Clinical Experience of Axillary Radiotherapy for Node-positive Breast Cancer.

AIMS: Patients with breast cancer who have positive lymph nodes are currently recommended axillary node clearance (ANC) or regional nodal irradiation (RNI). ANC is associated with complications such as lymphoedema, brachial plexopathy and shoulder stiffness. The AMAROS Group showed RNI to be non-inferior to ANC with regards to survival and recurrence, and with a better quality of life. We conducted a large real-world population study to show our centre's experience with the use of RNI and to contribute to the current discussion around the management of node-positive breast cancer. MATERIALS AND METHODS: We evaluated patients who received RNI as opposed to ANC between 2006 and 2009 (n = 190). Patients had a range of cancer subtypes/grades. All had positive axillary disease, identified by axillary node sampling or sentinel lymph node biopsy. Systemic therapy was given as per standard protocol. Our data were compared with those of patients who had RNI (n = 681) in AMAROS. Patients were followed up retrospectively and overall survival, breast cancer-specific survival, distant metastasis-free survival, locoregional recurrence and toxicity were recorded, including lymphoedema, brachial plexopathy and shoulder stiffness. Survival analysis was performed on R via the Kaplan-Meier method. Univariate and multivariate analyses were also performed. Toxicity data were reported as percentages. Patients meeting POSNOC trial criteria (one to two positive sentinel lymph nodes, macrometastasis, receiving adjuvant chemotherapy) including if oestrogen receptor-positive (stratified POSNOC) were identified for subgroup analysis in the regression model. RESULTS: Locoregional recurrence was 3.16% versus AMAROS RNI of 1.82%. Overall survival was slightly lower in our population, but cancer-specific survival was higher than AMAROS. Lymphoedema rates were 5.8% versus AMAROS 11% in RNI and 23% in ANC arms, respectively. Brachial plexopathy was 1.6% and arm/shoulder stiffness 7.4%. AMAROS conducted a quality of life survey pertaining to arm/shoulder stiffness, mobility and function, which seemed to affect about 18% in the RNI arm. Univariate analysis revealed POSNOC status, especially if also oestrogen receptor-positive, to be a low risk group with hazard ratio 0.42 (0.20-0.83, P = 0.015). Extracapsular extension of lymph node metastasis was a poor prognostic factor; hazard ratio 4.39 (1.45-14.0, P = 0.009). CONCLUSION: We support the conclusion of the AMAROS trial with survival and recurrence following RNI being non-inferior to ANC, and with similarly favourable toxicity data. We support the continuing use of RNI as a treatment option for patients with node-positive breast cancer. Further research is required to answer the key questions regarding personalised management for node-positive breast cancer, with regards to de-escalation and also intensification for the patients exhibiting adverse tumour biology.

Natural History of Brachial Plexus, Peripheral Nerve, and Spinal Schwannomas.

BACKGROUND: Management of sporadic schwannomas is often dictated by a patient's clinical presentation and the tumor's behavior. For patients who are managed nonsurgically, there are little data available about the expected natural history. OBJECTIVE: To evaluate the natural history and growth patterns of extracranial schwannomas including tumors of the distal peripheral nerves, spine, and brachial plexus. METHODS: A retrospective review was performed to identify patients with nonsyndromic extracranial schwannomas at a single tertiary care institution diagnosed between 2002 and 2019. Patient data and tumor characteristics including volume were recorded. RESULTS: Two hundred twenty-seven patients were identified (mean age 51 years, 42% male, average of 27.8-month follow-up). Tumor location was distal peripheral nerve in 82, brachial plexus in 36, and paraspinal in 109. At the time of diagnosis, peripheral lesions were significantly larger than spinal (59 m 3 vs 13 cm 3 ) and brachial plexus lesions (15 cm 3 ). Distinct growth patterns were seen with both distal peripheral nerve and spinal lesions; 34/82 peripheral nerve lesions had fast growth (ß = 0.176%/day), and 48 had slow growth (ß = 0.021%/day; P < .01). Spinal schwannomas similarly had 30 fast-growing (ß = 0.229%/day), 16 moderate-growing (ß = 0.071%/day), and 63 slow-growing (ß = 0.022%/day; P = .03) subtypes. The brachial plexus had relatively homogeneous growth patterns (ß = 0.065%/day). Females had 2.9 times greater odds of having the fast-growing subtype. CONCLUSION: Distinct growth patterns were seen in extracranial sporadic schwannomas based on tumor location and patient demographics. Fast (>80% volume change per year) vs slow (5%-10% per year) tumor growth can often be ascertained within 2 follow-up images. Awareness of these patterns might have implications for patient counseling and therapeutic decision-making.

