Chronic perineal fistula as a late failure manifestation of pseudomyxoma peritonei syndrome

Pseudomyxoma peritonei syndrome (PMP) is a rare but fascinating entity in surgical oncology. It consists of the accumulation of mucus in the peritoneal cavity, sometimes in huge amounts, in most of the cases after rupture of an appendiceal tumor. The diagnosis and management of PMP has changed significantly in the past 15 years, with the institution of an aggressive therapeutic combination: cytoreductive surgery and intraperitoneal perioperative chemotherapy. Few reports deal with the late manifestations and complications at endstage of the disease. The cases presented here are unique in that they illustrate a late 'failure' in the perianal area in three patients with long-term PMP.     

Immunohistochemical staining as supportive diagnostic tool for pseudomyxoma peritonei arising from intraductal papillary mucinous neoplasm: A report of two cases and literature review

Background/ObjectivesPseudomyxoma peritonei (PMP) arising from an intraductal papillary mucinous neoplasm of the pancreas (IPMN) is a rare condition. The diagnosis of IPMN as the origin of PMP is mainly inferred from the clinical course and the exclusion of PMP from other organs. The pathological diagnosis has not yet been established. To evaluate the usefulness of immunohistochemical staining for the diagnosis of the primary lesion of PMP as IPMN.MethodsThere are 2 cases of PMP arising from IPMN between March 2010 and December 2019 at National Center for Global Health and Medicine. A PubMed search that reported PMP arising from IPMN identified 16 additional cases. Diagnostic methods and clinicopathological features of 18 cases were compared.ResultsFour cases including our two cases used immunohistochemical staining for the diagnosis of PMP arising from IPMN. The correspondence of the immunohistochemical staining between PMP and IPMN was shown in the three cases including previously reported two cases and one of our two cases to identify the primary lesion of PMP as IPMN. In addition, we revealed that the comparison of the immunostaining pattern of PMP with the representative immunostaining pattern of the candidate primary lesions is helpful for the diagnosis of the primary lesion of PMP.ConclusionsImmunohistochemical staining is helpful to identify the primary lesion of PMP as IPMN.     

Pseudomyxoma peritonei arising from intraductal papillary neoplasm after surgical pancreatectomy: report of 2 cases and review of the literature

We report 2 cases of pseudomyxoma peritonei (PMP) combined with an intraductal papillary mucinous neoplasm (IPMN) and a review of the literature. In both cases, PMP emerged after surgical resection of the IPMN. In one case, neoplastic foci were present in the surgical margin and PMP was found 1 year after the initial resection, while PMP emerged 5 years after surgical resection in the other case. Including these 2 cases, 8 cases of PMP arising from IPMN have been reported. This condition occurs more frequently in males (7 males, 1 female), while the age at diagnosis ranges from 49 to 82 years, with a mean of 63.3 years. IPMNs occur more commonly in the tail of the pancreas (62.5%). Two different patterns regarding the mechanism of PMP arising from IPMN have been indicated; a rupture of the pancreatic duct, after which the neoplasm spreads through the fistula into the peritoneal cavity, and post-surgical development of PMP after insufficient surgical treatment for an IPMN. Our findings indicate that attention must be given to avoid mucous leakage and obtain a negative surgical margin during surgical treatment of an IPMN.     

Immediate-type hypersensitivity to pyridoxal 5'- phosphate: Study of in vivo and in vitro cross-reactivity and identification of the antigenic determinant

BackgroundA case in which a 45-year-old female patient with peritonitis experienced immediate-type hypersensitivity on two occasions after administration of preparations containing six different medications was referred to us for closer inspection.Methods/ResultsSkin tests performed on the six medications revealed a positive reaction to the vitamin B₆ preparation Biosechs (Wakamoto Pharmaceutical, Tokyo, Japan). Further investigation showed that the principal ingredient, pyridoxal 5'-phosphate (PLP), produced a positive reaction, whereas the injection solvent with the principal ingredient removed produced a negative reaction. When compounds similar to PLP were tested, pyridoxine (PN), pyridoxamine and pyridoxal produced a negative reaction, whereas pyridoxine 5'-phosphate and pyridoxamine 5'-phosphate (PMP) produced a positive reaction. Adenosine 2'-phosphate and adenosine 5'-diphosphate were also tested and these produced a negative reaction. When a histamine-release test was performed, PLP and PMP produced a positive reaction, whereas PN produced a negative reaction. When all tests were performed on three control subjects, the results were all negative.ConclusionsIn this very rare case, phosphate radical conjugates with a pyridine nucleus became haptenic-epitope and an immediate-type reaction occurred. In past cases involving hypersensitivity to vitamin B6, two cases involved a photoallergic reaction caused by PN and one case involved an immediate-type hypersensitivity caused by PLP In the past cases, closely related substances had not been tested and an epitope was not identified.     

