Thanatophoric dysplasia (TD) is a congenital, sporadic, and the most lethal skeletal dysplasia caused by new mutation in the fibroblast growth factor receptor 3 gene. At birth, it is characterized by shortening of the limbs (micromelia), small conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. TD is divided into two clinically defined subtypes: Type I and II which can be differentiated by the skull shape and femur morphology. Ultrasound examination in the second trimester is often straight forward in diagnosing the congenital anomaly. We report a case of preterm stillborn female baby with dysmorphic facies, macrocephaly, micromelia with short stubby fingers and deep skin creases, short limbs, narrow thorax, and protuberant abdomen delivered at our hospital to a 24-year-old multigravida mother with the previous history of first-trimester abortion. The antenatal ultrasound examination showed shortening of long bones with femur-shaped like a telephone receiver. Dysmorphic facial feature, skeletal abnormalities, and histopathological examination lead us to make the diagnosis of TD Type I. We report this case of TD in view of recurrence risk of around 1%, occurring mostly through autosomal dominant mode of inheritance, which may be the possibility in this case

Charan, Lakshmi

Jerry, Antony Leo

Raj, Sushmitha

Shankari, N Vidhya

English

Atharva Scientific Publications (E-Jounals)

Vol 4 | Issue 3 | Jul - Sep 2017 Indian J Child Health 453
Case Report
Thanatophoric dysplasia: A case report with probable recurrence
N Vidhya Shankari, Antony Leo Jerry, Lakshmi Charan, Sushmitha Raj
From Department of Paediatrics, Sree Balaji Medical College and Hospital, Chennai, Tamil Nadu, India
Correspondence to: Dr. N Vidhya Shankari, G-5, R-block, Staff Quarters, Sree Balaji Medical College and Hospital, Chrompet, 
Chennai - 600 044, Tamil Nadu, India. E-mail: drvidhyashankari@gmail.com
Received – 12 March 2017 Initial Review – 14 April 2017 Published Online – 18 May 2017
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 1 in 
20,000 to 1 in 50,000 of live births [1]. It is caused by de novo 
mutations [2] in the fibroblast growth factor receptor 3 (FGFR3) 
genes, which has been mapped to chromosome band 4p16.3. 
There are two subtypes with relative incidence: Type I - 80% and 
Type II - 20%. The two subtypes can be differentiated by the skull 
shape and femur morphology [3,4]. We report a stillborn female 
baby with TD with probable recurrence which merits importance.
CASE REPORT
A 24-year-old female, a multigravida with 5 months amenorrhea, 
visited our hospital for antenatal checkup. She had a history of 
one previous spontaneous abortion at 12 weeks of gestation. 
She was an unbooked case. She married for the last 3 years and 
was a second-degree consanguineous marriage. She was a non-
smoker, non-alcoholic, and not addicted to any drug. There was 
no history of fever, rashes, spotting per vaginum, and drug intake 
and radiation exposure during this pregnancy. There was no past 
or family history of congenital abnormalities. At the time of 
admission, her vitals were within normal limits. No abnormality 
was detected on respiratory, cardiovascular, or central nervous 
system examination. On per abdomen examination - fundal 
height was 22 weeks with fetus in the longitudinal lie, with 
increased liquor volume. Fetal heart rate was 144/min and uterus 
was relaxed.
Complete blood count of the mother showed raised leukocyte 
count. Her urine routine, blood sugar, liver, and renal function 
tests were within normal range. Human immunodeficiency 
virus, hepatitis-B surface antigen, and venereal disease research 
laboratory were non-reactive. Her C-reactive protein was negative. 
Ultrasound examination showed a single live intrauterine fetus 
with unstable presentation of around 20 weeks gestation. Placenta 
was anterior. Fetal skull was normal with no ventriculomegaly. 
Fetal thorax was abnormally small with reduced circumference, 
and abdomen showed gross ascites with no gastric bubble. Fetal 
limbs showed diffuse shortening of long bones, and femur was 
shaped like telephone receiver. Ribs were shorter and curved. 
Foot length was 3.2 cm on either side. Bilateral kidney showed 
pyelectasis (Figs. 1 and 2).
Her labor was induced in view of skeletal dysplasia in the fetus, 
most probably TD, a lethal condition, as suspected in antenatal 
ultrasonography. Patient delivered a preterm female baby of 
340 grams vaginally, a still born with phenotypic dysmorphism. 