Significant Asymmetry of the Bilateral Upper Extremities of a Skeleton Excavated from the Mashiki-Azamabaru Site, Okinawa Island, Japan.

The human skeleton of a young adult male with marked asymmetry of the bilateral upper extremities was excavated from the Mashiki-Azamabaru site (3000-2000 BCE) on the main island of Okinawa in the southwestern archipelago of Japan. The skeleton was buried alone in a corner of the cemetery. In this study, morphological and radiographic observations were made on this skeleton, and the pathogenesis of the bone growth disorder observed in the left upper limb was discussed. The maximum diameter of the midshaft of the humerus was 13.8 mm on the left and 21.2 mm on the right. The long bones comprising the left upper extremity lost the structure of the muscle attachments except for the deltoid tubercle of the humerus. The bone morphology of the right upper extremity and the bilateral lower extremities was maintained and was close to the mean value of females from the Ohtomo site in northwestern Kyushu, Japan, during the Yayoi period. It is assumed that the anomalous bone morphology confined to the left upper extremity was secondary to the prolonged loss of function of the muscles attached to left extremity bones. In this case, birth palsy, brachial plexus injury in childhood, and acute grey matter myelitis were diagnosed. It was suggested that this person had survived into young adulthood with severe paralysis of the left upper extremity due to injury or disease at an early age.

Estimating the tolerance of brachial plexus to hypofractionated stereotactic body radiotherapy: a modelling-based approach from clinical experience.

BACKGROUND: Brachial plexopathy is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose-response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor. METHODS: Two published SBRT datasets were pooled and modeled from patients at Indiana University and the Richard L. Roudebush Veterans Administration Medical Center from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events, and a probit dose response model was created with maximum likelihood parameter fitting. RESULTS: This analysis includes a total of 89 brachial plexus maximum point dose (Dmax) values from both institutions. Among the 14 patients who developed brachial plexopathy, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1-72.2) in the Karolinska dataset, and the Indiana dataset had a median of 13 months (range 1-71). Both studies had a median range of 3 fractions, but in the Indiana dataset, 9 patients were treated in 4 fractions, and the paper did not differentiate between the two, so our analysis is considered to be in 3-4 fractions, one of the main limitations. The probit model showed that the risk of brachial plexopathy with Dmax of 26 Gy in 3-4 fractions is 10%, and 50% with Dmax of 70 Gy in 3-4 fractions. CONCLUSIONS: This analysis is only a preliminary result because more details are needed as well as additional comprehensive datasets from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance.

Roles of preoperative and early postoperative electrodiagnosis in brachial plexus injury patients undergoing nerve transfer operations: retrospective feasibility study.

OBJECTIVE: The purpose of this retrospective observational study was to assess the feasibility of electrodiagnostic parameters, perioperatively, and to discover optimal values as prognostic factors for patients with brachial plexus injury undergoing nerve transfer operations. METHODS: We retrospectively reviewed the records of 11 patients who underwent nerve transfer surgery. The patients underwent perioperative electrodiagnosis (EDX) before and approximately 6 months after surgery. We evaluated the compound muscle action potential (CMAP) ratio, motor unit recruitment, and their interval changes. To evaluate motor strength, we used the Medical Research Council (MRC) grade, 6 and 12 months after surgery. We evaluated the relationships between improved CMAP ratio, and motor unit recruitment and MRC grade changes 6 and 12 months postoperatively. RESULTS: All parameters increased significantly after surgery. The CMAP ratio improvement 6 months after surgery correlated with the MRC grade change from baseline to 12 months, with a correlation coefficient of 0.813. CONCLUSION: EDX parameters improved significantly postoperatively, and the CMAP ratio improvement 6 months after surgery correlated with the clinical outcomes at 1 year. The results of perioperative EDX might help establish long-term treatment plans for patients who undergo nerve transfer surgery.

