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Background: Proteus syndrome is an overgrowth disorder caused by a mosaic activating AKT1 variant. Hair abnormalities in Proteus syndrome have rarely been reported, and frequencies of such findings have not been elucidated.Objective: To define the types and frequencies of hair findings in individuals with Proteus syndrome.Methods: A cross-sectional study was conducted of individuals with clinical features of Proteus syndrome and a confirmed pathogenic variant in AKT1 evaluated between November 1996 and June 2019 at the National Institutes of Health Clinical Center. Medical records were reviewed for patterning, density, and color of hair on the body and scalp.Results: Of 45 individuals evaluated, 29 (64%) had asymmetric hypertrichosis on the body. This included unilateral blaschkoid hypertrichotic patches overlying normal skin or epidermal nevi in 16 (36%), unilateral nonblaschkoid hypertrichotic patches in 11 (24%), and unilateral limb hypertrichosis in 10 (22%). Diffuse, scattered, or patchy changes in scalp hair density or color were present in 11 individuals (24%).Limitations: The retrospective, observational design, and limited longitudinal follow-up.Conclusions: Asymmetric variations in hair distribution, thickness, length, and color contribute to the overall mosaic appearance of the skin in Proteus syndrome, an observation that provides novel insights into the role of phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling in skin appendage development. [ABSTRACT FROM AUTHOR]

• Proteus Syndrome is an extremely rare case where only 200 cases has been reported. • Macrodactyly is a striking feature. • Biesker's criteria is a diagnostic tool, which assist in reaching the diagnosis. • Confirmation is by finding genetic variation in AKT1 and/or PTEN gene. • Our case had multiple intestinal lipomatosis which caused him small bowel volvulus. Proteus Syndrome is a very rare syndrome, where only 200 cases has been reported so far. We were presented with a 45 year male with features of chronic Intestinal Obstruction. On Examination he had a giant right middle finger (Fig. 1), giant left forearm, with amputated left hand, and massive abdominal distension with tenderness in upper abdomen. Proteus Syndrome (PS) is a very rare syndrome, diagnosis of which is based on Biescker's criteria, either one finding from Criteria A, or two from B, or three from C. Confirmation of the disease is by finding genetic variation in the AKT1 gene. In addition to the presence to some of the criteria in our patient, he also had numerous intestinal lipomatosis, involving almost most of his small intestine. This in addition to high riding caecum and a narrow long mesentery which contributed to the development of small Bowel volvulus. PS should be suspected whenever we encounter patients with macrodactyly and this should alert us to the possibility of other congenital anomalies. [ABSTRACT FROM AUTHOR]

Proteus syndrome (PS) is a complex genetic disorder, characterized by the sporadic appearance of hamartomatous lesions that follow a mosaic pattern and have a progressive evolution. It affects most of the mesodermal origin tissues, including the bones. Scoliosis is a common manifestation, with great variability and specific peculiarities, but little about it has been published. Presentation of 2 clinical cases of patients with PS that underwent scoliosis surgery and literature review. Two patients aged 17 years, a girl (patient 1) and a boy (patient 2), both diagnosed with PS, were being followed-up for scoliosis. Patient 1 had a right thoracic curve with a Cobb angle of 69.1°, whereas patient 2 also had a right thoracic curve of 106.8°. In both patients a posterior fusion was performed, associating rib and ponte osteotomies at the level of the apex in patient 2. A minimum 2-year follow-up was done. Both patients had a satisfactory evolution without neurologic or other complications, with a high degree of correction of their curves (Cobb angle 29.2° and 55.6°, respectively). Their total SRS-22 (Scoliosis Research Society Outcomes Questionnaire) score at the last visit was 4.77 and 4.64, respectively. Both PS and scoliosis are conditions associated with deformities and physical limitations that decrease the health-related quality of life of these patients. Because of the severity of the spinal deformities and their risk of progression, early diagnosis and prompt treatment is recommended. Despite being highly complex, scoliosis surgery allows a satisfactory deformity correction and consequently improves the health-related quality of life of patients with PS. [ABSTRACT FROM AUTHOR]

