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Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 776-779
Thanatophoric dysplasia type 1 with temporal lobe dysplasia: Report of a case along with differential diagnosis

1 Department of Pathology, IPGME&R, Kolkata, West Bengal, India
2 Department of Neonatology, IPGME&R, Kolkata, West Bengal, India
3 Department of Pathology, Coochbehar Government Medical College, Cooch Behar, West Bengal, India

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Date of Submission27-Jul-2020
Date of Decision12-Sep-2020
Date of Acceptance25-Sep-2020
Date of Web Publication20-Oct-2021


Thanatophoric dysplasia type 1 (TD1) is a lethal form of osteochondral dysplasia due to mutation of FGFR3 gene. In addition to severe shortening of the limbs there is temporo-occipital lobe dysplasia along with a range of other CNS anomalies. In this report we describe the radiological and anatomical features at autopsy in neonate with TD1 along with the CNS anomalies. We have also summarized the key distinguishing features of TD1 from other common types of osteochondral dysplasia. An accurate diagnosis is important for genetic counseling and impact on future pregnancies.

Keywords: Infantogram, temporal lobe dysplasia, thanatophoric dysplasia type 1

How to cite this article:
Mondal A, Mandal B, Das RN, Chatterjee U, Mukherjee S. Thanatophoric dysplasia type 1 with temporal lobe dysplasia: Report of a case along with differential diagnosis. Indian J Pathol Microbiol 2021;64:776-9

How to cite this URL:
Mondal A, Mandal B, Das RN, Chatterjee U, Mukherjee S. Thanatophoric dysplasia type 1 with temporal lobe dysplasia: Report of a case along with differential diagnosis. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Feb 2];64:776-9. Available from:

   Introduction Top

Thanatophoric dysplasia type 1 is a lethal form of osteochondral dysplasia characterized by short curved limbs, conical thorax, macrocephaly, and flattened nasal bridge. The unique feature of TD1 is that it is associated with changes in CNS unlike the other osteo-chondral dysplasias. Although the skeletal changes in TD1 are well documented, the CNS changes in this condition are less often reported.[1],[2] These changes can be subtle, easily missed and can be difficult to appreciate in macerated fetuses. These features are diagnostic and help to distinguish TD from other forms of osteochondral dysplasia; and can be invaluable in the absence of facilities for molecular testing. In this peri-natal autopsy report we have highlighted the key morphological and radiological features of TD1 along with the CNS changes.

   Case Report Top

A baby boy was born to a 25-year-old, primigravida mother at 32 weeks of gestation. The baby weighed 1800 g at birth. There was severe shortening of the limbs and the baby died of asphyxia 6 hours after birth. An autopsy was requested with clinical a diagnosis of achondroplasia. Antenatal checkup was irregular and USG done around 24 weeks of gestation from a rural health center was reported to be unremarkable.

Infantogram showed a relatively large head, short ribs with flared ends and a narrow thorax. All the four limbs were shortened in all aspects (rizomelic, mesomelic, and acromelic shortening). There was bowing of left ulna, both femora and tibia with broadening of the metaphysis. The left radius was dysplastic. The vertebral bodies were platyspondylic that is, flattened and “U” shaped [Figure 1]a.
Figure 1: (a) Infantogram showing bowing of left ulna and both femora and tibia, short ribs, and platyspondyly. (b) External features showing dolicocephalic head, depressed nasal bridge, short and bowed limbs, narrow thorax and protuberant abdomen

