PMC8415448_01
Findings on the skin and chest radiographs. Healed BCG site and dry skin with bruises and scars are evident. Prominent thymus (arrowed) at 8 mo of age is evident. Please also note the normal skeletal radiographs.
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F1
Ltd., India)] at birth (Figure 1, left upper panel). His physical examination was remarkable for the skin findings of dryness, bruises (petechiae and purpura), and a few scars, as shown in Figure 1 (middle and right upper panel). Figure 1 (lower panels). Findings on the abdominal ultrasound and echocardiogram were normal.
Leukocyte differential counts as function of age.
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F2
His white blood cell differential counts are shown in Figures 2A,B.
Peripheral blood and bone marrow morphology. (A) A low power view of the peripheral blood smear demonstrating significant leukocytosis. (B) A higher magnification of the smear showing the leukocytosis predominantly lymphocytes mixed with neutrophils; some of the neutrophils reveal abnormal nuclear lobation, like hypersegmentation (arrow). (C) Bone marrow aspirate showing normal maturation of erythroid and myeloid cells and increased lymphocytes with some immaturity suggestive of hematogones. (D) Section from the bone marrow biopsy showing about 70% cellularity (normal for age) of trilineage hematopoiesis with increased eosinophils, lymphocyte aggregates, and interstitial lymphocytes. Megakaryocytes were adequate with normal morphology [For comparison, please see for normal peripheral blood and bone marrow smears].
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F3
In addition, "left shift" (neutrophil bands, metamyelocytes, and myelocytes) was a frequent finding (Figures 3A,B). B cells [14,206/muL (53%), reference values = 610-2,600], and NK cells (426/muL, 2%). Bone marrow examination was normal; the megakaryocytes were adequate in number and had normal morphology (Figures 3C,D).
Structure and sequence of FERMT3. (A) Sequence of FERMT3 (NCBI Accession: NP_848537.1) with the site of truncation in p.Trp600* shown with a pair of scissors. Amino acids are colored based on their polarity: blue - basic; red - acidic; green - polar; olive - hydrophobic. (B) Three dimensional protein structure of FERMT3, generated using the Protein Data Bank structure 7C3M, depicted in cartoon representation. The region truncated in the p.Trp600* non-sense variant is shown in orange. (C) Protein sequence alignment of FERMT3 (NCBI Accession: NP_848537.1) and the p.*668Glufs*106 non-stop variant starting from position 640. Secondary structures, predicted using PSIPRED 4.0 (Predict Secondary Structure; http://bioinf.cs.ucl.ac.uk/psipred/), in the extended region of the variant are shown above the sequence. Violet cylinders represent alpha-helices. (D) Variations identified in the canonical Ensembl transcript (ENST00000279227.5) were from gnomAD v2.1.1 are shown with amino acids represented by their one letter codes. FERM domains (sub-domains F0, F1, F2a, F2b, and F3; InterPro classifies region 258-558 as FERM central domain) and pleckstrin homology (PH) are shown as rounded rectangles.
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F4
The non-sense variant FERMT3:p.Trp600* leads to a premature truncation of the protein and the loss of 68 residues from the C-terminal (Figure 4A). This truncation results in the loss of two alpha-helices and a beta-sheet, comprising of three beta-strands (Figure 4B). Search Tool (BLAST; https://blast.ncbi.nlm.nih.gov) searches did not identify any homologous sequences or structures. Secondary structure prediction with PSIPRED (http://bioinf.cs.ucl.ac.uk/psipred/) indicated that this region could potentially harbor six alpha-helices (Figure 4C). While secondary structures have been predicted in the extended sequence of p.*668Glufs*106 (Figure 4C), it is unclear if this extended part will cooperatively fold to produce a functional domain.