Highlights • Increase the data of anesthesia for Proteus Syndrome patients, which is a very rare deformity disease. • We compared the safety and effect of different anesthesia methods for PS patient's lower extremity surgery. • We compared the postoperative analgesia and anesthetic complications of different anesthesia methods for PS patient. • Ultrasound-guided nerve block may be more suitable for PS patients than neurostimulator guidance, to avoid complications. [ABSTRACT FROM AUTHOR]

Résumé Les malformations vasculaires sont des anomalies constitutionnelles souvent méconnues qui deviennent symptomatiques au cours du temps. Plusieurs classifications cliniques ont tenté d'individualiser les différentes entités recensées. Néanmoins, c'est grâce aux progrès récents de la biologie moléculaire que leur nosologie et leur prise en charge évolue depuis quelques années. Les malformations vasculaires syndromiques en sont un exemple : alors que les syndromes de Klippel-Trenaunay, de Protée ou CLOVES partagent de nombreuses caractéristiques cliniques, l'identification de mécanismes physiopathologiques communs et notamment le rôle de la voie PIK3/AKT/mTOR permet de repenser leur classification. Ainsi, plusieurs syndromes associant excès de croissance tissulaire et malformations vasculaires ont été regroupés sous le terme de « PIK3CA-related overgrowth spectrum » (PROS) et le nombre de pathologies associées à ce nouveau groupe ne cesse de croître. Cette nouvelle nosologie laisse entrevoir de nouvelles approches thérapeutiques. En effet, la rapamycine, un inhibiteur de la voie PIK3/AKT/mTOR , a montré son efficacité pour le traitement de certaines formes cliniques. Les thérapies ciblées (inhibiteurs sélectifs de PIK3 ou de mTOR) sont toujours en cours de développement et les premiers résultats sont encourageants. Il s'agit là d'un premier exemple de médecine personnalisée avec un bénéfice thérapeutique très important pour certains patients. Néanmoins, le rôle du génotype devra être précisé et les praticiens devront être attentifs aux conséquences de ces traitements chez des patients souvent jeunes. Abstract Vascular malformations are poorly recognized constitutional anomalies which arises during early childhood. Several classifications tried to draw a distinction across the different entities. Recent advances in molecular biology have contributed to the update of their nosology. Syndromic vascular malformations are an example: while Klippel-Trenaunay syndrome, Proteus or CLOVES syndrome share many common features, understanding of pathological mechanism and specially the role of the PIK3/AKT/mTOR pathway enables us to rethink their classification. Then, some syndromes associated with overgrowth and vascular malformation have been grouped under a single term: " PIK3CA -related overgrowth spectrum" (PROS), and this group continues to grow. This new approach suggests new treatment options. Rapamycin, a PIK3/AKT/mTOR pathway inhibitor, demonstrated its efficiency for some forms of PROS. Targeted therapies such as PIK3 or mTOR selective inhibitor are still in a developmental phase and results are encouraging. This is an example of personalized medicine with significant therapeutic benefit for some patients. However, genotype relation with therapeutic efficiency must be clarified and physicians should pay attention to possible negative effects of these drugs, especially for young patients. [ABSTRACT FROM AUTHOR]

Background: The plantar cerebriform connective tissue nevus (CCTN) is the most common and problematic cutaneous manifestation of Proteus syndrome.Objective: To gain insights into CCTN pathogenesis and natural history.Methods: The size and location of plantar CCTN was measured on 152 images from 22 individuals with Proteus syndrome by 2 independent, blinded reviewers. Average measures of plantar CCTN were transformed into a linear mixed model to estimate proportionate change in size with age.Results: Median patient age was 6.9 years at study onset. The intraclass correlation coefficient between 2 blinded reviewers was 0.946 for CCTN single measures. The CCTN relative area increased with age in children (n = 18, P < .0001) by 5.6% per year. Confluent papules and nodules extending beyond the boundaries of CCTNs were gradually replaced by typical CCTN over time. The location of CCTN in different individuals overlapped near the ball of the foot. A positive relationship between CCTN growth rate and AKT1 mutant allele frequency was observed (0.62, P = .10, n = 8).Limitations: This was a retrospective review using photographs.Conclusion: CCTN growth is affected by age and extent of the CCTN precursor lesion. Monitoring of CCTN size might prove useful for evaluating drug response in the treatment of Proteus syndrome. [ABSTRACT FROM AUTHOR]