The baby had macrocephaly with head circumference 30.2 cm 
(>3 standard deviation). Anterior and posterior fontanelles were 
wide and open, and sutures were separated. Face was coarse and 
edematous with frontal bossing, midfacial hypoplasia, depressed 
nasal bridge, low-set ears, and short neck. Upper and lower limbs 
ABSTRACT
Thanatophoric dysplasia (TD) is a congenital, sporadic, and the most lethal skeletal dysplasia caused by new mutation in the 
fibroblast growth factor receptor 3 gene. At birth, it is characterized by shortening of the limbs (micromelia), small conical thorax, 
platyspondyly (flat vertebral bodies), and macrocephaly. TD is divided into two clinically defined subtypes: Type I and II which can 
be differentiated by the skull shape and femur morphology. Ultrasound examination in the second trimester is often straight forward 
in diagnosing the congenital anomaly. We report a case of preterm stillborn female baby with dysmorphic facies, macrocephaly, 
micromelia with short stubby fingers and deep skin creases, short limbs, narrow thorax, and protuberant abdomen delivered at 
our hospital to a 24-year-old multigravida mother with the previous history of first-trimester abortion. The antenatal ultrasound 
examination showed shortening of long bones with femur-shaped like a telephone receiver. Dysmorphic facial feature, skeletal 
abnormalities, and histopathological examination lead us to make the diagnosis of TD Type I. We report this case of TD in view of 
recurrence risk of around 1%, occurring mostly through autosomal dominant mode of inheritance, which may be the possibility in 
this case.
Key words: Congenital, Platyspondyly, Thanatophoric dysplasia, Recurrence, Autosomal dominant inheritance
Vol 4 | Issue 3 | Jul - Sep 2017 Indian J Child Health 454
Shankari et al. Lethal skeletal dysplasia
Skeletal survey was done, which showed severe platyspondyly, 
short ribs, small ilia, markedly shortened limb bones with 
telephone receiver-like curved femoral and curved clavicles 
resembling bicycle handlebar (Figs. 4 and 5). Histopathological 
examination of the temporal bones showed non-specific 
disturbance of enchondral ossification with preservation of 
periosteal ossification. There was retardation of growth zone 
with disordered proliferative, hypertrophic chondrocytes (Fig. 6). 
The diagnosis of TD Type I was made based on antenatal 
ultrasonography, clinical dysmorphism, skeletal deformities, 
and histopathological examination. In this case, the previous 
spontaneous abortion may be most probably due to the same 
cause, which is rare autosomal dominant inheritance (recurrence 
risk-1%), as TD usually occurs sporadically.
DISCUSSION
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 1 in 20,000 to 1 in 50,000 of live births [1]. TD or 
dwarfism literally meaning death bearing dwarf was first described 
by Maroteaux et al. [5]. It is caused by de novo mutations [2] in 
the FGFR3 genes, which has been mapped to chromosome band 
4p16.3. Fibroblast growth factors, which are associated with 
cell growth, bind to the FGFR3 receptor and activate 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 development [6]. It has been 
recently proposed that mutated FGFR3 induces premature exit of 
proliferative cells from the cell cycle and their differentiation into 
Figure 1: Fetal biometry showing increased biparietal diameter 
(macrocephaly)
Figure 2: Fetal biometry showing small thorax with increased abdominal circumference and shortened long bones
were shortened with short stubby fingers and deep skin creases. 
Thorax was narrow with protruberant abdomen and spine was 
normal (Fig. 3a and b).
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Shankari et al. Lethal skeletal dysplasia
pre-hypertrophic chondrocytes, thus ascribing to the defective 
differentiation of chondrocytes, the main cause of long bone 
growth defects in TD Type I [7].
There are two subtypes with relative incidence: Type I - 80% 
and Type II - 20%. The two subtypes can be differentiated by 
the skull shape and femur morphology [4,6]. TD Type I, the 
most common subtype, is characterized by curved and short 
femur which is in a telephone receiver-like configuration and 
no cloverleaf-shaped skull. Furthermore, the abdomen appears 
protuberant in comparison with the chest which is narrow and 
small [4]. 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 [8]. Other features common to both types 
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, brachydactyly (short broad tubular bones in hands 
