RESEARCH LETTER
A Case of Restrictive Dermopathy With CompleteChorioamniotic Membrane Separation Caused by aNovel Homozygous Nonsense Mutation in theZMPSTE24 GeneMing Chen,1,2,3,4,5 Hsiang-Hsu Kuo,6 Yi-Chen Huang,7 Yu-Yuan Ke,1,2,8 Shun-Ping Chang,1,2
Chih-Ping Chen,9,10 Dong-Jay Lee,1,2 Meng-Luen Lee,1,2,8 Mei-Hui Lee,1,2 Tze-Ho Chen,1,2,3
Chia-Hsiang Chen,3 Hui-Mei Lin,1,2 Chin-San Liu,1,2,11 and Gwo-Chin Ma1,2,12*1Department of Genomic Medicine, Changhua Christian Hospital, Changhua, Taiwan2Department of Medical Research, Changhua Christian Hospital, Changhua, Taiwan3Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan4Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan5Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan6Department of Obstetrics and Gynecology, Puli Christian Hospital, Nantou, Taiwan7Department of Pediatrics, Puli Christian Hospital, Nantou, Taiwan8Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan9Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan10Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan11Department of Neurology, Vascular Biology and Genomics Center, Changhua Christian Hospital, Changhua, Taiwan12Institute of Biochemistry and Biotechnology, Chung-Shan Medical University, Taichung, Taiwan
Received 3 November 2008; Accepted 18 January 2009
TO THE EDITOR:
Restrictive dermopathy (RD; OMIM 275210) isan extremely rare but
lethal disorder that causes either stillbirth or early neonatal death. It is
generally diagnosed postnatally by tight adherent skin, multiple joint
contractures, distinctive facies, superficial vasculature, and pulmo-
nary hypoplasia. Yet only a few of fetal features, including intrauter-
ine growth retardation, decreased fetal movement, polyhydramnios,
fixed open mouth and preterm rupture of membranes, have occa-
sionally been reported [Mau et al., 1997; van der Stege et al., 1997;
Wesche et al., 2001]. RD was suggested following an autosomal
recessive inheritance since its prevalence in consanguineous siblings.
Recently, mutations in ZMPSTE24 and LMNA were found to be
associated with RD [Navarro et al., 2004, 2005]. Here, we report the
identification of a novel, biparental-origin homozygous ZMPSTE24
nonsense mutation in a neonate with clinical features of RD. We also
report the clinical findings (prenatally and postnatally) including
an uncommon fetal condition of spontaneous complete chorioa-
mniotic membrane separation (CCMS) in our patient, providing a
better understanding of the rare, devastating condition.
Our patient is a female infant who was born at 33 weeks gestation
(wGA) from a G2P1 31-year-old Taiwanese aboriginal woman. The
M. Chen and H.-H. Kuo contributed equally to this study.
*Correspondence to:
Gwo-Chin Ma, Department of Genomic Medicine, Changhua Christian
Hospital, Changhua, Taiwan. E-mail: [email protected]
Published online 5 June 2009 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.a.32768
How to Cite this Article:Chen M, Kuo H-H, Huang Y-C, Ke Y-Y,
Chang S-P, Chen C-P, Lee D-J, Lee M-L, Lee
M-H, Chen T-H, Chen C-H, Lin H-M, Liu
C-S, Ma G-C. 2009. A case of restrictive
dermopathy with complete chorioamniotic
membrane separation caused by a novel
homozygous nonsense mutation in the
ZMPSTE24 gene.
Am J Med Genet Part A 149A:1550–1554.