Abstract Proteus Syndrome is a rare complex overgrowth syndrome. We report a young female patient with Proteus Syndrome due to AKT1 mutation c.49G > A (p.Glu17Lys), presenting with a severe gynaecological involvement which necessitated a complete hysterectomy and a left adnexectomy. Cases of gynecological involvements in Proteus Syndrome are rare, not well known by physicians while they can be potentially severe. [ABSTRACT FROM AUTHOR]

Hashimoto's encephalopathy (HE) is a rare not well understood, progressive and relapsing multiform disease, characterized by seizures, movement disorders, subacute cognitive dysfunction, psychiatric symptoms and responsiveness to steroid therapy. The disorder is generally associated with thyroid diseases and the most common feature is the presence of anti-thyroperoxidase antibodies (TPOAb). Patients are usually euthyroid or mildly hypothyroid at presentation. All age groups can be affected. The pathophysiology is still unclear, especially the link between elevated serum TPOAb and the encephalopathy. Most reported cases occurred in women and girls. Unspecific symptoms, non-pathognomonic laboratory neurophysiology and neuroimaging features make its diagnosis a real challenge for clinicians. The case of a 16 year old boy, with a clinical picture of HE associated with hypothyroidism, demonstrating an excellent response to high dose steroids is presented together with a systematic review of the literature. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a rare disorder of asymmetric overgrowth of various tissues of the body and is associated with specific tumors appearing before the second decade. Although there have been reports of lesions of the genitourinary tract associated with Proteus syndrome, a case of serous borderline tumor of the paratestis has not been previously recorded. We report the first such case in a 20-month-old child who presented with a left-sided testicular mass that was found on histology to be a serous borderline tumor of the paratestis. Surgical management included a left inguinal radical orchiectomy and surveillance follow-up. [ABSTRACT FROM AUTHOR]

Proteus syndrome (PS), a rare hamartomatous disorder, manifests itself in asymmetric and disproportionate overgrowth of multiple body tissues. Because of complexity of the disorder, the anesthetic problems encountered during patients' perioperative management are very varied. We discuss the case of a 14-year-old adolescent boy diagnosed with PS who underwent corrective osteotomy of right knee joint under subarachnoid block. The salient points the anesthetists need to be aware of while caring for patients with PS are highlighted. [ABSTRACT FROM AUTHOR]

Tau is a normal microtubule-associated protein; mutations to phosphorylated or acetylated forms are neurotoxic. In many dementias of adult life tauopathies cause neuronal degeneration. Four developmental disorders of the fetal and infant brain are presented, each of which exhibits up-regulation of tau. Microtubules are cytoskeletal structures that provide the strands of mitotic spindles and specify cellular polarity, growth, lineage, differentiation, migration and axonal transport of molecules. Phosphorylated tau is abnormal in immature as in mature neurons. Several malformations are demonstrated in which upregulated tau may be important in pathogenesis. All produce highly epileptogenic cortical foci. The prototype infantile tauopathy is (1) hemimegalencephaly (HME); normal tau is degraded by a mutant AKT3 or AKT1 gene as the aetiology of focal somatic mosaicism in the periventricular neuroepithelium. HME may be isolated or associated with neurocutaneous syndromes, particularly epidermal naevus syndromes, also due to somatic mutations. Other tauopathies of early life include: (2) tuberous sclerosis complex; (3) focal cortical dysplasia type 2b (FCD2b); and (4) ganglioglioma, a tumor with dysplastic neurons and neoplastic glial cells. Pathological tau in these infantile cases alters cellular growth and architecture, synaptic function and tissue organization, but does not cause neuronal loss. All infantile tauopathies are defined neuropathologically as a tetrad of (1) dysmorphic and megalocytic neurons; (2) activation of the mTOR signaling pathway; (3) post-zygotic somatic mosaicism; and (4) upregulation of phosphorylated tau. HME and FCD2b may be the same disorder with different timing of the somatic mutation in the mitotic cycles of the neuroepithelium. HME and FCD2b may be the same disorder with different timing of the somatic mutation in the mitotic cycles of the neuroepithelium. Tauopathies must be considered in infantile neurological disease and no longer restricted to adult dementias. The mTOR inhibitor everolimus, already demonstrated to be effective in TSC, also may be a potential treatment in other infantile tauopathies. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Fibroadipose Hyperplasia versus Proteus Syndrome: Segmental Overgrowth with a Mosaic Mutation in the PIK3CA Gene" by Leila Youssefian is presented.