Therapy of pseudomyxoma peritonei of appendiceal origin--surgical resection and intraperitoneal chemotherapy.

Pseudomyxoma peritonei (PMP) is rare clinical entity presenting with mucus-producing lesions on the peritoneal surface. PMP is found in middle-aged or older patients in approximately two out of 10,000 laparotomies. Most of the reported cases are due to a primary process located in either appendix or the ovaries. PMP presents with an insidious onset of symptoms, and is characterized by long-term survival with good general health and absence of visceral invasion or distant metastasis. The treatment of choice for PMP is surgical resection and the removal of free mucus. Despite a high rate of disease recurrence, adjuvant or palliative chemotherapy has not yet been clearly established. In our opinion, intraperitoneal application may be more effective than a systemic regimen because only local treatment can provide sufficient concentrations of chemotherapeutic agents. In view of the lack of standardized treatment regimens and based on our experience, we recommend intraperitoneal chemotherapy with 5-FU and mitomycin C or cisplatin. We report ten cases of PMP of appendiceal origin and present a review of the literature on this disease and its treatment.     

Diagnosis of Pseudomyxoma peritonei via endoscopic ultrasound guided fine needle aspiration: a case report and review of literature

Introduction: Pseudomyxoma peritonei (PMP) is a rare condition caused by mucinous adenocarcinoma cancerous cells that produce abundance of mucin or gelatinous ascites. This cancer can cause tissue fibrosis and can impair normal organ function. Diagnosis can involve multiple imaging modalities including CT scan. There have been few cases of endoscopic ultrasound (EUS) being used as a means for diagnosis of this condition. Here we report a second case of PMP with a previous history of appendectomy diagnosed with EUS guided fine needle aspiration (FNA) biopsy.

Case study: A 66-year-old male with a history of an appendectomy presented with intermittent abdominal pain for two years and weight loss of 40 pounds over two months. EGD and colonoscopy performed at an outside hospital was unremarkable. CT abdomen revealed perigastric ascities and lesions of the liver. ESR was elevated at 75. At our facility, EUS was performed revealing a peri-gastric and omental mass measuring 36.6?mm?×?25.5?mm. FNA performed of both mass and ascetic fluid revealed low grade mucinous adenocarcinoma with mucinous deposits in the peritoneum consistent with PMP.

Conclusions: Endoscopic ultrasound guided FNA, although very rarely used, can be a reliable and safe technique in diagnosis of PMP.     

On or in the liver? Two cases with diffuse pseudomyxoma peritonei and synchronous hepatic pathology

Pseudomyxoma peritonei (PMP) is a borderline malignancy, simulating carcinomatosis and generally arising from perforation of an appendiceal mucinous tumour. Some patients have coincidental dual pathology. Liver abnormalities in particular may be overlooked and/or misclassified. We report 2 cases of patients who had diffuse PMP with synchronous hepatic pathology to highlight the need for vigilance and appropriate assessment of coincidental liver lesions. An assessment and management strategy is outlined.     

Expression of complement components and inhibitors on platelet microparticles

Platelet microparticles (PMP) are released from activated platelets and play an important role in hemostasis, thrombosis and inflammation. Since platelets were recently found to demonstrate an intrinsic capacity for activating both classical and alternative pathways of the complement system, the present study extended these observations to PMP. PMP were generated by treating platelets with 10 µM A23187 (37°C, 5 min). PMP were identified by flow cytometry, based on size, Annexin V binding, and expression of P-selectin and GPIIb (CD41). PMP expressed gC1qR/p33, a multifunctional cellular protein that was recently described to activate the classical complement cascade. PMP also expressed the classical pathway and contact system regulator, C1 inhibitor (C1-INH), as well as CD55 and CD59. Despite C1-INH expression, PMP supported classical pathway C4 activation in the presence of purified C1 and C4. Moreover, statistically significant deposition of C3b and C5b-9 was detected on PMP exposed to plasma, concurrently with expression of CD55 and CD59. These data provide the first evidence for the ability of PMP to support in situ complement activation. Complement activation contributes to a variety of vascular and inflammatory disease states including atherosclerosis and ischemia/reperfusion injury.     

