33-year-old female developed disseminated vesicular rash (40-50 non-synchronously evolving lesions) on trunk and extremities 2 weeks after receiving post-partum varicella vaccine. History of splenomegaly since age 5 (considered sequela of infectious mononucleosis). History of recurrent mild upper respiratory infections. No history of specific health complaints, hospitalizations, infectious complications, or lymphoadenopathy. Physical exam showed splenomegaly. Laboratory findings revealed selective IgA deficiency and CD4 lymphopenia (111-118 cells/μL). Flow cytometry showed CD4 lymphopenia (189 cells/μL), normal CD8 T cells (383 cells/μL), increased double negative T cells (4.3%, 33 cells/μL), high cycling CD4 T-cells and DNT (Ki67 12% and 42% respectively), increased PD-1 expression in CD4 T-cells (42%). Total IgG elevated (1,716 mg/dL), normal IgM (54 mg/dL), undetectable IgA.

(1) CT scan, coronal section, spleen. (2) CT scan, 3D reconstruction, spleen, splenic volume=1,034 mL. (3) CT scan, axial section, paraaortic and mesenteric lymph nodes.

CT scan showed splenomegaly and paraortic/mesenteric lymphadenopathy. (1) Coronal section: Splenomegaly. (2) Splenic volume estimation by 3D reconstruction: 1,034 milliliter (mL) (normal 200 ± 50 mL). (3) Axial section: Paraortic and mesenteric lymphadenopathy.

(1) Bone marrow biopsy, H&E staining, 200× magnification. (2) Bone marrow biopsy, CD3 immunohistochemistry staining. (3) Bone marrow biopsy, CD8 immunohistochemistry staining.

Bone marrow biopsy showed scattered lymphocytic aggregates with prevalence of CD8+ cells. (1) Lymphocytic aggregate in hematoxylin and eosin staining at 200x magnification. (2) CD3 Immunohistochemistry (IHC) staining. (3) CD8 IHC staining.

(C) Diagram of the FAS gene showing intron/exon structure and protein domains. (D) Ex vivo flow cytometric assay evaluating FAS-induced apoptosis in terminal effector memory cells (CD45RA−CCR7−CD27−) and TCRαβ+ double-negative T cells (CD4−CD8−), presenting average fold increase ± SEM of Annexin-V expression from 4 experiments with the index patient and 8 healthy controls using different concentrations of anti-FAS crosslinking antibody.

(C) Diagram of the FAS gene identifying intron/exon structure and protein domains. Mutations are indicated at their approximate location and identified by symbols corresponding to mutation type. The new mutation identified in the index patient indicated by the red arrow. Figure adapted by Hsu et al. (3). (D) FAS-induced apoptosis was evaluated in terminal effector memory cells (TEM) and TCRαβ+ DN T cells of index patient and healthy subjects using an ex vivo flow cytometric assay based on FAS crosslinking. (1) Average fold increase ± standard error of mean (SEM) of Annexin-V expression in TEM (CD45RA−CCR7−CD27−) from 4 independent experiments with index patient (red) and 8 different healthy controls (blue) with different concentrations of anti-FAS crosslinking antibody. (2) Average fold increase ± SEM of Annexin-V expression in DNT cells (TCRαβ+CD4−CD8−) from 4 independent experiments with index patient (green) and 8 different healthy controls (purple) with different concentrations of anti-FAS crosslinking antibody.

Autoimmune lymphoproliferative syndrome (ALPS-FAS) with paradoxical CD4 lymphopenia, caused by a novel germline missense mutation in FAS death-domain

Autoimmune lymphoproliferative syndrome

Lymphopenia


This case involves a 26-year-old man with consanguineous parents (cousins) who presented with weight loss, fever, hepatosplenomegaly, and coughing. His medical history includes lymphadenopathy in the neck at age 8 for which he received anti-tuberculosis treatment, and a diagnosis of pulmonary sarcoidosis at age 12 with subsequent corticosteroid treatment for an extended period. On examination upon admission, the patient was pale with low-grade pyrexia (37.5°C), normal cardiovascular examination, and cervical lymphadenopathy. He had crackles on the left side of his chest. Laboratory investigations revealed normal full blood counts, negative liver function tests, and negative autoimmune and virology screens. Moxifloxacin treatment for 2 weeks prior to admission failed to alleviate his symptoms of cough, hypoxia, night sweats, and fevers up to 40°C.

(A) Chest CT, lung window, at the level of the pulmonary artery. (B) Chest CT, lung window, at the level of the heart.

1 Lung imaging. a. There is extensive consolidation in the right lung (red arrow). Scattered patches of consolidation in the left lung are also seen (green arrow). Chest CT scans show the lung window at the level of the pulmonary artery (b) and heart (c). Note extensive consolidation in the right upper lobe (red arrow b). There are also smaller patches of consolidation in the right lower and middle lobes and in the left lung (green arrows b and c)

Flow cytometry analysis of peripheral blood neutrophils, DHR oxidation assay, with and without PMA stimulation (DHR 375 ng/ml, PMA 100 ng/ml), mean fluorescence intensity measured.

Figure 2 presents a flow cytometry analysis of dihydrorhodamine-123 (DHR) oxidation to assess reactive oxygen species (ROS) production by peripheral blood neutrophils, comparing the patient sample to healthy controls; cells were incubated with DHR (375 ng/ml), with and without phorbol 12-myristate 13-acetate (PMA) stimulation (100 ng/ml), and mean fluorescence intensity was measured, showing that the patient’s neutrophils produced low, subnormal levels of ROS after PMA stimulation, in contrast to the robust response seen in normal controls.

(A) Fungal culture of lung specimen obtained by bronchoscopy incubated for 7 days on Sabouraud dextrose agar at 30 °C. (B) Fungal culture after 12 days on potato dextrose agar and lactophenol cotton blue (LPCB) mounting slide. (C) Microscopy of septate and hyaline hyphae with biseriate phialides.

Microbiological culture of lung fungal species obtained by bronchoscopy. a 7-day-old culture on sabouraud dextrose agar at 30 °C shows light yellow to brownish colonies. b Fungal growth after 12 days sterile culture on potato dextrose agar (PDA) plates for sporulation and identification, and LPCB mounting slide showing details of hyphae and the accessory conidia. c Septate and hyaline hyphae with biseriate phialides extending from the upper portion of the vesicle and covering 2/3 of the plate

(A) Partial gene sequence analysis of the putative invertase gene from Aspergillus terreus isolated from the patient. (B) Partial gene sequence analysis of the putative invertase gene from standard Aspergillus terreus.

a Partial sequence of the putative invertase gene from Aspergillus terreus isolated from the patient. This is compared to the sequence of the‘standard’ A. terreus sp. (b)

Adult autosomal recessive chronic granulomatous disease with pulmonary Aspergillus terreus infection

Chronic granulomatous disease

aspergillus infection

Certain infectious or parasitic diseases


Patient 1: 3.5-year-old male from unrelated Polish parents. Born at 39 weeks gestation with birth weight 3700g (50th-75th centile), length 57cm (97th centile), head circumference 36cm (75th-97th centile), thorax circumference 33cm (25-50th centile), Apgar score 9 at 1 min. Family history unremarkable. Proteinuria, hematuria and glycosuria noted in early neonatal period. UTI at 12 months. At 3 years developed bronchopneumonia with elevated creatinine. Laboratory investigations showed constant proteinuria, glycosuria, hematuria, eGFR (Schwartz) 30.56 ml/min/1.73 m2, elevated serum creatinine, uric acid, urea, total cholesterol, and triglyceride; normal CBC, blood glucose, albumin, thyroid and liver function tests. Renal ultrasound showed increased cortex echogenicity and decreased corticomedullary differentiation. Normal male karyotype (46,XY).

(A) Clinical photographs of the face at age 3 years 7 months. (B) Clinical photograph, facial lateral view, at age 3 years 7 months. (C) Clinical photograph of the chest at age 3 years 7 months. (D) Clinical photograph of the feet at age 3 years 7 months. (E) Clinical photographs of the face at age 9 years 3 months. (F) Clinical photograph, facial lateral view, at age 9 years 3 months. (G) Clinical photograph, whole body, at age 9 years 3 months. (H) Clinical photograph of the right hand at age 9 years 3 months.

Dysmorphic features and changing phenotype of patient 1 at the age of 3 y 7 m (a-d) and 9 y 3 m (e-h) respectively. (a, e) Characteristic facial features. Facial features are dolichocephaly, high prominent forehead, thin sparse hair, full cheeks, strabismus, broad prominent nasal bridge, flat philtrum columns, narrow mucus upper lip, everted lower lip, open mouth, low-set prominent ears, microretrognathia. (b, f) A facial lateral view showing low set ears and sparse hair. (c) Narrow chest, pectus excavatum. (d) Brachydactyly and overlap of toes. (g) Whole body image showing proximal limb shortening, a short broad neck, a narrow thorax and obesity. (h) Brachydactyly of the right hand

Table 1: Clinical and genetic data of two male patients with cranioectodermal dysplasia, including examination age, DNA and protein variants in IFT140, and assessment of craniofacial, skeletal, ectodermal, renal, neurodevelopmental, and additional traits.

Table 1, found on page 4 of the document, presents detailed clinical features of two male patients with cranioectodermal dysplasia (CED) carrying compound heterozygous variants in IFT140. The table systematically compares the presence or absence of specific clinical characteristics, including dysmorphic craniofacial and skeletal features, ectodermal anomalies, renal involvement, and neurodevelopmental findings. It includes genetic details (DNA and protein changes), age at examination, sex, and assessment of traits such as dolichocephaly, craniosynostosis, frontal bossing, full cheeks, nasal bridge width, philtrum morphology, lip configuration, ear position, chest and rib shape, limb and digit shortening, nail/hair/teeth characteristics, abdominal protrusion, renal failure, nephritis, ophthalmological problems, respiratory infections, intelligence, and motor development for each patient.

Sensenbrenner syndrome (Cranioectodermal dysplasia) with compound heterozygous IFT140 variants

Sensenbrenner syndrome

Cranioectodermal dysplasia


A 31-year-old Caucasian man with multiple sclerosis who had received 24 natalizumab infusions and was switched to fingolimod due to persistent high anti-JCPyV antibody index (3.61). After 40 days of fingolimod treatment, he developed seizures and visual field defects. Neurological examination revealed lateral nystagmus to the left, homonymous hemianopia, distal tremor and spasm of the upper limbs. He presented with leukopenia (0.83 × 10^9/L) at hospital admission.

Laboratory results of cerebrospinal fluid.

CSF composition showed glucose: 54 mg/dl, proteins: 569 mg/L, cell count: 5 cells/μl, CD4/CD8 ratio: 0.45, CSF JCPyV-DNA: 1.62 × 10^6 IU/mL, NCCR organization: A-B*-C-E-F

(A) Brain MRI, T2-weighted and FLAIR sequences, frontal, occipital, and parietal lobes of the right hemisphere and frontoparietal lobes of the left hemisphere. (B) Brain MRI, T1-weighted sequence, contrast enhancement. (C) JCPyV NCCR analysis, block organization A-B*-C-E-F, deletion of nucleotides 117–180 (D-block), T to G transversion at position 37 (B-block Spi-B binding site). (D) JCPyV VP1 coding region analysis, wild type organization.

Brain MRI showed multiple hyperintense areas in T2-weighted and Fluid Attenuated Inversion Recovery (FLAIR) sequences in the frontal, occipital and parietal lobes of the right hemisphere, with analogous smaller areas in the frontoparietal lobes of the left hemisphere. Brain lesions showed poor contrast enhancement in T1-weighted sequences. JCPyV NCCR analysis showed block organization A-B*-C-E-F with deletion of nucleotides from 117 to 180 corresponding to D-block, and a T to G nucleotide transversion in position 37 corresponding to the Spi-B binding site in B-block. VP1 coding region showed wild type organization without mutations.