Proteus syndrome (PS) is a sporadic and rare congenital disorder characterized by a patchy or mosaic postnatal overgrowth, sometimes involving the face. The onset of overgrowth typically occurs in infancy and can commonly involve skin, connective tissue, central nervous system, eyes and viscera. The progressive overgrowth causes severe complications, such as skeletal deformities, cystic lung disease, invasive lipomas, connective tissue hyperplasia, benign and malignant tumours and deep venous thrombosis with pulmonary embolism, which can cause premature death. This disorder is caused by somatic mosaicism for a specific activating AKT1 mutation that would be lethal in a non-mosaic state. In this report, current knowledge of the aetiology, the diagnosis and the craniofacial manifestations of the disorder are reviewed. The short-term management of a 7-year-old patient with unusual oral manifestations is described. For the first time mutation of AKT1 (c.49G > A) gene was detected both in cranial exostosis and in central odontogenic fibroma of the lower jaw. [ABSTRACT FROM AUTHOR]

Proteus Syndrome (PS) is a rare congenital overgrowth disease affecting bones, skin, adipose and the central nervous system. The result is asymmetric, disfiguring hypertrophy which can manifest as craniofacial dysmorphia and aerodigestive tract abnormalities. We report the case of obstructive lingual tonsillar hypertrophy resulting in residual sleep disordered breathing after adenotonsillectomy in a child with PS, a previously unrecognized manifestation of the disease. Endoscopic treatment with coblation effectively and safely treated the obstructive symptoms. [ABSTRACT FROM AUTHOR]

Abstract: We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann–Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid–progeroid–lipodystrophy syndrome) and frameshift mutations at the 3′ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes. [Copyright &y& Elsevier]

Background: Fibrolipomatous hamartoma of the nerve is a rare benign infiltrating condition of peripheral nerves with prominent cutaneous findings that has not being well described in the dermatologic and dermatopathologic literature. Objective: We sought to evaluate the clinical and histopathological features of this rare condition. Methods: We reviewed the clinicopathologic features of 13 cases to delineate their clinical presentation and histopathologic spectrum. Results: All patients presented with unilateral lesions on the thenar areas, fingers, or both. In 7 cases the lesions presented congenitally and in 6 cases the lesions presented sporadically. Histologically, we found 2 patterns that have only been rarely mentioned before including cases with intraneural perineurioma-like features and cases with marked nerve hyperplasia. Limitations: Only 13 cases were included in our study. Conclusions: This condition is an uncommon entity. The diagnosis of this disorder can be highly suspected on its macroscopic features. Predilection of the median nerve and the frequent association with macrodactyly are characteristic clinical findings. [Copyright &y& Elsevier]

The article offers information on a research related to examination of correlation of levels of AKT1 gene mutation with type of dermatologic lesions in patients with Proteus Syndrome (PS). Topics of discussion included were characterization of PS with progressive, mosaic and segmental overgrowth, analysis of skin samples collected during surgical procedures or by punch biopsies from patients with PS and symptoms of Epidermal nevi including hyperkeratosis, papillomatosis and acanthosis.