Myocardial hypertrophy and function are related to age at onset in familial amyloidotic polyneuropathy

Heart complications are frequently encountered in hereditary transthyretin amyloidosis. Lately, reports of late onset familial amyloid polyneuropathy (FAP) cases presenting with a phenotype similar to that observed in senile systemic amyloidosis have emerged. The aim of the present study was to evaluate morphological and functional features of the heart by echocardiography including myocardial strain measurements, and to compare the outcome for early with those of late onset FAP cases. Eighty-one biopsy and genetically proven FAP, ATTR Val30Met patients were investigated with two-dimensional, M-mode echocardiography and myocardial strain with special attention to inter-ventricular septum (IVS) thickness. IVS thickness was closely related to the age at onset (P < 0.0001), but not to duration of disease. Seventeen percent of the patients had severe left ventricular hypertrophy (IVS > 15 mm). These patients were all late onset cases and represented 39% of all of the late onset cases. Strain measurements were also closely related to IVS thickness and age at onset thereby signifying a decreased function of the heart muscle in late onset cases. From the present investigation it appears that late onset Swedish FAP-cases more readily develop cardiomyopathy with an increased IVS thickness. Different pathways for amyloid formation in the heart may operate in early and late onset cases.     

Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization

OBJECTIVE: Platelet activation is accompanied by the release of microparticles. However, little is known about the role of platelet-derived microparticles (PMP) in the regulation of angiogenesis and related clinical situations. The aim of our study was to evaluate the effect of PMP on angiogenesis and to analyze its mechanisms. METHODS: Both in vitro (rat aortic ring model, cell invasion test) and in vivo (agarose bead transplantation, artificial cardiac ischemia in Sabra rats) approaches were used in the study. RESULTS: A dose-dependent pro-angiogenic effect of PMP was observed in the rat aortic ring model. This effect could be eliminated by inhibition of VEGF, bFGF, and PDGF, but not heparanase. PMP exerted their effect via PI 3-kinase, Src kinase, and ERK, whereas protein kinase C and p38 were not involved. Moreover, PMP induced invasion of endothelial cells through a layer of matrigel. This effect was mediated by VEGF, heparanase, and PDGF, but not bFGF. Furthermore, PMP induced angiogenesis in an in vivo model in which agarose beads containing PMP were transplanted subcutaneously into mice. In addition, the effect of PMP on angiogenesis was evaluated in the model of in vivo chronic myocardial ischemia in rats. Ischemia induced a decrease in the number of functioning capillaries (34+/-21.5 vs. 157+/-42.0 per view field), but their amount increased after injection of PMP into the myocarium (97+/-27.3; p<0.001 vs. ischemia without PMP). CONCLUSIONS: PMP induce angiogenesis both in vitro and in vivo. Injection of PMP into the ischemic myocardium might improve the process of revascularization after chronic ischemia.     

Peripheral myelin protein 22 is a constituent of intercellular junctions in epithelia

Alterations in peripheral myelin protein 22 (PMP22) gene expression are associated with a host of heritable demyelinating peripheral neuropathies, yet the function of the protein remains unknown. PMP22 expression is highest in myelinating Schwann cells of peripheral nerves; however, significant levels of PMP22 mRNAs can be detected in a variety of non-neural tissue, including epithelia. To date, PMP22 protein expression and localization in non-neural tissues have not been studied in detail. In adult rat liver and intestine, and cultured epithelial cells, we detected PMP22-like immunoreactivity associated with markers of the tight junctional complex, including zonula occludens 1 (ZO-1) and occludin. Upon disruption of intercellular contacts, PMP22 was internalized into vesicles that were immunoreactive for both anti-occludin and anti-PMP22 antibodies. Nonionic detergent extraction of cultured epithelial cells did not solubilize PMP22, as the majority of the protein remained in the detergent insoluble fraction, as did ZO-1 and occludin. We also observed the targeting of exogenous myc-tagged PMP22 to apical cell junctions in polarized epithelia and to anti-ZO-1 antibody immunoreactive cell contacts of L fibroblasts. These studies support a role for PMP22 at intercellular junctions of epithelia and may indicate a similar function in myelinating Schwann cells. Furthermore, our findings could provide an explanation for certain phenotypes of PMP22 neuropathy mice that cannot be accounted for by dysmyelination.     

