thanatophoric dysplasia: autopsy findings over a 25-year period

Thanatophoric Dysplasia: Autopsy FindingsOver a 25-Year PeriodCHRISTINA VOGT

1,2*AND HARM-GERD K. BLAAS

2,3

1Department of Pathology and Medical Genetics, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway2Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science andTechnology (NTNU), Trondheim, Norway3National Center for Fetal Medicine, Department of Obstetrics and Gynecology, St Olavs Hospital, Trondheim University Hospital,Trondheim, Norway

Received September 17, 2012; accepted January 15, 2013; published online January 16, 2013.

ABSTRACTThe aim of our study was to retrospectively assess

morphological findings in thanatophoric dysplasia, par-

ticularly, in how many cases were cerebral manifestations

with temporal lobe dysplasia identified. We also wanted

to register and analyze the proportions between lung,

brain, and body weight. Criteria for inclusion were an

autopsy performed during the period ranging from 1985

to 2009 with a diagnosis of thanatophoric dysplasia.

During a 25-year period 25 cases of thanatophoric

dysplasia were registered. Temporal lobe dysplasia was

recognized in 52% of the cases, and after 1998 temporal

lobe dysplasia was described in all cases. In 19 cases the

brain/body weight ratio was increased, and in all cases the

lung/body weight ratio was below the corresponding ratio

calculated according to standard measurements. In all but

one case the ratio of brain to lung weight was increased.

This study focuses on morphological findings, stressing

the importance of temporal lobe dysplasia in confirming a

diagnosis of thanatophoric dysplasia. Lung/body, brain/

body, and brain/lung weight ratios confirm macrocephaly

and lung hypoplasia, which are constant findings in cases

involving thanatophoric dysplasia. Femur and brain

morphology inclusive histology remains the ultimate tool

for confirmation of this lethal condition, although it has to

be seen in a context inclusive of radiological examination.

Key words: autopsy, congenital anomalies, dwarfism,

temporal lobe dysplasia, thanatophoric dysplasia, ultra-

sonography

INTRODUCTION

Thanatophoric dwarfism was first described in 1967 by

Maroteaux and colleagues [1], who distinguished it from

achondroplasia as an independent entity. It was classified

at the First International Conference on the Nomenclature

of Skeletal Dysplasias in 1969 in the group of

osteochondrodysplasias [2]. At the Second International

Conference in 1977, the term thanatophoric dwarfism was

changed to thanatophoric dysplasia (TD) [3], and

according to international nomenclature it was classified

into group 1, the achondroplasia group [4]. In the 2006

revision TD is classified in group 1, the fibroblast growth

factor receptor 3 (FGFR3) group, clearly illustrating new

molecular and pathogenetic insight [5].

Subclassification includes TD types 1 and 2 [6,7].

Thanatophoric dysplasia is one of the most common

lethal skeletal dysplasias, the prevalence of which varies

from 1:20 000 to 1:60 000 births [8–11]. The word

thanatophoric is derived from Greek and means death-

bearing. Thanatophoric dysplasia is caused by a mutation

of the FGFR3 gene located on chromosomal locus 4p16.3

[6,7]. This results in constitutive activation of the FGFR3

tyrosine kinase and leads to perturbation of processes in

bone formation and cerebral cortical development [12].

Thanatophoric dysplasia has been considered to be caused

by a dominant mutation and is therefore without

recurrence risk [13,14]. Familial occurrence has also

been described by Osoba and colleagues [15] and

Partington and colleagues [16] as an autosomal recessive

mode of inheritance, although germline mosaicism is

more probable [13].

In addition to TD, the platyspondylic lethal skeletal

dysplasias also include the San Diego, Torrance, and

Luton types; of these the San Diego type has been found

to be heterogeneous for FGFR3 mutations, while in the

other 2 types no mutations were identified [17].

The 2 types have been distinguished based on

cloverleaf skull phenotype and femur morphology.

