Download Expanding the clinical spectrum of SLC29A3 gene defects

European Journal of Medical Genetics 53 (2010) 309e313
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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
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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.
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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.
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