Thanatoporic Dysplasia with Polyhidramnios: A Case Report

Made Yudha Ganesa Wikantyas Widia, I Putu Gde Supriatmaja, Wayan Artana Putra
Department of Obstetrics and Gynecology, Surya Husadha Hospital, Denpasar, Bali
Maternal-Fetal Division, Department of Obstetrics and Gynecology, Sanglah Hospital,
Denpasar, Bali

1. Background

Skeletal dysplasia’s also known as osteochondrodysplasias or skeletal dysplasias, are a

large heterogeneous group of disorders comprising of abnormalities of bone or cartilage
development or texture. The most common form of lethal skeletal dysplasia is osteogenesis
imperfecta type II and thanatophoric dysplasia (TD).1 Thanatophoric Dysplasia is a congenital
syndrome, rare and potentially lethal with an estimated incidence 0.2-0.5 per 10.000 births. The
meaning for thanatophoric dysplasia is ‘death bearing’, which is derived from a Greek word. The
first person to describe thanatophoric dysplasia was Maroteaux and Lamy in 1967.1,2,3 Autosomal
dominant mutations of the FGR3 at the short arm of chromosome4, have been described as the
cause of TD.4 TD has two subtypes, type I and type II. Type I is characterized by short curved
femurs and wider bones and is rarely combined with cloverleaf skull. Type II has straight
femurs, wider bones and is nearly always associated with cloverleaf skull deformity.5

2. Objective

To show and study sonographic features about congenital anomaly from thanatoporic
dysplasia as prenatal diagnostic.

3.Case

A 31-years-old female patient, (G5P2A2) at 29 weeks of gestation was referred to Fetal

and Maternal Center of Sanglah Hospital with polyhydramnios and suspect abnormal fetus
development. Ultrasound was performed and showed polyhydramnios, shortened long bones,
macrocephaly (cephalic circumference above percentile 95). She always had regular menstrual
cycles. There was no past or family history of congenital abnormalities, diabetes mellitus,
hypertension, thyroid dysfunction or tuberculosis. She was a non-smoker, non-alcoholic and not
addicted to any drug. According to the history given by the patient, in 2009 and 2010 she had
history of spontaneous abortion of 2 months period of gestation followed by dilatation and
curettage. In 2011 Patient has delivered 3000 gram baby by vacuum extraction and 2013 her
pregnancy was full term and delivery by caesarian section.
At April 21st, 2017, patient came to Surya Husadha hospital with imminent premature of
labour. At the time of admission her vital signs were within normal limits. There was no pallor,
oedema, thyroid swelling or any significant lymphadenopathy. There were no abnormalities on
respiratory, cardiovascular or CNS examinations. Per abdomen examination - fundal height was
30-31 weeks with fetus in longitudinal lie, breech presentation. Fetal heart rate was 100 bpm and
uterus was relaxed. On vaginal examination leaking was observed and Bishop’s score was very
poor. After discus with her husband, patient chooses to terminate her pregnancy.
 After a caesarean, the patient gave birth to a female baby with 2030 grams, 26 cm of
body length, head circumference 30 cm, hypoactive, non-reactive and bradycardiac newborn.
The baby’s apgar score was 1-2, and needed to receive rescucitation after birth. The newborn
baby was died after 1 hours of treatment due to respiratory distress.
The Baby had macrocephaly, face was coarse and oedematous with frontal bossing, mid
facial hypoplasia, depressed nasal, and short neck. Upper and lower limbs were shortened with
short stubby fingers and deep skin creases. Based on facial features and skeletal abnormalities
the diagnosis of thanatophoric dysplasia was made. Procedures for X-ray and autopsy was not
performed due to family’s disagreement.

1a. 1b.

1.c 1.d

Figure 1a & 1b. Fetal biometry showing increased biparietal diameter and head circumference
(macrocephaly), 1c. Small thorax with increased abdominal circumference. 1d.Polyhydramnios
(AFI >5 ).
 2a. 2b.

Figure 2a,b: Lethal female baby with dysmorphic face, macrocephaly, depressed nasal bridge,
micromelia with short stubby fingers, deep skin creases, short limbs, narrow thorax, and
protuberant abdomen.

4.Discussion

Thanatophoric Dysplasia (TD) is a congenital, sporadic and usually lethal skeletal