Traditionally, TD without cloverleaf skull was designated

TD type 1, while TD with cloverleaf skull was designated

TD type 2 [2]. In this classification system TD type 1 has

a large head with craniofacial asymmetry, short extremities,

especially proximally, and a femur with a typical telephone

receiver curvature. In type 2 TD, craniosynostosis causes*Corresponding author, e-mail: [email protected]

Pediatric and Developmental Pathology 16, 160–167, 2013

DOI: 10.2350/12-09-1253-OA.1

ª 2013 Society for Pediatric Pathology

the characteristic cloverleaf skull, and the curving of the

long bones is usually less pronounced. Genetic studies of

mutations in TD have indicated a better correlation with

femur morphology, and in the current classification

craniosynostosis with cloverleaf skull can also occur in

type 1 TD but is more frequent and more severe in TD type

2 [18–20].

In both types of TD the vertebral bodies can have a

‘‘U’’ or ‘‘H’’ form, and the ribs are thinner and shorter

than normal; this reduces the volume of the thorax and

causes lung hypoplasia. The liver is large since it becomes

the main producer of hematopoietic tissue.

Megalencephaly and cerebral cortical disorganization

are characteristic central nervous system manifestations

of TD [21,22]. Reports on temporal lobe abnormalities

appeared in 1971 [23]. Since then several reports have

focused specifically on temporal lobe dysplasia (TLD)

[2,12,21,22,24–29], which has also been described [30]

in hypochondroplasia belonging to the achondroplasia

group. The activation of FGFR3 tyrosine kinase causes a

disturbance of cortical development, resulting in hippo-

campal dysplasia, temporal lobe hyperplasia, and prema-

ture development of aberrant sulci [12].

The aim of this study was to evaluate autopsy findings

associated with TD and to see whether cerebral manifesta-

tions with TLD were identified and how they were described.

MATERIALS AND METHODS

From January 1985 through December 2009, a total of

1102 autopsies of fetuses and infants with developmental

anomalies were performed at the Department of Pathol-

ogy and Medical Genetics, St Olavs Hospital, Trondheim

University Hospital. In all cases, an ultrasound (US)

examination during pregnancy had been performed at the

National Center for Fetal Medicine (NCFM), which in

1990 was established as the tertiary fetal medicine referral

center for Norway.

Obstetricians working at the NCFM performed the

targeted US examinations. The scan included assessment

of fetal anatomy with biometric measurements, localiza-

tion of the placenta, and evaluation of amniotic fluid.

