Incidentally Detected Transient Abnormal Myelopoeisis in a Placenta of Mosaic Down’s Syndrome: A Case Report Describing Approach to Diagnosis

Abstract

Examination of the placenta is the easiest and the most cost-effective method to evaluate fetal abnormalities which might be missed by other antenatal screening techniques. Transient abnormal myelopoeisis (TAM) in placenta is one such condition which is specific for trisomy 21. Its relevance especially lies in cases where phenotypical features of down’s syndrome are absent in fetus or the cytogenetic reports are negative, suggesting either confined placental mosaicism or low expression generalized mosaicism. This is imperative in parents’ counseling and deciding further patient management because though TAM is a transient phenomenon, it may relapse or progress to acute leukemia.

Introduction

Transient abnormal myelopoeisis (TAM) is a transient leukemic phase observed exclusively in newborns with both constitutional trisomy 21 and mosaic trisomy 21. It spontaneously resolves within 3 to 6 months of age. However, there is a risk of developing acute myeloid leukemia associated with Down’s syndrome (AML-DS) in approximately 20% of the patients [1, 2]. Through this article, we aim to highlight the sequence of events that led us to arrive at a diagnosis of mosaic DS in the absence of confirmatory cytogenetic analysis in a case where TAM was detected incidentally in a placenta which was otherwise sent for evaluation of the cause of intrauterine fetal death following severe IUGR. In doing so, we have also tried to explain the relevance and mechanism of each screening tool routinely used in antenatal fetal well-being evaluation. In the end, we have also proposed an algorithm describing the approach to similar cases.

Case Report

We received a placenta for examination following an IUFD with a gestational age of 22 weeks for histopathological examination. The patient was a primigravida aged 28 years with uneventful medical history. The 12-week scan was normal and aneuploidy screen showed high risk for trisomy 21 (PAPP-A MoM = 0.19, free bHCG MoM = 1.49) The anomaly scan at 18 weeks showed declining fetal growth. The patient was counseled regarding guarded prognosis and advised amniocentesis for chromosomal and fetal infection testing. Patient opted for conservative follow-up. At 22 weeks, the fetal growth restriction persisted. There were gross oligohydramnios, fetal cardiomegaly, and placentomegaly with heterogenous echotexture of placenta. After delivery, the fetus was brought for autopsy. Anthropometry was consistent with severe IUGR. There was no dysmorphism or gross anomaly. Placenta was received for histopathology. On gross examination, it was pale in appearance, small for gestational age, weighed 100gms and measured 9 × 7x5cm. The umbilical cord measured 13 cm in length, with normal coiling, three vascular lumens and a diameter of 1.0 cm. The cord was inserted marginally into the fetal membranes. There were multiple subchorionic thrombohematomas on the fetal surface, largest measuring 3.0 cm. No deposits, exudative material, or discoloration was observed on the membranes. The maternal surface was firm to touch. Microscopic examination revealed subchorionic infarction hematoma (Fig. 1a). The villous pattern of maturation was normal for gestation age. The mesenchymal core was separated from the trophoblastic basement membrane (BM) by a clear space. (Fig. 1b) Membranes showed ischemic necrosis (Fig. 1c). The vascular spaces were noteworthy for the presence of small round hyperchromatic cells which filled the lumen to an extent that normal blood flow was compromised. (Fig. 1d, e) The circulatory stasis was further exacerbated by a marginally inserted cord and large subchorionic thrombohematomas ultimately causing fetal hypoperfusion and involutionary changes like vascular stromal karyorrhexis (VSK) and BM mineralization in distal villous tree ultimately leading to fetal demise.

Fig. 1.

a Low-power view of a subchorionic hematoma (breus’ mole), b chorionic villi showing clear subtrophoblastic zone (suggestive of fetal malperfusion), c Ischemic necrosis of membranes.(H&E, 100X). d and e High-power view showing fetal chorionic vessels with abnormal hematological precursors (H&E, 400X)

On the other hand, presence of immature blast like hematopoietic precursor forms in the villous vessels grew a suspicion of leukemia associated with (DS). The possibility of maternal leukemic cells being transferred to the fetus was refuted because of normal hematology reports in mother. The main contrasting feature was the absence of any phenotypical abnormality attributable to Down’s syndrome in the fetus. Upon further checking the records, it has found that the patient tested positive for Trisomy 21 on antenatal combined biochemical screen test. Although the aneuploidy indicators (NT = 1.73 mm) and nasal bone (present) at 12 weeks of gestation were normal, her free beta HCG levels were elevated (70.9 ng/ml, MoM = 1.49). To confirm our doubt, chromosomal analysis was advised and the preserved fetal liver tissue was sent for QFPCR for the same. To our surprise, the results were negative for T21 including trisomy 13 and 18. To summarize, a phenotypically normal fetus with TAM in placenta, with a positive antenatal screen for T21 but negative genetic analysis raised a suspicion of mosaic T21. The parents were counseled about the low risk of recurrence in case of aneuploid cell line in placenta.