and feet), redundant skin folds along the limbs [4]. Dysmorphic 
facial features and skeletal abnormalities such as macrocephaly, 
wide open anterior and posterior fontanels with suture separation 
but absence of cloverleaf skull deformity, short upper and lower 
limbs, shape of femur as telephone receiver, short stubby fingers, 
deep skin creases, narrow thorax, and protuberant abdomen 
with ascites suggested a diagnosis of TD Type I in the baby that 
delivered in our hospital.
Although identification of a lethal skeletal dysplasia in the 
second trimester is often straight forward, establishing its specific 
diagnosis can be difficult. 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 [9]. Since our patient did not 
have antenatal checkup in the second trimester, early diagnosis 
could not be made. Diagnosis was made by ultrasonography 
when she reported to the hospital in early third trimester. Final 
diagnosis in our case was made by detecting the clinical features 
at birth - dysmorphic facial features and skeletal abnormalities 
through skeletal survey and histopathological examination.
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 [10]. 
Figure 4: Skeletal survey showing severe platyspondyly, short ribs, 
small ilia, markedly shortened limb bones
Figure 5: Skeletal survey showing telephone receiver-like curved 
femoral and curved clavicles resembling bicycle handlebars
Figure 6: Histopathological examination of the temporal bones 
showing non-specific disturbance of enchondral ossification with 
preservation of periosteal ossification. There was retardation 
of growth zone with disordered proliferative, hypertrophic 
chondrocytes
Figure 3: (a and b) Preterm stillborn female baby with dysmorphic 
facies, macrocephaly, micromelia with short stubby fingers, deep 
skin creases, short limbs, narrow thorax, and protuberant abdomen
ba
Vol 4 | Issue 3 | Jul - Sep 2017 Indian J Child Health 456
Shankari et al. Lethal skeletal dysplasia
Chromosomal analysis and DNA molecular testing for FGFR3 
can be done in suspected cases of TD. Almost all cases 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 [8]. 
Recurrence risk is also not increased over that of the general 
population as it is a de novo mutation [2].
Our case is reported for two specific reasons. Early abortion in 
first trimester in the first pregnancy and late detection in early third 
trimester in the second pregnancy occurred in the same patient. As TD 
is usually sporadic in occurrence, recurrence in this patient suggests 
the possibility of autosomal dominant mode of inheritance, which 
is relatively rare (recurrence risk-1%). Most of the fetuses with TD 
die in utero. The cause of death is due to respiratory insufficiency 
which may be secondary to the narrow chest cavity and hypoplastic 
lungs, brainstem compression by the narrow foramen magnum, or a 
combination of both. Surviving neonate is almost always ventilator 
dependent and mentally deficient [8,11]. Postnatal autopsy of the 
affected fetus shows disorganized chondrocyte columns, poor 
cellular proliferation, lateral overgrowth of metaphyses, and 
increased vascularity of cartilage [1,11].
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 imperfecta (generalized 
hypomineralization of bones with multiple bone fractures) [11,12]. 
The presence of a characteristic cloverleaf skull with telephone 
receiver appearance of humerus and femur with platyspondyly, 
small conical thorax, and a very high mortality differentiates TD 
from other causes of severe short stature with micromelia.
CONCLUSION
TD is a congenital, sporadic, and the most lethal skeletal dysplasia 
at birth. Ultrasonography highly indicates the diagnosis, but 
confirmation is done by molecular analysis in the prenatal period, 
clinical features at birth, skeletal survey, or by autopsy. Features 
such as macrocephaly, wide fontanels, micromelia, and telephone 
receiver-like femur, short stubby fingers, deep skin creases, 
narrow thorax, and protuberant abdomen are highly suggestive 
of TD Type I.
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Funding: None; Conflict of Interest: None Stated.
How to cite this article: Shankari NV, Jerry AL, Charan L, Raj S. 
Thanatophoric dysplasia: A case report with probable recurrence. Indian J 
Child Health. 2017; 4(3):453-456.


Thanatophoric dysplasia: A case report with probable recurrence

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Thanatophoric dysplasia: A case report with probable recurrence

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