Digital Gangrene as a Paraneoplastic Manifestation of Peripheral T-cell Lymphoma Not Otherwise Specified Type.

BACKGROUND: Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogenous group of predominantly nodal T cell lymphomas that generally presents with lymphadenopathy with or without extra nodal involvement. Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and acral cyanosis. Although, this condition is commonly associated with connective tissue disorder, smoking and vasculitis, its association with lymphoid malignancy is very rare. Here, we present a case report of a patient with digital gangrene of all toes and fingers as a presenting symptom of PTCL-NOS. CASE DESCRIPTION: A 62 year old male presented with digital ischemia associated with pain, low grade fever, loss of appetite and significant weight loss of 6 kilograms over a period of 3 months. On examination, he was found to have bilateral inguinal and axillary lymph nodes with gangrenous changes over toes and fingers but peripheral pulses were palpable. On evaluation he had anemia, elevated ESR and CRP. CT angiogram revealed thinned out digital arteries with multifocal areas of narrowing. Patient was screened for other causes of digital gangrene and was tested negative for ANCA, ANA, cryoglobulins and viral markers. Lymph node biopsy with IHC was suggestive of peripheral T-cell lymphoma-NOS and was started on CHOP regimen. Lymph nodes size decreased and gangrenous changes resolved. CONCLUSION: Though digital ischemia is a rare paraneoplastic presentation of lymphoma, it should be considered if there is a rapid progression of gangrene. Early initiation of chemotherapy may result in the reduction of further progression of digital gangrene and thus prevent permanent disability. In our patient, progression of gangrene was prevented even though it was an aggressive variant of T cell lymphoma.

Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.

PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.

Undergrowth Of First Toe In PiK3CA-Related Overgrowth Spectrum (PROS).

BACKGROUND: PIK3CA-related overgrowth syndrome (PROS) include a heterogeneous group of disorders characterized by segmental overgrowth secondary to somatic mosaic activating variants in PIK3CA. Segmental undergrowth is more uncommon and has been less studied but pathogenic variants in PIK3CA have also been found. With this in mind, we have noticed a group of patients with PROS that present an undergrowth component associated with their focal overgrowth. METHODS: Retrospective review of patients with PROS presenting overgrowth of the lower limb and undergrowth of the ipsilateral first toe was performed. RESULTS: Six patients were included, 4 female and 2 male with a median age of 16.8 years. All patients presented a PROS phenotype with overgrowth of the lower limb and undergrowth of ipsilateral first toe. A PIK3CA pathogenic variant was confirmed in all patients. Patients underwent multiple treatments, currently all are receiving alpelisib with a mean duration of 15.8 months (1-39) and partial response in lipomatosis and vascular anomalies but no response in overgrowth and undergrowth so far. CONCLUSIONS: Pathogenic variants in the same gene can create different phenotypes depending on the time and place of the mutation. There is little information regarding opposing phenotpyes in the same patient with PROS. The presence of undergrowth in our series might be explained by genetic, embryogenic, maternal, or placental factors but needs to be further investigated.

Foot Melanoma Localized to Subungual Toe Location Portends Poorer Prognosis.

Our group previously reported that melanoma of the foot is associated with advanced disease on diagnosis and decreased survival. Lesions localized to the toe appeared to have the worst outcomes. In this study, we both expanded our study to include a 10-year population of patient with invasive melanoma of the foot and ankle and investigated additional factors associated with prognosis. Between January 2007 and December 2016, 211 patients underwent biopsy diagnosis and surgery for invasive melanoma in the BLANK health care system. Demographic, pathologic, staging, and localization characteristics were studied for overall survival. Lesions were localized to dorsal foot, plantar foot, toe (nonsubungual), and toe (subungual) locations. Multivariable analysis found Breslow depth, ulceration, lymph node involvement, and subungual toe location to be associated with poorer survival. Overall survival rate for foot melanoma was 70.6%. Overall survival for nonsubungual toe melanoma was 60.7%, compared to 53.1% for subungual toe melanoma. Of the subungual melanomas, 37.5% of presented as deep lesions with a Breslow depth >4.0 mm. Subungual melanoma was statistically significant for and found to be an independent prognostic factor associated with poorer survival and advanced disease. Based on the results of this study, there should be a low threshold to biopsy suspicious lesions of the toe and foot with particular attention to be dedicated to subungual lesions.

Extraskeletal Ewing Sarcoma from Head to Toe: Multimodality Imaging Review.

