case_images: PMC9981804_01
case_images: Clinical and radiographic features observed in our patient. (A) Timeline of the patient's evaluation and treatment course. (B) Axial cut from T1-weighted MRI brain showing striking hemiatrophy of the entire left hemisphere, presumably due to the hemorrhagic stroke in the neonatal period. (C) Photograph of our patient at the time of evaluation at the NIH demonstrating patchy alopecia with sparse brittle hair as well as poikiloderma and conical fingers, which are characteristic of POIKTMP. (D) Muscle ultrasound revealing myositis evidenced by diffusely hyperechoic muscles in the upper and lower extremities. Yellow arrows point to increased echogenicity of muscle compared to a less echogenic area (yellow circle). (E) Abdominal MRI revealing complete fatty replacement of the pancreas (white arrows) consistent with the clinical history of exocrine pancreatic insufficiency. (F) CT of sinuses showing complete opacification of bilateral maxillary and ethmoid sinuses. (G) Coronal (right panel) view of non-contrast chest CT revealing bilateral ground glass opacities in the apices and scattered tree-in-bud nodular opacities throughout bilateral upper and lower lobes. (H) Upper panels show the frequencies of IL-17A+ (left) and IL-17F+ (right) producing cells within CD4+ T cells in the peripheral blood from our patient and four healthy donors. The lower panels display levels of salivary S100A9 (left) and CXCL9 (right) from our patient and 10 healthy donors.
case_images: fimmu-14-1133387-g001.jpg
case_images: PMC9981804_01_fimmu-14-1133387-g001.jpg
case_images: f1
case_images: A 9-year-old Ukrainian male presented at the NIH for clinical and genetic evaluation of potential APECED ( Figure 1A ). His father has type-2 diabetes, his younger brother is healthy, and his mother died from pancreatic cancer. ( Supplemental Figure 1 ). At 1.5-months-old, he developed cerebral hemorrhage leading to transient left hemiparesis and encephalomalacia ( Figure 1B ); hypoplasia of the right vertebral artery and the left middle cerebral artery (MCA) was noted with compensatory doubling of the right MCA. APECED natural history study for further evaluation ( Figure 1A ). At NIH admission, he had persistent cough and chronic myalgias of calves and thighs exacerbated by ambulation. He appeared thin with alopecia totalis, erythematous, dry, and hyper/hypopigmented skin with conical-shaped fingers ( Figure 1C ), and non-pitting edema in bilateral feet and ankles. Needle electromyogram (EMG) and nerve conduction studies identified small polyphasic units, mild muscle irritability, and sensory neuropathy, whereas muscle ultrasound showed diffusely hyperechoic muscles ( Figure 1D ). Abdominal MRI demonstrated complete fatty replacement of the pancreas ( Figure 1E ) which combined with undetectable fecal pancreatic elastase-1 confirmed exocrine pancreatic insufficiency. Computed tomography (CT) showed near complete opacification of bilateral maxillary and ethmoid sinuses ( Figure 1F ) and cultures grew Staphylococcus aureus and Streptococcus pyogenes for which he received amoxicillin/clavulanate. CT chest revealed bilateral pulmonary infiltrates in the apices and right lower lobe with scattered small nodules ( Figure 1G ;  Supplemental Figure 2 ). Given his history of CMC and the importance of IL-17 responses in mucosal anti-Candida defense, we assessed his proportion of circulating Th17 cells and found them normal ( Figure 1G ;  Supplemental Figure 3 ). Moreover, the IL-17-dependent antimicrobial peptide, S100A9, was within the normal range in his saliva ( Figure 1H ). Of note, although his circulating T-lymphocytes did not produce more IFN-gamma upon PMA/ionomycin stimulation ( Supplemental Figure 3B ), the IFN-gamma-inducible chemokine, CXCL9, was increased in the saliva ( Figure 1H ).
case_images: Histological features of affected skin in our patient. (A) H&E staining showing mild acanthosis, superficial perivascular lymphocytic infiltration, and pigmentary incontinence. (B) Double immunostaining with CD4 (brown) and CD8 (red) revealing focal presence of CD4+ T lymphocytes surrounding superficial dermal vasculature. (C) Immunostaining with CD20 depicting very few to rare B lymphocytes. (D) Fontana-Masson stain highlighting melanin pigments and melanophages in the superficial dermis, termed 'pigmentary incontinence'. (E) EVG (Verhoff Van Gieson) stain highlighting focally increased density of elastic fibers in the reticular dermis, corresponding to the region of solar elastosis. (F) Masson's Trichrome stain highlighting mild expansion of the papillary dermal collagen zone (blue areas). All scale bars correspond to 600 mum.