dysplasia at birth characterized by micromelia, small conical thorax, platyspondyly (flat vertebral
bodies) and macrocephaly. Its incidence is 0.2-0.5 in 10.000 of live births.6 Thanatophoric
dysplasia or dwarfism literally meaning death bearing dwarf was first described by Maroteaux et
al,.2 TD is caused by de novo autosomal dominant mutations in the fibroblast growth factor
receptor 3 (FGFR3) gene, which has been mapped to chromosome band 4p16.3. Fibroblast
growth factors which are associated with cell growth, bind to the FGFR3 receptor and activates a
signal transduction pathway that regulates endochondral ossification by inhibition of cell
division and stimulation of cell maturation and differentiation. Mutations in the FGFR3 gene
give rise to activation of the receptor in the absence of growth factors, thus causing abnormal
long bone development7. It has been recently proposed that mutated FGFR3 induces premature
exit of proliferative cells from the cell cycle and their differentiation into pre hypertrophic
chondrocytes thus ascribing to the defective differentiation of chondrocytes the main cause of
long bone growth defects in TD I.8
There are two subtypes of TD with relative incidence: Type I - 80% and Type II - 20%.
The two subtypes can be differentiated by the skull shape and femur morphology.9,10 TD type I,
the most common subtype, characterized by curved and short femur which is in a telephone
receiver like configuration and no cloverleaf shaped skull. Also the abdomen appears protuberant
in comparison with the chest which is narrow and small.9 The fetuses with type II TD are
reported to have cloverleaf skull which means a trilobed skull. The premature closure of coronal
and lambdoid sutures is commonly seen with the cloverleaf skull.10 Other features common to
both TD include small narrow thorax with horizontally placed short ribs, macrocephaly, large
anterior fontanel, a small foramen magnum, distinctive facial features (frontal bossing, low nasal
bridge, flat faces), severe platyspondyly, marked shortening and bowing of long bones,
brachydactly (short broad tubular bones in hands and feet), deep skin creases along the limbs.9
Dysmorphic facial features and skeletal abnormalities like macrocephaly, wide open anterior and
posterior fontanels with suture separation, short upper and lower limbs, shape of femur like
telephone receiver, short stubby fingers, deep skin creases, narrow thorax and protuberant
abdomen suggested a diagnosis of TD in the baby that delivered in our hospital. To determine
TD type I or Type II usually confirm with skeletal radiograph and molecular testing.
Although identification of a lethal skeletal dysplasia in the second trimester is often
straight forward but establishing its specific diagnosis can be difficult. As previous studies
reported, 40–80% of TD cases can be correctly diagnosed by ultrasonography in the prenatal
period.11 A three-dimensional ultrasound examination aids in visualizing facial features and other
soft tissue findings such as cloverleaf skull, very short extremities and small thorax which are
suggestive of TD.11,12 Polyhydramnios in the late second and third trimesters is common in both
types.13 Since our patient did not have antenatal check up in second trimester, early diagnosis of
TD could not be made. Diagnosis was made by ultrasonography when she reported to the
hospital in early third trimester. Final diagnosis of TD in our case was made by detecting the
clinical features at birth, dysmorphic facial features and skeletal abnormalities.
Prenatal diagnosis can be confirmed by molecular analysis of the mutation in FGFR3
gene extracted from fetal cells obtained by amniocentesis usually performed at 15-18 weeks
gestation or chorionic villous sampling at about 10-12 weeks gestation.14 Chromosomal analysis
and DNA molecular testing for FGFR3 can be done in suspected cases of TD but it was not cost
effective in our case because almost all cases of TD are caused by new mutation in the FGFR3
gene and occur in people with no history of the disorder in their family. Affected individuals
never survive so disorder never passes to next generation. Recurrence risk is also not increased
over that of the general population as it is a de novo mutation.10,15
Most of the fetuses with TD lethal in the neonatal period, but survival beyond 9 years of
age has been reported.Surviving neonate is almost always ventilator-dependent and mentally
deficient.Cause of death is respiratory insufficiency that occurs shortly after birth. Respiratory
insufficiency may be secondary to a small chest cavity and lung hypoplasia, compression of
brain stem by narrow foramen magnum, or a combination.16,17In this case, the newborn baby was
died 30 minutes after birth.
Postnatal autopsy of the affected fetus with TD can shows disorganized chondrocytes
columns, poor cellular proliferation, lateral overgrowth of metaphyses, and increased vascularity
of cartilage.18 Autopsy to confirm the diagnosis by histopathology and radiological examination
could not be performed in our case as consent was not given by the parents. Differential
diagnosis of TD includes homozygous achondroplasia (both parents suffer from the
achondroplasia), achondrogenesis (bones demineralization that are most marked in the calvarium
and vertebral bodies, shortened trunk length), campomelic dwarfism (bowing and angulation of
long bones with immature ossification), rhizomelic chondrodysplasia punctata (micromelia is
rhizomelic with characteristic stippling radiologically and punctuate calcification in cartilage),
severe hypophosphatasia and severe osteogenesis imperfect (generalized hypomineralization of
bones with multiple bone fractures).6,18
5. Conclusion
Thanatophoric Dysplasia is a congenital, sporadic and the most lethal skeletal dysplasia
at birth. The primary method of screening and study is the ultrasound on early second trimester
of gestation. Additionally a definitive diagnosis is possible using cell-free fetal DNA in maternal
plasma. It is important to know the most predictive signs and identify them in the ultrasound
study. Proper genetic counseling is important for families having fetus or babies with TD
regarding upcoming pregnancy.
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