Born with it: congenital KMT2A::MLLT1-type AML, a subdural haemorrhage that began before birth, and death on day four

Before birth. The pregnancy had been uncomplicated until 34 weeks, when pre-term labour began and then resolved; delivery was at 36 weeks by Caesarean section for fetal decelerations after spontaneous labour. Apgar scores were 5 and 5 at one and five minutes, and the infant was intubated shortly after birth for respiratory distress 1.

The first examination records the whole of it:

• a diffuse, non-blanching, bluish-red macular rash with some palpable areas, and multiple petechiae - the two skin findings of concept-leukemia-cutis-infant and concept-bruising-petechiae-thrombocytopenia at the same time on the same baby;
• a full, somewhat distended abdomen with marked hepatosplenomegaly (concept-hepatosplenomegaly-infant-leukemia);
• a slightly full anterior fontanelle;
• unequal pupils, 4 mm and minimally reactive on the right, 2 mm and trace reactive on the left;
• decreased spontaneous movement and reduced tone throughout the left arm and leg.

The last three are not leukaemia signs. They are the signs of a mass inside the skull.

The blood. WBC 188,000/cumm with 70% blasts (concept-hyperleukocytosis-emergency), haemoglobin 9.2 g/dL, platelets 110,000/cumm. The clotting was the striking part: prothrombin time 65.1 s, partial thromboplastin time 58.9 s, INR 7.7. Tumour lysis was already established at birth, with LDH above 76,000 IU (reference 130-700) and urate 9.1 mg/dL 1.

The cells. Blasts on the smear were mostly monoblasts or promonocytes; a subset was myeloperoxidase-positive and there was strong diffuse alpha-naphthyl butyrate esterase positivity - the monocytic pattern. Flow cytometry found a mixed phenotype, with 62% of events in the myeloid gate co-expressing CD56, CD64, HLA-DR, TdT and partial CD5, and 19% in a monocytic gate co-expressing HLA-DR, CD13, CD14, CD56 and CD64. The diagnosis given was AML with monocytic differentiation 1.

The chromosomes. 46,XX,t(11;19)(q23;p13.3) in 20 of 20 metaphases, with KMT2A rearrangement confirmed by FISH and no PML::RARA, RUNX1::RUNX1T1 or CBFB rearrangement (concept-cytogenetics-karyotype-kmt2a, concept-fish-split-signal-kmt2a). Mitogen-stimulated lymphocyte culture showed no germline chromosomal abnormality, so the translocation was somatic. The authors interpret t(11;19)(q23;p13.3) as a KMT2A to ENL/MLLT1 fusion; microarray additionally showed a ~533 kb interstitial deletion at 19p13.11, implying a more complex rearrangement than the karyotype suggests.

The proof it started in utero. Placental pathology showed abnormal fetal myeloid cells, with no other histopathological abnormality and no evidence of a TORCH agent. Fetal blood in the placenta contained immature myeloid cells consistent with AML blasts 1.

The head. Ultrasound at 15 hours of life showed a 5.8 x 3.9 cm mixed-density lesion in the right middle cranial fossa; MRI at 21 hours confirmed a mixed-intensity subdural haematoma with a fluid-fluid level containing both acute and subacute blood, smaller left temporal and right cerebellar subdural collections, uncal herniation, multifocal diffusion restriction consistent with ischaemia from vascular compression and microvascular emboli, entrapment of the left lateral ventricle and diffuse leptomeningeal enhancement. The authors conclude the haemorrhage likely occurred in utero.

Marrow biopsy was deferred because of the coagulopathy. The diagnosis was made on blood, cytochemistry, flow and cytogenetics alone.

She had serial exchange transfusions for the hyperleukocytosis and rasburicase for tumour lysis. Once the clotting had been corrected far enough to make it safe, the large right middle cranial fossa collection was tapped percutaneously through a patent coronal suture - the only intervention judged safe; craniotomy, drain placement and subdural shunting were discussed and not pursued 1.

A multidisciplinary group of neonatology, neurosurgery, haematology-oncology and neurology then counselled the parents on the options, which were palliative neurosurgical intervention or aggressive chemotherapy against an overall grim prognosis. The family chose comfort measures, and she died on the fourth day of her life.

Post-mortem confirmed the imaging and found more: the haematoma extended into the subarachnoid space and onto the parenchymal surface, with midline shift, transtentorial herniation and multifocal infarction, particularly in the head of the left caudate. Malignant cells were present intravascularly, perivascularly and in the leptomeninges. Outside the CNS, blasts diffusely involved the dermis in the rash-affected skin, the hepatic sinusoids, the splenic red pulp, the pleural surfaces, the submucosa of the upper airway, the lung interstitium around bronchovascular bundles, the full thickness of the oesophagus, stomach and small and large bowel, and sections of kidney, heart, thymus, pancreas, pituitary, lymph nodes, adrenals, uterus and ovaries. The marrow was near 100% cellular and almost entirely blasts.

After she died, the report states, verbal consent was obtained from her parents for public discussion of her case.

This is the outcome that the category entries describe in percentages. The clinical arm records that congenital leukaemia carries survival of roughly 23-26% in two large studies. This is one of the other 74%, and what it looked like was four days.

What it teaches that a category entry cannot:

1. The disease can be complete at birth. Not early, not aggressive - complete. Blasts were in the placenta, in every organ sampled at post-mortem, and had already caused an intracranial bleed before delivery. There was never a window in which a targeted agent could have been given to a healthy child.
2. What kills first is not the leukaemia. It was the coagulopathy, with an INR of 7.7, and the mass effect of the resulting haemorrhage. Nothing aimed at the menin-KMT2A interface addresses either.
3. Even the diagnostic pathway bends. Marrow biopsy, the standard first step, was deferred because taking it was unsafe.
4. The decision recorded is the family's. The report does not describe treatment failure. It describes a choice made after counselling, and then a death. Recording that honestly is part of what a patient-story arm is for.

It also instantiates the deep-tissue tropism that the graph theorises about elsewhere: skin, meninges, gut wall, lung interstitium, pituitary, ovaries. Whatever migratory programme KMT2A-rearranged monoblasts run, this post-mortem is what it does when nothing stops it.