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European Journal of Medical Genetics 53 (2010) 309e313 Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg Short report Expanding the clinical spectrum of SLC29A3 gene defects Ronen Spiegel a, b, c, *, Simon T. Cliffe d, Michael F. Buckley d, e, Yanick J. Crow f, Jill Urquhart f, Yoseph Horovitz b, c, Yardena Tenenbaum-Rakover c, g, William G. Newman f, Dian Donnai f, Stavit A. Shalev a, c a Genetic Institute, Ha’Emek Medical Center, Afula, Israel Department of Pediatrics A, Ha’Emek Medical Center, Afula, Israel c Rappaport Faculty of Medicine, Technion e Israel Institute of Technology, Haifa, Israel d Dept of Haematology and Genetics, South Eastern Area Laboratory Services, The Prince of Wales & Sydney Children’s Hospitals, Sydney, Australia e Dept of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands f Genetic Medicine, St Mary’s Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, UK g Pediatric Endocrine Unit, Ha’Emek Medical Center, Afula, Israel b a r t i c l e i n f o a b s t r a c t Article history: Received 14 December 2009 Accepted 28 June 2010 Available online 7 July 2010 H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID) are allelic autosomal recessive syndromes reported in the last year to be caused by mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Herein, we report three new patients from a single family who present with phenotypes that associate features of both PHID and H syndrome. Genetic analysis of the SLC29A3 gene revealed that two affected sisters are compound heterozygotes for the previously reported mutations p.G427S and p.G437R, while their nephew was homozygous for the p.G437R mutation. In addition to this intra-familial genetic heterogeneity, these patients demonstrate considerable phenotypic variability. One sister had clinical features consistent with classical PHID phenotype, while her nephew’s features were in keeping with the diagnosis of H syndrome. The second sister displayed the most severe phenotype which combined diagnostic features from both syndromes. This patient also had features not described previously, including severe seronegative polyarthritis involving large and small joints, and hypogonadotropic hypogonadism. These manifestations may be additional characteristics of the growing clinical spectrum of SLC29A3 defects. This report emphasizes the complex genotype phenotype correlation in SLC29A3 disorders and suggests that other factors are relevant to disease manifestations and severity. Ó 2010 Elsevier Masson SAS. All rights reserved. Keywords: SLC29A3 gene Diabetes mellitus Autosomal recessive Hyperpigmentation Hypertrichosis 1. Introduction Mutations in the SLC29A3 gene, also termed hENT3, have recently been reported to cause two allelic autosomal recessive syndromes, H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID) [4,10]. The pathognomonic hallmark of both syndromes is the presence of distinctive hyperpigmented, hypertrichotic indurated cutaneous patches and Abbreviations: IDDM, Insulin dependent diabetes mellitus; PHID, pigmented hypertrichosis with insulin dependent diabetes; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin disorders; GAD, glutamic acid decarboxylase; ESR, erythrocyte sedimentation rate; CRP, C reactive protein. * Corresponding author. Department of Pediatrics A and Genetic Institute, Ha’Emek Medical Center, Afula, Israel. Tel.: þ972 4 6494216; fax: þ972 4 6494425. E-mail addresses: [email protected], [email protected] (R. Spiegel). 1769-7212/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmg.2010.06.012 plaques with an underlying inflammatory cell infiltrate. H syndrome is characterized by additional features including hepatosplenomegaly, cardiac anomalies, sensorineural hearing loss, short stature, scrotal masses, hypergonadotropic hypogonadism and hyperglycemia [9]. PHID patients typically present with antibody negative insulin-dependent diabetes mellitus during childhood and have not been reported to have hearing loss [7,13]. A clinical entity previously described as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin disorders) in childhood shares features included in both H syndrome and PHID and may represent SLC29A3 defects not confirmed genetically [8]. Both phenotypes are characterized by elevated acute phase reactants, suggesting an abnormal regulation and/or activation of the immune system. Herein, we describe three additional patients from a single family who harbor SLC29A3 pathogenic mutations. Our report 310 R. Spiegel et al. / European Journal of Medical Genetics 53 (2010) 309e313 demonstrates an intra-familial allelic heterogeneity as well as phenotypic variability that shed more light on the complex genotype phenotype relations in SLC29A3 defects. 