Extraskeletal Ewing sarcoma (EES) is a rare subtype in the Ewing sarcoma family of tumors (ESFT), which also includes Ewing sarcoma of bone (ESB) and, more recently, primitive neuroectodermal tumors. Although these tumors often have different manifestations, they are grouped on the basis of common genetic translocation and diagnosis from specific molecular and immunohistochemical features. While the large majority of ESFT cases occur in children and in bones, approximately 25% originate outside the skeleton as EES. Importantly, in the adult population these extraskeletal tumors are more common than ESB. Imaging findings of EES tumors are generally nonspecific, with some variation based on location and the tissues involved. A large tumor with central necrosis that does not cross the midline is typical. Despite often nonspecific findings, imaging plays an important role in the evaluation and management of ESFT, with MRI frequently the preferred imaging modality for primary tumor assessment and local staging. Chest CT and fluorine 18 fluorodeoxyglucose PET/CT are most sensitive for detecting lung and other distant or nodal metastases. Management often involves chemotherapy with local surgical excision, when possible. A multidisciplinary treatment approach should be used given the propensity for large tumor size and local invasion, which can make resection difficult. Despite limited data, outcomes are similar to those of other ESFT cases, with 5-year survival exceeding 80%. However, with metastatic disease, the long-term prognosis is poor. ©RSNA, 2022.

Neurofibromatosis from Head to Toe: What the Radiologist Needs to Know.

Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are autosomal dominant inherited neurocutaneous disorders or phakomatoses secondary to mutations in the NF1 and NF2 tumor suppressor genes, respectively. Although they share a common name, NF1 and NF2 are distinct disorders with a wide range of multisystem manifestations that include benign and malignant tumors. Imaging plays an essential role in diagnosis, surveillance, and management of individuals with NF1 and NF2. Therefore, it is crucial for radiologists to be familiar with the imaging features of NF1 and NF2 to allow prompt diagnosis and appropriate management. Key manifestations of NF1 include café-au-lait macules, axillary or inguinal freckling, neurofibromas or plexiform neurofibromas, optic pathway gliomas, Lisch nodules, and osseous lesions such as sphenoid dysplasia, all of which are considered diagnostic features of NF1. Other manifestations include focal areas of signal intensity in the brain, low-grade gliomas, interstitial lung disease, various abdominopelvic neoplasms, scoliosis, and vascular dysplasia. The various NF1-associated abdominopelvic neoplasms can be categorized by their cellular origin: neurogenic neoplasms, interstitial cells of Cajal neoplasms, neuroendocrine neoplasms, and embryonal neoplasms. Malignant peripheral nerve sheath tumors and intracranial tumors are the leading contributors to mortality in NF1. Classic manifestations of NF2 include schwannomas, meningiomas, and ependymomas. However, NF2 may have shared cutaneous manifestations with NF1. Lifelong multidisciplinary management is critical for patients with either disease. The authors highlight the genetics and molecular pathogenesis, clinical and pathologic features, imaging manifestations, and multidisciplinary management and surveillance of NF1 and NF2. Online supplemental material is available for this article. ©RSNA, 2022.

Histopathology of persistent long COVID toe: A case report.

During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within 10 days of exposure. Biopsy specimen of the distal toe 16 weeks after initial exposure showed papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy specimen of "long COVID toe" following presumed SARS-CoV-2 exposure, with a demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.

A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review.

BACKGROUND: The abundance of publications of COVID-19-induced chilblains has resulted in a confusing situation. METHODS: This is a prospective single-institution study from 15 March to 13 May 2020. Thirty-two patients received PCR nasopharyngeal swabs. Of these, 28 patients had a thoracic CT-scan, 31 patients had blood and urine examinations, 24 patients had skin biopsies including immunohistochemical and direct immunofluorescence studies, and four patients had electron microscopy. RESULTS: COVID-19-induced chilblains are clinically and histopathologically identical to chilblains from other causes. Although intravascular thrombi are sometimes observed, no patient had a systemic coagulopathy or severe clinical course. The exhaustive clinical, radiological, and laboratory work-up in this study ruled-out other primary and secondary causes. Electron microscopy revealed rare, probable viral particles whose core and spikes measured from 120 to 133 nm within endothelium and eccrine glands in two cases. CONCLUSION: This study provides further clinicopathologic evidence of COVID-19-related chilblains. Negative PCR and antibody tests do not rule-out infection. Chilblains represent a good prognosis, occurring later in the disease course. No systemic coagulopathy was identified in any patient. Patients presenting with acral lesions should be isolated, and chilblains should be distinguished from thrombotic lesions (livedo racemosa, retiform purpura, or ischemic acral necrosis).

Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel FLNA variant.

Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X-linked filaminopathies caused by a variety of FLNA-variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in FLNA has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in FLNA in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis-splicing of exon 31 predicting the production of a FLNA-protein with an in-frame-deletion of 16 residues identical to the miss-splicing-effect of the recurrent TODPD c.5217G>A variant. This mis-spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X-inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the FLNA-variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy-related genes were found. Here we describe a novel variant in FLNA (c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before.

An Autopsy Review: "COVID Toes".

ABSTRACT: "Severe acute respiratory syndrome coronavirus-2" (SARS-CoV-2) infection has variable described dermatologic manifestations. "COVID (coronavirus disease) toes" became a hallmark of the disease in young and largely asymptomatic patients, who may have negative test results for SARS-CoV-2. Pernio (chilblains)-like lesions are seen mostly in infected pediatric patients and are purple painful, frequently bilateral, ill-defined plaques with prominent inflammation on histological examination. In contrast to pernio-like presentation in children, critically ill adult patients with SARS-CoV-2 develop "purple" digits that may be sharply demarcated and may demonstrate asymmetric areas of ischemia. These 2 contrasting entities are sometimes grouped together as "COVID toes" due to some similarities in clinical appearance and presentation. Here, we summarize histopathologic examination from an autopsy, including the cutaneous lesions from the affected and normal contralateral toes and correlate them with systemic findings. In contrast to pernio-like lesions, the skin of the affected necrotic toes contained thrombi in vessels without prominent inflammation, suggestive of an embolic event. This is further supported by the clinical history of and autopsy findings of popliteal artery thrombus and multiple subsegmental pulmonary emboli. Our findings suggest that critically ill patients with SARS-CoV-2 have different pathological processes affecting skin at peripheral sites (ie, fingers, toes, ears, and nose), which may be due to thromboembolic events. The skin is a mirror of the body and skin pathology may shed light into overall pathogenesis of systemic illness and processes.

COVID Purpura (Toes) Case Series: A Chilblains-Like Vasculopathy.

ABSTRACT: Biopsies were taken from 4 patients who presented to their dermatologist with violaceous papules and plaques of the dorsal toes (COVID Toes) associated with varying degrees of severe acute respiratory syndrome coronavirus 2 exposure and COVID-19 testing. Major histopathologic findings were lymphocytic eccrine inflammation and a spectrum of vasculopathic findings to include superficial and deep angiocentric-perivascular lymphocytic inflammation, lymphocytes in vessel walls (lymphocytic vasculitis), endothelial swelling, red blood cell extravasation, and focal deposits of fibrin in both vessel lumina, and vessel walls. Interface changes were observed to include vacuolopathy and apoptotic keratinocytes at the basement membrane. Immunostains showed a dominant T-cell lineage (positive for T-cell receptor beta, CD2, CD3, CD5, and CD7). B-cells were rare and clusters of CD123-positive dermal plasmacytoid dendritic cells were observed surrounding eccrine clusters and some perivascular zones. The consistent perieccrine and vasculopathic features represent important pathologic findings in the diagnosis of COVID toes and are suggestive of pathogenetic mechanisms. Clinicopathologic correlation, the epidemiological backdrop, and the current worldwide COVID-19 pandemic favor a viral causation and should alert the physician to initiate a workup and the appropriate use of COVID-19 testing.

Identification of a novel biallelic missense variant in the KIAA0825 underlies postaxial polydactyly type A.

Postaxial polydactyly (PAP) is characterized by development of extra digits, which mostly segregates in autosomal recessive pattern. The underlying genetic cause of recessive non-syndromic PAP type A has been associated with sequence variants in five different genes (ZNF141, IQCE, GLI1, FAM92A, KIAA0825). The present study was aimed to investigate clinical and genetic causes of PAPA in a consanguineous family of Pakistani origin. Microsatellite-based linkage analysis was used to search for the disease-causing gene. Linkage in the family was established at chromosome 5q15 harbouring a candidate gene KIAA0825. Subsequently, Sanger sequencing revealed a novel homozygous missense variant [c.50T>C; p. (Leu17Ser)] in the gene, which co-segregated with the disease within the family. Protein structural analysis predicted a substantial change in the secondary structure of the mutant protein affecting its function. This is the third disease causing variant identified in the KIAA0825. This has not only expanded spectrum of the mutations in the gene but also further substantiated its role in the limb development in human.

A Review of COVID-19 Chilblains-like Lesions and Their Differential Diagnoses.

GENERAL PURPOSE: To familiarize wound care practitioners with the differential diagnoses of chilblains-like lesions that could be associated with the complications of COVID-19. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Identify the population most often affected by COVID toes.2. Select the assessments that help differentiate the various conditions that cause chilblains-like lesions.3. Choose appropriate treatment options for the various conditions that cause chilblains-like lesions.