Primary meningococcal pericarditis: a disease of adults associated with serogroup C Neisseria meningitidis

Pericarditis due to Neisseria meningitidis is usually a consequence of meningeal disease or meningococcemia. This presentation includes a case report of primary meningococcal pericarditis (PMP) and a review of the clinical and epidemiologic features of 15 previously reported cases. All cases have been reported in the past 15 years. Most patients were older teenagers or adults. The median age and age distribution of PMP cases in the United States were significantly greater than that of patients with other meningococcal diseases reported to the Centers for Disease Control (CDC) (P = .005). Similarly, serogroup C N. meningitidis was isolated from 88% of U.S. patients with PMP, compared with isolation from 22% of patients with other meningococcal diseases reported to the CDC (P = .00016). Culture of pericardial fluid usually yielded meningococci, and most patients presented with signs and symptoms typical of purulent pericarditis. A positive pericardial culture was associated with the development of cardiac tamponade (P = .03). With appropriate antibiotic treatment and drainage of pericardial fluid when indicated, all 16 patients survived and experienced few or no sequelae.     

Platelet microparticles contain active caspase 3

During storage, platelets undergo processes resembling apoptosis, including microparticle release, aminophospholipid exposure, and procaspase 3 processing. Recently, we showed that microparticles from endothelial cells contain caspase 3, one of the executioner enzymes of apoptosis. In this study we determined whether platelet-derived microparticles (PMP) contain caspase 3 in vitro (stored platelet concentrate) and ex vivo (plasma from healthy humans). In addition, we studied the underlying mechanism of caspase 3 formation in PMP, and the ability of such PMP to induce apoptosis in human macrophages (THP-1 cells). The presence of caspase 3 (antigen) was studied by Western blot and flowcytometry, and activity was determined by Ac-DEVD-pNA and ROCK I cleavage. In vitro, PMP numbers increased during storage. From day one onwards, PMP contained procaspase 3, whereas caspase 3 (antigen and activity) was detectable after 5–7 days of storage. PMP contained caspase 9 but not caspase 8, and the time course of caspase 9 formation paralleled procaspase 3 disappearance and caspase 3 appearance. In addition, PMP in human plasma also contained detectable quantities of caspase 3. Incubation of THP-1 cells with PMP induced apoptosis. Taken together, PMP contain caspase 3 in vitro and ex vivo. Our data implicate that procaspase 3 is likely to be processed by caspase 9 in PMP during storage. PMP induce apoptosis of human macrophages, but whether this induction is due to the transfer of caspase 3 remains to be determined.     

Myocardial hypertrophy and function are related to age at onset in familial amyloidotic polyneuropathy.

Heart complications are frequently encountered in hereditary transthyretin amyloidosis. Lately, reports of late onset familial amyloid polyneuropathy (FAP) cases presenting with a phenotype similar to that observed in senile systemic amyloidosis have emerged. The aim of the present study was to evaluate morphological and functional features of the heart by echocardiography including myocardial strain measurements, and to compare the outcome for early with those of late onset FAP cases. Eighty-one biopsy and genetically proven FAP, ATTR Val30Met patients were investigated with two-dimensional, M-mode echocardiography and myocardial strain with special attention to inter-ventricular septum (IVS) thickness. IVS thickness was closely related to the age at onset (P < 0.0001), but not to duration of disease. Seventeen percent of the patients had severe left ventricular hypertrophy (IVS > 15 mm). These patients were all late onset cases and represented 39% of all of the late onset cases. Strain measurements were also closely related to IVS thickness and age at onset thereby signifying a decreased function of the heart muscle in late onset cases. From the present investigation it appears that late onset Swedish FAP-cases more readily develop cardiomyopathy with an increased IVS thickness. Different pathways for amyloid formation in the heart may operate in early and late onset cases.     

Combination therapy with pulsed methylprednisolone in rheumatoid arthritis.