Anatomy, Imaging, and Pathologic Conditions of the Brachial Plexus.

The brachial plexus is an intricate anatomic structure with an important function: providing innervation to the upper extremity, shoulder, and upper chest. Owing to its complex form and longitudinal course, the brachial plexus can be challenging to conceptualize in three dimensions, which complicates evaluations in standard orthogonal imaging planes. The components of the brachial plexus can be determined by using key anatomic landmarks. Applying this anatomic knowledge, a radiologist should then be able to identify pathologic appearances of the brachial plexus by using imaging modalities such as MRI, CT, and US. Brachial plexopathies can be divided into two broad categories that are based on disease origin: traumatic and nontraumatic. In the traumatic plexopathy group, there are distinct imaging findings and management methods for pre- versus postganglionic injuries. For nontraumatic plexopathies, having access to an accurate patient history is often crucial. Knowledge of the timing of radiation therapy is critical to diagnosing post-radiation therapy brachial plexopathy. In acute brachial neuritis, antecedent stressors occur within a specific time frame. Primary and secondary tumors of the brachial plexus are not uncommon, with the most common primary tumors being peripheral nerve sheath tumors. Direct extension and metastasis from primary malignancies such as breast and lung cancer can occur. Although diagnosing a brachial plexus anomaly is potentially perplexing, it can be straightforward if it is based on foundational knowledge of anatomy, imaging findings, and pathologic features. ©RSNA, 2020.

Characteristics of metastatic brachial plexopathy in patients with breast cancer.

PURPOSE: Brachial plexopathy in cancer patients is a rare but significant complication that causes pain and disability of the upper extremities. Clinical features of breast cancer patients with metastatic brachial plexopathy (MBP) have not been studied. We aimed to investigate the characteristics of MBP in breast cancer patients. METHODS: We retrospectively reviewed medical records of patients with breast cancer with MBP who visited Asan Medical Center from 2000 to 2016; we enrolled 44 patients. We comprehensively reviewed the characteristics, range of metastatic lymph nodes, initial symptoms, location, and severity of brachial plexus injury by electrodiagnostic study, radiologic findings, and associated complications. RESULTS: The mean age of patients with MBP was 51.9 ± 9.3 years; 25% were diagnosed with stage IV breast cancer at initial diagnosis. Weakness was the most common initial symptom of MBP (52.3%). Most patients showed limitation of shoulder range of motion and pain; 66% of patients exhibited malignant lymphedema. Forty-one patients were evaluated by electromyography; upper nerve trunk involvement (22.0%) was more frequent than lower nerve trunk involvement (9.8%). Nineteen patients underwent brachial plexus MRI, and supraclavicular area (SCA) metastasis was most frequent (57.9%). Sixteen patients were examined by both brachial plexus MRI and electromyography; patients with SCA metastasis exhibited significantly more frequent malignant lymphedema (p = 0.019) and upper nerve trunk involvement (p = 0.035), compared with patients with non-SCA metastasis. CONCLUSIONS: Our study revealed clinical features of MBP in breast cancer patients. Additional diagnostic evaluation focused on metastasis or aggravated metastatic tumor is needed when breast cancer patients are diagnosed with brachial plexopathy.

Incorporation of Biologic Response Variance Modeling Into the Clinic: Limiting Risk of Brachial Plexopathy and Other Late Effects of Breast Cancer Proton Beam Therapy.

