Cutaneous Myxoma Research Articles

Cutaneous Myxoma and Clinical Correlations to Carney Complex: A Case Report

Cutaneous Myxoma and Clinical Correlations to Carney Complex: A Case Report

Abstract 15843: Biatrial and Recurrent Cardiac Myxoma in a Rare Case of Carney Complex

Primary cardiac tumors (CTs) are exceptionally rare, and are predominantly benign masses. Myxomas make up more than 60% of these lesions and most frequently develop in the left atrium (LA), followed by the right atrium (RA). Carney complex (CNC) is a rare, typically autosomal dominant, multiple endocrine neoplasia characterized by cutaneous findings, myxomas, endocrine and/or nonendocrine neoplasms. We report a rare case of CNC involving biatrial and recurrent myxomas. A 36-year-old female presented to Cardiology Clinic at our center for management of CNC. Three years prior, she was evaluated at a local hospital for acute stroke where TTE showed a myxoma (2 x 2 x 2.5cm) attached to the left atrial septum, prompting resection. On followup TTE 2 years later, she had a mass in the LA, prolapsing through the mitral valve into the left ventricle. She underwent resection of the myxoma (2.9 x 3.9 cm) and left atrial appendage, which was complicated by recurrent stroke. She was found to have a PRKAR1A gene mutation (c.97 deletion) suggestive of CNC and was referred to our center. At Cardiology Clinic, she denied chest pain, dyspnea, presyncope, and syncope. Her father and children did not have the gene mutation. Exam revealed lentigines on her lower lip and pigmentation of an inner canthus. She was diagnosed with primary pigmented nodular adrenal disease by Endocrinology. On TEE, she was found to have a recurrent LA mass (1 x 1 x 0.8 cm) attached to the interatrial septum, but no right-to-left atrial shunt. This prompted surgery consultation. Numerous intracardiac myxomas were removed during surgery; one in the LA attached to the septum, 3-4 smaller ones, and one 2 cm myxoma located in the RA. The interatrial septum was also resected given recurrent myxoma in this region. She underwent cryoablation to prevent recurrence and did well post-surgery. CTs, which includes primary CTs and secondary metastatic disease, are uncommon where the former has an incidence of 0.001-0.3%. We presented a case of recurrent and biatrial cardiac myxomas in the setting of CNC, which is seldomly reported in the literature. Taken together, given the rarity of primary CTs, genetic predispositions or syndromes should be considered especially in the setting of recurrence and/or multiple masses.

Surgical removal of cutaneous myxoma in crossbred Jersey cow

Surgical removal of cutaneous myxoma in crossbred Jersey cow

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma

Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic variants in PRKAR1A are identified in most cases, while large exonic or chromosomal deletions have only been reported in a few cases. Our aim was to identify the causal genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and whole genome sequencing (WGS) were performed in the proband, one clinically affected and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7 + 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A in heterozygous form in the affected family members. The exact breakpoints and the increased enzyme activity in deletion carriers compared to wild type carrier were proved. Segregation analysis and functional evaluation of PKA activity confirmed the pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene was proved to be the cause of CNC. Our study underlines the need for WGS in molecular genetic testing of patients with monogenic disorders where conventional genetic analysis fails.

Genetic and clinical phenotypic analysis of carney complex with external auditory canal myxoma.

Background: Mutations in PRKAR1A gene can lead to Carney complex (CNC), and most CNC patients develop cardiac and cutaneous myxomas. In particular, cardiac myxomas are a common cause of mortality in CNC patients. Cutaneous myxomas of the external ear are extremely rare, and do not have any specific clinical features Methods: In this retrospective study, we analyzed the clinical and genetic data of the proband and his family and fifty whole blood control samples selected from the molecular genetic database of our hospital. Whole exome DNA sequencing analysis was used to detect the mutation in the peripheral blood samples. Results: The results of the clinical analysis showed the presence of spotty skin pigmentation and external auditory canal myxoma in the proband as well as in his sister and mother. Whole-exome DNA sequencing showed a novel heterozygous mutation in the PRKAR1A gene i.e., c.824_825delAG (p.Gln275Leufs*2), in the proband and his sister and mother. Conclusion: In conclusion, the family members had the same autosomal dominant PRKAR1A mutation. DNA sequencing revealed a novel c.824_825delAG in exon 9 of PRKAR1A. This pathogenic mutation has not been reported previously, and may be related to the occurrence of external auditory canal myxomas and spotty pigmentation. This study broadens the genotypic spectrum of PRKAR1A mutations in CNC.

