Page 156 - 2021_09-Haematologica-web

M. Germeshausen and M, Ballmaier
Figure 2. MPL expression on CD34+CD38lo hematopoietic progenitors from congenital amegakaryocytic thrombocytopenia patients The figure shows CD110 expression levels, calculated from cumulative subtraction on CD34+CD38lo hematopoietic progenitors of patients with nonsense, frame shift mutations or splice site mutations predicted to lead to a complete loss of MPL function (A), missense mutations (B), or patients who are compound heterozy- gous for different types of mutations (mix), in comparison to normal donors (ND). Horizontal lines represent the mean and standard error of the mean. Data from samples with special genotypes are labeled with the same colors, respectively. A+B: red: p.Arg43Ter, orange: p.Phe126LeufsTer5, grey: c.79+2T>A; green: p.Arg454Pro, pink: p.Leu169His, violet: p.Asp295Tyr, blue: p.Arg102Pro (half: compound heterozygous with p.Phe104Ser); mix: dark green/blue: c.391+5G>C/p.Arg102Pro, dark green/black: c.391+5>C/p.Arg257Cys.
pura at birth or in the first week of life were the present- ing symptoms of thrombocytopenia in the majority of cases (25 of 38)†. Only few patients (five of 38)† presented with severe bleedings at birth (n=3) or shortly thereafter (n=2). Intracranial bleedings was reported only during pregnancy (n=7), at birth (n=2) or within the first 4 weeks of life (n=4). Hematemesis as an indication of gastroin- testinal bleeding was observed in one patient (at birth). In contrast to intracranial and gastrointestinal bleeding, severe episodes of epistaxis were reported mainly during the later stages of the disease (n=3).
Data regarding platelet courses confirmed our concept of CAMT I and CAMT II distinguishing between patients with severely low platelet counts over the whole course of the disease due to loss-of-function mutations in MPL (CAMT I) and those patients showing a spontaneous increase of platelet counts in the first months of life due to a residual function of the receptor (CAMT II):4,14,15 platelet counts over 50 G/L (not trans- fused) within the first year of life have been documented for 14 of 33† patients. For nine more patients with a late diagnosis of thrombocytopenia we can also assume higher platelet counts in the first months of life. None of these 23 patients bore a mutation predicted to lead to a complete loss of function. Nearly all CAMT I and CAMT II patients demonstrated a further decline of platelet counts during the development of aplastic ane- mia. Platelet counts of heterozygously affected parents and siblings of patients were in a normal range with the exception of one parent (c.305G>C) with mild thrombo- cytopenia (130-150 G/L).
Development of pancytopenia
Development of additional anemia or neutropenia and reduced bone marrow cellularity are signs of developing bone marrow exhaustion. Bone marrow analyses from the first 6 months of life usually showed normal cellular- ity with reduced or absent megakaryocytes (13 of 15).† Accordingly, most of the patients presented with isolated
Data available
No non-hematological findings
Abnormality of fetal development hydrops fetalis
Anomalies of the nervous system optic nerve hypoplasia cerebellar hypoplasia agenesis of corpus callosum
Dandy-Walker anomaly arachnoid cyst ventriculomegaly colpocephaly hydrocephalus
Mental/psychomotor retardation
Abnormality of the skin eczema
hypopigmentation atopic dermatitis
Abnormalities of the eye impaired vision nystagmus strabismus
Abnormalities of the face hypertelorism
high palate
small uvula
Skeletal abnormalities
Cardiovascular abnormalities
Abnormalities of the genitourinary system
Other abnormalities obstructive sleep apnea diabetes
short stature
# of patients (with ICH)
50 25
1 (1) 1 (1)
7 (6)
1 (1) 1 (1) 1 (1) 2 (2) 3 (2) 1 (1) 1 (1) 1 (1)
7 (5) 4
2 (0) 1 (0) 1 (0)
10
1 (1) 4 (3) 9 (5)
4 (1)
2 (1) 2 (0) 1 (0)
0 0 0
2 (0)
1 (0) 1 (0) 1 (0)
HPO-designation
HP:0001197
HP:0001789
HP:0000707
HP:0000609 HP:0001321 HP:0001274 HP:0001305 HP:0100702 HP:0002119 HP:0030048 HP:0000238
HP:0001263 HP:0000951
HP:0000964 HP:0001010 HP:0001047
HP:0000478
HP:0000505 HP:0000639 HP:0000486
HP:0000271
HP:0000316 HP:0000218 HP:0010812
HP:0000924 HP:0001626 HP:0000119
HP:0002870 HP:0000819 HP:0004322
Table 3. Non-hematological findings in congenital amegakaryocytic thrombocy- topenia patients.
Non-hematologic abnormalities found in congenital amegakaryocytic thrombocytopenia (CAMT) patients with homozygous or compound heterozygous mutations in MPL with the respective designations according to the human phenotype ontology (HPO)57 Number of patients with documented intracranial hemorrhages (ICH) in parentheses.
thrombocytopenia at birth or in the first weeks thereafter (36 of 51).† Only six patients showed signs of multi-lin- eage cytopenia within the first 6 months of live, four of them were already anemic immediately after birth (hemoglobin 56-76 g/L). For two patients a hypocellular bone marrow is documented in the first month after birth.
Provided the data available at time of analysis only seven of 49 patients showed no signs of developing pan- cytopenia. Five of these patients were younger than 2 years at last examination.
From the remaining 42 patients with documented apla- sia only 24% were older than 4 years (n=10). Seventy-six percent (n=32) were younger than 4 years, half of them even younger than 2 years (Online Supplementary Figure S1). CAMT011 is the only patient without any signs of pancytopenia till adulthood.
† Here and in all subsequent ratios, the denominator is the number of patients for whom information is available for a specific parameter. E.g., for “intracranial bleeding” 46 is the number of questionnaires with a yes-no-infor- mation from the attending physicians.
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