Pathologists participated at regular meetings with obste-

tricians working at the NCFM, reviewing videotapes with

the sonographic findings. Whole-body radiography and

photographic documentation were routinely performed at

the postmortem examination. The fetuses/infants were

examined according to a standardized autopsy protocol,

which included examination of all organs. The heart was

examined in situ and the brain removed under water in

order to minimize postmortem changes. In addition to

microscopic examination of organs, a sample of the ribs,

including the costochondral junction, a longitudinal

section from the vertebral column, and a section from

Table 1. Twenty-five cases of thanatophoric dysplasia listed chronologically

No. Year GA LMP (weeks) Weight (g) Length (cm) Diagnosis

1 1989 21 300 21 TD type not specified, hydrocephalus

2 1989 29 1600 35.5 TD type I, brain described as normal; Meckel’s diverticulum

3 1990 19 450 29 TD type I, brain autolytic

4 1990 21 410 26 TD type II, brain described as normal; hydronephrosis

5 1994 21 380 23 TD type I, hydrocephalus

6 1994 38 3450 40 TD type I, hydrocephalus

7a 1995 18 150 17 TD type II, fetal hydrops/cystic hygroma,

hydronephrosis, brain described as normal

8 1995 19 255 20 TD type I, brain autolytic

9a 1995 13 218 8.6 TD type II, fetal hydrops/cystic hygroma, brain

described as normal

10 1996 24 405 24.5 TD type I, hydrocephalus

11 1998 36 2350 35 TD type I, brain described as normal

12 1998 21 680 24.5 TD type I with TLD

13 1998 19 249 21 TD type I, brain fragmented

14 2002 20 21 TD type I with TLD

15 2002 19 247 20.5 TD type I with TLD

16 2003 19 285 19.5 TD type I with TLD

17 2004 23 530 25 TD type I with TLD

18 2005 17 198 19 TD type II with TLD

19 2007 25 465 24 TD type I with TLD

20 2007 19 257 18.5 TD type I with TLD

21 2007 19 290 21 TD type I with TLD

22 2007 19 286 21 TD type I with TLD

23 2007 20 364 23 TD type I with TLD

24 2008 19 240 21.5 TD type I with TLD

25 2008 15 98 15.5 TD type I with TLD

GA indicates gestational age; LMP, last menstrual period; TD, thanatophoric dysplasia; TLD, temporal lobe dysplasia.aSiblings.

THANATOPHORIC DYSPLASIA AND AUTOPSY 161

the diaphragm and the psoas muscle, was also included.

In cases in which a skeletal dysplasia was suspected by

US, a section from the calvarium was taken and the right

femur was removed for further examination. The femur

was decalcified and longitudinal sections were taken. In

most cases the body weight and brain and lung weights

were accessible for further study. Established reference

values for measurements and weights were used in order

to calculate gestational age and lung/body, brain/body,

and brain/lung weight ratios [31–33]. Crown-rump length

(CRL) and foot length were measured at autopsy.

RESULTSClinical data

During the 25-year period 61 cases of skeletal dysplasia

were autopsied. Thanatophoric dysplasia was the most

frequent finding with these 25 cases, representing 41%

of skeletal dysplasias (25/61). Thanatophoric dysplasia

constituted 2.3% (25/1102) of all registered developmen-

tal anomalies during this time period.

The women were referred from all parts of Norway;

only 6 of 25 (24%) of the cases came from the county of

Sør-Trøndelag, which represents the local referral area for

the hospital. The mean age of the 25 women at the time of

abortion or birth was 28 years (range, 19 to 40 years).

Seven (28%) women had experienced a previous

abortion, 2 more than once. Twenty-three pregnancies

were terminated. Two infants were born alive at

gestational ages of 29 and 38 weeks but died immediately

after birth. The mean gestational age at the time of

abortion/birth was 21 weeks (range, 13 to 38 weeks). The

sex distribution was 14 females (56%) and 11 males

(44%). Karyotyping was performed in 19 of the 25 cases

(76%): 18 had a normal karyotype, and in 1 case a

possible deletion in the proximal part of chromosome 6q

was found in some of the cultured cells. The placenta was

examined in 22 cases; in 3 cases hemorrhages or infarcts

were found. The umbilical cords were described as

normal.

Table 1 lists chronologically all cases of TD. There

was an US diagnosis of skeletal dysplasia in all cases,

though the diagnosis of TD was not always specified. Four

cases were TD type 2, and 2 of these had hydronephrosis,

which was not seen in any of the TD type 1 cases. In 2 cases

hydrops/cystic hygroma was present. These 2 cases

involved siblings, and both were TD type 2.

There was no mention of TLD in the cases diagnosed

before 1998. In 1998, 1 of the 3 cases (case 12) was

diagnosed with TLD; in case 13 the brain was fragmented

and therefore was difficult to examine. After 1998 TLD

was described in all cases.

Table 2 summarizes the different measurements and

weight ratios. The cases are organized according to

Table 2. Measurements and weights: evaluations of gestational age (GA) after foot length and crown-rump

length (CRL) according to Streeter [31] and weight ratios calculated after tables by Maroun and Graem [32].

Cases arranged according to last menstrual period (LMP) GA

No.