2. Clinical reports The family is of Moslem Arab origin residing in a village in Northern Israel. The three affected individuals include two sisters and their nephew. Their ages ranged between 5 and 28 years. The family pedigree is illustrated in Fig. 1. The clinical data of the patients are summarized in Table 1. 2.1. Patient II-1 The patient is a 23-year-old female. Her pregnancy and delivery were unremarkable. Her psychomotor development was normal. She was first admitted at the age of two years for the investigation of microcytic anemia. Her hemoglobin level on admission was 6.7 g/dL, iron level was 23 mg/dL (normal range 60e120 mg/dL). Bone marrow aspiration was consistent with iron deficiency and hemoglobin electrophoresis revealed sickle cell trait. At the age of four years she was referred for the evaluation of hepatosplenomegaly and dysmorphic features including bilateral exophthalmus, hypertelorism, flat and broad nasal bridge, upturned nares, prominent maxillary bone and gingival hypertrophy (Fig. 2B). In addition, she had relatively short and broad fingers, and camptodactyly (Fig. 2D). At this time she was noted to harbor well demarcated, extended areas of thick and hyperpigmented skin with overlying hypertrichosis that involved mainly the lower abdomen, the genital area, arms, and legs with a remarkable sparing of the knees (Fig. 2A). Abdominal ultrasound showed enlarged liver and spleen with normal homogenous texture and normal portal blood flow. Laboratory investigation revealed 46,XX karyotype and skeletal survey was unremarkable except for generalized osteopenia of the metacarpal and metatarsal bones. Metabolic screen was normal including urinary mucopolysaccharide and oligosaccharide electrophoresis and biochemical assays of lysosomal enzymes. Biopsy obtained from affected thigh skin showed intact epidermis with nonspecific inflammatory changes of the dermis, characterized by lymphocytic and histiocytic infiltration of the deep dermis and intensive septal fibrosis of the subcutaneous fat. These findings were classed as septal panniculitis. Needle liver biopsy revealed microvesicular steatosis but a repeated biopsy three years later was unremarkable. Fig. 1. Pedigree of the family. Table 1 Summary of clinical findings. Sex Age (years) Height (centile) Skin changes Hearing loss IDDM Proptosis Arthropathy Camptodactyly Delayed puberty ESR (mm/h) CRP mg/dL Polyclonal gammopathy Patient II-1 Patient II-2 Patient III-1 Female 23y 142 cm (4SD) Classical & extended Severe Yes Moderate Yes Severe Yes 80e120 60e120 severe Female 28y 157 cm (20) Classical & extended No Yes No No Mild No 70e120 70e150 moderate Male 5y 105 cm (7) Mild & localized Moderate-severe No Moderate No No Not relevant 64 76 mild SD ¼ standard deviation, ESR ¼ erythrocyte sedimentation rate, CRP ¼ C reactive protein. At the age of nine years she was admitted with new onset IDDM. Insulin antibodies were elevated while glutamic acid decarboxylase (GAD) and islet cell antibodies were absent. Her diabetes was poorly controlled despite high daily insulin doses. An attempt to use an insulin pump failed due to the thickening of the skin. A year later she developed bilateral sensorineural hearing loss and required the use of hearing aids. Echocardiogram demonstrated moderate pericardial effusion without hemodynamic decompensation, which resolved spontaneously over several months. At the age of 13 years, she presented with joint pain and experienced limited joint mobility resulting in an inability to walk independently more than several hundred meters. Additionally, she suffered from progressive generalized morning stiffness. On examination she had marked loss of bilateral hip and shoulder motion together with flexion deformities of the proximal interphalangeal phalanges (PIPs) and metacarpo-phalangeal (MCPs) joints, in the absence of obvious effusion. Her ankles were warm and swollen with partial loss of tibiaetalar and subtalar motion. Other joints were normal. An MRI scan of the hands showed camptodactyly and subcutaneous edema of the fingers and palms. She showed no improvement on non-steroidal anti-inflammatory drugs and was treated with intra-articular steroid injections to the inflamed joints and subsequent oral methotrexate. Although initially she experienced