Progressive multifocal leukoencephalopathy (PML) confirmed by clinical presentation, MRI imaging and JCPyV-DNA detection in CSF


21-year-old woman presented with one day history of fixed grey-dark spots in the vision field of both eyes, with most spots in her left eye. She described the scotomas as 'tear drop' shaped and could draw them precisely on an Amsler chart. This episode was preceded by a single day of flu-like illness with elevated temperature (39°C). Medical history notable for varicella-zoster infection in infancy. Had stopped contraceptives for the previous three months. Denied other pathologies, trauma, or travel history. Medication history notable solely for paracetamol. Best-corrected visual acuity was 20/20 in both eyes. Color vision was normal. Slit lamp examination showed no abnormality.

(A) Infrared imaging and optical coherence tomography (OCT) of the left eye at presentation. (B) Infrared imaging and OCT of the left eye one week later. (C) OCT of the left eye 40 days later. (D) OCT of the left eye one year later. (E) Infrared imaging and OCT of the left eye 30 months later.

Optical coherence tomography (OCT) and infrared (IR) images of left eye. (A) At presentation IR shows hyporeflective parafoveal lesion. Corresponding OCT shows a hyperreflective band of outer plexiform layer (OPL) and outer nuclear layer (ONL), and alteration of inner segment/outer segment (IS/OS) and retinal pigment epithelium (RPE). (B) Imaging one week later. (C) 40 days later, the OCT features started to normalize. (D) One year later, the OCT shows a smaller band in the OPL. (E) 30 months later, the lesion on the IR image is reduced and there are hyperreflective spots in the OPL and hyporeflective band of the ellipsoid zone.

(A) Infrared imaging and OCT of the right eye at presentation. (B) Infrared imaging and OCT of the right eye one week later. (C) Infrared imaging and OCT of the right eye 40 days later. (D) OCT of the right eye one year later. (E) Infrared imaging and OCT of the right eye 30 months later.

OCT and infrared images (IR) of right eye. (A) At presentation IR shows two hyporeflective parafoveal lesions. Corresponding OCT shows two hyperreflective band of outer plexiform layer (OPL) and outer nuclear layer (ONL), and alteration of inner segment/outer segment (IS/OS) and retinal pigment epithelium RPE in the region of the bigger lesion in IR (nasally). (B) Image one week later. (C) 40 days month later, the OCT features started to normalize. (D) One year later the OCT shows a smaller band in the OPL corresponding to the smaller lesion in IR (infero-temporally). (E) 30 months later the lesions on the IR image are strongly reduced and there are rare hyperreflective spots in the OPL and hyporeflective band of the ellipsoid zone.

(A) Visual field examination of the right eye at presentation. (B) Visual field examination of the left eye at presentation.

Visual field at presentation showed paracentral scotomas in both eyes (OS > OD) in the central region, corresponding to the rounded lesions noted in fundus and SLO images. Bilateral paracentral decrease in retinal sensitivity was also seen. right eye (A), left eye (B)

Bilateral Acute Macular Neuroretinopathy

Bilateral acute macular neuroretinopathy

Acute macular neuroretinopathy


54-year-old woman presented with a rapidly enlarging left neck mass that had developed over the past four months, causing milintentional weight loss. She had a remote 20+ year smoking history but denied any family history of head and neck malignancies. Physical examination revealed an eight-centimeter nodal conglomerate in the left supraclavicular area and diffusely enlarged thyroid gland with a roughly 5 cm right thyroid mass. Previous fine needle aspiration (FNA) of the neck mass at an outside facility demonstrated rare degenerated atypical cells suspicious for malignancy. Repeat FNA cytology of the supraclavicular mass revealed a poorly differentiated carcinoma.

(A) Neck CT, cross section. (B) Neck CT, coronal section. (C) Chest CT angiogram, axial section. (D) Chest CT angiogram, coronal section.

Computed tomography (CT) scan of the neck showed a large mass located at level 4 with central cystic necrosis (cross section and coronal section). CT angiogram of the chest showed metastatic lung lesions and tracheal deviation secondary to mass effect. (A): cross section and (B): coronal section. Axial section (C) and coronal section (D)

Histological sections of the left thyroid lobe(A–F)  H&E staining. (G) TTF-1 staining. (H) PAX-8 staining.

Histological sections showed a dense, monotonous mass of cells with abundant amphophilic cytoplasm and open nuclei containing coarse chromatin and prominent perinuclear hof. A large fraction of cells were binucleated with features consistent with mature plasma cells. The lesion was positive for cytokeratin AE1/AE3, TTF-1, and PAX-8 with a markedly increased Ki-67 proliferative index at over 50%. Stains for Calcitonin, p63, SOX10, CD3, CD20, CD45, CD79a, CD138, and MUM-1 were negative. Areas of papillary thyroid carcinoma were present in both specimens. The supraclavicular lymph node showed metastatic papillary thyroid carcinoma with solid, undifferentiated components. A,B,C,D,E,F: H&E. G: TTF-1. H: PAX-8

Anaplastic thyroid carcinoma with a plasmacytic morphology arising from papillary thyroid carcinoma, with BRAF (V600E) mutation

anaplastic carcinoma of thyroid gland

Papillary carcinoma of thyroid gland


A 58-year-old man presented with a 3-month history of abdominal pain, diarrhea, and weight loss. He also experienced urinary symptoms including frequency, urgency, and dysuria. Initial colonoscopy revealed prominent congestion and edema, loss of vascular pattern, and multiple moth-eaten ulcers with purulent exudates involving the entire colon. A repeat colonoscopy showed scattered irregular ulcers with with granular background mucosa and 'fuzzy' vasculature. The ileum appeared normal.

(A) Colonoscopy of the descending colon. (B) Colonoscopy of the sigmoid colon. (C) Colonoscopy of the rectum. (D) Rectal biopsy, histological examination. (E) Rectal biopsy, low power view. (F) Rectal biopsy, higher magnification of (E). (G) Rectal biopsy, immunohistochemistry for CD8. (H) Rectal biopsy, immunohistochemistry for CD56. (I) Rectal biopsy, immunohistochemistry, Ki-67 (high index).

Colonoscopy with biopsies for case 1. (a) Ulcers in the descending colon. (b) Ulcers in the sigmoid. (c) Mild congestion and edema in the rectum. (d) In contrast to the relatively mild endoscopic findings of the rectum, histologically the infiltration is marked by dense atypical lymphoid cells with loss of crypts. (e) Low power view of the rectal lymphomatous infiltrate. (f) Higher power view of (e). Immunohistochemically the tumor cells are positive for (g) CD8, (h) CD56, (i) with high Ki-67 index.

(A) Esophagogastroduodenoscopy of the gastric body. (B) Narrow band imaging of the gastric body. (C) Biopsy of the gastric body mucosa. (D) Biopsy of the gastric body mucosa, high-power view.

Esophagogastroduodenoscopy and biopsies of case 1. (a) Erosions in the gastric body. (b) Narrow band image of the gastric body. (c) Biopsy of the body mucosa showing marked atrophy. (d) High power view showing intraepithelial infiltrate by lymphomatous cells.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)

Intestinal T-cell lymphoma


39-year-old Hispanic woman presented 1 year ago with progressive proteinuria (initially 1-2 g/24h), and hypertension. No known diabetes, obesity, or malignancies. Extensive infectious disease evaluation negative for hepatitis A, HBV, HCV, HIV, treponemal serologies, tuberculosis, and coccidiomycosis. Extensive serological evaluation negative for lupus (ANA, anti-dsDNA, anti-histone, anticentromere, RNP, anti-smith, SSA/SSB antibodies all negative), rheumatoid factor negative, scleroderma antibodies negative, anti-CCP negative, cardiolipin antibodies negative, and ANCA panel negative. Complement titers (CH50) near lower limit of normal at 43 units/mL (reference 42-95), isolated depression of C3 at 67 mg/dL (reference 76-165), normal C4 at 23 mg/dL (reference 16-48). Serum and urine electrophoresis with immunofixation showed no monoclonal spike. Free light chain kappa to lambda ratio normal at 1.66.

(A, B) Renal biopsy, light microscopy, silver stain, 40× magnification. (C, D) Renal biopsy, light microscopy, hematoxylin and eosin stain, 40× magnification. (E) Renal biopsy, immunofluorescence, IgG staining. (F) Renal biopsy, immunofluorescence, C3 staining greater than IgG staining. (G) Renal biopsy, electron microscopy. (H) Renal biopsy, electron microscopy. (I) Renal biopsy, electron microscopy.

Renal biopsy data for Case 1: (A) light microscopy 40× silver stain Double contours and segmental scar; (B) light microscopy 40× silver stain Double contours with endocapillary hypercellularity and segmental scar; (C) light microscopy 40× hematoxylin and eosin cellular crescent with segmental karyorrhexis; (D) light microscopy 40× hematoxylin and eosin tubulointerstitial inflammation; (E) immunofluorescence IgG staining; (F) immunofluorescence showed C3 staining > IgG staining. (G) Electron microscopy, subendothelial deposits (red arrows); (H) electron microscopy, subepithelial deposits (red arrows); (I) electron microscopy, mesangial deposits (red arrows).

(A) Light microscopy of kidney biopsy. (B) Immunofluorescence of kidney tissue. (C) Electron microscopy of kidney tissue. (D) Complement profile. (E) Genetic analysis. (F) Laboratory test results.

Shows Case 1 as 41-year-old Hispanic female with MPGN, endothelial swelling, crescents on light microscopy; C3 > Ig on immunofluorescence; subendothelial and subepithelial deposits on electron microscopy; low C3 with normal sC5b-9 on complement profile; no genetic mutations found; peak protein 4-6 g/g creatinine and peak serum creatinine 3 mg/dL.

Immune-complex mediated membranoproliferative glomerulonephritis with C3 dominant staining


A 7.8-year-old Caucasian girl presented with short stature and excess body mass. Her height was 114 cm and weight was 24 kg (+14.7% excess body weight, BMI 18.5 kg/m2, 87th percentile, Z-score 1.12). She had lost 6 kg within the previous 6 months due to lifestyle modifications. Mid-parental height was between 50th-75th percentiles. Physical examination showed pubarche stage II (Tanner scale) without axillarche, and doubtful thelarche difficult to differentiate from steatomastia. Initial laboratory tests showed normal urinary-free cortisol, morning serum ACTH, cortisol, and 17-OHP concentrations. GnRH stimulation test did not confirm central precocious puberty. Initial MRI of hypothalamic-pituitary area was normal. Six months later, she returned with rapid weight gain, skin darkening, nocturnal anxiety, depressive behavior, insomnia, and excessive sweating. She showed obesity mainly on face, neck and abdomen, acanthosis nigricans on neck, hirsutism on back, thighs and upper lip, with pubarche stage II but no breast development. Subsequent tests showed 10-fold elevated UFC (219-284 µg/24h, normal <27), reversed cortisol profile (8am: 9.5 µg/dl, 8pm: 18.5 µg/dl, midnight: 25.4 µg/dl), and ACTH of 37.9 pg/ml.

Growth chart tracking height over time relative to age- and sex-specific percentiles, with initial measurement at the 25th percentile, subsequent trajectory at the 3rd percentile, and mid-parental height range between the 50th and 75th percentiles.

Figure 1 presents a growth chart illustrating the patient's height trajectory over time, with reference to age- and sex-specific percentiles; it visually demonstrates linear growth at the 3rd percentile following an initial measurement at the 25th percentile in early childhood, alongside the patient's mid-parental height range between the 50th and 75th percentiles. The chart details the pattern of linear growth deceleration associated with cyclic Cushing’s disease in this prepubertal patient, integrating standard clinical growth chart methodology without subjective interpretation or additional imaging modalities.

Body mass chart showing body weight versus age in years.