� 2009 Wiley-Liss, Inc. 1550
parents are of the same Taiwanese aboriginal tribe (Atayal) but
unaware of any link; they have already one healthy daughter before
this pregnancy. The personal and family histories of both parents
were unremarkable. Genetic amniocentesis at 18 wGA showed
the patient has a normal 46,XX karyotype (the indication of
amniocentesis is high risk maternal serum screening). Level-II
fetal ultrasonographic exams performed at 20 and 25 wGA were
unremarkable. A repeat scan made at 31 wGA revealed an anato-
mically normal fetus with appropriate estimated fetal weight
(1,609 g, 50th centile). However, decreased fetal movement, mild
oligohydramnios (amniotic fluid index, AFI¼ 8) and spontaneous
CCMS were noted. The separated amniotic sac appeared as a
floating ‘‘balloon’’ surrounding the fetus, which simply attached
to the placenta along with the umbilical cord (Fig. 1). A close
surveillance of the pregnancy was advised. Two weeks later, preterm
labor with preterm premature rupture of membrane was developed
and tocolysis were offered. Poor variability of fetal heart beat with
occasional spontaneous variable deceleration was observed during
the tocolysis. Under the indication of non-reassuring fetal heart rate
patterns with possible fetal distress, a cesarean was performed. A
female infant weighing only 1,200 g (<3rd centile) was born. The
Apgar score was 10 (1 min), and 10 (5 min), respectively. The baby
showed multiple features typical of RD (Fig. 2). She had depressed
nasal bridge, palpebral conjunctival eversion, low-set ears, micro-
gnathia and a rigid posture caused by generalized fixed joint
contractures of the four extremities. Her mouth was slightly open
at birth but rapidly became a fixed O-shaped position (within
10 min). The skin was tight and shiny and firmly adherent to the
underlying muscle. Desquamation of scalp and joint skin was
observed. The dermis was markedly thin and subcutaneous fat was
absent. The blood vessels were very fragile and easily seen below the
surface. Radiography revealed no remarkable bony abnormalities.
The baby died of severe respiratory insufficiency after 3 hr of birth.
Necropsy and skin biopsy were declined.
FIG. 1. Ultrasonography of the fetus with restrictive dermopathy
(RD) at 31st week of gestation showing complete chorioamniotic
membrane separation (CCMS). [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
FIG. 2. Clinical features of the RD infant showing thin, shiny and rigid
skin that was easily eroded, multiple joint contractures,
superficial vasculature, a fixed O-shaped mouth, ectropion,
depressed nasal bridge, micrognathia, low-set ears and enlarged
fontanel. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
CHEN ET AL. 1551
FIG. 3. The ZMPSTE24 mutations associated with RD. a: The pedigree and the chromatograms of the patient’s family. A c.715G> T (p.E239X)
homozygous nonsense mutation was identified in the exon 6 of the ZMPSTE24 gene in the patient (indicated by an arrow). * Members for genome DNA
was available and who were included in the mutation screening. b: The ZMPSTE24 mutations described to date in RD. The mutations shown below the
schematic structure of the ZMPSTE24 gene have been reported in compound heterozygous status, and the mutations on top of the scheme have been
reported in homozygous status. The mutation c.715G> T (E239X) identified in this study is marked in bold. Notably, the mutation c.1085dupT
(p.F363fs) has been reported in the homozygous and compound heterozygous statuses. Gray bars, untranslated regions; black bars, coding regions.
[Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
1552 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Molecular genetic analyses were further performed in the patient
and her family members. DNA was extracted from peripheral blood
samples using standard methods. Mutation screening in all
coding exons and their corresponding flanking intron sequences
of the ZMPSTE24 and LMNA genes was carried out by direct
sequencing. A novel homozygous nonsense mutation c.715G>T
(p.E239X) was discovered in the exon 6 of the patient’s ZMPSTE24
(Fig. 3a). The substitution of the signal nucleotide leads to a
premature stop codon at amino acid (aa) 239 instead of the normal
glutamic acid, removing 237 aa from the predicted 475-aa protein.
This mutation was also found in the heterozygous status in the
patient’s unaffected mother and father, pointing to the biparental
origin of the described mutation and further supporting an auto-
somal recessive inheritance. The patient’s elder sister is normal and
does not inherit the mutation (Fig. 3a). No other ZMPSTE24 or
LMNA nucleotide variations were detected in the patient. Since the
two parents are presumably unrelated (or distantly related), we
considered this allele may be a result of founder effect instead of
consanguinity.