PURPOSE: The relative biologic effectiveness (RBE) rises with increasing linear energy transfer toward the end of proton tracks. Presently, there is no consensus on how RBE heterogeneity should be accounted for in breast cancer proton therapy treatment planning. Our purpose was to determine the dosimetric consequences of incorporating a brachial plexus (BP) biologic dose constraint and to describe other clinical implications of biologic planning. METHODS AND MATERIALS: We instituted a biologic dose constraint for the BP in the context of MC1631, a randomized trial of conventional versus hypofractionated postmastectomy intensity modulated proton therapy (IMPT). IMPT plans of 13 patients treated before the implementation of the biologic dose constraint (cohort A) were compared with IMPT plans of 38 patients treated on MC1631 after its implementation (cohort B) using (1) a commercially available Eclipse treatment planning system (RBE = 1.1); (2) an in-house graphic processor unit-based Monte Carlo physical dose simulation (RBE = 1.1); and (3) an in-house Monte Carlo biologic dose (MCBD) simulation that assumes a linear relationship between RBE and dose-averaged linear energy transfer (product of RBE and physical dose = biologic dose). RESULTS: Before implementation of a BP biologic dose constraint, the Eclipse mean BP D0.01 cm3 was 107%, and the MCBD estimate was 128% (ie, 64 Gy [RBE = biologic dose] in 25 fractions for a 50-Gy [RBE = 1.1] prescription), compared with 100.0% and 116.0%, respectively, after the implementation of the constraint. Implementation of the BP biologic dose constraint did not significantly affect clinical target volume coverage. MCBD plans predicted greater internal mammary node coverage and higher heart dose than Eclipse plans. CONCLUSIONS: Institution of a BP biologic dose constraint may reduce brachial plexopathy risk without compromising target coverage. MCBD plan evaluation provides valuable information to physicians that may assist in making clinical judgments regarding relative priority of target coverage versus normal tissue sparing.

The morphologic change of the elbow with flexion contracture in upper obstetric brachial plexus palsy.

BACKGROUND: Contracture of the elbow after obstetric brachial plexus palsy (OBPP) is well known; however, details of the 3-dimensional (3D) morphologic changes in the elbow joint in OBPP have not been clarified. This study aimed to clarify the 3D morphologic changes in the elbow joint by focusing on the distal humerus with flexion contracture in upper OBPP. We tested the hypothesis that the shape of the distal humerus with flexion contracture in upper OBPP is hypoplastic in the trochlea, capitellum, and olecranon fossa. METHODS: We retrospectively studied 20 patients with elbow flexion contracture and residual OBPP. The approximate radius of the distal humerus, the shortest distance between the olecranon and coronoid fossa, and the size of the olecranon fossa were measured and compared between the affected and normal sides using 3D bone models to assess the distal humerus morphology. RESULTS: The average radius of the distal humerus was smaller on the affected side than on the normal side. Furthermore, the average distance between the olecranon and coronoid fossa was greater and the average size of the olecranon fossa was smaller on the affected side than on the normal side. The size of the distal humerus was significantly smaller and the olecranon fossa was significantly shallower on the affected side. CONCLUSIONS: Consistent with our original hypothesis, the distal humerus with flexion contracture in upper OBPP was hypoplastic. The shallow olecranon fossa might prevent full extension of the elbow even though soft tissue contracture release is performed. We recommend evaluation of the morphology of the olecranon fossa to determine the treatment plan for elbow flexion contracture with OBPP.

Contralateral C7 transfer to lower trunk via a subcutaneous tunnel across the anterior surface of the chest and neck for total brachial plexus root avulsion: a cadaveric study.

BACKGROUND: Restoration of hand function after total brachial plexus root avulsion (tBPRA) is a difficult problem in surgical management. A new modified approach in repairing tBPRA is to use a subcutaneous tunnel across the anterior surface of the chest and neck, and then transfer the contralateral C7 root (cC7) to the lower trunk. However, the anatomical details of this method have not yet been fully described and assessed. The objective of this study was to quantitatively describe the nerve transfer using a cadaveric surgical simulation. MATERIALS AND METHODS: Brachial plexuses were dissected from 12 adult cadavers, producing 24 sides of brachial plexuses for nerve transfer experiments. We performed simulated cC7 transfers to the lower trunk via a subcutaneous tunnel across the anterior surface of the chest and neck. Measurements of the nerves were made and transfers quantitatively documented. RESULTS: With the affected shoulder and arm in a neutral position, cC7 and C8-T1 could be sutured directly together in 75% of the cadavers. A nerve graft length of 4.6 ± 1.18 cm was needed to bridge the gap in the remaining cadavers. For cadavers where distal cC7 was directly connected with the lower trunk, 54.17% could be sutured, and an average nerve graft length of 3.9 cm was needed in the remains. CONCLUSIONS: For surgical management of total tBPRA, transfer of the cC7 nerve to the C8-T1 or lower trunk via a subcutaneous tunnel across the chest and neck will likely be superior to a conventional cC7 root transfer in the clinic. This approach shortens the nerve graft needed and nerve regeneration distance, decreases the number of neurorrhaphy sites, and makes full use of the donor nerves, which may benefit hand flexion restoration.