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   Autopsy Report Top

On external examination, the baby was dolicocephalic with shortened overall length. The nasal bridge was depressed with frontal bossing. Both upper and lower limbs were extremely short and bowed. There were redundant skin folds on the nape of the neck, back, and the limbs. There was constriction of the chest and the abdomen was protuberant. Bluish discoloration was present around the mouth, nose, and over the palms. The baby was normodactylic in all the 4 limbs [Figure 1]b. On opening up the chest cavity, the lungs were hypoplastic and together weighed 16g. The lungs/bodyweight ratio was 0.008 indicating hypoplasia; the normal lungs/body weight ratio beyond 28 weeks being 0.012 ± 0.002. [Figure 2]. Abdominal viscera were apparently normal. The brain was enlarged and weighed 300 g. The meninges were congested and there was subarachnoid hemorrhage at the base. On stripping the meninges, the brain showed polymicrogyria. Infero-lateral surface of temporal lobes showed transverse sulcation. On slicing the brain, the occipital horns of the lateral ventricles were dilated, indicating hydrocephalus. On microscopic examination there was evidence of sub-ependymal neuronal heterotopias [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d. The microscopic sections taken from the metaphyseal end of femur showed disruption of normal column like pattern of growth with haphazard arrangement of the chondrocytes. Based on the radiological and postmortem features a diagnosis of thanatophoric dysplasia, type 1, was made.
Figure 2: (a) Gross photographs of the hypoplastic lungs and the heart. (b) Photomicrographs of the lung showing collapsed alveoli with thickened and congested alveolar septae (H and E ×40)

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Figure 3: (a) Gross photograph of the brain showing polymicrogyria. (b) Gross photograph of the ventral aspect showing transverse sulci in the infero-medial aspect, marked with arrows. (c) Serial slices following brain cutting showing dilatation of the occipital horns, marked with arrow. (d) Photomicrograph of the cerebrum showing neuronal hetertopia in subependymal location. (H and E X100)

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   Discussion Top

Thanatophoric dysplasia is a sporadic, congenital anomaly with severe skeletal defects along with changes in the brain. Thanatophoric dysplasia (TD) constitutes 16% of all osteochondral dysplasias.[3] The prevalence varies between 1:20,000 and 1:60,000 live births.[4],[5] The affected fetus shows severe shortening of the limbs with an enlarged head. There is increase in fronto-occipital diameter, flat nasal bridge, and protruding tongue. The chest is bell-shaped, constricted and the abdomen is distended. The limbs are short in all respects that is, rizomelic, mesomelic, and acromelic.[1],[2],[3]

TD is divided into two clinical subtypes TD type 1 and TD type 2, based on thy shape of the skull and morphology of the femur. TD type 2 fetus shows “clover leaf” shaped skull due to cranial synostosis and relatively straight long bones. Other clinical and radiologic manifestations of TD type 2 are milder than TD type 1.[5],[6] Autosomal dominant mutation of FGFR3 on chromosome 4q16.3 is the underlying cause of TD.[6],[7],[8] TD type 1 is caused by mutation of FGFR3 gene, where arginine at 248 position is replaced by cysteine [R248C]. The extracellular domain of FGFR3 binds to FGF, setting in motion a cascade of downstream signaling, which ultimately influence cell mitogenesis and differentiation. In TD type 2, a milder form of the disease, lysine is replaced by glutamate at position 650 of the gene [K650E].

Fetal x-ray/infantogram shows platyspondyly with “H” or “U” shaped vertebral bodies. Ribs are short and horizontal. Both upper and lower extremities are short (micromelia). All long bones are curved, especially femur which resembles a “telephone receiver”. The bone changes in TD type 2 is less pronounced. Long bones show cupping and flaring of the metaphysis. These features more pronounced in the second trimester of pregnancy and become more prominent as the pregnancy advances.[1],[2]

Apart from axial and appendicular skeleton, TD also involves brain of the fetus. These changes in brain are characteristic in thanatophoric dysplasia. The brain shows increased gyration and sulcation of the cerebral cortex (polymicrogyria). There is evidence to suggest that FGFR3 activation disturbs three important processes in cortical development: areal patterning, progenitor proliferation and apoptosis. Imperfect patterning accounts for hippocampal dysplasia, whereas polymicrogyria is due to excessive neuronogenesis and decreased apoptosis of the neurons.[2],[9],[10] Dysplasia is more prominent in occipito-temporal lobe, hippocampal gyrus and dentate nucleus. These changes can by visualized by USG or MRI by the end of second trimester.[10]