Figure 2, as presented on page 4 of the document, is a body mass chart depicting the weight trajectory of the patient diagnosed with cyclic Cushing’s disease. The chart, which visually represents body mass against age in years, illustrates the marked fluctuations and rapid increases in the patient’s body weight over time, corresponding to episodes of hypercortisolemia and remission phases characteristic of the disorder. The graph serves as an objective record of the cyclical nature of weight gain associated with the disease course in this prepubertal patient.

MRI of the pituitary gland.

MR image showing 3x4mm pituitary adenoma in the right-sided part of anterior pituitary gland

(A) Clinical photograph at age 7 years and 2 months. (B) Clinical photograph at age 7 years and 8 months. (C) Clinical photograph at age 8 years and 6 months.

Patient photos showing cyclic changes in appearance at ages 7 2/12, 7 8/12, and 8 6/12 years

Cyclic Cushing's Disease caused by an atypical, densely-granulated pituitary corticotroph adenoma

Cushing disease

Endocrine, nutritional or metabolic diseases

Corticotroph pituitary adenoma


45-year-old female with 13-year history of papular spiny eruptions on trunk and limbs with severe pruritus. Patient was otherwise in good health. Family history positive for psoriasis in sister. Treatment history included topical steroids and oral antihistamines without relief. Papular lesions on body presented before the alopecia of scalp and pubis, while axillae had been involved for 6 years.

(A) Clinical photograph of the left shoulder. (B) Dermoscopic examination of the left shoulder, 20× magnification. (C) Clinical photograph of the scalp. (D) Dermoscopic examination of the scalp, 20× magnification. (E) Clinical photograph of the pubic region. (F) Dermoscopic examination of the pubic region, 20× magnification. (G) Clinical photograph of the right thigh. (H) Dermoscopic examination of the right thigh, 20× magnification.

Baseline clinical and dermoscopic evaluation: a Spiny papules of the left shoulder (red arrow); b dermoscopic pattern (20×) of affected skin of the shoulder: multiple round-to-oval yellowish areas with keratotic follicular plugs surrounded by mild erythema (yellow arrows); c scarring alopecia of the scalp and detail (inset); d dermoscopic pattern of scarring alopecia of the scalp (20×): blue-gray dots in a target pattern, tufted hair (yellow circle) and perifollicular scaling (asterisk); e clinical picture of non-scarring alopecia of pubis; e dermoscopic pattern (20×) showing isolated yellow dots (black arrow); g spiny papules of the right thigh (red arrow); h dermoscopic pattern (20×) of affected skin of the thigh: multiple round-to-oval yellowish areas with keratotic follicular plugs surrounded by mild erythema (yellow arrows)

In vivo reflectance confocal microscopy of a shoulder papular lesion.

In vivo RCM of papular shoulder lesion shows hyperreflective multiple round-to-oval areas with keratotic follicular plugs and hyperkeratosis, and loss of papillae cyclicity as indirect sign of junctional inflammatory infiltrate.

(A) Left shoulder skin biopsy, H&E staining. (B) Scalp biopsy, H&E staining. (C) PAS staining of left shoulder skin biopsy.

Histologic examination of 5-mm punch biopsy from left shoulder papular lesion revealed dilated follicular ostia with compact hyperkeratosis, focally associated with perifollicular and perivascular lichenoid inflammatory infiltrate composed of little non-atypical lymphocytes. Junctional vasculopathy and rare acidophilic bodies were detected. PAS staining was negative for mycotic hyphae and spores. Features compatible with lichen spinulosus. Additional scalp biopsy showed diffuse fibrotic tissue, mild perivascular and perifollicular mononuclear inflammatory infiltrate and presence of arrector pili muscles without associated follicles, confirming scarring alopecia.

Graham Little-Piccardi-Lassueur syndrome (GLPLS)

Lassueur-Graham-Little syndrome


42-year-old Caucasian male presented with progressive fatigue, chills, night sweats, and unwanted weight loss. He was found to have left cervical lymphadenopathy.

(A) Cervical lymph node biopsy, H&E staining. (B) Cervical lymph node biopsy, H&E staining. (C) Cervical lymph node biopsy, immunohistochemistry for CD3. (D) Cervical lymph node biopsy, immunohistochemistry for CD30. (E) Cervical lymph node biopsy, immunohistochemistry for ALK1. (F) Cervical lymph node biopsy, immunohistochemistry for TIA1. (G) Cervical lymph node biopsy, immunohistochemistry for CD68.

Cervical lymph node biopsy showed effacement of architecture (A) with atypical cells, often containing “hallmark” cells with kidney-shaped nuclei (B).Immunohistochemical stains showed these neoplastic cells to be weak or negative for CD3 (C) and strongly positive for CD30 (D). ALK1 immunostain showed granular cytoplasmic positivity (E) while TIA1 was variably positive (F). Staining for histiocyte CD68 showed increased histiocytes.

Genetic analysis, next-generation sequencing translocation analysis, E-score reported.

Next-generation sequencing translocation analysis showed reads aligned with exon 20 of ALK1 were found to be adjacent with reads aligned with exon 7 of the TRAF1 gene. E-score represents a confidence score whereby lower values reflect higher confidence of sequence alignment in the reads.

(A) Bone marrow biopsy, H&E staining, low magnification, performed at disease staging. (B) Bone marrow biopsy, H&E staining, high magnification, performed at disease staging.

Figure 3 consists of photomicrographs from a bone marrow biopsy, showing in panel A a low-power hematoxylin and eosin (H&E) stained section with diffuse involvement by lymphoma, and in panel B a higher-power H&E image depicting atypical cells that are morphologically similar to those observed in the lymph node biopsy, including hallmark features. There are no immunohistochemical stains or molecular analyses shown in this figure, and the biopsy was performed at the time of disease staging, following the initial diagnosis.

Anaplastic large cell lymphoma (ALCL), ALK+ with TRAF1-ALK fusion

Anaplastic large cell lymphoma, ALK-positive


13-year-old boy with a previous history of Hashimoto's thyroiditis presenting with muscle pain, dry skin, and subtle memory complaints. Six months after initial diagnosis, cognitive complaints worsened and school performance declined, indicating further deterioration in cognitive abilities. One year after first memory complaints, patient was referred with suspicion of autoimmune encephalitis. Family history was positive for hypothyroidism. At time of admission, patient was suffering from amnesia and had long lapses of concentration with absence-like episodes. Neurological examination showed no focal deficits or other abnormalities.

(A) Clinical timeline of serological values for creatinine kinase, thyroid-stimulating hormone, TPO autoantibodies, and thyroxine levels. (B) Wechsler intelligence scale for children results at ages 6, 8, and 13: total IQ, verbal IQ, and performance IQ. (C) EEG during photic stimulation at 50 Hz.

Clinical timeline, IQ, and EEG. (A) Clinical timeline representing the evolution of serological values of creatinine kinase, thyroid-stimulating hormone (TSH),
TPO autoantibodies and thyroxine levels. Treatment intervention is also illustrated as well as qualitative disease progression. (B) IQ progression by Wechsler intelligence scale for children. Total IQ (TIQ), verbal IQ (VIQ), and performance IQ (PIQ) at the age of 6, 8, and 13. The average score for the test is 100, and any score between 90 and 109 is considered to be in the average intelligence range. (C) EEG showing generalized spike and wave discharge with right frontal dominance during photic stimulation with 50 Hz.

(A–D) Rat brain immunohistochemistry, IgG reactivity of patient serum at first presentation (A), 1 month after first presentation (B), 1 year after first presentation (C), and after IVIG infusion (D). (E) Rat brain immunohistochemistry, IgG reactivity of serum from a patient with epilepsy and TPO autoantibodies. (F) Rat brain immunohistochemistry, IgG reactivity of serum from a non-disease control. (G) Quantification of relative optical density in different areas of the rat hippocampus.

Identification and quantification of a novel neuropil-like hippocampal pattern in rat brain sections. (A–F) Rat brain immunohistochemistry IgG reactivity of serum. (A–D) Brain immunoreactivity of sera of the Hashimoto’s encephalopathy patient case at different time points: (A) At first presentation, (B) 1 month after first presentation, (C) 1 year after first presentation, and (D) after IVIG infusion. (E) brain immunoreactivity of serum from a patient with epilepsy and TPO autoantibodies. (F) brain immunoreactivity of serum from a non-disease control. The arrows in panels (C,F) point at areas shown at higher magnification in panel (C1,F1), respectively. Note the predominance of a neuropil-like pattern in panel (C1). (G) Relative optical density quantification in different areas of the hippocampus, outlined in yellow. SO, stratum oriens; SR, stratum radiatum; SML, stratum lacunosum; ML, molecular layer of dentate gyrus; GL, granule cell layer. Scale bars are 100 and 20 μm.

(A)–(C) Immunofluorescence staining of cultured, live primary hippocampal neurons, with human IgG (green), microtubules (MAP2; red), and nuclei (Hoechst; blue). (A1,B1,C1) Merged nuclear and dendrite staining. (A2,B2,C2) Merged nuclear and human IgG staining. (A3,B3,C3) Merged nuclear, dendrite, and human IgG staining. (A4,B4,C4) High magnification immunofluorescence staining of a dendrite. 50 μm scale bars.

Patient’s autoantibodies recognize an unidentified neuronal surface antigen in cultured primary hippocampal neurons. Immunofluorescent photomicrographs of cultured, live primary hippocampal neurons. Human IgGs are stained in green fluorescence, microtubules (MAP2) in red fluorescence, and cell nuclei (Hoechst DNA stain) in blue fluorescence. Serum immunostaining of (A) a patient with DPPX antibodies, as a control, (B) the Hashimoto’s encephalopathy patient case, and (C) a non-disease control. (A1,B1,C1) show the merge of nuclear and dendrite staining, (A2,B2,C2) show the merge of nuclear and human IgG staining, (A3,B3,C3) show the merge of all three fluorescent stainings. (A4,B4,C4) show the immunofluorescence staining of a dendrite at higher magnification. Scale bars are 50 μm.

Graph: TPO antibody levels (IU/mL) measured at six consecutive steps of immune-adsorption using recombinant human TPO protein, in sera from a patient with TPO antibody-positive thyroiditis, a patient with Hashimoto’s encephalopathy, a patient with autoimmune encephalitis and DPPX antibodies, a non-disease human serum control, a positive calibrator control, and a negative calibrator control. (A1–D1) Rat brain immunohistochemistry using non-immune-adsorbed sera; (A2–D2) rat brain immunohistochemistry using immune-adsorbed sera; scale bar=100 μm.

TPO autoantibodies are not responsible for the neuronal reactivity and TPO immuno-adsorption shows co-existence of autoantibodies. Graph on the left panel: TPO antibody levels (IU/mL) at six consecutive steps of immune-adsorption using wells coated with recombinant human TPO protein. TPO antibody was depleted from the sera of the following patients: a patient with TPO antibody-positive thyroiditis (purple squares), the Hashimoto’s encephalopathy patient (green closed circles), a patient with autoimmune encephalitis and dipeptidyl-peptidase-like protein 6 (DPPX) antibodies (magenta inverted triangles), and a non- disease human serum control (NHS) (blue triangles). A positive (open diamond) and a negative (open circle) calibrator control were included without absorption. Right panel: Rat brain immunohistochemistry using non-immuno-adsorbed sera (A1–D1) and immune-adsorbed sera (A2–D2) from panel (A) a patient with DPPX antibodies, (B) the Hashimoto’s encephalopathy patient, (C) a patient with TPO positive antibody thyroiditis, and (D) a non-disease control. Scale bar is 100 μm.

