Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype.
ABSTRACT We report on three sibs who have autosomal recessive Clericuzio-type poikiloderma neutropenia (PN) syndrome. Recently, this consanguineous family was reported and shown to be informative in identifying the C16orf57 gene as the causative gene for this syndrome. Here we present the clinical data in detail. PN is a distinct and recognizable entity belonging to the group of poikiloderma syndromes among which Rothmund-Thomson is perhaps the best described and understood. PN is characterized by cutaneous poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, neutropenia, short stature, and recurrent pulmonary infections. In order to delineate the phenotype of this rare genodermatosis, the clinical presentation together with the molecular investigations in our patients are reported and compared to those from the literature.
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ABSTRACT: Recent studies from independent laboratories have decisively disclosed the identity of the long-sought 3-5' RNA exonuclease that trims posttranscriptionally the oligouridine tail of U6, which is the small catalytic non-coding RNA promoting premRNA splicing within the spliceosome. This exonuclease, dubbed Mpn1 or Usb1, is a highly conserved enzyme that specifically removes uridines from the 3' end of U6, and directly generates terminal 2',3' cyclic phosphate groups. Mutations in the human gene encoding hMpn1 have been reported in patients diagnosed with the rare genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1-associated functions in U6 small nuclear RNA posttranscriptional regulation suggest the existence of sophisticated cellular pathways involved in surveillance and stabilization of U6. In this light, PN pathology might turn out to be a consequence of disturbed quality control of RNAs involved in crucial biological events.FEBS letters 05/2013; · 3.54 Impact Factor
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ABSTRACT: Considerable progress has been made in recent years in understanding of the genetic basis for congenital neutropenia syndromes. With the advent of high-throughput genomic analyzing technologies, the underlying genetic causes of other congenital neutropenia syndromes are expected to be resolved in the near future. This knowledge will provide the foundation for genotype-phenotype correlations for infection susceptibility, response to therapy, and risk of malignant transformation, enabling optimal care for individual patients depending on their molecular pathophysiology. It is hoped that these investigations will enable the development of tailored molecular therapies to specifically correct the aberrant signaling cascades.Hematology/oncology clinics of North America 02/2013; 27(1):43-60. · 2.05 Impact Factor
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ABSTRACT: Poikiloderma with neutropenia (PN, OMIM 604173) is a rare autosomal-recessive genodermatosis. Mutations in the C16orf57 gene have been recently identified as the cause. Here we describe a new case of PN in a white patient, review the literature, and point out the attention on importance of differential diagnosis.Journal of Pediatric Hematology/Oncology 07/2013; · 0.96 Impact Factor
Clericuzio-Type Poikiloderma With Neutropenia
Syndrome in Three Sibs With Mutations in the
C16orf57 Gene: Delineation of the Phenotype
D. Concolino,1* G. Roversi,2,3G.L. Muzzi,1S. Sestito,1E.A. Colombo,2L. Volpi,4L. Larizza,2
and P. Strisciuglio5
1Dipartimento di Pediatria, Universit? a ‘‘Magna Graecia,’’ Catanzaro, Italy
2Genetica Medica, Dipartimento Medicina, Chirurgia e Odontoiatria, Universit? a degli Studi di Milano, Milano, Italy
3Unit? a di Genetica Medica, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy
4Dipartimento di Biologia e Genetica per le Scienze Mediche, Universit? a degli Studi di Milano, Milano, Italy
5Indirizzo attuale: Dipartimento di Pediatria, Universit? a ‘‘Federico II’’, Napoli, Italy
Received 19 September 2009; Accepted 24 May 2010
type poikiloderma neutropenia (PN) syndrome. Recently, this
consanguineous family was reported and shown to be informa-
syndrome. Here we present the clinical data in detail. PN is a
distinct and recognizable entity belonging to the group of
poikiloderma syndromes among which Rothmund–Thomson is
perhaps the best described and understood. PN is characterized
by cutaneous poikiloderma, hyperkeratotic nails, generalized
hyperkeratosis on palms and soles, neutropenia, short stature,
and recurrent pulmonary infections. In order to delineate the
phenotype of this rare genodermatosis, the clinical presentation
together with the molecular investigations in our patients are
reported and compared to those from the literature.
? 2010 Wiley-Liss, Inc.