This review article focuses on the pathogenesis, clinical features, and diagnostic testing of the common pathologies that can manifest as chilblains-like lesions. These differentials include "COVID toes," Raynaud phenomenon, acrocyanosis, critical limb ischemia, thromboangiitis obliterans, chilblains associated with lupus erythematosus, and idiopathic chilblains. The authors present a helpful mnemonic, ARCTIC, to assist clinicians in recognition and diagnosis.

Preoperative Japanese Society for the Surgery of the Foot Lesser toe score and erythrocyte sedimentation rate influence wound healing following rheumatoid forefoot surgery.

OBJECTIVES: Delayed wound healing is one of the most common complications following forefoot surgery in patients with rheumatoid arthritis. We aimed to identify the risk factors for delayed wound healing following rheumatoid forefoot surgery. METHODS: Consecutive patients who underwent primary rheumatoid forefoot surgery (86 feet; 53 patients) between April 2008 and February 2019 were retrospectively evaluated. Clinical data, including smoking history, duration of the disease, presence of diabetes mellitus, medication, white blood cell count, erythrocyte sedimentation rate (ESR), C-reactive protein, the surgical procedure performed, and the Japanese Society for Surgery of the Foot (JSSF) scores, were collected. RESULTS: Delayed wound healing was identified in 20 of 86 (23.3%) feet. In univariate analysis, participants showing delayed healing were older at the time of surgery (p = .04), their ESR was higher (p = .0006), and their total (p = .019) and pain (p = .016) scores on the JSSF Lesser toe scale were lower than those showing normal healing. In multivariable analysis, both the total preoperative JSSF Lesser toe scale score (p = .0239) and ESR (p = .0126) remained significant risk factors for delayed wound healing. CONCLUSIONS: After rheumatoid forefoot surgery, surgeons should pay more attention to wound care in patients with lower preoperative JSSF Lesser toe score and high ESR.

Challenges in the clinical diagnosis of psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic heterogeneous inflammatory musculoskeletal disease. The non-specific and often subtle manifestations make early diagnosis and subsequent treatment challenging. In the absence of diagnostic criteria and biomarkers, the diagnosis is often delayed leading to poor long-term outcomes. In addition, the differential diagnosis of a patient presenting with arthritis in the setting of skin psoriasis is wide due to symptom overlap with many other diseases. Peripheral arthritis, dactylitis, enthesitis and axial arthritis are the 4 domains of musculoskeletal involvement in PsA and careful examination of each domain by a rheumatologist is the first step for a correct diagnosis. Other extra-musculoskeletal features such as the presence of uveitis, inflammatory bowel disease, nail psoriasis and elevated acute phase reactants aid in the diagnosis of PsA. Screening patients with skin psoriasis using validated questionnaires might help in early diagnosis especially when coupled with imaging.

Recurrent novel THBS1-ADGRF5 gene fusion in a new tumor subtype "Acral FibroChondroMyxoid Tumors".

Acral soft tissue tumors are common neoplasms, a subset of which pose a diagnostic challenge. We report 10 cases of a previously unrecognized acral benign soft tissue tumor. These tumors arose on the fingers and toes and involved bone in half of cases. Histologically, the tumors were lobulated and displayed an abundant stroma made of variable fibrous, chondroid and myxoid material reminiscent of cartilaginous or myoepithelial differentiation. Tumor cells harbored small round to reniform nuclei with clear chromatin and inconspicuous nucleoli along with scant eosinophilic cytoplasm. The cells were mostly arranged haphazardly in the stroma but also in small clusters. No mitotic activity was detected. No specific feature was identified in recurrent cases. By immunohistochemistry, the cells consistently stained for CD34 (10/10), ERG (9/10), and SOX9 (7/10). Whole RNA sequencing identified a previously undescribed recurrent in frame THBS1-ADGRF5 gene fusion in all cases. The transcript was confirmed by RT-PCR and was not found in the control group of mimickers including soft tissue chondromas. We propose the name of Acral FibroChondroMyxoid Tumors for this new entity.

A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote.

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.

Brachydactyly type A3 is caused by a novel 13 bp HOXD13 frameshift deletion in a Chinese family.