Hashimoto's encephalopathy with unidentified neuronal surface IgG autoantibodies

Hashimoto’s encephalopathy

Autoimmune encephalopathy associated with neuronal surface IgG autoantibodies

Autoimmune encephalopathy


A 47-year-old woman admitted with left lumbar pain and macroscopic hematuria. Medical history unremarkable. Physical examination showed pale skin without peripheral edema, blood pressure 130/80 mmHg, diuresis 1000 mL/day. Had moderate normocytic anemia. Negative for ANA, anti-ds-DNA, anti-Ro, anti-La, anti-Sm, anti-RNP, anti-β2-glycoprotein 1, antiphospholipid, cANCA, pANCA, anti-GBM antibodies, cryoglobulins, and rheumatoid factor. Negative for hepatitis B, C, and HIV. No monoclonal spike on serum protein electrophoresis.

Laboratory results.

Laboratory data shows serum creatinine 4.29 mg/dL, eGFR 12 mL/min/1.73 m², serum albumin 2.8 g/dL, proteinuria 13.4 g/24h, hematuria 1937 RBC/μL, anti-C1q antibodies 75.8 U/mL, C3 58.4 mg/dL, C4 9.24 mg/dL, CRP 37.5 mg/L

(A) Immunofluorescence for IgG in the glomerulus. (B) Immunofluorescence for C3 in the glomerulus. (C,D) Light microscopy with Toluidin Blue staining of the glomerulus. (E,F) Electron microscopy of the glomerulus.

(A) Immunofluorescence. Moderate staining for IgG in the mesangium and along the glomerular capillary walls. (B) Immunofluorescence. Minimal staining for C3 in the mesangium and along the glomerular capillary walls. (C) Light microscopy (Toluidin Blue). Glomerulus with a membranoproliferative pattern of injury, fibrinoid necrosis and a fibro-cellular crescent. (D) Light microscopy (Toluidin Blue). Glomeruli showing a membranoproliferative pattern with diffuse lobular accentuation (mesangial expansion with hypercellularity, endocapillary hypercellularity and fibrous crescents). There is also moderate tubular atrophy and interstitial fibrosis. (E,F) Electron microscopy. There are subendothelial, unstructured, electron-dense deposits. Podocytes show diffuse foot process effacement. Additionally, there is severe endothelial injury with swollen glomerular endothelial cells and loss of fenestrations.

Immune complex mediated membrano-proliferative glomerulonephritis with positive C1q immunostaining, crescent formation, circulating anti-C1q antibodies and complement activation consistent with hypocomplementemic urticarial vasculitis syndrome (HUVS)

Hypocomplementemic urticarial vasculitis syndrome

Raynaud syndrome[Hypocomplementaemic urticarial vasculitis]


36-year-old female with no past medical history who developed lower limbs and para-spinal muscle spasms that progressed over 3 months. Her symptoms continued to progress and she became wheelchair-bound 6 months later. When reviewed at institution, she was severely disabled requiring regular IVIG treatments at a dose of 90g every 12 days. She was taking regular diazepam at a dose of 30mg per day and morphine up to 60mg a day to control pain. On examination, she had brisk reflexes and severe clonus. The muscle spasms were severe enough to compromise her breathing and she required intermittent oxygen.

Table summarizing demographics, clinical phenotypes, neurophysiological and serological profiles, treatments attempted, disease duration before transplantation, and neurological outcomes after autologous haematopoietic stem cell transplantation for patients with stiff-person syndrome.

Table 1 summarizes the demographics, clinical phenotypes, neurophysiological and serological profiles, treatments attempted, disease duration before transplantation, and neurological outcomes after autologous haematopoietic stem cell transplantation (auto-HSCT) for all patients with stiff-person syndrome (SPS) referred for consideration of auto-HSCT at the studied institution. It includes details such as patient age, gender, SPS phenotype, co-morbidities, findings on EMG and blink reflex studies, circulating antibody titers (including anti-GAD and anti-glycine where applicable), immunotherapies previously used (e.g., IVIG, plasmapheresis, rituximab, mycophenolate), duration of disease before HSCT, and post-HSCT neurological status—describing whether the patient experienced clinical and serological improvement, remained seropositive, discontinued immunotherapy, or was not transplanted due to clinical reasons or funding constraints. This table integrates crucial patient-specific and procedural data for the cohort assessed for stem cell transplantation in refractory SPS.

EEG/EMG polygraphy recording during presentation of a low intensity auditory stimulus (approximately 50dB).

EEG/EMG polygraphy recording capturing exaggerated startle response to an unanticipated auditory stimulus. Low intensity unanticipated auditory stimulus around 50dB elicited prominent muscle jerks within 92ms from stimulus presentation followed by protracted spasms in multiple muscle groups

Blink reflex study, R2 component.

Blink reflex study showing marked amplification of the R2 component recorded following test stimulus in keeping with brainstem hyperexcitability. The pre-HSCT study shows clear enhancement of the R2 response that follows the test stimulus in comparison to the earlier R2 waveform

Classical form of SPS (Stiff Person Syndrome)

Stiff person syndrome


A 35-year-old female patient attended the outpatient clinics of the Thoracic Surgery Service, referred by her general practitioner for dyspnea and persistent episodes of coughing. Physical examination revealed bilateral diffuse crackles upon auscultation of the lungs. She had a 4-year history of recurrent episodes of pneumonia, which had required hospitalization and antibiotic management. There was no past history of cigarette smoking or secondhand smoke exposure and her family history was negative.

(A, C) Chest CT with contrast, axial view, posterior segment of the left lower lobe, lesion size 67×69×88 mm, cysts 15–35 mm. (B, D) Chest CT with contrast, coronal view, posterior segment of the left lower lobe, lesion size 67×69×88 mm, cysts 15–35 mm.

Chest CT scan shows a multicystic mass vascularized by an aberrant vessel in the posterior segment of the lower left lobe. The axial(a,c) and coronal(b,d) images with contrast show a hypodense, cystic avascular lesion with multiple internal septa (multicystic) measuring greater than 67×69×88 mm (PA×T×L). The cysts measure between 15 and 35 mm, are located in the posterior segment of the left lower lobe, and contain air-fluid levels. Peripheral parenchyma bronchial wall thickening and centrilobular micronodules are also evidenced. Images obtained using multiplanar reformation outline the course of an aberrant arterial vessel originating from the left lateral aspect of the thoracic aorta and supplying the left basal cystic lesion.

Laboratory test results on admission.

Clinical laboratory test results on admission show elevated white blood cell count of 22.2×10⁹/L with neutrophil predominance (20.7×10⁹/L). Normal serum values were found for hemoglobin (12.2 g/dL), electrolytes (sodium 142 mmol/L, potassium 3.9 mmol/L, chloride 106 mmol/L), creatinine (0.5 mg/dL), glucose (103 mg/dL), pH (7.37) and lactic acid (0.6 mmol/L).

(A) Histopathological examination, H&E staining, 10× magnification. (B) Histopathological examination, H&E staining, 100× magnification. Gram staining.

Histopathological examination shows Actinomyces colonies with characteristic 'sulfur granules' at low magnification (10×; H&E stain)(A), and at higher magnification (100×; H&E stain)(B) demonstrates filamentous nonsporulating microorganisms. Gram-positive bacteria consistent with Actinomyces spp. were visualized by Gram staining technique using crystal violet as reagent. Other staining procedures for fungi and acid-alcohol-resistant microorganisms were negative.

Intralobar bronchopulmonary sequestration associated with Actinomyces infection

Intralobar sequestration of lung

actinomyces infection

Cardiovascular and respiratory disorders


67-year-old female patient presented with chief complaint of swelling in right cheek. History of unhealed tooth extraction sockets from right upper posterior tooth extraction performed approximately one month previously. Past medical history significant for colorectal cancer treatment. Intraoral examination revealed localized, well-defined swelling measuring 4 cm × 5 cm obliterating buccal and palatal vestibules in region of unhealed extraction sockets of teeth 14, 15, and 16. Laboratory examination showed abnormal GTP level and slightly elevated serum CRP level.

(A) Intraoral view at the first examination. (B) Coronal computed tomography of the maxilla. (C) Axial computed tomography of the maxilla.

(a) An intraoral view at the first examination. A localized, well-defined swelling of size 4 cm × 5 cm in its greatest dimensions was obliterating the buccal and palatal vestibules in the region of the unhealed extraction sockets of 14, 15 and 16. Coronal (b) and axial (c) computed tomography imaging showed the osteolytic focus in the maxilla (white arrowhead).

(a) Oral specimen, Giemsa staining, 40× magnification. (b) Oral specimen, Giemsa staining, 100× magnification. (c) Liquid-based cytology of oral specimen, Papanicolou staining, 40× magnification. (d) Liquid-based cytology of oral specimen, Papanicolou staining, 100× magnification.

Microscopic view of oral specimens harvested from suspicious lesions. Large atypical lymphocytes with an irregular nuclear shape (Giemsa staining, (a) magnification 40×, bar = 20 μm (b) magnification 100×, bar = 5 μm). In the liquid-based cytology (LBC) specimen, (c) large atypical lymphocytes with a high nuclear/cytoplasmic ratio were recognized with prominent nucleoli (Papanicolou staining, magnification 40×, bar = 20 μm); (d) The nuclear strips implied nuclear fragility (Papanicolou staining, magnification 100×, bar = 5 μm).

Cell block immunohistochemistry, Ki-67 positive, positive for MUM1, BCL6, BCL2, CD79a, CD20, negative for CD10, CD3, CD25, CD30, CD56.

Cell block immunohistochemistry showed large lymphocytes positive for MUM1, BCL6, BCL2, CD79a, CD20, and Ki67, while negative for CD10, CD3, CD25, CD30, and CD56. Expression pattern CD10-/BCL6+/MUM1+ classified as ABC phenotype

Primary oral diffuse large B cell lymphoma (DLBCL), activated B-cell (ABC) phenotype

Primary oral diffuse large B-cell lymphoma

Diffuse large B-cell lymphomas


28-year-old male patient admitted on November 27, 2013, complaining of diarrhea (loose stool, three to five times per day) for over 10 years and hematochezia for about 1 month. Had been diagnosed with iron deficiency anemia 5 months after birth, with hemoglobin level remaining 70-80 g/L (normal range 110-150 g/L) for most of the time. On admission, albumin level was 26 g/L (normal range 35-52 g/L). Liver and renal function were otherwise normal. Patient reported recurrent arthralgia in the knee and ankle joints.

CT of the small intestine, contrast-enhanced.

Contrast-enhanced CT showed abnormal enhancement of the mucosa and thickening of the small intestinal wall

Clinical photograph obtained during gastroscopy of the gastric fundus.

B: Gastroscopy showed a clinical photograph of the gastric mucosa revealing fundic gland polyps, acquired during endoscopic examination of the stomach; no staining or magnification applies to this modality, and the anatomical site examined is the gastric fundus as indicated in the caption and body text on page 3.

Colonoscopy image of the terminal ileum and colon, including the ileocecal valve.

C: Colonoscopy image of the terminal ileum and colon showing an ulcer and hemorrhagic spots on the ileocecal valve, indicating mucosal abnormalities during endoscopic examination in a patient with primary hypertrophic osteoarthropathy and gastrointestinal involvement.

Capsule endoscopy of the ileum.

Capsule endoscopy revealed ulcer of the ileum

Double balloon enteroscopy of the ileum.

Double balloon enteroscopy showed ileum stenosis

X-ray of the ulna and radius.

X-ray showed periostosis of ulna and radius

Clinical photograph of the face.

G: Skin thickening and furrowing on the face are shown in a clinical photograph, demonstrating cutaneous changes associated with primary hypertrophic osteoarthropathy in patient 1.

(H) Clinical photograph of the hand.

H: Clubbed finger; the subfigure presents a clinical photograph of the patient’s hand showing digital clubbing, which is a typical finding in primary hypertrophic osteoarthropathy, with no additional imaging modality or staining applicable.

Genetic sequence analysis of SLCO2A1 (homozygous c.1807C>T, R603X) from peripheral blood.

I: GeneScreen display of SLCO2A1 mutation (homozygous c1807 C > T, R603X), showing the results of genetic sequence analysis from a peripheral blood sample acquired during the patient's diagnostic workup.