Key words: poikiloderma; genodermatosis; congenital neutropenia
Clericuzio-type poikiloderma with neutropenia (PN OMIM
#604173) represents a well-defined phenotype characterized by
In this article Concolino and colleagues describe the phenotype in
three sibs with the Clercuzio-type poikiloderma with neutropenia
syndrome (PN). Most of the authors are also co-authors on the
article by Volpi et al. published in the January issue of the
American Journal of Human Genetics where the causative gene for
PN is identified in this family. In the ensuing report herein
Concolino et al. provide comprehensive phenotypic data on the
sibs who were succinctly presented in the AJHG paper. Continuing
on this theme, I would turn the reader’s attention to a related
article on this topic by Tanaka and colleagues, published in the
June issue of the Journal [Tanaka et al., 2010. Identification of a
homozygous deletion mutation in C16orf57 in a family with
Clericuzio-type poikiloderma with neutropenia, Am J Med Genet
Part A 152A:1347–1348] where the authors identify a homozygous
deletion in sibs previously reported in the Journal in 2008.
John C. Carey
Grantsponsor:Nando PerettiFoundation; Grantnumber: 2007/14; Grant
sponsor: Associazione Italiana per la Ricerca sul Cancro (AIRC); Grant
D. Concolino, M.D., Department of Pediatrics, University ‘‘Magna
Graecia’’ of Catanzaro, c/o Ospedale Civile ‘‘A. Pugliese,’’ Viale Pio X,
88100 Catanzaro, Italy. E-mail: firstname.lastname@example.org
Published online 23 August 2010 in Wiley Online Library
How to Cite this Article:
Concolino D, Roversi G, Muzzi GL, Sestito S,
Colombo EA, Volpi L, Larizza L, Strisciuglio
P. 2010. Clericuzio-type Poikiloderma with
neutropenia syndrome in three sibs with
mutations in the C16orf57 gene: Delineation
of the phenotype.
Am J Med Genet Part A 152A:2588–2594.
? 2010 Wiley-Liss, Inc.
poikiloderma, hyperkeratotic nails, generalized hyperkeratosis
on palms and soles, neutropenia, short stature, and recurrent
pulmonary infections [Clericuzio et al., 1991].
The dermatologic onset consists of the occurrence of a papular
the limbs centrifugally. When the papulae vanish, hypo/hyper
pigmentation and telangiectasia develop.
The differential diagnosis includes other poikiloderma condi-
tions, that is, RAPADALINO and Rothmund–Thomson syn-
dromes (RTS, OMIM #268400) [Van Hove et al., 2005]. Due
to the overlap of some distinctive clinical features, PN patients
may be misdiagnosed as RTS, even if cataract and digestive tract
involvement (hallmark features of RTS) are not preset. In PN
patients chronic neutropenia is a distinguishing manifestation. At
in all PN patients, strengthening the hypothesis of distinct genetic
mechanism responsible forPN [Wang etal.,2003;Van Hove et al.,
2005; Mostefai et al., 2008]. Recently, we demonstrated that muta-
tions in the C16orf57 gene are responsible for the PN phenotype in
the clinical data in more detail.
The sibship reported underlines the intrafamilial variable
expressivity and the natural history of PN syndrome. Moreover,
we compare the clinical features in our patients with the 11 so far
2005; Mostefai et al., 2008] to better delineate the spectrum of this
Family history and genetic testing: Three siblings, one male
(Patient 1) and two females (Patients 2 and 3), from healthy
consanguineous (Fig. 1) Italian parents were born at term after
uneventful pregnancy, absence of perinatal problems; all growth
parameters were in the normal range. At birth none showed skin
manifestations and/or dysmorphic signs. As shown in the simpli-
fied pedigree (Fig. 1) [see full pedigree, Volpi et al., 2010] the
son of a consanguineous marriage.
The cutaneous manifestations began at 6 months of age as a rash
involving primarily the cheeks, extensor surface of the arms, and
then the knees (Fig. 1, V2). During his first months of life the child
had recurrent pulmonary infections, otitis media, and sinusitis
until the age of 3 years. He showed poor growth starting in infancy
reticular pattern of hyper- and hypopigmentation with slight
ties, allowed a clinical diagnosis of RTS at the age of 5 years. At the
and at that time he showed a weight of 17.7kg (10th centile), a
height of 106cm (3rd centile), and normal mental development.