some improvement in the range of motion of her ankles and hands with this regimen, there has been no reduction in the thickness of the skin and long term effects have not been successful, eventually leading to cessation of these medications. In addition to her poorly controlled diabetes mellitus, endocrinopathy also manifested, with short stature and hypogonadotropic hypogonadism. At 23 years her height is 141 cm (4SD below median height). Serum insulin growth factor 1 (IGF-1) at the age of 14 years was markedly reduced to 42 mg/dL (normal range 120e480 mg/dL) and stimulation studies of growth hormone (GH) with either arginine or clonidine were not responsive consistent with GH deficiency. She also displayed delayed puberty and gonadotropin releasing hormone (GnRH) stimulation test was performed which showed blunted increase of serum LH and FSH consistent with hypogonadotropic hypogonadism. Thyroid and adrenal function were normal. Cranial MRI scan was normal with normal signal and size of the pituitary gland. Over time her skin lesions progressed with further hyperpigmentation and thickening of the skin and involvement of previously unaffected body parts. In several areas the previous hypertrichosis was replaced by normal hirsute skin (Fig. 2C,E). R. Spiegel et al. / European Journal of Medical Genetics 53 (2010) 309e313 311 clinic for evaluation of hyperpigmented sclerodermoid-like skin patches with overlying hypertrichosis extending to the lower abdomen, genital region, anterior and inner aspects of both thighs and the upper arms. These lesions, which were non painful, had a progressive course over several years. Interestingly, in several areas the hypertrichosis was replaced by normal hirsute skin (Fig. 2G). On examination she showed flat facies, gingival hypertrophy and mild brachydactyly. In contrast with her sister she had no organomegaly, no hearing impairment, and her joints were unaffected. In addition, she underwent normal puberty and her adult height was 157 cm (20th centile [target height 165 cm, 50th centile]). Laboratory studies showed persistently raised ESR and CRP of 70e100 mm/h and 70e150 mg/dL respectively. Immunologic studies showed mild polyclonal gammopathy and autoantibody panels were all negative. 2.3. Patient III-1 This 5-year-old child is the nephew of patients, II-1 and II-2. He first presented at the age of 2.5 years for the evaluation of speech delay that was found to result from severe sensorineural hearing loss that required the installation of hearing aids. His height at the age of 5 years was 105 cm (7th centile). The rest of his physical examination revealed bilateral proptosis with mild facial coarsening. The dorsum of his both feet was thickened up to the ankle level with mild hyperpigmentation but without hypertrichosis (Fig. 2F). Abdominal sonography showed a normally sized homogenous liver but mild splenomegaly with a normal homogenous texture. Laboratory tests showed normal serum glucose levels, increased ESR and CRP (64 mm/h and 76 mg/dL respectively). Serum IgG and IgA were both mildly elevated. 3. Methods Fig. 2. Characteristic dermatologic and clinical features. Patient II-1 at the age of 10 years with extended areas of hyperpigmented, thickened, hypertrichotic skin distributed over the legs, abdomen and arms with prominent sparing of the knees (A). Typical facial features of this patient showing upturned nares, prominent maxillae and gingival hypertrophy (B). Patient II-1 at the age of 20 years showing the evolution of the cutaneous changes (CeE), and the typical hand changes with marked shortening of palms and metacarpals, and associated camptodactyly (D). Feet of patient III-1 indicating thickened and mildly hyperpigmented skin up to the ankle level without hypertrichosis (F). Typical demarcated hyperpigmented skin lesions overlying the legs and groins of patient II-2 (G). Laboratory investigation revealed consistent and marked elevation of acute phase reactants including erythrocyte sedimentation rate (ESR), ranging between 80 and 120 mm/h, (normal values < 25 mm/h), C reactive protein (CRP), ranging between 65 and 120 mg/dL (normal values < 5 mg/dL), non specific polyclonal hypergammaglobulinemia with IgG levels of 2.5e2.8 g/dL (normal range 0.7e1.8 g/dL) and hypoalbuminemia of 2.4 g/dL (normal range 3.2e4.0 g/dL). Antibody screens for autoimmune diseases were negative. 