H&E staining of the ileum.

HE stain of the ileum showing superficial ulcers involving mucosa and submucosa of the small intestine

Primary hypertrophic osteoarthropathy (PHO) based on clinical characteristics, radiological findings, and gene mutation

Primary hypertrophic osteoarthropathy

Diseases of the musculoskeletal system or connective tissue

Orthopedic and connective tissue disorders


A 54-year-old man from rural area of the department of Risaralda (Colombia), coffee farmer in his youth and then worked as a butcher for 30 years. Medical history includes type 2 Diabetes Mellitus (recently diagnosed, receiving Metformin) and former smoker with a pack-year of 1.5 for 10 years. Presented with 3 years of a papule-like lesion in the lower lip that increased in size and evolved to a deforming ulcer with extension towards the right labial commissure, progressive deformity in the right nasal wing, spontaneous loss of teeth, weight loss of 15 Kg, dry cough and dyspnea, without other B symptoms. Interestingly, he had the habit of consuming armadillo meat and blood in his youth.

(A) Clinical photograph of the lower lip at presentation. (B) Clinical photograph of the right nasal wing at presentation.

Figure 1 consists of two clinical photographs documenting mucocutaneous findings at presentation: A shows a deforming and infiltrating ulcer located on the lower lip, while B depicts a deformity of the right nasal wing; both are gross clinical images obtained during physical examination prior to biopsy or treatment, demonstrating cutaneous and mucosal involvement in chronic multifocal paracoccidioidomycosis.

Lip biopsy, silver methenamine stain.

Silver methenamine stain reveals budding yeasts that resembles a 'mariner's wheel' from lip biopsy showing pseudoepitheliomatous hyperplasia associated with suppurative granulomatous dermatitis

(A) Chest x-ray. (B) High Resolution CT of the chest, lung window.

(a) Chest x-ray showing interstitial opacities and fibrotic tracts in the lung bases. (b) High Resolution Tomography of the chest. Lung window showing centrilobular and paraseptal emphysematous foci

Nasofiberoptic bronchoscopy of the upper airway.

Figure 4 depicts nasofiberoptic bronchoscopy images of the upper airway, showing granulomatous lesions and ulcerated lesions covered with punctiform white secretion observed during endoscopic examination in a patient with chronic multifocal paracoccidioidomycosis.

Paracoccidioidomycosis


A 15-year-old Caucasian male with a history of acne vulgaris during puberty presented with severe acne and low back pain with inability to walk. Three months before admission, he developed a dramatic worsening of acne. He was treated with systemic isotretinoin therapy at 0.5 mg/kg/daily for 10 weeks without benefit. During this time, he also developed depressive symptoms associated with insomnia and irritability, for which sertraline therapy was started. Ten weeks after starting isotretinoin, the patient experienced increasing low-back pain with progressive inability to walk and restriction of daily activities. At admission, he was suffering and unable to walk. Physical examination revealed decreased axial range of movement and sacroiliac pain. HLA-B27 testing was negative.

(A) MRI STIR sequences of the lumbar spine and sacroiliac joints performed prior to adalimumab treatment. (B) MRI STIR sequences of the lumbar spine and sacroiliac joints performed after twelve months of therapy.

Figure 1 consists of magnetic resonance imaging (MRI) STIR sequences demonstrating lumbar and sacroiliac involvement in a patient with SAPHO syndrome; specifically, the images show bone marrow oedema and osteitis of the transverse process of the fifth lumbar vertebra as well as symmetrical sacroiliitis prior to adalimumab treatment (upper images) and resolution of these findings after twelve months of therapy (lower images).

(upside) Clinical photographs of the face, back, and sternal region, standard view, prior to adalimumab treatment. (downside) Clinical photographs of the face, back, and sternal region, standard view, following adalimumab treatment.

Figure 2 presents clinical photographs of cutaneous lesions on the face, back, and sternal region before and after treatment with adalimumab; the upper row shows pre-treatment lesions and the lower row shows post-treatment outcomes, with each anatomical site (face, back, sternal region) represented accordingly. These images document the dermatological manifestations of SAPHO syndrome, specifically severe acne and hidradenitis suppurativa, using gross clinical photography at standard view and ambient lighting, captured at unspecified time points prior to and following adalimumab administration.

SAPHO syndrome (synovitis, acne, pustolosis, hyperostosis and osteitis syndrome)

SAPHO syndrome


87-year-old woman living in a nursing home admitted to the emergency department with abdominal pain, cough, and high-grade fever starting four days prior to hospital admission. Past medical history included polymyalgia rheumatica, giant cell arteritis, and slight cognitive impairment. No previous history of abdominal surgery or gastrointestinal symptoms. No reported contact with people at high-risk for SARS-CoV-2 infection, but nasopharyngeal swab PCR tested positive for SARS-CoV-2. On admission: blood pressure 100/60 mmHg, pulse 100 bpm rhythmic, SatO₂ 95% in ambient air and 97% in O₂ at 40%. Physical examination showed reduction of murmur to the pulmonary bases bilaterally, distended abdomen that was diffusely tender and positive for Blumberg's sign, bowel sounds not audible, and rectal examination revealed rectorrhagia. Laboratory results: white blood cell count 5990 cells/mm³, hemoglobin 15 g/dL, platelet count 233.000 10⁹/L, C-reactive protein 290 mg/dL, INR 1.22, aPTT 29.2 s, fibrinogen 790 mg/dL, D-Dimer 2.1 mg/LFEU, fecal calprotectin 290 mg/kg. Renal, liver, and pancreatic function tests were within normal range. Patient experienced rapid deterioration with development of septic shock.

CT of the rectum, axial and coronal views.

Axial and coronal CT images show wall thickening of the lower-third of the rectum, surrounded by extraluminal free air, findings suggestive of rectal perforation

CT of the pelvis, axial and coronal views.

Axial and coronal CT images show perivisceral fat stranding and thickening of the mesorectal fascia

CT of the chest, axial view.

Axial CT image shows ground-glass opacity superimposed by interlobular and intralobular septal thickening, consistent with typical imaging features of COVID-19 interstitial pneumonia with patchy bilateral ground-glass opacities

Spontaneous rectal perforation in a patient with SARS-CoV-2 infection

SARS-CoV-2 disease

Traumatic rectal perforation

Injury, poisoning or certain other consequences of external causes


A 64-year-old male patient from Smoljanci, Istria presented with firm, migrating nodules in the brachial region without history of serious disease. He had no travel outside Croatia but spent recreational time in forests and islands near his residence and owned a pet dog. Physical examination revealed a painless, well-demarcated subcutaneous nodule in his right upper arm measuring 1.5 × 1.5 × 1.0 cm. Ultrasonographic findings of the nodule appeared normal. Laboratory tests showed total blood counts, erythrocyte sedimentation rate and C-reactive protein within normal values. Serologic results for trichinosis, toxocariasis, schistosomiasis, distomatosis and cysticercosis were negative.

Histological cross-section, H&E staining.

Hematoxylin and eosin-stained histological cross-section shows typical features of Dirofilaria repens including external longitudinal ridges, thick cuticula, well-developed musculature and internal structure

infection by dirofilaria


19-year-old man presented with acute onset of shock, multiple organ failure, and rash. Had been well until 20 hours before admission when developed diffuse abdominal pain and nausea after eating restaurant leftovers. Symptoms progressed to include multiple episodes of vomiting (bilious or red-brown), chills, generalized weakness, diffuse myalgias (rated 8/10), chest pain, shortness of breath, headache, neck stiffness, and blurry vision. History of anxiety, depression, and intermittent childhood ear infections. Social history: smokes 2 packs cigarettes weekly, daily marijuana use, drinks alcohol 2x/week, recreational use of dextromethorphan and diphenhydramine. Lives in northern New England, had been staying with friend for 5 days, visited beach and music venue. Works part-time at restaurant. Family history: father with coronary artery disease, mother with hypothyroidism, brother had viral meningitis at 6 weeks.

Laboratory results on admission and peripheral blood smear.

Laboratory results on admission showing hemoconcentration (hematocrit 48.8%, hemoglobin 16.4 g/dl), severe thrombocytopenia (platelet count 12,000/μl), profound coagulopathy (PT 69.9 sec, INR 7.9, aPTT >150 sec), undetectable fibrinogen (<60 mg/dl), severe lactic acidosis (9.4 mmol/L), acute kidney injury (creatinine 2.31 mg/dl), hypoproteinemia (total protein 2.7 g/dl, albumin 1.6 g/dl), elevated bilirubin (2.5 mg/dl), markedly elevated D-dimer (>10,000 ng/ml), severely depressed anticoagulant proteins (protein C activity 5%, protein S activity 25%, antithrombin III activity 28%), positive lupus anticoagulant, severe metabolic acidosis (pH 7.17), and blood smear showing toxic granulation, Döhle bodies, vacuolated neutrophils, and burr cells.

Clinical photographs of chest, abdomen, arms, and legs.

Clinical photographs showing rapidly evolving diffuse reticular purpuric rash on chest, abdomen, arms, and legs, sparing palms and soles, consistent with purpura fulminans pattern.

Meningococcal infection

Purpura fulminans


A 63-year-old man presented with a 6-month history of dry cough and fatigue. He was previously healthy except for a 20-year history of asthma. One year prior to presentation, he had worked as a miner for 6 months in Mexico. He did not exhibit fever, headache, or night sweats. Laboratory tests showed decreased levels of total protein (60.6 g/L), albumin (33.6 g/L), and alkaline phosphatase (33 IU/L), with other routine laboratory examinations being normal. Serum galactomannan (GM) and 1,3-beta-D-glucan (G) assays were negative. Mycobacterium tuberculosis culture results were negative.

(A) Chest CT, lung window. (B) Chest CT, soft tissue window.

Chest computed tomography (CT) scans showed a 1.4 × 1.3 × 1.1 cm solitary solid nodule with a smooth margin in the right lower lobe and multiple small 0.1- to 0.2-cm nodules with mild ground-glass opacity in the bilateral lungs. CT images of the lung window (A) and soft tissue window (B)

(A) Biopsy tissue, PAS staining. (B) Biopsy tissue, GMS staining.

Histological examination of biopsy tissue from thoracoscopic right lower lobectomy revealed multiple granulomas with caseous necrosis, with scattered thick-walled spherules containing endospores observed following PAS and GMS staining. PAS staining (A) and GMS staining (B)

Pulmonary coccidioidomycosis


41-year-old male with unremarkable previous medical history except type 2 diabetes mellitus diagnosed 5 years prior. Presented with leukocytosis. No hepatosplenomegaly on physical examination.

(A–C) Peripheral blood smear. (D–F) Bone marrow smear.

Peripheral blood (PB) and bone marrow (BM) smears of patient 1. Panels a-b-c: the PB shows hyperleukocytosis with neutrophil precursors (promyelocytes, myelocytes, and metamyelocytes) representing ≥ 10% of the leukocytes, with monocytes < 10% and rare blasts. The neutrophils show pseudo-Pelger-Huet nuclear abnormalities and hypogranulated cytoplasm. Panels d-e-f: the BM is hypercellular due to an increase of neutrophils and their precursors. The myeloid/erithroid ratio is > 10:1 due to myeloid hyperplasia. Of note, the myeloid lineage shows evident signs of dysplasia similar to those present in the PB. Moreover, the megakaryocytes show signs of dysplasia with micro-megakaryocyte and cells with hypolobated nuclei.

Laboratory results, peripheral blood counts and differential, bone marrow blast percentage, genetic analysis including next generation sequencing, and karyotype analysis.