Discussion

Mosaicism is a condition where there is a mixture of two types of cells and is usually described in percentages depending upon the proportion of cells having an extra chromosome out of the total cells analyzed. Mosiacism can be either confined to placenta or generalized (affecting the embryo as well as the placenta) [3, 4] (Fig. 2). After fertilization, the zygote undergoes cleavage divisions to form blastomeres, polarization, and compaction. Unequal compaction, which means exclusion of one or more blastomeres from the compacted morula, is suggested as a potential aneuploidy rescue mechanism, ensuring exclusion of defective ones from mosaic embryos which contribute to the outer cell mass and eventually end up in the placenta (confined placental mosaicism) or there is a mixture of euploid and aneuploidy blastomeres forming the placenta as well the fetus (generalized mosaicism) [4]. The implantation and adhesion of blastocyst involve the trophectoderm cells of the blastocyst which form the primitive syncytiotrophoblasts paving their way through endometritum. Aneuploid trophloblasts undergo abnormal trophoblastic differentiation which could be the reason for elevated Beta hcg levels and a positive screen for T21.

Fig. 2.

a Flow chart describing the various scenarios of Trisomy 21 in a pregnancy and b flow chart describing the step wise approach to aneuploidy screening during pregnancy and the findings in each step according to the different scenarios

TAM is a transient process of abnormal myeloid precursors seen in babies with Down’s syndrome. Children with mosaic DS that are phenotypically normal pose a diagnostic dilemma as seen in our case. As TAM is universally associated with trisomy 21, we suggested low level mosaicism insufficient to cause phenotypic manifestations of DS. The diagnosis can be confirmed by presence of GATA1mutation in addition to trisomy 21 on cytogenetics. However, GATA1 mutation is not always helpful and may be negative especially in cases where the blast count is very low. Secondly, it is not specific for DS. Patients without trisomy 21 who have GATA 1 mutation develop thrombocytopenia and not TAM or AML-DS. Trisomy 21 is the initial driving force behind abnormal hematopoeisis and precedes GATA 1 acquisition [1]. Cytogenetic analysis on fetal liver tissue did not show any trisomy 21 and no viable placental tissue was available for genetic analysis on the blasts cells, it was deduced that the placenta and probably also the fetus had low level mosaicism for Down’s syndrome. Even so, it is essential to recognize and diagnose TAM because around 10% of patients with TAM die from hepatic or multi-organ failure. If detected and treated well in time using chemotherapy, children can be protected from other solid tumors and hematological malignancies associated with DS. The death of fetus in our case was not due to TAM or DS but fetal hypoperfusion due to large subchorionic thrombohematomas and blasts in the fetal vessels.

Conclusion

Figure 2 summarizes our observations and explains our approach to the diagnosis.

The fetus in this study had.

1. Generalized low level of mosaicism.

2. Biochemical first trimester aneuploidy screening is an important tool to assess mosaicism and should not be replaced by NIPT or amniocentesis because the latter two procedures are sample dependent. Elevated BHcg levels suggest abnormal trophoblastic proliferation and are a marker of aneuploidy.

3. Placental examination is the simplest and most cost-effective screening tool that can suggest possible developmental abnormalities. It should be performed on all cases where the screening tests show positive results because placenta acts as a reservoir of all the abnormal cells that have been separated from the inner cell mass to ensure a healthy fetus.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by [Kriti Chauhan], [Meenakshi Lalllar], and [Aastha Sharma]. The first draft of the manuscript was written by [Kriti Chauhan] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

Ethical approval was waived by the local Ethics Committee of the Institution in view of the observational retrospective nature of the study and all the procedures being performed were part of the routine care.

Informed Consent

Written informed consent was obtained from the parents.

Consent for Publication

The authors affirm that human research participants provided informed consent for publication of the images in Figure 1a–d.