Steroidogenic Factor-1 Lineage Origin of Skin Lesions in Carney Complex Syndrome

Carney complex is a rare familial multineoplastic syndrome predisposing to endocrine and nonendocrine tumors due to inactivating mutations of PRKAR1A, leading to perturbations of the cAMP‒protein kinase A signaling pathway. Skin lesions are the most common manifestation of Carney complex, including lentigines, blue nevi, and cutaneous myxomas in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. In this study, we show that embryonic invalidation of the Prkar1a gene in steroidogenic factor-1‒expressing cells leads to the development of familial skin pigmentation alterations, reminiscent of those in patients with Carney complex. Immunohistological and molecular analyses, coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occur in skin areas specifically enriched in dermal melanocytes. In lentigines- and blue nevi‒prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of protein kinase A signaling, the production of promelanogenic EDN3 and hepatocyte GF signals. Our model strongly suggests that the origin of the typical Carney complex cutaneous lesions is the result of noncell-autonomous promelanogenic activity of a dermal fibroblast population sharing a community of origin with steroidogenic factor-1 lineage.

Abstract #1162392: Family Ties: Management of Carney Complex Across the Lifespan

Carney Complex is a multiple endocrine neoplasia syndrome caused by a mutation in PRKAR1A gene. Tumor sites include skin (lentigines, blue nevus, cutaneous myxomas, palpebral lentigines), pituitary (somatotroph hyperplasia/adenomas), adrenal (primary pigmented nodular adrenal hyperplasia (PPNAD)), cardiac (myxomas), and testes (large cell calcifying sertoli cell tumor).We will present a family with a variety of distinct conditions related to Carney Complex, who were effectively treated to prevent secondary endocrine complications.

A clinicopathologic analysis of 54 cases of cutaneous myxoma

Cutaneous myxoma (CM) is an uncommon benign neoplasm of skin, which may be sporadic or arise in association with syndromes such as Carney complex. There has been only one large case series describing CM. We report 54 additional cases of CM; patients had a mean age of 55 years (range = 7-91), with a female-to-male ratio of 1.3. Most occurred on the trunk (n=19), with the back being the most common site. The remainder presented on the lower extremity (n=18), head and neck (n=10), and arm (n=7). Histopathologically, they were relatively circumscribed, nodular, and centered in the dermis. All had abundant myxoid stroma, a thin, arborizing vascular network, and spindled to stellate cells with no to mild atypia without mitotic activity. Follicular induction, stromal neutrophils, and intranuclear inclusions were present in 35%, 25%, and 61% of cases, respectively. Collagen trapping, splitting of collagen fibers, and encircling of hair follicles or eccrine glands were encountered in a subset. Thirty-nine cases were treated with shave excision, whereas 12 cases underwent wide local excision. Follow-up data were available for 28 of 54 cases (mean = 50 months). Only one case recurred at 36 months. This study suggests CM has a lower risk of local recurrence than previously reported.

Imaging features of Carney complex with external auditory canal myxoma.

A 46-year-old man, with Carney complex (CC) and a history of recurrent atrial and ventricular myxomas, experienced left ear fullness for 18 months. He complained of hearing difficulties, temporarily resolved by ear canal manipulation, with no vestibular symptoms, earache or ear drainage. The patient also had a family history of cardiac myxoma and biochemical evidence of adrenal cortex autonomy. Physical examination and dedicated head and neck imaging showed a nearly occlusive soft tissue nodule in the left external auditory canal (Fig. 1A and B). Surgical resection and histopathologic examination revealed a myxoma (Fig. 1C). CC is a rare genetic syndrome related to inactivating mutation, either of random occurrence or from autosomal dominant transmission, of the protein kinase A (PRKAR1A) located on chromosome 17. CC is characterized by cardiac myxoma (Fig. 2A and B), cutaneous or mucosal myxoma, lentiginosis, multiple blue nevi, endocrinopathies with dominant...