2.2. Patient II-2 This 28-year-old female, is the older sister of patient II-1. She first presented with IDDM at the age of 12 years. Since then her glucose levels were well controlled, with subcutaneous insulin injections. Two years later she was referred to the dermatological Prior to the identification of SLC29A3 as the cause of H syndrome [10], autozygosity mapping of affected individuals was undertaken using the Affymetrix 250k SNP array, as described previously [12]. The coding region of the SLC29A3 gene (NM_001814.4) was screened for mutations by DNA sequencing, as previously described [4]. 4. Results Autozygosity mapping failed to define a region of homozygosity in the two affected siblings (II-1 and II-2) at chromosome 10q22 which contains SLC29A3. However, a 2 Mb region of homozygosity was present in their nephew at the 10q locus. Sequence analysis of SLC29A3 identified two heterozygous point mutations in exon 6. The first mutation is a nucleotide transition c.1279G > A resulting in the missense amino acid substitution p.Gly427Ser. The second mutation is the nucleotide transition c.1309G > A causing the missense amino acid substitution p.Gly437Arg. Patients II-1 and II-2 were compound heterozygotes for these mutations whereas patient III-1 was homozygous for the p.G437R mutation (Fig. 1). 5. Discussion H syndrome and PHID syndrome have been described as two autosomal recessive disorders, recently reported to be caused by mutations in the SLC29A3 gene encoding an equilibrative nucleoside transporter hENT3 expressed in mitochondria [4,10]. The cutaneous hallmark of both syndromes are progressive hyperpigmented, hypertrichotic, sclerodermatous skin lesions. 312 R. Spiegel et al. / European Journal of Medical Genetics 53 (2010) 309e313 PHID patients typically develop antibody negative IDDM within the first or second decade of life [7,13]. In contrast, in the initial report of H syndrome diabetes was not included among the diagnostic criteria [9]. Nevertheless, later descriptions included either hyperglycemia or overt diabetes in the clinical phenotype of H syndrome [3,10]. Moreover, H syndrome has been characterized by multi system manifestations, including sensorineural hearing loss, cardiac abnormalities, hepatosplenomegaly, endocrinopathy (short stature, hypogonadism), genital abnormalities (scrotal masses, micropenis, gynecomastia), exophthalmus and fixed flexion contractures of the hands and feet resulting in various deformities such as hallux valgus and camptodactyly [8e11]. Based on the above clinical descriptions, patient II-2 fits well with the diagnostic categorization of PHID whereas patient III-1 complies with the H syndrome phenotype. Patient II-1 presented with the most severe phenotype, and has features consistent with the clinical diagnosis of both syndromes. Considering this striking intra-familial variability with the previously reported clinical overlap, it now appears that PHID is not a distinct condition but a milder form of SLC29A3 associated defects. Similar intra-familial variability was recently reported by Broshtilova et al. They described two siblings, the younger showed the full range manifestations of H syndrome, whereas his older brother presented with only diabetes mellitus. Both brothers were homozygous for the same mutation [3]. Hence, in addition to our report it now seems that intra-familial variability is a common finding in SLC29A3 disorders. Our report serves to further expand the clinical spectrum of these disorders with features not described previously. Hypergonadotropic hypogonadism was evident in several affected males with micropenis, variable degree of small testes, adult azoospermia and hormone studies demonstrating elevated gonadotropins with low serum testosterone [8,9]. In addition, one affected female aged 50 years lacked secondary sexual signs but her hormonal profile was not reported [10]. In the current report, patient II-1 displayed delayed puberty with low basal gonadotropins and unresponsive GnRh stimulation study consistent with hypogonadotropic hypogonadism. Hypergonadotropic hypogonadism is the result of target organ failure (male/female genitalia) as opposed to hypogonadotropic hypogonadism which is caused by either pituitary or hypothalamic failure [14]. High levels of SLC29A3 expression have been demonstrated in the gonads and in the uterus which explain the resulting hypogonadism when mutated ([2], supplementary on line materials). We speculate that the two different pathogenic mechanisms of hypogonadism in SLC29A3 defects are explained by hENT3 pleiotropy. Non specific arthralgia was reported in five of six recently described patients. Although SLC29A3 confirmation was not