Prenatal diagnosis of Pfeiffer syndrome type 2 with increased nuchal
translucency
Zhi-yang Hu1, Sheng-mou Lin2,3,
Meng-jie Zhu2, Cindy Ka-Yee CHEUNG2,
Tao Liu4, Jin Zhu5
1Department of Obstetrics, Shenzhen People’s Hospital, Shenzhen, China
2Department of Obstetrics and Gynecology, The University of Hong Kong -
Shenzhen Hospital, Shenzhen, China
3The First School of Clinical Medicine, Southern Medical University,
Guangzhou, China
4Department of Ultrasound, Shenzhen People’s Hospital, Shenzhen, China
5Department of Radiology, Shenzhen People’s Hospital, Shenzhen, China
Correspondence author: Sheng-mou Lin
Department of Obstetrics and Gynecology, The University of Hong Kong -
Shenzhen Hospital, Haiyuan 1st road, Futian District, Shenzhen, China
Telephone number: +86 13500056765
E-mail: linsm@hku-szh.org
Funding information
Shenzhen Municipal Committee of Science and Technology Innovation,
Shenzhen, China, Grant/Award Number: JCYJ20170307171743182. High
Level-Hospital Program, Health Commission of Guangdong Province, P. R.
China, Grant/Award Number: HKU-SZH201902017.
Key Clinical Message
Pfeiffer syndrome (PS) is a rare autosomal dominant genetic disorder
characterized by craniosynostosis, broad thumbs / toes. Here we report a
case of PS type 2 with increased nuchal translucency at early trimester.
Keywords:Pfeiffer syndrome; increased nuchal translucency; prenatal
diagnosis
INTRODUCTION
Pfeiffer syndrome (PS, OMIM #101600) is a rare autosomal dominant
genetic disorder characterized by craniosynostosis, broad thumbs / toes
with an incidence of 1/100,000 live birth [1]. There are three
clinical subtypes [2]. Type 1 is associated with midface hypoplasia,
broad thumbs, great toes, and is compatible with life, with normal
intelligence. Type 2 is characterized by cloverleaf skull, severe ocular
proptosis, elbow ankyloses, and large halluces and thumbs. Type 3 is
similar to type 2 except for cloverleaf skull, but with visceral
malformation. Fetuses with type 2 or type 3 usually die in utero or in
early infancy. With development of ultrasound technology and application
of 3-D ultrasound examination, prenatal diagnosis of Pfeiffer syndrome
has been reported since 1996 [3]. However, craniosynostosis, limb
and visceral malformation are mostly be detected in the second or third
trimester. Little is known about the ultrasound manifestation of
Pfeiffer syndrome in early pregnancy. Although increased NT has been
observed as indirect fetal signs of syndromic or non-syndromic
craniosynostosis at first trimester ultrasound examination, Pfeiffer
syndrome with increased NT has not been reported so far[4,5]. Here
we report a case of Pfeiffer syndrome type 2 with increased nuchal
translucency at early trimester.
CASE REPORT
A healthy 30-year-old nulliparous woman underwent first-trimester fetal
ultrasound scan at 12+1 weeks’ gestation, which showed
a single fetus with an increased nuchal translucency (NT) of 3.1mm and a
crown-rump-length of 51 mm (Figure 1 A). Her husband was 41 years old
and healthy. The couple was non-consanguineous. There was no family
history of congenital anomalies. Non-invasive prenatal test (NIPT) at 16
weeks’ gestation showed low-risk for fetal Down syndrome.
Morphologic scan at 22 weeks showed acrocephaly, temporal indentation,
prominent lateral ventricle with anteroposterior diameter of the
posterior horn measuring 10mm, lordosis of the thoracic spine, and broad
thumbs and great toes (Figure 1 B C; Figure2). The fetal sagittal suture
was narrow. Its coronal and lambdoid sutures were nearly closed whereas
the metopic suture was wide. Pfeiffer syndrome type 2 was suspected
based on the typical ultrasound findings. Cordocentesis was performed
for molecular diagnosis followed by termination of pregnancy. A 420g
female abortus was delivered. Examination revealed cloverleaf head,
proptosis, hypertelorism, low-set ears, flat nasal bridge, abducted
broad thumbs and toes, and overriding fingers (Figure 3). Sacrococcygeal
eversion was noted by 3D computed tomography (CT) scan which was
consistent with prenatal ultrasound pictures in retrospect (Figure 2).
Whole genome exon sequencing showed a heterozygous pathogenic variants
on FGFR2 gene [c.870G>T] (located at exon 7),
predicted to encode a Trp290Cys substitution. ParentalFGFR2 sequencing showed normal findings, therefore the fetal
mutation was de novo.
DISCUSSION
There are a number of genetic syndromes with craniosynostosis, such as
Apert syndrome, PS, Crouzon’s disease, and Saethre-Chotzen syndrome. To
our knowledge, 18 prenatally diagnosed PS have been reported [6].