Pulsed methylprednisolone (PMP) has been shown to produce clinical improvement and reduction in the ESR and acute phase protein concentrations in patients with active rheumatoid arthritis and has been advocated for use either as an alternative to slow-acting antirheumatoid drugs (SAARDs) or in conjunction with SAARDs to accelerate the response to treatment. To test these potential roles for PMP 45 patients with active RA were randomly allocated to treatment with PMP alone, PMP + sulphasalazine (SAS - at a maintenance dose of 2.0 g/day), or PMP + D-penicillamine (DPA - at a maintenance dose of 500 mg/day). In each case three 1 g intravenous infusions were given on alternate days during the first week of the trial. Patients were monitored for 24 weeks by standard clinical and laboratory measurements. All three treatment groups showed significant clinical and laboratory improvements at two weeks. With PMP + DPA and PMP + SAS these improvements were sustained and were not significantly different in these two treatment groups. However, in the 'PMP only' group ESR and CRP rose to pretreatment values by eight weeks. Twelve patients withdrew from the study owing to a relapse of the RA. No serious adverse effects were seen in the 'PMP only' group. Both combination regimens were well tolerated; adverse effects seen were attributable to either DPA or SAS. We conclude that PMP alone is insufficient for treatment of RA but can be used successfully in combination with either DPA or SAS. A comparison between these results obtained from two previous groups of 15 patients treated with DPA alone and SAS alone (using the same study design) shows that PMP accelerated the response to therapy by at least six weeks.     

Expression of complement components and inhibitors on platelet microparticles

Platelet microparticles (PMP) are released from activated platelets and play an important role in hemostasis, thrombosis and inflammation. Since platelets were recently found to demonstrate an intrinsic capacity for activating both classical and alternative pathways of the complement system, the present study extended these observations to PMP. PMP were generated by treating platelets with 10 microM A23187 (37 degrees C, 5 min). PMP were identified by flow cytometry, based on size, Annexin V binding, and expression of P-selectin and GPIIb (CD41). PMP expressed gC1qR/p33, a multifunctional cellular protein that was recently described to activate the classical complement cascade. PMP also expressed the classical pathway and contact system regulator, C1 inhibitor (C1-INH), as well as CD55 and CD59. Despite C1-INH expression, PMP supported classical pathway C4 activation in the presence of purified C1 and C4. Moreover, statistically significant deposition of C3b and C5b-9 was detected on PMP exposed to plasma, concurrently with expression of CD55 and CD59. These data provide the first evidence for the ability of PMP to support in situ complement activation. Complement activation contributes to a variety of vascular and inflammatory disease states including atherosclerosis and ischemia/reperfusion injury.     

Collagen-induced generation of platelet-derived microparticles in whole blood is dependent on ADP released from red blood cells and calcium ions

We have evaluated the effects of different anti-coagulants or agonists on the generation of platelet-derived microparticles (PMPs) using flow cytometry. Twenty microg/ml of collagen induced significantly greater PMP formation in whole blood anti-coagulated with argatroban, a selective thrombin inhibitor, as compared with platelet-rich plasma, or whole blood anti-coagulated with citrate. Thus, whole blood kept at the physiological Ca2+ concentration provides an optimal condition for the formation of PMP. Convulxin, a GPVI-selective agonist, also induced PMP formation at the magnitude which far exceeds those of other agonists, such as thrombin receptor-activating peptide, ADP or epinephrine. These findings suggest that GPVI-mediated platelet activation plays a key role in the formation of PMP in the presence of physiological Ca2+ in whole blood. The addition of red blood cells to PRP potentiated PMP formation induced by collagen. Pretreatment of whole blood with the combination of creatine phosphate and creatine phosphokinase reduced PMP formation induced by collagen. Blockade of ADP receptors, P2Y12 with AR-C69931MX and P2Y1 with A3P5P, respectively, further suppressed collagen-induced PMP formation. We conclude that ADP released from red blood cells enhances PMP formation induced by collagen, and that both P2Y12 and P2Y1 contribute to ADP-potentiation of PMP generation induced by collagen.     

A Case of Primary Meningococcal Pericarditis Caused by <Emphasis Type="Italic">Neisseria Meningitidis</Emphasis> Serotype Y with Rapid Evolution into Cardiac Tamponade

Primary meningococcal pericarditis (PMP) is a rare form of acute purulent pericarditis that often evolves into cardiac tamponade and usually requires pericardial drainage. PMP is a rare, difficult to diagnose, rapidly progressive form of meningococcal infections. PMP is typically caused by Neisseria meningitidis of serotype C, or, less commonly, B or W135. We report the second case of PMP caused by Neisseria meningitidis of serotype Y. Our patient was not critically ill at presentation, and her presentation could have been consistent with viral uncomplicated pericarditis with the exception of the mild leukocytosis with a left shift in the differential. Clinicians should be aware that early in the course of PMP, the illness may not be severe. Mild leukocytosis with a left shift or bandemia in the setting of what otherwise seems to be a case of uncomplicated viral pericarditis should prompt suspicion for PMP and further evaluation and/or monitoring. Disclosure: There is no grant or other extramural support for this work.     

