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: 128729@cch.org.tw

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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