All were diagnosed at or beyond 20 weeks of gestation, and 5 cases were
diagnosed before 24 weeks of gestation. The typical cloverleaf skull
might not be detectable prior to 20 weeks. Only two prenatal cases
mentioned an abnormal skull shape related to Pfeiffer syndrome prior to
21 weeks of gestation [7,8]. Gomez-Gomez revealed strawberry-shaped
cranium, hypertolerism, a supernumerary bone at frontal level, small
thorax, kyphosis and dorsal level scoliosis, and suspicious bladder
exstrophy at 20 weeks of gestation as clues for the diagnosis [7].
Nazzaro detected bilateral temporal indentation and hypertelorism at 20
weeks [8]. Gorincour has reported fetus with PS presenting with a
thickened nuchal fold and choroid plexus cysts at 20 weeks’ gestation,
frontal bossing and temporal indentation at 23 weeks’ gestation, and
typical cloverleaf skull, broad thumbs and slight hypertelorism at 24.5
weeks’ gestation [9]. The relatively late presentation of cloverleaf
head might be a result of rapid growth of the brain in the late half
pregnancy and craniosynostosis. Among all the prenatal ultrasound
features, abnormal fetal skull shape (72.2%) was most frequently
reported, while proptosis and hypertelorism were noted in 44.4% cases,
whereas malformation of thumbs and toes were found prenatally in 33.3%
and 38.9% [6].
The ultrasound presentation of PS type 2 in the first trimester has not
been described before. In our case, the first abnormal ultrasound
appearance was increased nuchal translucency, which might be the first
detectable sign in severe craniosynostosis. In fact, increased nuchal
translucency has been reported in a case with Apert syndrome which is
also a craniosynostosis syndrome with FGFR2 mutation [10].
Gorincour’s case of PS type 2 was found to have thick nuchal fold (NF)
at 20 weeks. Thicken NF or increased NT is a result of abnormal
accumulation of lymph fluid which might be due to malformation of blood
and lymphatic vessels.
Fibroblast growth factors (FGFs) are consisted of a family of nine
heparin-binding polypeptides which enroll cell proliferation,
differentiation, and migration. Any alteration of FGFR can have
influence on cellular response to FGFs. FGF/FGFR genes play a key
role in complex branched structures development, such as tracheal
bifurcation and lung system[11], limb[12], cranial
sutures[13], and angiogenesis[14,15]. Clinical researchers have
paid great attention to the role of FGFR in tumor genesis and
targeted it for cancer therapy [16-18]. Mutation in FGFR2 can
cause abnormal angiogenesis of fetus which might explain the increased
NT in this case and David’s case [10].
PS mutations have been reported in the ligand binding region of bothFGFR1 and FGFR2 . However, mutations affecting theFGFR2 have been reported not only in PS cases, but also in other
syndrome with craniosynostosis including Crouzon, Apert, and
Jackson-Weiss syndromes[19]. Combined with our case, 11 of 14
prenatal diagnosed cases of PS with genetic test were found to have
mutations in FGFR2 (78.5%)[6], and five of them wereTry290Cys substitution (45.5%)[6-8,20].
The correlation between Trp290Cys substitution in FGFR2and PS has been reported since 1997 [8, 20-23]. The codon 290 exon 7
of FGFR2 is characterized by immunoglobulin-like hoops formed bycys crosslinking, whereas an additional cys at the site
caused by a Trp290Cys substitution as our case forms abnormal
crosslinking, and changes 3D structure of FGFR2 [19]. Although
cases with such mutations can have variable phenotypes presenting as PS
type 2 [8, 20, 21] or type 3 [8,24], their clinical
manifestations are always sever. However, a try to arg orgly mutation at the site seems to have much milder manifestation
as previously reported [25,26].
Acknowledgement
This work has been supported by High Level-Hospital Program, Health
Commission of Guangdong Province (HKU-SZH201902017), P. R. China and
research grants JCYJ20170307171743182 from the Shenzhen Municipal
Committee of Science and Technology Innovation, Shenzhen, China.
Conflict of Interest
There is no any conflict of interest in relation to the work.
Informed consent
Written informed consent was obtained from the patient.
Authorship List
Zhi-yang Hu: Conceptualization, Methodology, drafting and Writing
manuscript.
Sheng Mou Lin: Conceptualization, Methodology, drafting and Writing
manuscript.
Meng-jie Zhu: Conceptualization, reviewing and editing.
Cindy Ka-Yee CHEUNG: Data collection and curation.
Tao Liu: Data collection and curation.
Hong-tao Jin: Data collection and curation.
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FIGURE 1. (A) Increased nuchal translucency of the fetus at
12+1 weeks of gestation.
(B) Acrocephaly, protruding forehead, bilateral temporal indentation of
the skull and mild ventriculomegaly. (C) Broad thumbs and great toes
found by prenatal ultrasound.
FIGURE 2. Thoracic spine lordosis and narrow, sacrococcygeal eversion
found by prenatal ultrasound (A) and postnatal 3D CT (B).
FIGURE 3. Postmortem examination. (A) Frontal view, showing the typical
cloverleaf head, hyertelorism, and contractures of multiple joints. (B)
Lateral view, showing the low-set posteriorly rotated ear, mid-face
hypoplasia, proptosis. (C-D) Abducted broad thumb. (E) Broad great toes
of feet and overriding toes of the left foot.