case_images: fimmu-14-1133387-g002.jpg
case_images: PMC9981804_01_fimmu-14-1133387-g002.jpg
case_images: f2
case_images: CT chest revealed bilateral pulmonary infiltrates in the apices and right lower lobe with scattered small nodules ( Figure 1G ;  Supplemental Figure 2 ). Skin histological examination revealed mild superficial perivascular chronic inflammation in the dermis ( Figure 2A ) primarily composed of CD4+ T-lymphocytes ( Figures 2B, C ). Scattered pigmented melanin-containing macrophages were seen in the superficial dermis ( Figure 2D ) consistent with pigmentary incontinence, which can occur in post-inflammatory hyper- or hypopigmentation. There was focally increased density of elastic fibers in the reticular dermis ( Figure 2E ) and expansion of papillary dermal collagen ( Figure 2F ), consistent with histologic features of solar elastosis.
case_images: Histological features of affected muscle in our patient. (A) Cross sections of H&E staining of skeletal muscle revealing variation in the diameter/caliber of the skeletal muscle fibers with focal infiltrate of the mature adipose tissue. (B) High magnification view of H&E staining of skeletal muscle revealing focal lymphocytic infiltrate surrounding a degenerate muscle fiber, consistent with myositis. (C) Double immunostaining with CD4 (brown) and CD8 (red) depicting lymphocytic infiltration by CD4+ T lymphocytes. (D) Immunostaining with CD20 showing no B lymphocyte infiltration. (E) Immunostaining with CD56 staining depicting CD56+ N-CAM fibers. (F) Masson-Trichrome stain highlighting focally increased collagen between the smooth muscle bundles. Scale bars, 2 mum (A, E), 6 mum (F) or 200 mum (B-D).
case_images: fimmu-14-1133387-g003.jpg
case_images: PMC9981804_01_fimmu-14-1133387-g003.jpg
case_images: f3
case_images: Given his history of CMC and the importance of IL-17 responses in mucosal anti-Candida defense, we assessed his proportion of circulating Th17 cells and found them normal ( Figure 1G ;  Supplemental Figure 3 ). Of note, although his circulating T-lymphocytes did not produce more IFN-gamma upon PMA/ionomycin stimulation ( Supplemental Figure 3B ), the IFN-gamma-inducible chemokine, CXCL9, was increased in the saliva ( Figure 1H ). Muscle histological examination revealed focal areas of skeletal muscle fibers arranged in a predominately myopathic pattern associated with focal fatty infiltration ( Figure 3A ). A focal lymphocytic infiltrate surrounding degenerate muscle fibers was noted, consistent with myositis ( Figure 3B ). Figures 3C, D ). Focally increased CD56+ N-CAM fibers were noted ( Figure 3E ) as well as slightly increased collagen between the smooth muscle bundles ( Figure 3F ).
case_images: Genetic, clinical, and treatment response characteristics of our patient. (A) Chromatograms of FAM111B sequencing on our patient and his mother and father shown over corresponding normal amino acid sequence (top row) with patient's missense change displayed in red (bottom row). (B) Schematic of the FAM111B gene demonstrating all previously reported variants and their location along with our patient's variant that is highlighted in yellow. (C) Temporal evolution of serum transaminase levels. ALT (red) and AST (black) are increased at baseline and decline nearly to normal levels by 5-months following initiation of azathioprine treatment. Red and black dotted lines represent the upper limit of normal range for ALT and AST, respectively. (D) Venn diagram depicting our patient's disease manifestations, thereby demonstrating the shared and distinct clinical features between POIKTMP and APECED syndromes.
case_images: fimmu-14-1133387-g004.jpg
case_images: PMC9981804_01_fimmu-14-1133387-g004.jpg
case_images: f4
case_images: NM_198947], which was confirmed by Sanger sequencing ( Figures 4A, B ). No copy number variants (CNVs) were identified at the FAM111B locus, but a copy number loss was noted within chromosome band 6p25.2 spanning approximately 0.006 Mb in a non-disease associated region involving the SERPINB9 gene. Neither parent carried the FAM111B variant, thereby this was a de novo change in the patient ( Figure 4A ). Within 6 months, cough resolved, transaminases decreased ( Figure 4C ), and skin dyspigmentation, xerosis, skin breakdown, and myalgias improved with an associated decrease in creatine kinase (270 U/L).