41-year-old patient with WBC 32.12 × 10^9/L, differential showing hypogranulated neutrophils 46%, band-cells 12%, eosinophils 2%, monocytes 6%, lymphocytes 14%, promyelocytes 2%, metamyelocytes 12%, myelocytes 6%. Hemoglobin 13.5 g/dL, platelets 103 × 10^9/L, bone marrow blasts 2%. Screening for JAK2, CALR, MPL mutations and BCR/ABL were negative. Next generation sequencing revealed TET2 p.Q635* (VAF 37.09%), TET2 p.C1221Y (VAF 42.23%), and EZH2 p.R690H (VAF 82.89%). ETNK1 mutations screening was negative. Normal karyotype 46, XY (20).

Atypical chronic myeloid leukemia (aCML)

atypical chronic myeloid leukaemia


36-year-old female patient, never smoker, admitted with chronic cough, expectoration, chest tightness and wheezing. Chronic sinusitis since age 12, started experiencing cough and purulent sputum at age 20 with progressive worsening, exertional dyspnea and constant wheezing. At age 25, underwent thoracotomy drainage and biopsy for empyema and pleural effusion. Physical examination revealed diffuse expiratory wheezes and coarse crackles in both lungs. Blood gas analysis showed hypoxemia with PaO2 of 62 mmHg and oxygenation index of 155 mmHg. No obvious abnormalities in routine blood tests, procalcitonin, sputum smear microscopy, sputum culture, tuberculosis bacili gamma interferon release test, rheumatoid factors, humoral immunity, connective tissue related antibodies, anti-neutrophil cytoplasmic antibody. Cold agglutinin level was in normal range.

Pulmonary function test at first admission.

Pulmonary function test showed FEV1/FVC ratio of 43.39% at first admission

Chest HRCT scan.

Chest HRCT scan showed well-defined multiple centrilobular nodules and diffuse tree-in-bud pattern

CT of the paranasal sinuses.

Paranasal sinus CT showed bilateral maxillary sinus inflammation

HLA genotyping.

HLA genotyping showed patient was positive for HLA-A24:02:01 (homozygous) and HLA-B13:01/40:01, with 25 years history of sinusitis

Diffuse panbronchiolitis


7-day-old female newborn born at full-term to a G1P1 mother with birth weight of 4,380 gm. Parents denied poor feeding, poor activity, or weak crying. On examination at Day 7, she had normal muscle power, normal reflex, no macroglossia, but slightly decreased facial folds. Newborn screening for Pompe disease showed GAA activity 0.18 uM/h (critical cutoff <0.5) and ratio 42.87 (critical cutoff acid β-glucosidase/GAA ≥20). Laboratory examination revealed elevated pro-BNP (8,738 pg/mL), CK (722 U/L), and ALT (112 U/L). Confirmatory testing showed deficient lymphocyte GAA activity (1.33 nmol/g pro/hr, normal mean 66.7). Patient did not have the common CRIM-positive Taiwan Pompe disease p.D645E variant. Mutation analysis revealed heterozygous c.2024_2026del (p.N675del) and c.2040+1G>T variants in trans.

Chest X-ray performed on day 7.

Chest X-ray at Day 7 shows mild cardiomegaly

Western blot analysis of blood lymphocytes detecting GAA and α-tubulin.

Western Blot analysis of blood GAA showing 110 kDa precursor GAA band, indicating CRIM-positive status. Blood lymphocytes were sonicated and blotted with antibodies to detect human GAA and α-tubulin protein presence

Infantile Pompe disease


A 36-year-old Chinese man presented with a 1-month history of persistent fever. He was previously healthy with no significant past medical history, specifically no prior TB infections, chronic illnesses, liver or kidney disease, transfusions, malignancy, or immune diseases. He was not taking any regular prescription medications and had not travelled abroad. On admission, vital signs showed temperature 37.2°C, heart rate 119 beats/min, blood pressure 90/48 mmHg, respiration rate 38 breaths/min with oxygen saturation 88%. Physical examination revealed an acutely ill appearance and pulmonary rales in both lungs. He presented with persistent fever, pancytopenia, and hyperferritinemia with clinical deterioration including acute respiratory failure.

CT of the chest.

Chest CT showing diffuse infiltrates in both lungs with possible cavitation in the left upper lobe, and mediastinal and hilar lymph node enlargement

CT of the abdomen, liver.

Abdominal CT showing multiple focal lesions in the liver without hepatosplenomegaly

Laboratory results on day 1. Arterial blood gas analysis on day 1. Pre-treatment laboratory results. Coagulation tests.

Laboratory results on day 1 showed WBC count 1.25 × 10^9/L, hemoglobin 78 g/L, platelet count 41 × 10^9/L, fibrinogen 1.79 g/L, and ferritin 375,554 ng/ml. Additional pre-treatment lab values included AST 121 U/L, ALT 47 U/L, total bilirubin 48.4 μmol/L, direct bilirubin 40.9 μmol/L, BUN 11.35 mmol/L, creatinine 106.0 μmol/L, LDH 508 U/L, serum ferritin 17,208.98 ng/ml. Coagulation tests showed PT 16.9 s, PTA 62%, fibrinogen 1.74 g/L. Arterial blood gas analysis revealed pH 7.45, PO2 57 mmHg, PCO2 35 mmHg, lactate 2.0 mmol/L

Bone marrow aspiration on day 4. (A), red cells (B) and neutrophil (C) engulfed by macrophages

Bone marrow aspiration on day 4 revealed increased macrophage activity with hemophagocytosis, showing macrophages (A) with phagocytosed blood cells (B) and cell debris (C)

Lung biopsy performed on day 22, acid-fast staining.

Pathological result of lung biopsy performed on day 22 showing positive acid-fast bacilli

Mycobacterium infection associated hemophagocytic lymphohistiocytosis (HLH)

mycobacterial infection, unspecified

haemophagocytic lymphohistiocytosis NOS


51-year-old Caucasian male patient with terminal kidney disease presenting with a 10-month history of pruritic papules on sun-exposed areas of extremities. Patient suffered from severe pruritus with impaired sleep. Medical history includes arterial hypertension, hyperuricemia, coronary heart disease, terminal kidney disease due to idiopathic nephropathy, kidney transplants in 1990 and 2001 with rejections in 2000 and 2007, peritoneal dialysis from 2007-2017, ongoing hemodialysis since 2017, and factor V Leiden mutation. No history of habitual UV-light exposure or carcinogen exposure. Medications included felodipine, bisoprolol, clonidine, ramipril, urapidil, cholecalciferol, acetylsalicylic acid, allopurinol, phenprocoumon, thyroxine, iodine, fluvastatin, calcium acetate, omeprazole, and sevelamer carbonate.

Clinical photographs of the left arm acquired at multiple time points over a 25-month period.

Figure 1 presents a time series of clinical photographs documenting the left arm of the patient over a 25-month period, illustrating the anatomical site of the upper extremity at various stages of disease progression and treatment. The content consists of sequential clinical photographs that display multiple follicular papules and nodular lesions, some featuring a central hyperkeratotic (horny) plug; one image shows post-surgical sites with isomorphic response (Koebner phenomenon) manifesting as new lesions along suture lines. Subsequent photographs demonstrate changes after local therapy with lapacho tea dressings, with visible amelioration of the lesions. The figure type is a serial set of clinical photographs, with acquisition timing annotated along a horizontal timeline spanning key moments such as first presentation, postsurgical response, disease progression, and initiation of local therapies. No imaging modality or histopathological staining is used; these are gross clinical photos focused on the left arm. The key findings are the appearance and distribution of keratoacanthomatous papules and nodules, the Koebner phenomenon after surgery, and improvement following topical lapacho tea application.

(A) Serial clinical photographs of the right upper extremity, macroscopic view, acquired over a 25-month period at initial presentation, progression, and post-treatment intervals.

Figure 2 presents a series of clinical photographs forming a timeline of the right arm over a 25-month period in a patient with Grzybowski’s generalized eruptive keratoacanthomas. The figure documents the anatomical site as the right upper extremity and demonstrates the evolution of numerous scaly and ulcerated papules and nodules. The images show the progression of the lesions without treatment, followed by visible amelioration after initiation of local therapy with topical imiquimod 5% cream. No imaging modality or histological technique is involved; rather, the content type is serial clinical photography. The views are macroscopic, ex vivo photographs with consistent orientation to facilitate clinical monitoring. Acquisition timing is annotated above each photo, corresponding to key points in the patient’s clinical course: initial presentation, progression, and post-treatment intervals.

Histopathology of representative fusiform excisions.(A) H&E staining, 2.5× magnification. (B) H&E staining, 10× magnification. (C) H&E staining, 2.5× magnification. (D) H&E staining, 10× magnification.

Histopathology of representative fusiform excisions. Fifteen excised lesions displayed exophytic and endophytic keratinized masses with epidermal hyperplasia featuring pale cells with mild atypia consistent with keratoacanthoma. a H&E ×2.5 original magnification. b H&E ×10 original magnification. Three lesions showed endophytic growth with reteacanthosis, hypergranulosis, and prominent nucleoli consistent with inverted verruca vulgaris/ viral papilloma. c H&E ×2.5 original magnification. d H&E ×10 original magnification

Grzybowski's generalized eruptive keratoacanthomas (GEKA)

Generalised eruptive keratoacanthomas


26-year-old pregnant woman at 32 weeks gestation with monochorionic, diamniotic twins. Medical history includes childhood asthma, obesity, anxiety, depression, gestational diabetes mellitus, and polyhydramnios of one fetus. Two previous uncomplicated pregnancies. Three weeks prior to presentation, her children had ear infection and sore throat; patient developed eye erythema with greenish drainage, then nonproductive cough, sore throat, ear pain, and new leg edema. One week before admission, developed progressive right leg pain. Physical examination at first hospital showed temperature 37.0°C, pulse 113 bpm, blood pressure 90/50 mmHg, pitting leg edema without erythema or warmth. Five days later developed left leg tenderness with worsening bilateral edema, severe coughing episodes, temperature 36.9°C, pulse 110 bpm, blood pressure 96/51 mmHg, oxygen saturation 98% on room air, and expiratory wheezes on lung auscultation. Subsequently developed sudden severe crushing chest pain, became unresponsive and pulseless with monomorphic ventricular tachycardia at 178 bpm with right bundle-branch block pattern and superior axis, leading to cardiac arrest.

Laboratory results. Blood gas analysis.

Laboratory results show progressive changes including hemoglobin drop from 10.9 to 9.6 g/dl, white cell count increase from 8920 to 19,500 per μl with neutrophilia, low albumin (1.9-1.6 g/dl), elevated troponin T (28.32 ng/ml), markedly elevated creatine kinase (11,012 U/liter), and creatine kinase MB (552.0 U/liter). Blood gases show pH 7.31 with oxygen saturation maintained.

(A) Contrast-enhanced coronal CT in the pulmonary angiographic phase, chest. (B) Contrast-enhanced axial CT in the pulmonary angiographic phase, chest. (C) Chest radiograph obtained at the time of transfer to this hospital.

A contrast‑enhanced coronal CT image in the pulmonary angiographic phase (Panel A) shows bilateral patchy ground‑glass opacities with interlobular septal thickening compatible with pulmonary edema. A contrast‑enhanced axial CT image in the pulmonary angiographic phase (Panel B) shows cardiomegaly with biventricular enlargement and small bilateral pleural effusions with associated relaxation atelectasis in the lower lobes (arrows). A chest radiograph obtained at the time of transfer to this hospital (Panel C) shows interstitial pulmonary edema, cardiomegaly, a trace left pleural effusion, and left basilar atelectasis. The venous extracorporeal membrane oxygenation (ECMO) inflow cannula and the tip of a central venous catheter are visible in the right atrium, and an endotracheal tube and enteric tubes are in appropriate positions.

(A) Electrocardiogram. (B) Transthoracic echocardiography, left ventricular ejection fraction 11%, estimated pulmonary-artery systolic pressure 53 mmHg.