carried, their clinical description is highly consistent with H syndrome [5]. Our report further expands the spectrum of joint involvement in H syndrome. Patient II-1 displayed symmetric seronegative polyarthritis involving both large and small joints. Interestingly, the association of polyarthritis and persistently elevated acute phase reactants in this patient was highly suspicious for rheumatoid arthritis and indeed this was her working diagnosis for several years. Hence, rheumatologic symptoms, specifically arthritis should be considered in the clinical spectrum of SLC29A3 related syndromes. We identified two different mutations in a single extended family. The two sisters were compound heterozygotes for the p.G437R and p.G427S mutations whilst their nephew was homozygous for the p.G437R mutation. These two mutations have been found in nine separate families of Arab Muslim origin residing in a small region near Jerusalem. The carrier rate of both mutations in this population was assessed to be 1% [10]. Our patients live in a small village in Northern Israel more than 200 km away. The family denied any genealogical relationships with the Arab families from the Jerusalem area. It was previously shown that among the Palestinian Arab population in Israel many autosomal recessive diseases are present at a high frequency within a limited region or even in a single village [16] and it was for presumed distant relatedness in the siblings’ parents that we undertook autozygosity mapping. Therefore the geographic distribution of these two SLC29A3 mutations indicate that they originated from ancient founder ancestors [15] and may be more common among the general Arab population living in Israel and in the Palestinian territories. Haplotype analysis of affected patients from the two regions will be necessary to determine if these two recurrent SLC29A3 mutations represent ancient founder mutations or mutation hotspots. Our report further emphasizes the previously reported clinical variability even in patients who share the same pathogenic SLC29A3 mutation(s) [3,10]. The suggested correlation of specific mutations with discrete phenotype (either H syndrome or PHID) is likely to be more complex than previously thought [4]. There does not appear to be a simple relationship between the severity of tissue involvement and the levels of SLC29A3 expression. Mitochondrial disorders classically demonstrate greater variability in organ involvement and disease severity than do autosomal recessive disorders. The SLC29A3 gene encodes a pH-dependant equilibrative nucleoside transporter protein (hENT3) that is widely expressed and is believed to play a role in nucleotide salvage. The hENT3 protein has been recently shown to be an integral membrane protein of mitochondria [6], where it joins hENT1 as one the two known nucleoside/nucleobase transporters of mitochondria. Given hENT3’s role in nucleotide salvage and its expression in mitochondria it is not an unexpected finding that multiple tissues are involved in disorders of this protein and therefore explain some of the observed variation in these patients. There is at this time no data to explain why some symptoms appear explicable on the basis of loss of SLC29A3 function (e.g. the sensorineural deafness, alterations in insulin signaling) whereas the immunological findings appear to relate to cellular proliferation and dysregulation of the immune response, although paradoxical autoimmunity is not uncommon in inherited immune disorders such as common variable immunodeficiency [1]. We speculate that other factors, either genetic (for example modifier genes, tissue to tissue variation in mitochondrial density and function), or environmental variation play significant role in determining the inter-individual variation in tissue involvement and disease severity. More data from a larger cohort of patients should be accumulated to better understand genotype and phenotype in SLC29A3 associated disorders and their interaction. Acknowledgements We are grateful to the patients and their families. The study was funded by the NIHR Manchester Biomedical Research Centre. MF Buckley is a recipient of a Marie Curie International Incoming Fellowship from the European Science Directorate. References [1] S. Agarwal, C. Cunningham-Rundles, Autoimmunity in common variable immunodeficiency, Curr. Allergy Asthma Rep. 9 (2009) 347e352. [2] S.A. Baldwin, S.Y. Yao, R.J. Hyde, A.M. Ng, S. Foppolo, K. Barnes, M.W. Ritzel, C.E. Cass, J.D. 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