLD2 BSCL2 9q34.3 AR #269700 CGLD3 CAV1 11q13 AR #612526 CGLD4 PTRF 17q21.2 AR #613327 MAD-A type LMNA 1q22 AR #248370 Partial CPLD1/Köbberling variety NK NK AD #608600 CPLD2/Dunnigan variety LMNA 1q22 AD #151660 CPLD3 PPARγ 3p25.2 AD #604367 CPLD4 PLIN1 15q26.1 AD #613877 CPLD5 CIDEC 3p25.3 AR #615238 CPLD6 LIPE 19q13.2 AD #615980 CPLD7 AKT2 19q13.3 AD #125853 CPLD8 ADRA2A 10q25.2 AD #104210 MAD-B type ZMPSTE24 1q34.2 AR #608612 HGPS LMNA 1q22 Heterozygous/de novo #176670 SHORT syndrome PIK3R1 5q13.1 AD #269880 Werner syndrome WRN 8p12 AR #277700 Nestor-Gullermo progeria syndrome BANF1 11q13.1 AR #614008 PRAAS/JMP PMMB8 6p21.32 AR #256040 MDPL syndrome POLD1 19q13.33 Heterozygous/de novo #615381 CGLD, congenital generalized lipodystrophy; CPLD, congenital partial lipodystrophy; MAD, mandibuloacral dysplasia; MDPL, mandibular hypoplasia, deafness, progeroid features, lipodystrophy; HGPS, Hutchinson-Gilford Progeria syndrome; PRSSA, proteasome- associated autoinflammatory syndrome; JMP, joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy; AD, autosomal dominant; AR, autosomal recessive; OMIM, Online of Mendelian Inheritance in Man; NK, not known resulting in lipodystrophy and progeroid features caused disease through repeated Sanger sequencing [10]. by mutations of the lamin A/C gene (LMNA) in type A Notably, a new causal factor of progressive lipodystro‐ and the zinc metalloprotease (ZNPTSTE24) gene in type phy associated with MDPL syndrome has been identified B [8, 9]. However, many others remain to be elucidated [11-17]. Mutations in the polymerase delta 1 (POLD1) [1-4]. Currently, the comprehensive definition and classi‐ gene have been detected in several patients with MDPL, fication of lipodystrophy is a work in progress with up to suggesting that MDPL is the result of POLD1 gene 20 loci described as being associated with infrequent li‐ mutation. Furthermore, the reported clinical features of podystrophy syndromes [2, 4, 5] (Table 1). MDPL possessing POLD1 gene mutations were very Recently, we reported a case of congenital partial lipo‐ similar to and overlapped with those of our case. This dystrophy with mandibular hypoplasia, deafness, and prompted us to question whether our case in fact repre‐ progeroid features (MDPL) syndrome as a novel subtype sented MDPL syndrome caused by a POLD1 gene muta‐ of lipodystrophy, distinct from known types of congeni‐ tion, as no mutation had yet been detected. Therefore, in tal partial lipodystrophy (CPLD) and/or MAD, because the current study we investigated the complete POLD1 we could not detect any gene mutations related to such a gene in our patient along with her parents and elder MDPL syndrome caused by a POLD1 mutation 229 brother using whole exome sequencing analysis. In addi‐ infusion was 167 mg/dL (RV: 73 ± 13.4) [18]. Antibod‐ tion, we summarized 21 previously reported cases with ies to insulin or the insulin receptor as well as mitochon‐ MDPL syndrome in the literature and compared them drial DNA mutations (A3243G, A8296G, A8344G, with classical Werner syndrome. T8356C G8361A, and G8363A) were all negative. She was suspected to have “atypical progeroid syndrome Case Description (Werner syndrome)” [19, 20], although no definitive diagnosis was obtained. There was no family history of A Japanese female (currently more than 46 years old) any similar disorders (Fig. 1). When she was 33 years was born at full term to non-consanguineous parents with old (Wt 30.8 kg, Ht 142.7 cm, body mass index [BMI] a normal birth appearance (weight [Wt] 3.65 kg, height 15.1 kg/m2), she presented with an overall paucity of [Ht] 49.5 cm). Her parents first noted her muscle spasms subcutaneous fat (total fat mass 14.9% by bioimped‐ and fat loss in her limbs during later infancy, and she ance). She had prominent eyes with conjunctival telean‐ subsequently developed poorly overall. Bilateral sensori‐ giectasia, but no juvenile cataracts. Her menarche had neural hearing loss was detected, and she required hear‐ occurred at age 13 followed by regular cycles for five ing aids before puberty. At 14 years of age, she was years. In addition, she showed mild hirsutism in the admitted to the university hospital for her short stature lower extremities and acanthosis nigricans in the axillae (Wt 28.6 kg, Ht 139.2 cm; both <3.0 SD, despite hyper‐ and neck regions with alopecia aerate of the scalp. She phagia) and frequent muscle cramps. Subcutaneous fat developed oligo-/amenorrhea owing to polycystic ovary loss was noted predominantly on her facial cheeks and syndrome (POCS) with abnormal sex hormone levels, extremities with pigmentation over a wide area. An oral including low sex hormone binding globulin (SHBG), glucose tolerance test (O-GTT: 1.7 g glucose/kg) showed elevated luteinizing hormone (LH)/follicular-stimulating normal glucose tolerance with increased insulin resis‐ hormone (FSH) ratio on GnRH stimulation test, and a tance (homeostatic model assessment-insulin resistance multi-cystic pattern on magnetic resonance imaging (MRI). [HOMA-IR] score of 5.3, reference value [RV]: <1.6; Furthermore, both abdominal computed tomography fasting plasma glucose [FPG] and immunoreactive insu‐ (CT) and MRI confirmed marked visceral fat accumula‐ lin [F-IRI] of 74 mg/dL and 29 μU/mL, respectively). An tion (visceral and