Current status of magnetic resonance neurography in evaluating patients with brachial plexopathy.

Magnetic resonance neurography (MRN) is recognized as the imaging modality of choice in the evaluation of patients with brachial plexopathy. It adds vital information to the results of the clinical evaluation and electrodiagnostic tests and facilitates patient management. Its indications include both trauma and non-traumatic forms of plexopathy such as inflammatory, neoplastic and compressive. This article will familiarize readers with the routine MRN protocol in clinical practice and discuss the utility of the different sequences. The timing of the scan is important, especially with reference to trauma and this has been discussed. Both the advantages and limitations of MRN have been elaborated upon.

Ultrasound of the Brachial Plexus.

Examination of the brachial plexus with ultrasound is efficient because it allows many parts of the brachial plexus as well as the surrounding soft tissues to be assessed with high spatial resolution. The key to performing good ultrasound of the brachial plexus is being familiar with the anatomy and the common variants. That makes it possible to concentrate solely on the ultrasound appearances free of simultaneously wondering about the anatomy. Ultrasound of the brachial plexus is particularly good for assessing nerve sheath tumor, perineural fibrosis, metastases, some inflammatory neuropathies, neuralgic amyotrophy, and posttraumatic sequalae. It is limited in the assessment of thoracic outlet syndrome and in the acute/subacute trauma setting. This review addresses the anatomy, ultrasound technique, as well as pathology of the brachial plexus from the cervical foramina to the axilla.

Development of a Device-Assisted Nerve-Regeneration Procedure in Disruptive Lesions of the Brachial Plexus.

BACKGROUND: We describe the development of a new surgical procedure to be used in the treatment of disruptive brachial plexus (BP) lesions. It is centered on an artificial device designed to assist nerve regeneration by providing a confined and protected environment. Nerve fibers can repair inside the device, while the adverse massive scar-tissue formation is limited to the outside of the device. METHODS: Steps in the development of the procedure were (1) definition of the rationale, (2) design of the device, (3) choice of an in vivo translational model, (4)refinement of the surgical procedure, and (5) performance of an in vivo pilot study as a proof of concept. An interdisciplinary team from several laboratories was involved in this work over a period of 6 years. RESULTS: Results showed the absence of significant scar tissue in the regenerate and the presence of myelinated fibers aligned proximodistally between the stumps. This surgical approach can be seen not only as a definitive treatment but also as an early examination and stabilization before some different surgery will be later performed. It may also be used as additional protection for traditional surgery like end-to-end coaptation. CONCLUSIONS: We conclude that the availability of a suitable device-assisted early treatment, even if not to be considered definitive, could help in addressing the BP lesions at an earlier stage and this may improve the final outcome. Our evidence justifies further experimentation on this approach.

Perineural Spread of Nonmelanoma Skin Cancer to the Brachial Plexus: Identifying Anatomic Pathway(s).

BACKGROUND: Perineural spread leading to brachial plexopathy has recently been described in cases of melanoma. The occurrence and mechanism for nonmelanoma skin cancer spread to the brachial plexus is poorly understood. METHODS: A retrospective chart review of the Mayo Clinic database was conducted to identify patients with nonmelanoma skin cancer and brachial plexopathy between 2000 and 2017. Inclusion criteria were a history of nonmelanoma skin cancer, a clinical diagnosis of brachial plexopathy, imaging features of perineural spread, and a positive result of examination of a biopsy specimen showing tumor in a skin nerve. RESULTS: Thirty-seven patients with a history of nonmelanoma skin cancer and brachial plexopathy were identified. Inclusion criteria were fulfilled in 2 cases of cutaneous squamous cell carcinoma. One case of recurrent basal cell carcinoma with perineural spread confirmed in the brachial plexus by pathologic examination was excluded because confirmatory evidence of perineural spread from the skin to the brachial plexus was not available. CONCLUSIONS: Perineural spread of nonmelanoma skin cancer leading to brachial plexopathy is rare. Our 2 cases and the cases found in the literature demonstrate different entry points to the neural highway resulting in neurologic deficits. The cervical plexus serves as a hub for further spread in certain cases of perineural spread of skin cancer.