Electrocardiogram(A) shows normal sinus rhythm, right bundle-branch block, borderline-low QRS voltage, and Q waves with T-wave inversions in anterior and lateral leads. Transthoracic echocardiography(B) reveals dilated left ventricular cavity with severe diffuse hypokinesis (ejection fraction 11%), moderate mitral and tricuspid regurgitation, moderate right ventricular dysfunction and dilatation, estimated pulmonary-artery systolic pressure 53 mmHg, small pericardial effusion, and pleural effusion.

Coronary angiography of the coronary arteries.

Coronary angiography shows proximal left anterior descending artery and proximal left circumflex artery are smaller in caliber than distal portions, suggesting possible spontaneous coronary-artery dissection in left main coronary artery.

Pregnancy-associated myocardial infarction, probably due to spontaneous coronary-artery dissection

myocardial infarct NOS

spontaneous coronary artery dissection


A 48-year-old man from Eurasia who had lived in the United States for 20 years presented with transient vision loss. One hour before evaluation, he noticed white 'sparkles' flickering in the left eye vision, followed by sudden blurriness that worsened over 2 minutes to complete darkness in the left eye. On presentation, vision was improving but remained blurry. Vital signs: temperature 36.7°C, blood pressure 120/65 mmHg, heart rate 92 bpm, BMI 24.2. Visual acuity was 20/20 in right eye and limited to hand motions at 0.9m in left eye (improved to 20/40 distance, 20/30 near with correction 2 hours later). Physical examination revealed severe ptosis of left upper eyelid (margin reflex distance 4mm right, 1mm left), nontender irregular mass palpable under left superior orbital rim without proptosis, and prominent temporal arteries bilaterally (more on right). Review of systems notable for fatigue, 4.5kg weight loss over past year, 2-month history of bilateral jaw pain with chewing firm foods, bilateral lateral hip soreness after walking, sensation of locking when flexing/extending right first finger, and temporal headache on right side 2 days prior that resolved. Past medical history significant only for presbyopia. Social history: formerly smoked half pack for 5 years but quit 20 years ago, rare alcohol use, university professor with international travel.

Laboratory results on admission.

Laboratory results on admission showed normocytic anemia (hemoglobin 11.6 g/dl, hematocrit 35.0%), elevated erythrocyte sedimentation rate (53 mm/hr), elevated C-reactive protein (11.8 mg/liter), significantly elevated liver enzymes (alanine aminotransferase 245 U/liter, aspartate aminotransferase 154 U/liter, alkaline phosphatase 1924 U/liter), elevated total bilirubin (2.8 mg/dl), and elevated total cholesterol (280 mg/dl). White cell count and differential were normal.

(A) MRI of the head and orbits, coronal short-tau inversion recovery sequence. (B) MRI of the head and orbits, coronal T1-weighted fat-saturated sequence with intravenous gadolinium. (C) MRI of the orbits, axial three-dimensional fast spoiled gradient echo sequence with intravenous gadolinium. (D, E) CT of the abdomen and pelvis, axial and coronal images with intravenous contrast. (F) CT of the abdomen, axial image with intravenous contrast.

MRI of the head and orbits was performed. A coronal short-tau inversion recovery image (Panel A) and a coronal T1-weighted fat-saturated image obtained after the administration of intravenous gadolinium (Panel B) show enlargement of the right medial rectus muscle (arrows), which is associated with marked T2-hypointense signal (Panel A) but shows enhancement similar to that of the other extraocular muscles (Panel B). Mild enhancement and fat stranding are present in the adjacent extraconal fat. An axial three-dimensional fast spoiled gradient echo image (Panel C), obtained after the administration of intravenous gadolinium, shows an enhancing masslike lesion (arrow) in the left anterior superior orbit, abutting the left lacrimal gland. CT of abdomen and pelvis was also performed. Axial and coronal images (Panels D and E, respectively), obtained after the administration of intravenous contrast material, show diffuse coalescent mesenteric and retroperitoneal lymphadenopathy (Panel D, arrows). An additional axial image (Panel F) shows geographic areas of heterogeneous hypoattenuation in the right lobe of the liver. Multiple small calcifications of varying shapes and sizes are shown throughout the liver (Panels E and F, arrows). In addition, coarse calcifications are shown within some of the mesenteric and retroperitoneal lymph nodes (Panels D and E, arrowheads).

(A) Hematoxylin and eosin staining of retroperitoneal lymph node biopsy. (B) Congo red staining of retroperitoneal lymph node biopsy, polarized light. (C) Hematoxylin and eosin staining of liver biopsy. (D) Congo red staining of liver biopsy, polarized light. (E) Hematoxylin and eosin staining of liver biopsy, higher magnification. (F) Immunohistochemical staining for kappa light chains in liver biopsy. (G) Immunohistochemical staining for lambda light chains in liver biopsy.

Hematoxylin and eosin staining of a biopsy specimen of a retroperitoneal lymph node (Panel A) shows fragments of fibroadipose tissue with calcifications and acellular eosinophilic deposits (arrows), with associated reactive osseous metaplasia (left arrowhead) and scattered multinucleated giant cells (right arrowhead). On Congo red staining (Panel B), the eosinophilic deposits show apple-green birefringence under polarized light, a feature characteristic of amyloid. Hematoxylin and eosin staining of a biopsy specimen of the liver (Panel C) shows portal-based, well-delineated nodules of eosinophilic deposits (arrows); the deposits within the dashed outline show apple-green birefringence under polarized light on Congo red staining (Panel D). At higher magnification (Panel E), there is a focal dense cluster of plasma cells adjacent to the amyloid deposits in the liver parenchyma. On immunohistochemical staining for kappa and lambda light chains (Panels F and G, respectively), the plasma cells show kappa restriction.

(A) Bone marrow core biopsy, H&E staining. (B) Bone marrow core biopsy, H&E staining, higher magnification. (C) Bone marrow core biopsy, kappa light-chain mRNA in situ hybridization. (D) Bone marrow core biopsy, lambda light-chain mRNA in situ hybridization. (E) Bone marrow aspirate smear, Wright–Giemsa staining, plasma cells: 8.5%. (F) Bone marrow aspirate, flow cytometry, fluorescence intensity for cytoplasmic kappa and lambda light chains.

Hematoxylin and eosin staining of a core biopsy specimen of the bone marrow (Panel A) shows mildly hypocellular marrow for the patient’s age with maturing trilineage hematopoiesis. At higher magnification (Panel B), scattered and clustered plasma cells are present. On kappa and lambda light-chain mRNA in situ hybridization (Panels C and D, respectively), the plasma cells show kappa restriction. On Wright–Giemsa staining of a smear of bone marrow aspirate (Panel E), the mature plasma cells (arrows) account for 8.5% of the marrow cellularity on a differential count. On flow cytometry of the aspirate (Panel F), the vertical and horizontal axes show fluorescence intensity measurements for cytoplasmic kappa and lambda light chains, respectively. There is a predominance of clonal kappa-positive plasma cells (K+ PC), as indicated by red dots, with very few lambda-positive plasma cells (L+ PC), as indicated by blue dots; purple and green dots indicate non–plasma cell populations.

Primary systemic amyloidosis affecting skin or oral cavity


A 34-year-old woman presented with acute abdominal and back pain 3 years before evaluation at the oncology clinic. She had been well until this onset. Her medical history was notable for migraines. She did not smoke cigarettes, drink alcohol, or use illicit drugs. She worked full time as a social worker and lived in New Jersey with her husband and child. Family history included breast cancer in maternal grandmother (70s), uterine cancer in paternal aunt (40s), and colon cancer in two paternal cousins (30s and 50s). On physical examination: temperature 36.5°C, blood pressure 108/78 mm Hg, heart rate 78 beats per minute, body-mass index 27.7. The abdomen had well-healed surgical scars; remainder of physical examination was normal. Laboratory results showed elevated tumor marker CA 19-9 at 110 IU per milliliter (reference <35), while alpha-fetoprotein and carcinoembryonic antigen levels were normal.

(A) MRI of the liver, right hepatic lobe. (B) Coronal T2-weighted MRI of the liver. (C) Axial diffusion-weighted MRI of the liver. (D) MRI of the liver, arterial phase, following gadoxetate disodium administration. (E) MRI of the liver, portal venous phase. (F) MRI of the liver, delayed phase.

A lobulated hypoenhancing mass (Panel A, arrows) is seen in the right hepatic lobe. Although this finding is not specific for a single cause, the characteristics of the mass are atypical of common benign lesions found in this patient’s age group such as hemangiomas, focal nodular hyperplasia, and hepatic adenoma. Peripheral biliary dilatation (Panel B, arrowheads) seen on a coronal T2-weighted image suggests obstruction of the central bile duct related to the mass. Such a finding more commonly results from cholangiocarcinoma than from other malignant conditions, such as hepatocellular carcinoma or metastases. On an axial diffusion-weighted image, the mass shows marked restricted diffusion (Panel C, arrows). The periphery of the tumor shows the brightest signal, leading to a targetoid appearance, a finding often seen with cholangiocarcinoma. Restricted diffusion is typically seen in areas of high tissue density such as malignant tumors or abscesses. On an arterial phase image obtained after the administration of contrast material (gadoxetate disodium), areas of peripheral rim enhancement (Panel D, arrowheads) reflect well-vascularized areas of the periphery of the tumor, a finding that is typical of cholangiocarcinoma. It is important to distinguish this pattern of enhancement from discontinuous peripheral nodular arterial enhancement, which is typical of a hemangioma, a more common liver lesion that is benign. Gradual enhancement of the more central components of the tumor (Panel E, arrows) is seen during the portal venous phase. This finding reflects the diminished central vascularity of the tumor that is typical of cholangiocarcinoma and would be unusual with hepatocellular carcinoma. Further enhancement of the center of the tumor (Panel F, arrows) can be seen on an image obtained during the delayed phase, again reflecting a paucity of vascularity. Washout of contrast material did not occur owing to the presence of extensive fibrosis, which retains contrast material within the expanded extracellular space — a typical finding of cholangiocarcinoma. Fibrosis typically causes hepatic capsular retraction, but this feature is not seen in this case because of the central location of the tumor.

(A) H&E staining of liver tissue, unspecified magnification. (B) H&E staining of liver tissue, higher magnification.

Hematoxylin and eosin staining shows a poorly differentiated adenocarcinoma and adjacent liver tissue (Panel A, right upper region). At this magnification, no gland formation is visible. At higher magnification, the tumor cells are found to be organized in a cholangiolar pattern that resembles antlers (Panel B, arrow). Abundant desmoplastic stroma is also present.

Intrahepatic cholangiocarcinoma


Three-month-old Caucasian male infant, second child of healthy non-consanguineous parents. Born by spontaneous delivery after normal pregnancy with no birth-related complications. Apgar scores 8 and 9 at 1 and 5 minutes. Birth weight 2390g (4th centile), length 47cm (12th centile), head circumference 33cm (19th centile). Presented with decreased sweating, dry skin, and absence of hair on scalp. Physical examination revealed scaphocephaly, prominent forehead, forehead bumps, rings under eyes, hypertelorism, epicanthic fold, everted nose, depressed nasal bridge, prominent lips, sparse eyelashes on upper and lower lids, thin pale dry exfoliating skin with widespread eczematous dermatitis especially on scalp, linear wrinkled and hyperpigmented skin around eyes and mouth. Parents reported eye dryness. Neuromotor and mental development index scores of Bayley II scale were normal. Family history for inherited diseases was unremarkable, with normal facial features, hair, teeth, skin and nails in the mother and healthy female sibling.

(A) Clinical photograph of the periocular region at initial presentation, three months of age. (B) Clinical photograph of the scalp at initial presentation, three months of age.

Figure 1 consists of clinical photographs illustrating the key dermatological and craniofacial features of X-linked hypohidrotic ectodermal dysplasia in a three-month-old boy at the time of presentation. Subfigure A shows the absence of eyebrows and sparse eyelashes, focusing on periocular skin, while subfigure B displays scaphocephaly, complete absence of scalp hair, and areas of eczematous dermatitis on the scalp. These images provide direct visual documentation of the ectodermal anomalies characteristic of the disorder, captured during initial clinical examination.