Survivability of a fetus is generally determined by ultrasound criteria. Prenatal ultrasound can detect cases of dwarfism and several other skeletal malformations. Sonographic measurements are good predictors of lethality. Lethality is usually due to thoracic underdevelopment and lung hypoplasia. Thanatophoric dysplasia type 1 is invariably fatal causing death by asphyxia due to dysplastic lungs. TD can be diagnosed prenatally by 2D or 3D ultrasound, mainly during second trimester. Diagnosis in the first trimester requires a high degree of clinical suspicion. 3D ultrasound aids in the detailed evaluation of the fetal extremities. On USG, any fetus with length of long bones less than 5th percentile or less than 2SD from the mean should raise the suspicion of osteochondrodysplasia.[11] The femur-to-feet ratio approaches 1.0 at the end of pregnancy, but in TD and other rizomelic dwarfism this ratio is <1.0.[11],[12] TD can be confirmed antenatally by molecular analysis of FGFR3 gene mutation from amniocentesis specimen. Recurrence risk of TD is almost nil in subsequent pregnancy as TD is caused by sporadic mutation of FGFR3 gene.

The other common forms of OCD are hypochondroplasia, achondroplasis, osteogenesis imperfecta and short rib syndrome with or without polydactyly. The salient features of these compared to TD is summarized in [Table 1]. The CNS changes should be looked for carefully as it helps to separate out TD from other forms of skeletal dysplasias-like achondroplasia with overlapping skeletal changes and also due to mutations associated with FGFR3 gene. Although molecular analysis was not done in our case, in the absence of a molecular laboratory the associated CNS changes are helpful in making the diagnosis.
Table 1: A summary of imaging, morphologic, and genetic features of thanatophoric dysplasia and other common skeletal dysplasias

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   Conclusion Top

Here we describe the morphological features at autopsy in a case of TD1 along with the associated CNS anomalies; its differential diagnoses and distinguishing features from other osteochondral dysplasias. A precise diagnosis is important for genetic counseling.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Vogt C, Blass HG. Thanatophoric dysplasia: Autopsy findings over a 25 year period. Pediatr Dev Pathol 2013;16:160-7.  Back to cited text no. 1
Wainwright H. Thanatophoric dysplasia: A review. S Afr Med J 2016;106:50-3.  Back to cited text no. 2
Konstantinidou AE, Agrogiannis G, Sifakis S, Karantanas A, Harakoglou V, Kaminopetros P, et al. Genetic skeletal disorders of the fetus and infant: pathologic and molecular findings in a series of 41 cases. Birth Defects Res A Clin Mol Teratol. 2009;85:811-21.  Back to cited text no. 3
Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986;23:328-32.  Back to cited text no. 4
Martiniz-Frias ML, Ramos-Arroyo MA, Salvandor J. Thanatophoric dysplasia: An autosomal dominant condition? Am J Med Genet 1988;31:815-20.  Back to cited text no. 5
Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 2011;155:943-68.  Back to cited text no. 6
Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, et al. Molecular, radiologic and histologic correlations in the thanatophoric dysplasia. Am J Med Genet 1998;78:274-81.  Back to cited text no. 7
Partington MW, Gonzales-Crussi F, Khakee SG, Wollin DG. Cloverleaf skull and thanatophoric dwarfism: Report of four cases, two in the same sibship. Arch Dis Child 1971;46:656-64.  Back to cited text no. 8
Yamaguchi K, Honma K. Autopsy case of thanatophoric dysplasia: Observations on the serial sections of the brain. Neuropathology 2001;21:222-8.  Back to cited text no. 9
Hevner R.F. The cerebral cortex malformation in thanatophoric dysplasia: Neuropathology and pathogenesis. Acta Neuropathol 2005;110:208-21.  Back to cited text no. 10
Krakow D, Lachman RS, Rimoin DL. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med 2009;11:127-33.  Back to cited text no. 11
Noel AE, Brown RN. Advances in evaluating the fetal skeleton. Int J Womens Health 2014;6:489-500.  Back to cited text no. 12

Correspondence Address:
Uttara Chatterjee
Professor, Department of Pathology, Institute of Post Graduate Medical Education and Research, Kolkata - 700 020, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_917_20

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