GA LMP

(weeks)

Foot length

(cm)

Foot length cm

GA (weeks) CRL (cm)

CRL cm GA

(weeks)

Ratio lung/

body weight

Ratio brain/

body weight

Ratio brain/

lung weight

9 13 0.8 11.5 7 13 0.0229 – –

25 15 2.1 16 12.3 16.5 0.0220 0.1735 7.87

18 17 2.4 17.5 14 18 0.0192 0.2020 10.53

7 18 1.8 15 13 17 0.0208 0.1733 8.33

3 19 2.4 17.5 17 20.5 0.0140 0.1111 7.94

8 19 2.7 18 16.7 20 0.0229 0.1020 4.45

13 19 2.6 18 16.5 20 0.0184 0.1888 10.24

20 19 2.5 17.5 15 19 0.0146 0.2412 16.53

15 19 2.7 18 16.5 20 0.0208 0.2024 9.75

16 19 2.8 18.5 19.5 23 0.0136 0.1554 11.45

22 19 2.8 18.5 17 20.5 0.0185 0.2161 11.66

24 19 2.8 18.5 16.5 20 0.0247 0.2013 8.15

21 19 2.8 18.5 17 20.5 0.0196 0.1862 9.51

14 20 3.5 21 17.5 21 – – 8.82

23 20 3.5 21 18 21.5 0.0163 0.1538 9.43

1 21 2.5 17.5 15.5 19 0.0180 0.1833 10.17

4 21 3 19 21 24 0.0124 0.1829 14.71

5 21 3 19 18.8 22 0.0139 0.1605 11.53

12 21 4 22 21 24 0.0153 0.1838 12.01

17 23 3.8 21.5 19.5 23 0.0138 0.1698 12.33

10 24 3.4 20.5 16.5 20 0.0148 0.1086 7.35

19 25 3.5 21 19 22.5 0.0146 0.2022 13.82

2 29 5 26 29 33 0.0101 0.1313 12.90

11 36 5.2 27 30.5 34 0.0057 0.1851 32.51

6 38 6.4 32.5 34.5 38.5 0.0081 0.2029 25.00

162 C. VOGT AND H-G.K. BLAAS

gestational age after last menstrual period (LMP). With

the exception of 2 cases (cases 10 and 14), CRL indicated

a higher gestational age compared to foot length [31]; the

average difference was 2.38 weeks (range, 0.5 to 7 weeks).

The lung/body weight ratios decreased during

pregnancy, with smaller ratios as gestational age

increased. In all of our cases the ratios were below

0.025. The brain/body weight ratios varied from 0.10 to

0.24. In 19 cases the brain/body weight ratios were higher

than expected for the correspondent gestational age. Four

cases had lower ratios, though in 2 of these cases the brain

was described as autolytic (cases 3 and 8). In 2 cases

(cases 9 and 14) the values are missing. The brain/lung

weight ratios were also calculated; except for 1 case (case

8) all were higher than expected for their gestational age.

Fourteen cases had ratios measuring from 2- to 5-fold

above calculated average ratios [32].

Radiological descriptions

The radiological findings varied depending on age and

type of TD. The cranium was usually large with frontal

bossing, the vertebrae flat with a ‘‘U’’ or ‘‘H’’ shape, the

ribs short, and in type 1 cases the long bones were short

and curved with cupping and flaring of the metaphyses. In

the type 2 cases cloverleaf skull and more straight femora

were present. In all cases radiological findings were

described as consistent with TD.

Morphological findings

The curved form of the femur (old-fashioned telephone

receiver) was most prominent in TD type 1 and became

more pronounced as gestational age increased (Fig. 1).

Slides from the vertebral bodies, ribs, and femur

demonstrated disorderly and severely disturbed enchondral

ossification. Longitudinal sections from the femur demon-

strated an uneven ossification zone (Fig. 2). The resting

cartilage was mostly unremarkable, but the epiphyseal

growth plate was severely retarded and disorganized, with

disorderly arranged chondrocytes in the cartilage columns,

which were short and reduced in number. In the

proliferating zone the chondrocytes were arranged partly

horizontally. This was seen both in the proximal and distal

epiphysis. In many of the cases there was disorganized

ossification along the periosteum, with lateral overgrowth

of metaphyseal bone with short and widened metaphyseal

trabeculae. There was also ingrowth of vascularized

fibrous tissue in cartilage (Fig. 3). These findings varied

in the different cases, with varied perturbation of cartilage

and overgrowth of metaphyseal bone.