Carney Complex With Endocrine Involvement Isolated to the Thyroid Gland

Abstract Introduction: Carney complex is a rare autosomal dominant disorder characterized by pigmented lesions of skin and mucosae, endocrine neoplasms or overactivity, and myxomas of the heart, skin, and other organs. Most patients have at least two affected endocrine organs at time of diagnosis. We present a case of Carney complex with endocrine involvement limited to the thyroid gland. Case: A 48-year-old female was referred for evaluation of thyroid nodules incidentally discovered on imaging for submandibular salivary gland swelling. Ultrasound evaluation of the thyroid revealed numerous, bilateral nodules that were mostly cystic or spongiform, though some had irregular borders and microcalcifications. A brother with Carney complex had been diagnosed with papillary carcinoma, and the patient decided to undergo thyroidectomy. Fortunately, no thyroid carcinoma was found on postsurgical histopathology. Initial biochemical evaluation showed no evidence of hypercortisolemia (8 AM cortisol 1.7 mcg/dL on 1 mg dexamethasone suppression test; 24-h urine cortisol 26.1 mcg [reference: 4-50]), growth hormone excess (IGF-1 190 ng/mL [reference: 52-328]), or hyperprolactinemia (prolactin 10 ng/mL [reference: 2.74-26.72]). Imaging showed no pituitary or adrenal masses. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy for endometrial cancer prior to referral. She was diagnosed with Carney complex at age 19 years, and her manifestations included atrial and ventricular myxomas, intraductal adenoma of the breast, multiple skin lesions (lentigines, blue nevi, and cutaneous myxomas), and myxomas of the external auditory canals. She is in a Carney complex kindred that includes her mother, two brothers, and a niece. Discussion: Carney complex is usually caused by inactivating mutations or large deletions in the protein kinase A type I alpha regulatory subunit (PRKAR1A) gene located on chromosome 17q22-24. Most mutations are inherited in an autosomal dominant manner, though approximately 30% of cases are due to de novo mutations. In a review of 365 cases, the median age at diagnosis was 20 years. Growth hormone adenomas or somatomammotroph hyperplasia occurs in approximately 75% of patients, and most have at least one additional endocrine abnormality including multinodular goiter, primary pigmented nodular adrenocortical hyperplasia, and testicular or ovarian masses. There is an approximately 10% chance of developing well differentiated thyroid carcinoma. Treatment for Carney complex is individualized depending on the patient’s presentation and includes excision or surgical removal of myxomas, neoplasms, and skin lesions, as well as regular evaluation for cardiac myxomas and endocrine overactivity. This case of Carney complex is unusual because the only endocrinopathy is multinodular goiter.

Predicting the risk of cardiac myxoma in Carney complex

PurposeCarney complex (CNC), is an autosomal dominant multiple neoplasia and lentiginosis syndrome. We aimed to identify risk factors associated with the occurrence and recurrence of cardiac myxomas, the predominant cause of death in CNC patients. MethodsPatients with CNC were monitored prospectively between 1995 and 2020 for the development of cardiac myxomas. ResultsOf the 319 patients studied, 136 (42.6%) developed myxomas. The mean age at diagnosis was 28.7±16.6 years in females and 25.0±16.4 years in males. By age 30, 35% of females and 45% of males had at least one myxoma. The CNC-related lesions, lentigines, cutaneous, mucosal, or breast myxomas, thyroid nodules, pituitary adenoma, and schwannoma were significantly more frequent (all p < 0.05) among patients with myxomas. Forty-four percent of patients had recurrences; nearly all within the first 8 and 16 years for males and females, respectively. Recurrences were more common in females. ConclusionThis is the largest study to date and provides the first-time risk estimates by age and gender for cardiac myxomas in CNC patients. Cardiac myxomas are common by age 30 and often recur, especially in women, but the risk drops in 10 to 20 years. These findings may guide patient counseling, screening intervals, and surgical approaches. Clinical Trial RegistrationClinical Trial Registration: Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease and the Carney complex, Registration number: NCT00001452 URL: https://clinicaltrials.gov/ct2/show/NCT00001452.

MANAGEMENT OF ENDOCRINE DISEASE: Carney complex: clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene.

Described for the first time in 1985, Carney complex (CNC) is a rare dominantly inherited multiple neoplasia syndrome with almost full penetrance and characterized by both endocrine - primary pigmented nodular adrenocortical disease with Cushing's syndrome, acromegaly and thyroid tumors - and non-endocrine manifestations such as cardiac, cutaneous and mucosal myxomas, pigmented cutaneous lesions, psammomatous melanotic schwannoma, osteochondromyxoma and a wide range of other tumours with potential malignancy. The pathophysiology of CNC is a model of dysregulation of the cAMP/PKA signalling in human diseases. As described 20 years ago, inactivating heterozygous mutations of PRKAR1A formerly known as CNC1, encoding the regulatory subunit 1α of protein kinase A, are identified in more than 70% of the index cases, while inactivating mutations of genes encoding phosphodiesterases are found in rare and particular forms of the complex. There is at present no medical specific treatment for CNC, every confirmed or suspected CNC patient should be managed by a multi-disciplinary team according to each manifestation of the disease and offered a long-term follow-up and genetic counselling. The better knowledge that we have now of this fascinating rare disease and its genetics will help to improve patients outcome.