Dynamic alterations of the levels of tumor necrosis factor-α, interleukin-6, and interleukin-1ß in rat primary motor cortex during transhemispheric functional reorganization after contralateral seventh cervical spinal nerve root transfer following brachial plexus avulsion injuries.

The transfer of a contralateral healthy seventh cervical spinal nerve root (cC7) to the recipient nerve in the injured side is considered a reliable and effective procedure for restoration of the physiological functions of an injured hand after brachial plexus root avulsion injury (BPAI). Growing evidence shows that the transhemispheric cortical reorganization is induced after cC7 nerve transfer surgery. However, little is known about the underlying molecular mechanism. Proinflammatory cytokines reportedly play an important role in the neural plasticity. We hypothesize that proinflammatory cytokines are involved in the transhemispheric functional reorganization after cC7 transfer. In the present study, we investigated the level of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) in the rat primary motor cortex after cC7 transfer following BPAI by enzyme-linked immunosorbent assay. The results showed that, in the sham group, no statistical significance was observed between the level of TNF-α, IL-6, and IL-1ß at each time point after the operation compared with that at day 0, respectively. However, in the unrepaired and repaired groups, the level of TNF-α, IL-6, and IL-1ß changed dynamically. The study is the first to provide evidence for the involvement of proinflammatory cytokines in transhemispheric functional reorganization after cC7 transfer following BPAI, which are useful for understanding the underlying mechanism.

CTNNB1 Mutations and Estrogen Receptor Expression in Neuromuscular Choristoma and Its Associated Fibromatosis.

Neuromuscular choristoma (NMC) is a very rare, developmental malformation characterized by the endoneurial intercalation of mature muscle fibers among peripheral nerve fibers. NMC typically arises in the major proximal peripheral nerves, most commonly the sciatic nerve, and may involve the lumbosacral and brachial plexus. Patients present clinically with progressive neuropathy or plexopathy. NMC is strongly associated with development of a fibromatosis, histologically identical to conventional desmoid-type fibromatosis (NMC-fibromatosis). The development of NMC-fibromatosis is often precipitated by iatrogenic trauma (ie, biopsy). Desmoid-type fibromatosis is characterized by CTNNB1 exon 3 mutations, which result in aberrant nuclear ß-catenin localization and dysregulated canonical Wnt signaling. In contrast, the pathogenesis of NMC and NMC-fibromatosis is unknown. Desmoid-type fibromatosis expresses estrogen receptors (ER), specifically the ER-beta isoform (ERß), and endocrine therapies may be used in surgically unresectable cases. In contrast, the ER expression profile of NMC-fibromatosis is unknown. We evaluated a series of NMC and NMC-fibromatosis for CTNNB1 mutations, ß-catenin expression, and ER isoform expression. Five NMCs occurred in 2 female and 3 male patients (median age: 14 y, range <1 to 42 y), as masses involving the sciatic nerve (N=4) or brachial plexus (N=1). Four (of 5) NMCs had CTNNB1 mutations: 3 c.134 C>T (p.S45F) and 1 c.121 A>G (p.T41A). Four patients subsequently developed NMC-fibromatosis, and all 4 cases contained CTNNB1 mutations, including 1 p.T41A and 3 p.S45F mutations. In 3 patients, the NMC and NMC-fibromatosis had identical CTNNB1 mutations. Only 1 NMC had no detectable CTNNB1 mutation; however, the patient's subsequent NMC-fibromatosis had a CTNNB1 p.T41A mutation. All NMC and NMC-fibromatosis showed aberrant nuclear localization of ß-catenin, nuclear ERß expression, and no ERα expression. The presence of CTNNB1 mutations both in NMC and NMC-fibromatosis may be a shared molecular genetic abnormality underlying their pathogenesis.