Nine ZMPSTE24 mutations have so far been identified in RD
[Navarro et al., 2004, 2005; Moulson et al., 2005; Sander et al., 2008;
this study] (Fig. 3b). All mutations described are either in homo-
zygosis or compound heterozygosis with truncations, splicing site
defects or deletions/insertions of a small number of bases causing
frameshifts; all are predicted to lead to ZMPSTE24 deficiency.
Navarro et al. [2005] found complete lack of ZMPSTE24 in all
cases explored and proposed null activity of ZMPSTE24 causes RD
(of which affected children die within the first hours or days after
birth). Nevertheless, Sander et al. [2008] reported two cases living
up 2 months after birth and suggested a residual activity of
ZMPSTE24 may lead to ‘‘less severe’’ RD. The fact that our
patient is clinically severe and died shortly after birth strongly
suggests null function of the truncated ZMPSTE24 protein; that is,
homozygous c.715G>T (p.E239X) may completely inactivate
ZMPSTE24. This seems true since Navarro et al. [2005] have
confirmed no ZMPSTE24 activity in the mutation c.1249C>T
(p.Q417X), predicting a truncated protein with a 59-aa
C-terminal deletion which is much shorter than that found in our
case (237 aa). The mutation c.715G>T (p.E239X) adds the short
list of the RD-associated genetic defects. To our knowledge, it is the
first pathogenic mutation of RD detected in the ethnic Chinese
population.
Another notable finding in our case is that the patient manifested
an uncommon prenatal condition of spontaneous CCMS at third
trimester (31 wGA). Similar observation was recently reported by
Kim et al. [2007] who showed two consecutive pregnancies of fetal
RD manifested CCMS at 29þ 4 and 26þ 3 wGA, respectively. Late-
onset CCMS is relatively rare and abnormal [Lewi et al., 2004]. The
repeated observations of the same sign in different cases suggest
CCMS could be associated with RD. Histopathological studies have
demonstrated a lack of elastic tissue and abnormally arranged
collagen bundles in RD [Witt et al., 1986; Mau et al., 1997];
therefore, decreased strength of the chorion and amnion that
permit amniotic fluid leaking into the chorionic cavity, resulting
in premature rupture of membranes may account for the associa-
tion of CCMS and RD. This hypothesis may also explain the
oligohydramnios appeared in our case as well as that was noted
in Kim et al. [2007]. Our case also showed decreased fetal movement
after 25 wGA. In reported cases of RD, decreased fetal movement
was not felt until after 6 months of GA or not at all [Witt et al., 1986;
Kim et al., 2007]. The present result is in agreement with the
previous reports. Other previously reported fetal features of RD,
including continuously opened mouth, polyhydramnios and fetal
akinesia/hypokinesia (or fetal akinesia deformation sequence;
FADS), were not observed in our case at the antenatal ultrasound
examinations. Our patient manifested a fixed O-shaped mouth
after birth due to the increased rigidity of the skin but she did
show some slight movement of her mouth in utero. Continuous
fetal swallowing and/or ongoing amniotic fluid leaking due to
CCMS (see above) may explain the lack of polyhydramnios in
our case. We need to point out that despite RD was considered by
many researchers as one of the main mechanisms leading to FADS
whereas defective acetylcholine receptor was also considered as
one of the primary etiologies causing FADS [Toriello, 1986;
Witt et al., 1986]. Besides, in utero skin biopsy failed to
demonstrate any abnormalities in one case of RD [van der Stege
et al., 1997], rendering ultrasonographic assessment of fetal skin
thickness a non-helpful tool to diagnose RD. So far, the exact nature
of fetal RD remains unclear. We considered our prenatal
findings, especially the characteristic sign ‘‘CCMS,’’ as well as a
novel genetic defect in the RD causative locus ZMPSTE24 will
significantly contribute to the prenatal diagnosis, counseling, and
management.
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