Genetic analysis (pedigree). Pedigree analysis showed an X- linked pattern of inheritance

Pedigree analysis showing X-linked inheritance pattern with affected male proband, heterozygous carrier mother, and unaffected father and sister

Intraoral examination at 24 months.

Intraoral examination at 24 months revealing severe oligodontia with only two conical anterior teeth and a wide midline diastema

X-linked hypohidrotic ectodermal dysplasia (XLHED) with hemizygous variant c.1142G>C (p.Gly381Ala) in the EDA gene


29-year-old pregnant woman (gravida 5, para 3) at 26 weeks 3 days gestation with undifferentiated connective tissue disease presenting with cough and shortness of breath. Two weeks prior to presentation, she noted gradually increasing exertional dyspnea, 5 days of nonproductive cough, nasal congestion, subjective fevers, and fatigue. She experienced chest tightness, palpitations, and presyncope after carrying laundry up stairs. Medical history notable for undifferentiated connective tissue disease diagnosed 10 months prior with diffuse lymphadenopathy, biopsy-proven leukocytoclastic vasculitis of feet and legs, and intermittent cytopenias. Serologic tests positive for antinuclear antibody titers, anti-Ro (SSA) and anti-La (SSB) antibodies, and low complement levels. Tests negative for anti-dsDNA, anti-Smith, ANCA, antiphospholipid, anticentromere, anti-Scl-70, and anti-RNP antibodies. Previous episode at 10 weeks gestation with shortness of breath, syncope, hemoglobin 6.2 g/dL, platelet count 40,000/mm3, positive direct antiglobulin test, low reticulocyte count, and parvovirus B19 infection. Current medications include hydroxychloroquine 200mg twice daily, prednisone 30mg daily, prenatal vitamins, and aspirin 81mg daily. Smoking history of 2 pack-years, quit 8 years ago. Physical examination: temperature 38°C, BP 106/54 mmHg, HR 122 bpm, RR 22/min, oxygen saturation 94% on room air. Elevated jugular venous pressure with prominent v wave, tachycardia with regular rhythm, splitting of S2, holosystolic murmur at right sternal border, left parasternal heave, tachypnea, increased work of breathing, scattered crackles, gravid nontender abdomen, reticular hyperpigmentation and trace pitting edema of lower legs.

(A) Chest X-ray, posteroanterior view. (B) Chest X-ray, lateral view.

Chest X-ray initially read as normal but further review revealed prominence of the right descending pulmonary artery, large left central pulmonary artery with obliteration of the aortopulmonary window, and diminished retrosternal clear space. Panel A is a posteroanterior view, and Panel B a lateral view.

Electrocardiogram.

Electrocardiogram showed sinus tachycardia with right-axis deviation and T-wave inversion in leads II, III, aVF, and V3 to V5, consistent with right heart strain

(A,B) CT pulmonary angiography, axial view.

CT pulmonary angiography revealed diffuse, mild tree-in-bud nodularity, ground-glass opacities, and right ventricular enlargement without evidence of pulmonary embolism.Both panels are axial views.

(A) Transthoracic echocardiogram, apical four-chamber view, ejection fraction 75%, estimated right ventricular systolic pressure 74 mmHg, systolic excursion of tricuspid annular plane 17 mm. (B) Transthoracic echocardiogram, parasternal short-axis view.

Transthoracic echocardiogram showed small, hyperdynamic left ventricle with ejection fraction 75%, marked dilation of right ventricle with severely reduced systolic function and septal flattening, severely dilated right atrium, severe tricuspid regurgitation, estimated right ventricular systolic pressure 74 mmHg, systolic excursion of tricuspid annular plane 17mm, and small pericardial effusion. Panel A is an apical four-chamber view, and Panel B a parasternal short-axis view.

Severe connective tissue disease-associated pulmonary arterial hypertension (Group 1.4.1 in the World Symposium on Pulmonary Hypertension classification) with right ventricular failure

Mixed connective tissue disease

Pulmonary arterial hypertension

Right ventricular failure


A 70-year-old man with bipolar disorder presented with depressed mood, suicidal ideation, and progressive gait disturbance. He had a history of bipolar depression with suicide attempts, obsessive-compulsive disorder, and skin picking. Medical history included long-standing urinary incontinence, hypertension, sleep apnea, and prior prostate laser ablation. He had a remote head injury (~20 years prior) with 4-cm laceration from construction beam. Over the past 4 years, he experienced progressive gait instability with multiple falls, cognitive decline, and worsening motor function requiring wheelchair use. On admission, he was wheelchair-bound, well-groomed, oriented, with depressed mood and suicidal ideation. Physical examination showed reduced facial expression, mildly increased tone in lower legs and left arm with bradykinesia, and characteristic gait described as 'slow to start' with 'magnetic quality' then 'shuffling.' Temperature 36.1°C, heart rate 74 bpm, blood pressure 110/61 mmHg, oxygen saturation 97%, BMI 28.5.

(A) MRI of the head, axial fluid-attenuated inversion recovery (FLAIR) sequence. (B) MRI of the head, T2-weighted sequence.

Initial MRI head shows old lacunar infarct in left corona radiata, mild scattered hyperintensities suggestive of small-vessel ischemic changes, and mild generalized brain parenchymal volume los. An axial fluid‑attenuated inversion recovery image (Panel A) and a T2‑weighted image (Panel B)

Laboratory results.

Laboratory results show sodium 130-136 mmol/L, potassium 4.4-4.6 mmol/L, normal glucose, creatinine, and other basic metabolic panel values. Valproic acid levels 50.8-66.8 μg/ml (reference 50-100). Thyrotropin elevated at 6.66 μIU/ml then normalized to 3.21 (reference 0.40-5.00). Normal folate, vitamin B12, and glycated hemoglobin. Negative HIV and treponemal antibodies

(A) Axial T1-weighted MRI of the brain with contrast. (B) Coronal reformatted MRI of the brain with contrast, callosal angle=66°.

An axial T1‑weighted image obtained after the administration of contrast material (Panel A) shows no abnormal enhancement. A coronal reformatted image obtained after the administration of contrast material (Panel B) shows an acute callosal angle of 66 degrees and mild prominence of the sylvian fissures (arrow).

Normal-pressure hydrocephalus


Sudden clinical deterioration in intensive care unit patient with longstanding pneumonia. The patient had severe chest pain. Lab tests showed signs of infection. Normal ECG. No abdominal pain or vomiting.

CT of the chest, contrast-enhanced.

Contrast-enhanced CT of the chest showing pneumococcalastinum around the oesophagus. A large fluid collection with air fluid level is seen transversing the mediastinum. The fluid collection communicates with both pleural cavities.

CT of the chest with contrast.

Contrast-enhanced CT of the chest showing large fluid collections in the pleural cavities. Air is noted in the pleural cavities.

Spontaneous rupture of oesophagus


A 51-year-old woman presented to the emergency department with a 3-day history of dyspnoea, fatigue, and cough, occurring 11 days after receiving the ChAdOx1 nCoV-19 vaccination. On examination, she was afebrile with peripheral oxygen saturation of 98% (FiO2 21%), blood pressure 150/90 mm Hg, heart rate 98 beats per minute, and BMI 31 kg/m². Laboratory findings showed severe thrombocytopenia (37 × 10⁹ platelets per L, down from 178 × 10⁹ three days prior), elevated D-dimer (>34 mg/dL), and increased C-reactive protein (42 mg/L). Other parameters including prothrombin time, partial thromboplastin time, fibrinogen, creatinine, electrolytes, liver enzymes, and troponin T were within normal range. SARS-CoV-2 RT-PCR was negative.

CT pulmonary angiography.

CT pulmonary angiography showed central pulmonary embolism without right ventricular dysfunction

Magnetic resonance venography of the left internal iliac vein, common iliac vein, and inferior vena cava.

Magnetic resonance venography revealed venous thrombus in the left internal iliac vein including the common iliac vein, with extension into the inferior vena cava

Pulmonary embolism and thrombocytopenia following ChAdOx1 vaccination, with multiple thromboses and severe thrombocytopenia

pulmonary embolism NOS

Thrombocytopenia

Diseases of the blood or blood-forming organs

Multiple personality

Mental, behavioural or neurodevelopmental disorders

Severe fever with thrombocytopenia syndrome


32-year-old female with a 2-year history of cyclical attacks of angioedema, urticaria, and periodic weight gain (up to 10 kg) occurring approximately weekly. Attacks mainly involved the face, arms, and left leg, sometimes associated with mild itching. Edema lasted approximately 3-4 days if not treated. Past and family medical history were negative for angioedema episodes, allergic disorders, autoimmune diseases, and other common eosinophilic diseases. History of rhinitis and chronic sinusitis. Physical examination showed unilateral periorbital edema of the face, normal vital signs, and BMI of 31.9 kg/m².

Noncontrast axial maxillofacial CT scan.

Noncontrast axial maxillofacial computed tomography scan shows the inferior portion of the left maxillary sinus lumen filled with fluid inflammatory material, indicating unilateral maxillary sinusitis with no bony erosion of the sinus wall

(A–C) Upper gastrointestinal endoscopy. (D) Upper gastrointestinal endoscopy, mucosal breaks ≤5 mm in length.

Upper gastrointestinal endoscopy in a patient with episodic angioedema with eosinophilia. The squamocolumnar junction “Z-line” is displaced cranially, which is suggestive of sliding hiatal hernia; incontinence of the cardia is observed (a–c). The presence of nonconfluent mucosal breaks that are ≤5 mm in length (d) revealed mild esophagitis.

(A) Total body PET/CT scan, cervical, mediastinal, and axillary lymph nodes, maximum diameter 1.3 cm, no FDG uptake. (B) Total body PET/CT scan, inguinal lymph nodes.

Figure 3. Positron Emission Tomography/Computed Tomography (PET/CT) total body scan. The exam revealed multiple cervical, mediastinal, and axillary (yellow arrows) lymphadenopathy (maximum diameter 1.3 cm) in the absence of fluoro-D-glucose (FDG) uptake (a). Reactive lymphadenopathies (yellow arrows) were also detected at the examination of the inguinal regions (b).

Laboratory results. Blood cell immunophenotyping. Upper GI endoscopy with random biopsies. Spirometry. Echocardiography. CT of the chest. Bone marrow biopsy. Genetic tests for BCR/ABL and FIP1L1-PDGFRA mutations.

Laboratory findings show AEC 9.617 g/L (normal 0-0.45), ANC 9.009 g/L (normal 1.8-7), normal immunoglobulins (IgM 2.080 g/L, IgG 9.410 g/L, IgA 1.320 g/L), normal total IgE 30.90 KU/L (<100), normal ESR 10 mm/h and CRP <0.33 mg/dL, negative ANA (0.11), negative ANCA-MPO and PR3-ANCA, normal complement levels (C3 1.28 g/L, C4 0.27 g/L, C1-inhibitor 0.292 g/L, C1q 19 mg/dL). Blood cell immunophenotyping shows CD3 83%, CD4 54%, CD8 14%, CD19 7%, CD56 7%, no aberrant T-cell population. Additional investigations: normal tumor markers, negative parasite tests, negative specific IgE for common allergens, upper GI endoscopy shows mild esophagitis with no eosinophilic infiltrate on random biopsies, normal spirometry and echocardiography, CT chest shows subcentimetric anterior mediastinal lymph nodes and axillary lymphadenopathy, bone marrow biopsy shows increased eosinophilic precursors and mild T-cell infiltrate but no atypical cells, negative genetic tests for BCR/ABL and FIP1L1-PDGFRA mutations

Episodic Angioedema with Eosinophilia (Gleich's syndrome)

Episodic angioedema with eosinophilia

Gleich syndrome