A. P. Oranje

C. A. L. Ruivenkamp

K. B. M. Hansson

K. Mulder

M. C. van Rij

M. L. Grijsen

N. M. Appelman-Dijkstra

R. van Doorn

S. G. Kant

Springer - Publisher Connector

Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome

SHORT COMMUNICATION
Rothmund-Thomson syndrome and osteoma cutis in a patient
previously diagnosed as COPS syndrome
M. C. van Rij1 & M. L. Grijsen2 & N. M. Appelman-Dijkstra3 & K. B. M. Hansson1 &
C. A. L. Ruivenkamp1 & K. Mulder2 & R. van Doorn2 & A. P. Oranje4 & S. G. Kant1
Received: 1 April 2016 /Revised: 12 December 2016 /Accepted: 18 December 2016 /Published online: 30 December 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract We present a patient with poikiloderma, severe os-
teoporosis and a mild intellectual disability. At the age of
9 years, this patient was proposed to suffer from a novel dis-
ease entity designated as calcinosis cutis, osteoma cutis,
poikiloderma and skeletal abnormalities (COPS) syndrome.
At the age of 35, he was diagnosed with Hodgkin’s lympho-
ma. Recently, biallelic pathogenic variants in the RECQL4
gene were detected (c.1048_1049delAG and c.1391-1G>A),
confirming a diagnosis of Rothmund-Thomson syndrome
(RTS). In the brother of this patient, who had a milder pheno-
type, a similar diagnosis was made.
Conclusion: We conclude that COPS syndrome never existed
as a separate syndrome entity. Instead, osteoma cutis may be
regarded as a novel feature of RTS, whereas mild intellectual dis-
ability and lymphoma may be underreported parts of the
phenotype.
What is new:
•Osteoma cutis was not a known feature in Rothmund-Thomson patients.
• Intellectual disability may be considered a rare feature in RTS; more
study is needed.
What is known:
•RTSisawell-describedsyndromecausedbymutationsintheRECQL4gene.
• Patients with RTS frequently show chromosomal abnormalities like, e.g.
mosaic trisomy 8.
Revisions received: 1 November 2016; 13 December 2016; 8 December
2016
Arnold P. Oranje has passed away shortly before submitting the final
version of the paper.
Communicated by Jaan Toelen
* M. C. van Rij
m.c.vanrij@lumc.nl
M. L. Grijsen
m.l.grijsen@lumc.nl
N. M. Appelman-Dijkstra
N.M.Appelman-Dijkstra@lumc.nl
K. B. M. Hansson
K.B.M.Hansson@lumc.nl; klaassen_hansson@hotmail.com
C. A. L. Ruivenkamp
C.Ruivenkamp@lumc.nl
K. Mulder
K.M.Mulder@lumc.nl
R. van Doorn
R.van_Doorn@lumc.nl
A. P. Oranje
arnold.oranje@gmail.com
Eur J Pediatr (2017) 176:279–283
DOI 10.1007/s00431-016-2834-3
S. G. Kant
S.G.Kant@lumc.nl
1 Department of Clinical genetics, Leiden University Medical Centre,
Postzone K5-R, PO box 9600, 2300 RC Leiden, The Netherlands
2 Department of Dermatology, Leiden University Medical Centre,
Leiden, The Netherlands
3 Department of Endocrinology, Leiden University Medical Centre,
Leiden, The Netherlands
4 Kinderhuid.nl Teledermatology, Rotterdam, Dermicis Skin Clinic
Alkmaar, Practice for Hair and skin, Breda, The Netherlands
Keywords Rothmund-Thomson syndrome . Poikiloderma .
RECQL4 gene .Mental retardation/developmental delay/
intellectual disability . Osteoporosis . Aneuploidy .
Chromosomal instability . COPS syndrome . Osteoma cutis .
Calcinosis cutis
Abbreviations
BMD Bone marrow density
COPS syndrome Calcinosis cutis, osteoma cutis,
poikiloderma and skeletal abnormalities
DNA Deoxyribonucleic acid
FISH Fluorescent in situ hybridisation
ID Intellectual disability
LSI MYC Locus-specific identifier (LSI) MYC,
2 FISH probes used to visualise locus
8q24 on chromosome 8
RECQL4 DNA helicase, RECQ-like, type 4
RTS Rothmund-Thomson syndrome
Case description
A 34-year-old man with dysmorphic features, osteoporosis and
recurrent fragility fractures with non-union was referred to the
department of clinical genetics. At age 9, a clinical diagnosis of
calcinosis cutis, osteoma cutis, poikiloderma and skeletal abnor-
malities (COPS syndrome) was made and reported in this jour-