Cutaneous Myxoma Coexisting with an Epidermal Cyst: A Case Report and Brief Literature Review

Cutaneous Myxoma Coexisting with an Epidermal Cyst: A Case Report and Brief Literature Review

SUN-940 Carney Complex: A Case of a Rare Multiple Endocrine Neoplasia Misdiagnosed as Peutz-Jeghers Syndrome

Carney Complex (CNC) is an extremely rare multiple endocrine neoplasia caused by germline inactivating mutation in protein kinase A type I-alpha regulatory subunit (PRKAR1A gene). Mode of inheritance is mostly autosomal dominant; 25% of cases are due to de novo mutations. Only 750 world-wide cases have been reported. Most patients are diagnosed in the second or third decade. Clinical features include cutaneous myxomas, angiomyxoid nodules, lentiginous skin pigmentation, cardiac myxomas, and benign and rare malignant endocrine tumors. These endocrine tumors include and are not limited to prolactinomas, thyroid tumors, primary pigmented nodular adrenocortical disease (PPNAD), and large cell-calcifying Sertoli cell tumors (LCCSCT). Diagnosis is often challenging as disease manifestations can occur sporadically over a large span of time, and patients may present with various conditions such as Cushing syndrome, like our case. We present a case that demonstrates the importance of early recognition of this rare disorder.A 28-year-old Caucasian male with PMH of HFrEF, HTN, Sertoli cell tumor status post orchiectomy, vertebral fractures, and surgical removal of lip angiomyxoma presented to clinic for hypogonadism. Physical examination revealed marked Cushingoid features and facial lentigines above his eyes and on his lips. His eclectic medical history and unique exam findings lead to finding of a unifying diagnosis. His labs revealed severe Cushing syndrome, and computed tomography (CT) of his abdomen was performed due to ACTH independent hypercortisolism, demonstrating a bilateral lobular appearance of the adrenal glands.Combination of labs and physical exam findings of lentigines, skin myxomas, cushingoid features, rare angiomyxoma, LCCSCT and hypercortisolism lead to diagnosis of Carney Complex. He was misdiagnosed with Peutz-Jeghers in his adolescence due to LCCSCT and mucosal lentigines; therefore, hormonal screening was not routinely performed. Untreated Cushings led to severe osteoporosis with vertebral fractures and heart failure. Treatment included bilateral adrenalectomy. Pathology report confirmed rare PPNAD. PPNAD and LCCSCT are extremely rare tumors almost exclusively linked to Carney Complex. Interestingly, family history did not reveal endocrine disorders, cancers, or severe illnesses. Genetic testing returned positive for the PRKAR1A gene mutation. Given the consequences of untreated hormonal aberrations seen in this disorder, an early and accurate diagnosis is imperative.

Dermal fibroma in a tawny nurse shark, Nebrius ferrugineus (Lesson, 1831)

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Giant Fungating Cutaneous Myxoma of the Head and Neck: An Unusual Presentation

Introduction: Virchow first describes Myxomas in 1871; they are benign tumors of primitive indifferent mesenchyme that have preference for the cardiac muscles, genitourinary tract, gastrointestinal tract, liver and spleen. The rarity of the tumor, especially in the head and neck region makes us to report this case.&#x0D; Case Report: A 16-year-old male secondary student who presented with a 9-year history of painless progressive submandibular swelling, no extension to the mouth. Examination revealed a huge fungating submandibular mass, 20 cm x 16 cm x10 cm in dimension, mobile, non-tender and firm in consistency. Other findings were unremarkable, and routine hematological and biochemical tests were all within normal limits. He subsequently had excision of the mass (weighs 950 g) under general anesthesia via an elective tracheostomy with split thickness skin grafting of the exposed strap muscles. Histopathological report revealed cutaneous myxoma.&#x0D; Conclusion: Cutaneous myxoma of the Head and Neck region is presented for its rarity, and although is a histologically benign neoplasm, treatment is extremely challenging with high incidence of recurrence.