In the cases with TLD, typical findings were folded

gyri and deep aberrant sulci. The temporal lobe

hyperplasia was most pronounced in medial and lateral

directions, resulting in deep fissures oriented transversally

across the medial and inferior surfaces of the temporal

lobe (Fig. 4). The number of clefts and depth of the sulci

varied in the different cases. Microscopically uneven

migration, polymicrogyria, and heterotopias were found

in the temporal lobe (Fig. 5). The hippocampus was

completely disorganized, and the rudimentary gyrus

dentatus and hippocampal dysplasia were evident in all

cases with TLD (Fig. 6). Sections from the brain in cases

2, 4, 7, 9, and 11 were reviewed; uneven migration was

found in all cases except case 9, although the quality of

the slides was not optimal for a conclusion of TLD.

DISCUSSION

This study presents 25 cases of TD; in 13 of these cases

TLD was recognized. The diagnosis of a lethal skeletal

Figure 1. Thanatophoric dysplasia with femur at 38 weeks’gestational age (GA) compared to femur at 20 weeks’ GA.

Figure 2. Longitudinal section of femur with ossificationzone in thanatophoric dysplasia (38 weeks’ gestationalage).


dysplasia is generally easy to make at the routine 18th-

week US examination; however, prenatal detection of

TLD in TD has only recently been described [34]. We do

not know when the characteristic curving of the long

bones develops, and to evaluate the femur at autopsy

during the 1st trimester may be challenging. Generally, it

has been assumed that curving of the long bones increases

with increasing gestational age [19,35], although this

assumption has been somewhat controversial [18]. In any

case, radiologic and histopathologic verification is

necessary. Subclassification into TD types 1 or 2 may

also be difficult except in those cases in which the femur

has the characteristic telephone receiver form. Discus-

sions are ongoing about which criteria should be used to

diagnose TD types 1 and 2. The cases in the present study

are based on the traditional classification scheme, with

classical curved femur in TD type 1 and straight femur

and cloverleaf skull in TD type 2 [2].

Figure 3. Disorganized ossification in femur (20 weeks’ gestational age) (hematoxylin and eosin, original magnification340).

Figure 4. Transversal fissures in the temporal lobe intemporal lobe dysplasia (19 weeks’ gestational age).


Femur morphology seems to better distinguish the 2

types; this is also supported by genetic studies on specific

mutations. Wilcox and colleagues [18] performed exten-

sive molecular mapping of the FGRF3 gene, concluding

that TD type 1 is most often caused by a substitution of

Arg248Cys, Tyr373Cys, or Ser249Cys, while TD type 2

is due to a Lys650Glu substitution [14,18]. In this context,

cases with TD type 1 have curved, short femora with or

without a cloverleaf skull deformity, while those with

type 2 have longer and straighter femora and constant and

Figure 5. Polymicrogyria and uneven migration in temporal lobe in temporal lobe dysplasia (19 weeks’ gestational age)(hematoxylin and eosin, original magnification 320).

Figure 6. Completely disorganized hippocampus (20 weeks’ gestational age) (hematoxylin and eosin, original magnification340).


more severe cloverleaf skull deformity [19,20]. Mutations

in the FGFR3 gene are also found in achondroplasia and

hypochondroplasia [20,30]. In achondroplasia the muta-

tion is in the transmembrane domain, in TD type I in the

extracellular domain, and in TD type 2 in the intracellular

domain [14]. If molecular genetic services are available,

establishing the domain and location of the mutation will

aid in classifying the 2 types of TD.