nal [11]. In summary, he had dysmaturity (birth weight 2400 g at
40 weeks gestational age) and severe diarrhoea requiring paren-
teral feeding. At the age of 3, he suffered frommeningitis due to
mumps infection. Furthermore, at the age of 4, subcutaneous
tumours, osteomas, with a maximal diameter of 3 cm were
removed from the ankles, knees and forehead. Skeletal abnor-
malities were observed with hypoplastic patellae and delayed
bone maturation. At the age of 15 years, a diagnosis of coeliac
disease was made for which he was started on a diet and vitamin
D supplementation. He suffered frommultiple fragility fractures
of both the tibiae, the right elbow, the left patella and the meta-
tarsal bone Vof his right foot, complicated by pseudo arthroses.
A bone mass density measurement was performed at age 27,
showing a T-score of −2.6 femur and 2.4 lumbar vertebrae,
consistent with a diagnosis of osteoporosis. Treatment with
alendronate was initiated and while on treatment his bone mass
increased and no fractures occurred. Treatment was
discontinued at the age of 30 and at age 34. He suffered from
a mild intellectual disability for which he attended special edu-
cational programs.
At age 34, he was referred to our hospital for a second opin-
ion regarding his osteoporosis and non-union of a tibia fracture.
Physical examination showed a slender man with a short stature
(height 167 cm, (−2.1 SDS), with a saddle nose, absence of
eyelashes and eyebrows and facial poikiloderma, (Fig. 1). He
had sparse hair on the scalp, with two spots of alopecia areata
and multiple small hyperpigmented macules on the trunk and
arms. He had small but normal hands (Fig. 2); at the right foot, a
partial 2–3 syndactyly of the right foot was observed.
His 5 years older brother has a milder phenotype, with a
similar physical appearance and a mild intellectual disability.
He was diagnosed with osteopenia and recurrent fragility frac-
tures with non-union, but not with celiac disease (Table 1).
Their parents were non-consanguineous.
Altogether, this presentation was compatible with a clinical di-
agnosisofRothmund-Thomsonsyndrome(RTS,OMIM268400).
Cytogenetic testing at the age of 13 showed a normal male
karyotype in a total of 50 analysed nuclei without signs of
Fig. 1 Facial features at age 34. Note: absent eye brows and eye lashes,
small nose
Fig. 2 Hands at age 34. Note: relatively small hands, with small though
normally shaped nails, normal thumbs
280 Eur J Pediatr (2017) 176:279–283
chromosomal instability, while a CytoScan HD Array
(Affymetrix) at the age of 34 showed a slight excess of chro-
mosome 8q, suggestive for a mosaic chromosome 8q duplica-
tion (presumably between 12 and 18%). Subsequently,
karyotyping and FISH analysis were performed on cultured
lymphocytes from both brothers, showing a mosaicism for
trisomy 8, isochromosome 8q and a normal karyotype
(Table 1). Sanger sequencing of the RECQL4 gene (OMIM
603780) showed two compound heterozygous recurrent path-
ogenic mutations in both brothers: one frame shift mutation:
Table 1 Clinical features in our patient and his brother compared with the frequencies of these features among previously reported Rothmund-
Thomson patients
Our patient Brother of the patient Reported frequency of RTS featuresa
Skin
Poikiloderma + + All
Hyperpigmentation + + +
Hypopigmentation + + +
Calcinosis cutis + − Uncommon
Osteoma cutis + − −
Palmoplantar hyperkeratosis − − 30%
Photosensitivity − − +/−
Hair 50%
Sparse hair + +
Absent eyelashes + +
Sparse/absent eyebrows + +
Alopecia areata + −
Dental abnormalities + − 27–59%
Growth
Low birth weight + + +
Short stature + + +
Skeleton 68–75%
Radial ray defects − − 20%
Metaphyseal changes + − +
Osteopenia/osteoporosis + + +
Small patellae + − +
Ocular lesions
Cataract − − 10–50%
Gastrointestinal features 17%
Oesophageal or pyloric stenosis + −
