Case 1073 - Female Child with 21q Deletion

Contributed by Shikha Malhotra, MD, Grant Bullock, MD, Svetlana Yatsenko, MD, Melanie Babcock, MD, Marie DeFrances, MD, PhD, and Eric Carlsen, MD


The patient is a 15-month-old female who was born to a GP2A4 healthy mother following an uncomplicated antenatal course. The birth was complicated by shoulder dystocia and tight nuchal cord. Following birth, the patient required NICU admission for respiratory support. Additionally, the neonate showed oozing of blood, hypotonia, possible seizures and lack of feeding cues or interest. Investigations revealed thrombocytopenia (55,000/ÁL), multiple cardiac anomalies (including persistent pulmonary hypertension, perimembranous ventricular septal defect, secundum atrial septal defect and bidirectional patent ductus arteriosus), intracranial bleeding (including left parietal cephalohematoma, multiple subdural hematomas and findings suggestive of prior intraventricular hemorrhage) and central nervous system anomalies (extensive polymicrogyria involving the posterior cerebral hemispheres and simplified gyration in bilateral frontal lobes).

In view of the MRI findings suggestive of a congenital abnormality, a complete genetic workup was pursued. Hearing screen, renal ultrasound and skeletal survey were normal. Chromosomal microarray analysis revealed an interstitial loss in copy number in the 21q22.11-q22.12 region of the long arm of chromosome 21, spanning at least 4.119Mb. This deletion comprised 107 genes, 31 of which are listed in the OMIM (Online Mendelian Inheritance in Man) database and 11 of which are associated with known diseases. OMIM genes include MIS18A, MRAP, URB1, TCP10L, PAXBP1, OLIG2, OLIG1, C21orf59, SYNJ1, IFNAR1, IFNAR2, TMEM50B, IL10RB, GART, IFNGR2, SON, DONSON, CRYZL1, ITSN1, ATP5O, MRPS6, SLC5A3, KCNE2, KCNE1, RCAN1, CLIC6, RUNX1, MIR802, CBR1, CBR3, DOPEY2. Of these, deletions involving the SON, and RUNX1 genes are the cause of autosomal dominant conditions. Heterozygous loss of function variants and deletions in the SON gene are associated with Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome. ZTTK syndrome is a severe multisystem developmental disorder which may present with brain malformations, neurologic complaints such as dystonia and seizures, heart defects and feeding difficulties, as noted in our patient. Deletions of the RUNX1 gene are associated with a familial platelet disorder and a predisposition to myeloid malignancy.

Hematology was consulted in view of symptomatic thrombocytopenia. The hematology team noted that although the patient had a RUNX1 deletion, the patient's mother had never been diagnosed with a bleeding disorder. The patient had received a platelet transfusion early in the neonatal period with subsequent improvement in platelet count. The patient's follow up included a quarterly complete blood count and reticulocyte count. However, because of multiple hospital visits for complaints such as bradycardia, increased work of breathing, feeding intolerance etc., the patient was subjected to more frequent analyses at a monthly frequency. Her platelet count remained steadily below 100,000/ÁL and she suffered three bleeding episodes up till an age of 14 months (Figure 1). These episodes presented as bleeding upon nasal suctioning, bright red G-tube drainage, and blood-stained saliva. Intermittent bruising was also noted. No other significant cytopenias were observed. As a consequence of Vitamin K deficiency, there was a transient rise in INR which was controlled with Vitamin K supplementation. Baseline bone marrow examination was planned to be performed post 1 year of age in conjunction with other potential procedure requiring sedation.

The patient presented to the hospital at 15 months with fever. Upon evaluation the patient was found to have a platelet count of 30,000/ÁL. Other hematologic findings included increased mean platelet volume, mild neutrophilia, mild monocytosis, mild lymphopenia, and slight prolongation of PT/INR. Consequently, a bone marrow aspiration and biopsy were performed during the admission. The bone marrow core biopsy was deemed inadequate due to subcortical sampling and crush artefact. Representative microscopic images of the peripheral blood smear and bone marrow aspirate smear are shown in Figures 2, 3 and 4. Selected bone marrow flow cytometry plots are also shown below in Figure 5. CBC data is tabulated. What are your findings and diagnosis?


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