Two of our cases were siblings; both had straight

femora, the 1st one was aborted in the 18th week, while

the 2nd one was aborted in the 13th week. These 2 cases

were sent to H.J. van der Harten in 1996 (Department of

Pathology, Free University Hospital, Amsterdam, The

Netherlands) for consultation. Since TD has been

considered an autosomal-dominant condition, germ-cell

mosaicism was suggested for this event. Except for

monozygotic twins, there are few reports in siblings

[15,16,36,37].

Obtaining correct gestational age based on fetal

measurements (femur and humerus length, CRL, and foot

length) is not possible in cases involving skeletal

dysplasias. Therefore, gestational age according to LMP

is presented in Table 1. In Table 2, since femur and

humerus lengths are unreliable, LMP-based gestational

age is compared with estimation of age according to

external measurements. We did not find complete

correspondence in any of the cases. Generally, CRL

indicated a higher gestational age than did foot length.

We suppose that the large head in TD cases accounts for

the larger CRL and that the short foot length reflects the

general shortening of bones. The table used for measuring

CRL and foot length in this study [31] showed either

equal or slightly higher gestational age than do more

recent measurements [32,33].

Normally the fetal lung/body weight ratio decreases

slightly as pregnancy proceeds, on average being 0.032

(none to mild maceration) at 13 weeks and 0.022 at

38 weeks, calculated from the tables of Maroun and

Graem [32]. As expected, according to these tables, the

lungs were hypoplastic in all TD cases. This confirms the

effect a small thoracic cage has on lung development,

being the one event that prevents survival after birth. The

brain/body weight ratios were not completely consistent

according to gestational age, though 19 of our cases had

increased brain/body weight ratios according to standard

measurements [32]. In 2 cases we could not calculate the

ratio because of missing data, and 4 cases had lower ratios

than expected, though in 2 of these cases the brains were

macerated. Most of our cases thus had megalencephaly.

With hypoplastic lungs and megalencephaly it is not

surprising that the brain/lung weight ratios were over the

values expected, in one case by over a 5-fold measure.

We did not make the diagnosis of TLD until 1998,

when TLD was described in 1 of 3 cases. After 1998 TLD

was described in all cases. The extent of temporal lobe

folding differs from case to case, and failure to see this

phenomenon may have several causes. The most

important reason is lack of awareness related to the

condition (‘‘you find what you look for’’). If the brain is

not inspected carefully, discrete folding on the inferior

surface of the temporal lobe can easily escape detection,

and the correct slides for microscopy will also be missed.

Variable expression of the FGFR3 mutation influenced by

environmental conditions remains a theoretical/specula-

tive possibility. Except in the case of macrocephaly, not

much has been written in textbooks about cerebral

manifestations [38], although they were described already

in 1971 [23] and further emphasized in later publications

[12,21,22,24–27,29]. A comprehensive review has been

written by Hevner [12], who describes both macroscopi-

cal and microscopical findings in detail.

FGFR3 is important for development of bone, where

it regulates chondrocyte differentiation and proliferation

[39]. This explains the severely disturbed ossification of

bones. FGFR3 mutations activate the receptor tyrosine

kinase [40], which also disturbs processes of cerebral

cortical development. This leads to hippocampal dyspla-

sia, with increased proliferation and decreased apoptosis

contributing to temporal lobe hyperplasia and premature

development of aberrant sulci [12]. The accessory sulci

seem to be formed because of increased migration of

neuronal cells from the ependymal layer, necessitating

more space in the cortex.

CONCLUSIONS

Temporal lobe dysplasia is characteristic for TD, and

finding this abnormality together with other radiological

and morphological findings consistent with TD is

therefore pathognomonic for the diagnosis. Fetal mea-

surements, with ratios confirming lung hypoplasia and

megalencephaly, offer useful additional information.

Most fetuses with TD are diagnosed correctly by US

examination, though confirmation by postmortem exam-

ination is still important in order to confirm the diagnosis

and also to facilitate correct subtyping. In most cases TD

is a sporadic mutation; correct genetic guidance can then

be communicated to the parents.

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thanatophoric dysplasia: autopsy findings over a 25-year period

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