Feeding problems + −
Chronic emesis/diarrhoea + −
Hematologic abnormalities Hodgkin’s lymphoma − Occasionally
Cancer
Osteosarcoma − − 30%
Skin cancer − − 5%
Lymphoma + − Two casesb
Neurocognitive development No specific data available
Mild intellectual disability + +
Cytogenetic abnormalities Mosaic trisomy 8 (15%) Mosaic trisomy 8 (13%) Cases reported with Mosaic trisomy 2, 7 or 8
Mosaic isochromosome 8q
(13%)c
Mosaic isochromosome 8q
(9%)c
Mosaic isochromosome 2, 7 or 8
RECQL4 gene mutations + + 66%
a Frequencies derived from [2, 8, 16, 17]
b Cases reported by Siitonen 2009 and Simon 2010 [13, 14]
c Based on interphase FISH (2 probes: LSI MYC, 8q24) on 400 lymphocytes nuclei in blood
Eur J Pediatr (2017) 176:279–283 281
c.1048_1049delAG (p.(Arg350fsX21)) and one splice site
mutation c.1391-1G>A (p.(?)). Carrier testing in the parents
confirmed biallelic inheritance. Altogether, these findings
confirmed the clinical diagnosis of RTS in both brothers.
One year later, the index patient was diagnosed with a stage
I Hodgkin’s lymphoma in the neck for which he was started
on three cycles of adriamycin, bleomycin, vinblastin,
darcabazin and prednisone in combination with involved node
radiation with 12 × 1.8 Gy resulting in a complete remission.
He developed fever and neutropenia after the first chemother-
apy. The neutropenia has resolved after a temporary break of
chemotherapy and treatment with antibiotics. Neutropenia did
not return after continuation of the ABVD therapy. The radio-
therapy did not lead to considerable side effects.
Discussion
In this report, we presented a case of RTS alternatively diag-
nosed as COPS. RTS is a rare autosomal recessive
genodermatosis with a distinctive phenotype, characterised
by poikiloderma, sparse hair, skeletal abnormalities and an
increased risk for osteosarcoma [8]. RTS had been considered,
but was assumed less likely, due to the absence of cataract and
photophobia, a major sign, and the presence of osteoma cutis,
whereas genetic confirmation was not possible in that period
[11]. However re-evaluation of the patient and his brother
changed the diagnosis to RTS and later the cataract was not
associated with RECQL4 mutations anymore.
The absence of the cataract makes the distinction between
the two clinical variants of RTS: the form with poikiloderma
and ocular defects, named RTSI, and poikiloderma, skeleton
defects, predisposition to cancer and RECQL4 mutations,
named RTSII, which accounts for approximately 66% of
RTS patients (Table 1). Osteoma cutis has not been described
before; calcinosis cutis has been linked to RTS [1, 4].
The RECQL4 gene on the long arm of chromosome 8
(8q24.3) codes for anATP-dependentDNAhelicase,which plays
a role in regulating DNA replication, DNA repair and chromo-
somal integrity [6, 13]. RECQL4-deficient mice show abnormal
karyotypes and aneuploidy [10], as well as defects in osteoblast
progenitors [18]. In patients with RTS, these defects in osteoblast
progenitors make them prone to osteosarcoma and low-turnover
osteoporosis with a predisposition for fracture non-union [9, 18].
Chromosomal abnormalities, like the mosaic trisomy 8 and i(8q)
have been reported in RTS patients [7]. The specific RECQL4
mutations, c.1048_1049delAG in exon 5 and c.1391-1G>A in
intron 7, were both previously reported in patients with RTS [3,
8]. One patient was reported with the exact combination of mu-
tations; contrary to our patient, this patient showed additional
humoral immune deficiency and granulomatous skin lesions [3].
Generally, intellectual disability is not considered to be a
feature of RTS [8, 13, 17]. As a consequence, the number of
RTS patients with a mild intellectual disability, like our pa-
tients, may be underestimated. Mild to moderate intellectual
disability has been reported in a small number of cases [5, 8,