During hospitalization the biological data as laboratory inves-
tigations showed leukopenia (2.5?103mL) with neutropenia
(700mm3), increased creatine phosphokinase (CPK, 250U/L,
n.v.<180), and lactate dehydrogenase (LDH, 700U/L, n.v.<500)
while viral serology, erythrocyte sedimentation rate, C reactive
protein,immunoglobulinsubclasses(IgA, IgM,IgG), complement
factors (C3 and C4), AGA, EMA, tTG, and thyroid hormones were
maturation of neutrophil lineage, with increased numbers of
immature cells, but no abnormal clonality. The skeletal investiga-
were normal. No ophthalmologic abnormality and specifically no
cataracts were found.
The patient came to our attention for the first time at the age of
17 years and though a history of persistent neutropenia was
reported, no recent infectious episodes were recorded. At that
time his weight was 49kg (<5th centile), his height 156cm
(<3rd centile), his head circumference 56cm (50th centile),
and Tanner stage was P5B5. Until age 3 years, growth velocity had
always been under 5th centile; his genetic target for the height was
170?8cm. Puberty had begun at age 14 years without pubertal
The clinical exam at the age of 21 (Fig. 2) showed dysmorphic
signs including eyebrows hypoplasia with normal hair, frontal
bossing, widely spaced eyes without telecanthus, midface hypopla-
sia, small nosewith depressed nasal bridge,and mild prognathism.
Generalized fine hyperkeratosis with poikiloderma on the face and
arms withseveral areasofskinatrophy wasdetected. Hyperkerato-
soles and pachyonychia. A bilateral hyperlaxity of fingers (Fig. 2)
and a joint stiffness in elbows were present.
The skin biopsy showed edema in the papillary derma, necrosis
of keratinocytes with apoptosis, acute perivascular inflammation
with granulomatous vasculitis of derma middle blood vessels.
Standard karyotype on skin biopsy was normal. No screening for
increased breakage was performed. No bone abnormalities were
found. Skeletal X-rays were normal, and MRI showed normal
intensity of medullar bone signal of explored segments. The bone
age was appropriate for chronological age.
FIG. 1. Pedigree of the family.
CONCOLINO ET AL.
FIG. 2. Patient 1 at the age of 21 years. Note eyebrows hypoplasia, severe midface hypoplasia, the pattern of the poikiloderma, pachyonychia and
plantar hyperkeratosis, hypermobile fingers.
2590 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
The mental development was normal. Mild splenomegaly was
detected by abdominal ultrasonography. Laboratory investiga-
tions showed a leukopenia (GB 2.2?103mL) with neutropenia
(550mm3), elevated LDH (800U/L, n.v.<500), and CPK (280U/
The skin manifestations appeared at 8 months of age with a rash
involving primarily the face and the extensor surface of the arms
evolving in classic poikiloderma (Fig. 1, V4). During the first
years of life no history of recurrent infections was reported but
showed a reduction of height velocity with a height age of 2 years.
At age 4 a high-resolution cytogenetic analysis confirmed a 46,XX
When she first came to our attention at the age of 9 years and
52cm (50th centile), prepubertal stage and mental development
were normal. Exam showed poikiloderma on the face, arms, and
thorax, nail dystrophy, hypoplasia of eyebrows, mild midface
(3.5?109mL) with neutropenia (600mm3). CPK and LDH were
elevated. Viral serology, AGA, EMA, tTG, were normal. Normal
levels of all immunoglobulin classes and of complement factors
Electromyography, electroencephalography, and bone scintigra-
phy with technetium were normal. Abdominal ultrasonography
showed a spleen size of 16cm.
Physical examination at the age of 16 years showed
midface hypoplasia with a small mandible, hypoplasia of lateral
eyebrows, hypertelorism (interpupillar distance >95th centile),
long philtrum, hypermobile fingers with ‘‘beak of swan’’ appear-
ance (Fig. 3b).
The child was evaluated at our hospital at the age of 8 years and 8
months (Fig. 1, V5). She showed the characteristic poikiloderm-
atous rash that had first appeared at age 10 months as a facial rash.
The rash was erythematous and macular with few atrophic areas.
During the first months of life the girl had recurrent pulmonary
infections, otitis media, and sinusitis until 3 years of age.
Leukopenia (3.2?103mL) was found with severe neutropenia
(0.6?103mL) at age 18 months. The short stature was discovered
at the age of 3 years and her growth velocity was always under 5th
centile in the following years. High-resolution karyotype was
a height of 121.5cm (<3rd centile), a head circumference of 52cm
normal. The patient showed poikiloderma, microretrognathism,
and a low posterior hairline (Fig. 4a). At the age of 12 years a
dysmorphic examination revealed lateral hypoplasia of eyebrows,
hypoplasia alae nasal, mild retromicrognatia, and hypermobile
fingers with ‘‘beak of swan’’ appearance (Fig. 4b).