A rare case of pseudomyxoma peritonei presenting an unusual inguinal hernia and splenic metastasis

Pseudomyxoma peritonei (PMP) is a rare clinical entity in which a diffuse collection of intraperitoneal gelatinous fluid is associated with gelatinous implants on the peritoneal surfaces and omentum. Hematogenic or lymphatic metastasis is extremely rare. In addition, an inguinal mass as an initial presentation is also relatively rare. This is a case report of a PMP patient who had splenic metastasis and showed an inguinal tumor as an initial presentation. A 59-year-old female patient, who had undergone bilateral oophorectomy because of a ruptured ovarian mucinous tumor of boderline malignancy 12 years previously, presented a presumptive diagnosis of a left inguinal irreducible hernia. Computed tomography revealed a low density mass in the pelvic cavity and in the inguinal lesion, as well as in the spleen without any diseases around the organ. The preoperative serum carcinoembryonic antigen (CEA) level was elevated. The patient underwent a resection of gelatinous tumor in the pelvic cavity, splenectomy, and appendectomy, as well as left inguinal herniorrhaphy. Histological examinations revealed a splenic metastasis of PMP originating from the ovarian low-grade mucinous tumor. She received postoperative intraperitoneal lavage as well as chemotherapy, and has survived for over 7 years postoperatively without any evidence of recurrence, as confirmed by repeated follow-up CT examinations and CEA determination. Splenic metastasis of PMP is extremely rare; this represents only the third reported case of its kind in the literature. Furthermore, it should be noted that an inguinal tumor can sometimes be an initial presentation of PMP.     

A novel PMP22 insertion mutation causing Charcot–Marie–Tooth disease type 3: A case report

Rationale:Charcot–Marie–Tooth disease (CMT) is a group of hereditary neuropathies with clinical features of muscle atrophy, sensory loss, and foot deformities. CMT is related to a number of genes, such as peripheral myelin protein 22 gene (PMP22). Missense mutations, small deletion mutations, and duplications of PMP22 are common in CMT patients, but few insertion mutation cases of PMP22 have been reported.Patient concerns:A 26-year-old male patient with the complaint of general weakness, peroneal atrophy, and deformities in the extremities visited our hospital. The patient was born with bilateral thumbs and feet dystonia. Additionally, delayed feet arch development and delayed walking was observed when he was a child.Diagnosis:Using whole-exome sequencing and electrophysiological test, we identified a novel insertion mutation of PMP22 ({"type":"entrez-nucleotide","attrs":{"text":"NM_153322","term_id":"1674986609"}}NM_153322, c.54_55insGTGCTG, p.(L19delinsVLL)) in a 26-year-old male patient with peroneal atrophy and nerve conduction was not elicited in electromyography (EMG) study. The Protein Variation Effect Analyzer (PROVEAN) program analysis predicted that the variant is likely to be “deleterious.” SWISS-MODEL program predicted that alpha helix in original location was disrupted by inserted 6 bases, which may account for the occurrence of CMT3.Interventions:The patient received symptomatic and supportive treatments, and routine rehabilitation exercises during hospitalization.Outcomes:The condition of the patient was improved, but the disease could not be cured. At 1- and 3-months follow-up, manifestations of the patient were unchanged, and he could take care of himself.Lessons:Our findings link a novel PMP22 mutation with a clinical diagnosis of CMT3. The link between gene variation and CMT phenotype may help to reveal the structure and function of PMP22 protein and the pathogenesis of CMT. This study adds further support to the heterogeneity of PMP22 related CMT and provides solid functional evidence for the pathogenicity of the p.(L19delinsVLL) PMP22 variant. Moreover, with the development of high-throughput sequencing technology, the combination of next-generation sequencing (NGS) and conventional Sanger sequencing is becoming one of the comprehensive, inexpensive, and convenient tools for genetic diagnosis of CMT.