Brachydactyly type A (BDA) is defined as short middle phalanges of the affected digits and is subdivided into four types (BDA1-4). To date, the molecular cause is unknown. However, there is some evidence that pathogenic variants of HOXD13 could be associated with BDA3 and BDA4. Here, we report a Chinese autosomal dominant BDA3 pedigree with a novel HOXD13 mutation. The affected individuals presented with an obviously shorter fifth middle phalanx. The radial side of the middle phalanx was shorter than the ulnar side, and the terminal phalanx of the fifth finger inclined radially and formed classical clinodactyly. Interestingly, the index finger was normal. The initial diagnosis was BDA3. However, the distal third and fourth middle phalanges were also slightly affected, resulting in mild radial clinodactyly. Both feet showed shortening of the middle phalanges, which were fused to the distal phalanges of the second to the fifth toes, as reported in BDA4. Therefore, this pedigree had combined BDA3 and atypical BDA4. By direct sequencing, a 13 bp deletion within exon 1 of HOXD13 (NM_000523.4: c.708_720del13; NP_000514.2: p.Gly237fs) was identified. The 13 bp deletion resulted in a frameshift and premature termination of HOXD13. This study provides further evidences that variants in HOXD13 cause BDA3-BDA4 phenotypes.

Multiple synostoses syndrome: Clinical report and retrospective analysis.

Multiple synostoses syndrome (SYNS1; OMIM# 186500) is a rare autosomal dominant disorder reported in a few cases worldwide. We report a Chinese pedigree characterized by proximal symphalangism, conductive hearing loss, and distinctive facies. We examined the genetic cause and reviewed the literature to discuss the pathogeny, treatment, and prevention of SYNS1. Audiological, ophthalmological, and radiological examinations were evaluated. Whole-exome sequencing (WES) was performed to identify mutations in the proband and her parents. Sanger sequencing was used to verify the results for the proband, parents, and grandmother. The literature on the genotype-phenotype correlation was reviewed. The patient was diagnosed with multiple synostoses syndrome clinically. WES and bioinformatic analysis revealed a novel missense mutation in the NOG gene, c.554C>G (p.Ser185Cys), cosegregated in this family. The literature review showed that the phenotype varies widely, but the typical facies, conductive hearing loss, and proximal symphalangism occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there are regional hot spots for these mutations. However, no distinct genotype-phenotype correlations have been identified for mutations in NOG in different races. Regular systematic examinations and hearing aids are beneficial for this syndrome. However, the outcomes of otomicrosurgery are not encouraging owing to the regrowth of bone. This study expanded the mutation spectrum of NOG and is the first report of SYNS1 in a Chinese family. Genetic testing is recommended as part of the diagnosis of syndromic deafness. A clinical genetic evaluation is essential to guide prevention, such as preimplantation genetic diagnosis.

Intraosseous epidermoid cysts of adjacent digits in a dog.

BACKGROUND: Intraosseous epidermoid cyst (IEC) is a rare, non-neoplastic, pathology in animals and humans that most commonly affects the distal phalanx. In dogs, it is important to differentiate this lesion from malignant digital tumours causing bone lysis. In previous reports, IEC has been described to affect only a single digit at the time of diagnosis which is usually based on histopathology. This is the first case report to describe immunohistochemically confirmed IECs affecting simultaneously multiple digits. CASE PRESENTATION: A 4-and-a-half-year-old female spayed Great Dane was presented with a 2-month history of progressive swelling of the distal phalanx (PIII) of digits IV and V of the right pelvic limb. Eleven weeks prior to presentation, the dog had a low-grade cutaneous mast cell tumour completely excised from the craniolateral base of its left pinna. A history of trauma to 1 of the nails of the same pes 4 years prior to referral was also reported. Examination of the right pelvic limb identified firm non-painful swelling of PIII of digits IV and V, with concurrent deformation of the nails. Radiographs of the right pes obtained by the primary veterinarian identified an expansile lesion of PIII of digits IV and V. Computed tomography identified large expansile lesions of PIII of digits IV and V, with associated cortical thinning and soft tissue swelling. Neoplasia was considered the most likely radiographic diagnosis. Histopathology of Jamshidi bone biopsies was consistent with intraosseous epidermoid cyst, which was confirmed with immunohistochemistry. Amputation of PIII of digits IV and V at the level of mid-PII was performed as definitive treatment. No recurrence of the lesion occurred during the 10-month follow-up period. CONCLUSIONS: Intraosseous epidermoid cysts should be included in the differential diagnosis for expansile lesions affecting the canine digit. It is important to differentiate them from other digital lesions, with bone involvement, such as malignant digital tumours, which often require more extensive surgery for definitive treatment. The case herein highlights that this lesion can affect simultaneously multiple digits. Definitive diagnosis can be achieved by identification of keratin-producing epithelial cells on histopathology and confirmed by pancytokeratin labelling.