The routine laboratory investigations showed increased CPK
and LDH, leukopenia (GB 3.2?103mL) with marked neutropenia
(500mm3). Levels of immunoglobulin classes and complement
factors (C3 and C4) were normal. Abdominal and cardiac ultraso-
and biochemical analyses) were normal.
FIG. 3. Patient 2: (a) at the age of 10 years: note poikiloderma of face and arms and foot pachyonychia and (b) at the age of 16 years: note a mild
midface hypoplasia with a small mandible, hypoplasia of lateral eyebrows, hypertelorism, long philtrum, hypermobile fingers with ‘‘beak of swan’’
CONCOLINO ET AL.
In both sisters the bone age matched the chronological age and
endocrine exams showed that IGF1 and IGFBP3 levels, arginine/
L-dopa-stimulated growth hormone analysis, TSH, and T3 levels
were in the normal range. The growth velocity was between 5 and
10th centile and the puberty started at the age of 11 and 12 years,
respectively, without pubertal spurt. Their genetic target was
At the 6-month follow-up, evaluation of the patients’
neutropenia found a persistent neutropenia with a mean value of
700mm3(range of500–1,100mm3).Bone marrow smearsshowed
myelodysplastic features, abnormal maturation of neutrophil
lineage, and an increased number of immature cells. None of
the three patients showed skin sensitivity to sun exposure and
there were no evidence of cancer skin lesions. None of them
To exclude a possible diagnosis of RTS, the RECQL4 gene was
capillary sequenced in the propositus, Patient 1, and no mutations
the three affected sibs do not share intragenic RECQL4 SNPs (data
not shown). Autozygosity mapping performed by a genome-wide
affected family members. Next generation sequencing of the entire
of the C16orf57 gene. Details of the multimethod procedure used
to hunt and validate the causative gene have been reported [Volpi
et al., 2010].
We report on the clinical features of three siblings affected with
Clericuzio poikiloderma with neutropenia syndrome, all carrying
data conclusively confirm the notion that this rare poikiloderma
syndrome is a genetically distinct entity [Van Hove et al., 2005;
Mostefai et al., 2008].
Since the first description by Clericuzio in 14 Navajo Indians
[Clericuzio et al., 1991], 5 other kindreds have been described
[Wang et al., 2003; Van Hove et al., 2005; Mostefai et al., 2008]
(2 Navajo, 1 Turkish/British, 2 Scottish, 2 Turkish, and 3
Moroccan). All reported patients, including ours, had a clinical
diagnosis of PN and absence of RECQL4 mutations. Moreover, an
et al., 2001] but displayed a typical PN phenotype, was found to
be a compound heterozygote for C16orf57 mutations (c.502A>G
and c.666-676þ1del12) [Volpi et al., 2010]. This confirms that
PN is a genetic disease likely occurring in all ethnicities and not
restricted to the American Navajo population [Erickson, 1999].
We compared the phenotype of our affected sibs with that of
previously described patients (Table I) including the first patients
who have been molecularly assessed to delineate the spectrum of
recruit and select patient candidates to be tested for the C16orf57
With regard to RTS, which enters in the differential diagnosis
with PN, we underline the differential profile of the skin changes;
they start in both syndromes in the first year of life with the same
morphology and evolution of the lesions (from acute rash to
involvementofarmsandlegs attheonset, thenspreadingcentrifu-
the initial localization of the rash as one of the main differential
hallmarks between PN and RTS, where the rash starts on the face
[Wang et al., 2003; Van Hove et al., 2005]. In our patients the skin
FIG. 4. Patient3:(a)attheageof8years:notefacepoikiloderma.b:Attheageof12:noteeyebrowshypoplasia,mildretromicrognatia,hypermobile
fingers with ‘‘beak of swan’’ appearance.
2592 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. Clinical and Laboratory Findings in 14 Patients With Poikiloderma Neutropenia Syndrome
Mostefai et al.
Van Hove et al.
Wang et al. 
Pianigiani et al.
Arms, legs Arms, legs
500–1,100 600–800 350–700 220–884 345–1,541 183–5,200 150–500
/, not reported; ?, absent; þ, present; S, sinusitis; FC, facial cellulitis; A, adenitis; BL, blepharitis; GS, gastroenteritis; CO, conjunctivitis; mo, months, y, years; d, days.