15, 16]. Co-occurring features like hydrocephalus and cranio-
synostosis may have played a role in the ID [16], and in some
cases the diagnosis of RTS was not confirmed [5]. In our case,
the history of meningitis may have attributed to some part of
the intellectual disability; however, the brother was affected as
well, implying a relationship with RTS. We hypothesised that
the mosaic chromosomal abnormalities observed are respon-
sible for the development of intellectual disability. However,
the chromosomal imbalances were apparently acquired.
Additionally, mutations in RecQ DNA helicase genes may
mildly impact intellectual development, such as observed in
Bloom syndrome (OMIM 210900), a chromosomal breakage
syndrome, caused by mutations in the RECQL3 gene (OMIM
604610). Althoughmost affected individuals with Bloom syn-
drome have normal intellectual ability, many exhibit learning
disability [12]. Likewise, a relative mild intellectual disability,
such as in our patients, may be underreported in RTS patients
and considered to be normal variability of intelligence.
Modifier genes and co-morbidity may also play a role in the
variability and atypical expression with or without ID; these
may explain the phenotypic differences between the brothers.
In conclusion, we reclassify a patient with COPS as RTS
with osteoma cutis and a mild intellectual disability, refuting
COPS as a separate entity, since there were no reports in lit-
erature after 1991. To link mild intellectual disability to RTS,
more studies are needed.
Acknowledgments We are grateful to the patients and their family for
their cooperation in this publication. Additionally, we thank Prof. Dr. M.
Mearadji, Paediatric Radiologist, ErasmusMedical Centre Rotterdam, for
proofreading and commenting on the radiologic findings, and Dr. Laura
J.C.M. van Zutven, Department of Clinical genetics, Erasmus Medical
Centre, Rotterdam, The Netherlands, for providing additional details on
the chromosomal analysis performed at childhood.
Authors’ contribution M.C. van Rij: involved in writing the case re-
port, literature research.
M.L. Grijsen: dermatologist in training who was involved in the pa-
tients’ dermatologic follow-up and description of the phenotype.
N.M. Appelman-Dijkstra: internist involved in treatment of osteopo-
rosis of the patient, intellectually contributing to the article, and proof-
reading the english language.
K.B.M. Hansson: cytogeneticist involved in diagnosing the chromo-
somal abnormalities of both brothers and contributing to the description
of these findings in the article.
C.A.L. Ruivenkamp: molecular geneticist involved in the array anal-
ysis and proofreading the article.
K.Mulder: dermatologist in training involved in the intellectual work-
up for the article.
R. van Doorn: supervising dermatologist specialised in geno-
dermatologic syndromes, and contributing to the intellectual content of
the article.
A.P. Oranje: dermatologist who wrote the initial case report (1991),
now involved from a distance by proofreading the article. Sadly, this co-
author passed away very recently (Oct 19, 2016).
282 Eur J Pediatr (2017) 176:279–283
S.G. Kant: clinical geneticist who first diagnosed the patient with RTS
syndrome, and who contributed to the article by critical reading.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Funding There was no funding applied to complete this case report.
Informed consent of the patient involved was provided, including
permission to publish pictures.
Open Access This article is distributed under the terms of the Creative
Commons At t r ibut ion 4 .0 In te rna t ional License (h t tp : / /
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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Rothmund-Thomson syndrome and osteoma cutis in a patient previously diagnosed as COPS syndrome

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