2789 Abdominal Pain Unveils a Gastric Psammoma Fascinoma

INTRODUCTION: Carney Complex (CNC) is a rare multiple neoplasia syndrome of autosomal dominant inheritance characterized by skin pigment abnormalities, myxomas, endocrine tumors or hormonal hypersecretion, and schwannomas. The clinical presentation varies and median age at detection is age 20. CASE DESCRIPTION/METHODS: A 22-yr-old African American male presented with 3-months of intermittent left-sided abdominal pain. He had a large cell calcifying Sertoli cell testicular tumor (LCCSCT) removed by right orchiectomy at age 12. CT showed a 12.9 × 11.8 cm well circumscribed retroperitoneal mass involving the left adrenal gland with mass effect on adjacent organs and a 4.0 × 3.0 cm well-defined mass in the gastric body. EUS revealed a cystic gastric body sub-epithelial mass measuring 3.5 cm × 2 cm. The patient underwent partial gastrectomy, orchiectomy, and adrenalectomy revealing pathology consistent with a gastric psammomatous melanotic schwannoma (PMS), adrenocortical carcinoma, and a second LCCSCT. H&amp;E stained sections of the gastric lesion show a well-demarcated subepithelial lesion with multiple psammomatous calcifications. Marked accumulation of melanin in tumor cells and melanophages were identified. Histological and immunophentypic features were consistent with a gastric melanotic schwannoma with psammomatous calcifications. These findings are diagnostic of CNC. DISCUSSION: CNC is caused by a harmful mutation in the PRKAR1A gene, which this patient was found to have upon genetic testing. Many individuals with CNC will have distinctive skin pigmentation and an increased risk for development of cutaneous and cardiac myxomas. As a result of this patient’s diagnosis, his mother was evaluated and was found to also have a PRKAR1A mutation; imaging led to discovery of a cardiac myxoma requiring surgical removal. CNC is also associated with multiple endocrine tumors with or without hormonal hypersecretion. LCCSCT occur in almost all adult males with CNC and are typically bilateral and benign. PMS, tumors of the nerve sheath, occur in approximately 8% of individuals with CNC. These can occur anywhere in the central and peripheral nervous system but most frequently occur in the GI tract (stomach/esophagus) or in the paraspinal sympathetic chain. PMS have distinct pathology including heavy pigmentation (melanin), frequent calcifications, and the presence of psammoma bodies. The importance of recognizing these pathological features is emphasized by the fact that approximately half of patients with PMS have CNC.

A Case of Sporadic Carney Complex Diagnosed with Cutaneous Myxoma of the Right Cheek

A Case of Sporadic Carney Complex Diagnosed with Cutaneous Myxoma of the Right Cheek

Cutaneous myxomas and a psammomatous melanotic schwannoma in a patient with Carney complex

Journal of Cutaneous PathologyVolume 46, Issue 2 p. 93-96 COVER QUIZLET Cutaneous myxomas and a psammomatous melanotic schwannoma in a patient with Carney complex Akua Sarfo, Corresponding Author asarfo@pennstatehealth.psu.edu orcid.org/0000-0001-5439-5261 Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania Correspondence Department of Dermatology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033 Email: asarfo@pennstatehealth.psu.eduSearch for more papers by this authorKlaus Helm, Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PennsylvaniaSearch for more papers by this authorAlexandra Flamm, Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PennsylvaniaSearch for more papers by this author Akua Sarfo, Corresponding Author asarfo@pennstatehealth.psu.edu orcid.org/0000-0001-5439-5261 Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania Correspondence Department of Dermatology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033 Email: asarfo@pennstatehealth.psu.eduSearch for more papers by this authorKlaus Helm, Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PennsylvaniaSearch for more papers by this authorAlexandra Flamm, Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PennsylvaniaSearch for more papers by this author First published: 11 January 2019 https://doi.org/10.1111/cup.13385Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Citing Literature Volume46, Issue2February 2019Pages 93-96 RelatedInformation

Diseases Predisposing to Adrenocortical Malignancy (Li-Fraumeni Syndrome, Beckwith-Wiedemann Syndrome, and Carney Complex).

Adrenocortical malignancies can occur in the context of several tumor predisposition syndromes.The Carney complex (CNC) is responsible for the majority of primary pigmented nodular adrenal diseases and is more rarely associated with adrenocortical carcinoma (ACC). Other core manifestations of CNC include cardiac and cutaneous myxomas, lentiginosis, somatotroph pituitary adenomas, Sertoli tumors, melanocytic schwannoma, and thyroid, breast, and bone tumors. CNC is mostly due to germline inactivating mutations of PRKAR1A.The majority of childhood ACC are related to genetic predisposition. The Beckwith-Wiedemann syndrome (BWS) is an overgrowth and tumor predisposition syndrome due to genetic or epigenetic alterations at the 11p15 locus. Classical tumor spectrum of BWS includes embryonal tumors and childhood ACC. The Li-Fraumeni syndrome (LFS) is a devastating tumor predisposition syndrome, due to germline inactivating mutations of TP53, and characterized by a high, various, and early-onset cancer risk. LFS spectrum includes premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, and ACC, accounting for 50-80% of pediatric cases. Finally, germline predisposition affects up to 10% of adult ACC patients, mostly in part of LFS and Lynch syndrome.This chapter focuses on the diagnosis, screening, and management of adrenal tumors in part of these tumor predisposition syndromes.