CONCOLINO ET AL.
the cheeks, then spreading to extensor surface of the arms and
finally to the knees. The same onset was also reported in the
Moroccan PN patients [Mostefai et al., 2008]. Thus, we posit out
that the first localization of the rash may be variable and does not
represent per se a criterion for establishing or excluding PN
diagnosis. The histology on the skin was not diagnostic and was
not a distinctive feature compared with RTS.
Isolated persistent severe neutropenia is the hallmark of this
genodermatosis, appearing between the first weeks and 20 months
of neutropenia was at age 6, being unavailable previous measure-
ments. We followed up the evolution of neutropenia in all three
patients for 4 years, and we never found a significant variation in
neutrophils absolute number (500–1,100mm3) suggesting that
neutropenia is not cyclic as reported by Wang et al. . The
leukopenia can explain the several pulmonary infections, otitis
media, and sinusitis while it is not clear why the infective episodes
became less frequent during the adolescence and adult age as
observed in our patients though the neutropenia is persistent in
the long-term follow-up. Besides neutropenia, myelodysplasia
could be another distinctive feature of PN, as pointed out in
previous reports [Pianigiani et al., 2001; Van Hove et al., 2005;
Mostefai et al., 2008]. The detection of C16orf57 mutations in the
patient described by Pianigiani et al.  is consistent with the
Conter, 1996] who also show myelodysplasia probably belong to
this syndromic entity.
Increase of enzymes as LDH and CPK has been reported by Van
Hove et al.  and a possible muscle involvement has been
suggested. Our three sibs all had a slightly and episodic increase of
CPK (250–380U/L), while LDH was significantly increased with
and muscular biopsy did not show any abnormality either in our
patients or in the patient described by Van Hove, preventing to
be distinctive biochemical markers of PN, as they have never been
reported in RTS patients.
Growth delay is reported in some PN patients and it is probably
due to recurrent infectious diseases common in this syndrome.
Shortstature,inour patients appearedinthefirstyearsof life,with
a deceleration of growth velocity after the age of 3 years, but no
sib had GH deficiency based on provocative GH test, or other
apparent causes of short stature.
Moreover, dysmorphic features such as hypoplasia of eyebrows,
depressed nasal bridge, and prognatism are common signs in our
siblings. Though an examination has not been made in all previ-
ously reported cases, the high similarity of craniofacial dysmor-
phisms between our male patient (Fig. 2) and the male patient
described by Van Hove et al. , in particular, midface hypo-
plasia is recognizable by photographs. Moreover, moderate facial
dysmorphisms like ‘‘saddle nose’’ and hypertelorism are also
reported in the other Italian compound heterozygote for C16orf57
mutations [Pianigiani et al., 2001; Volpi et al., 2010]. Our clinical
which deserves other observations to be further defined. Careful
bone marrow smears examination and follow-up for the hemato-
logic disease are needed to check the onset of myelodysplasia or
Genome-wide SNPs array-based homozygosity mapping and
targeted next generation sequencing have proven to be the best
strategy to appoint C16orf57 as Clericuzio-type poikiloderma with
neutropenia gene, allowing to provide a complete genetic counsel-
ing from carrier testing through at-risk relatives, and hence to
plan out a targeted onco-hematologic surveillance for the affected
This work was supported by the Nando Peretti Foundation (grant
2007/14) and by Associazione Italiana per la Ricerca sul Cancro
(AIRC) (grant 2008–2009/4217 to L.L.).
a new genodermatosis. Am J Hum Genet 49:A661.
disease. Genet Med 1:151–157.
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McGrath J, Ta€ ıeb A. 2008. Poikiloderma with neutropenia, Clericuzio
Pianigiani E, De Aloe G, Andreassi A, Rubegni P, Fimiani M. 2001.
Rothmund–Thomson syndrome (Thomson-type) and myelodysplasia.
Pediatr Dermatol 18:422–425.
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diseases, and treatment opportunities. Pediatr Hematol Oncol 13:
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Verbeken E, Demunter A, Boogaerts M. 2005. Clericuzio type poikilo-
derma with neutropenia is distinct from Rothmund–Thomson syn-
drome. Am J Med Genet 15:152–158.
Volpi L, Roversi G, Colombo EA, Leijsten N, Concolino D, Calabria A,
Mencarelli MA, Fimiani M, Macciardi F, Pfundt R, Schoenmakers EF,
as Clericuzio-type poikiloderma with neutropenia gene. Am J Hum
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2594 AMERICAN JOURNAL OF MEDICAL GENETICS PART A