Abstract: Beckwith–Wiedemann syndrome is an overgrowth disorder with an increased risk of childhood tumors that results from a dysregulation of imprinted gene expression in the 11p15 region. Since epigenetic defects are the most frequent anomalies, first-line diagnostic methods involve methylation analysis. When paternal isodisomy is suspected, it should be confirmed by a second technique capable of distinguishing true 11p15 paternal disomy (patUPD) from paternal 11p15 duplication or 11p15 trisomy. We sought to evaluate the interest of using SNP arrays in the Beckwith–Wiedemann syndrome diagnostic strategy. We analyzed the SNP profiles of 25 Beckwith Wiedemann patients with previously determined methylation indexes. Among them, 3 had 11p15 trisomies, 13 had patUPD, 8 had an inconclusive methylation index and 1 had a normal result. All known trisomies and known patUPDs were detected. Moreover we found 7 low-rate mosaicisms 11p15 patUPDs among the 8 patients with an inconclusive methylation index. We were able to precisely characterize the sizes and mosaicism rates of the anomalies. We demonstrate that SNP arrays are of real diagnostic interest in Beckwith–Wiedemann syndrome: 1) they help to distinguish patUPDs from trisomies more precisely than karyotyping and FISH, 2) they help determine the size and mosaicism rate of patUPDs, 3) they provide complementary information in inconclusive cases, helping to distinguish low-rate patUPD mosaicism from other BWS-related molecular defects. [Copyright &y& Elsevier]

Abstract: INTRODUCTION: Crohn''s involvement of duodenum is a rare event and may be associated to proteiform symptoms and uncommon pathological aspects which make diagnosis and treatment complex. PRESENTATION OF CASE: The peculiar aspect of this case was a suspected duodeno-biliary fistula. The patient (female, 22 years old) was affected by duodenal Crohn''s disease. Magnetic resonance imaging showed a dilated common bile duct, whose final part linked to a formation containing fluid, and characterized by filling of the contrast medium in the excretory phase. Abdominal ultrasound showed intra-hepatic and intra-gallbladder aerobilia. At surgery, the duodenum was mobilized showing an inflammatory stricture and a slight dilatation of the common bile duct, with no signs of fistulas. The opened duodenum was anastomized side to side to a transmesocolic loop of the jejunum. After surgery, the general condition of the patient improved. DISCUSSION: Only two cases of fistula between a narrow duodenal bulb and the common bile duct have been described in literature and the Authors were not be able to verify the occurrence of a duodenal biliary fistula at surgery. The association between duodenal Crohn''s disease and Sphincter of Oddi incontinence is a very rare finding with different etiology: chronic intestinal pseudo-obstruction, common bile duct stones, progressive systemic sclerosis. CONCLUSION: The treatment to resolve Sphincter of Oddi incontinence for primary duodenal Crohn''s disease is not clear. Strictureplasty could be the treatment of choice, because, resolving the stricture, the duodenal pressure is likely to decrease and the reflux through the incontinent sphincter can be avoided. [Copyright &y& Elsevier]

Background: Connective tissue nevi (CTN) are circumscribed hamartomas of the skin in which there is an abnormal mixture of normal components of the dermis that may be sporadic or associated with syndromes such as Buschke-Ollendorff, tuberous sclerosis, and Proteus. Objective: We sought to specify the clinical and histologic features of CTN in childhood and to propose a diagnostic approach and updated classification. Methods: This was a retrospective study in a tertiary pediatric outpatient population, accessing clinical and histopathological records. Results: We classified 114 cases of CTN from 1980 to 2008. Limitations: The majority of cases were confirmed by histopathological examination. Therefore, our series excludes many CTN that were not biopsied. In addition, follow-up was variable. Conclusion: Our series demonstrates the usefulness of a modified classification for CTN. Biopsy should be done when clinical diagnosis is uncertain, or in multiple lesions. When biopsy is performed it should include normal-appearing skin for comparison and, in Buschke-Ollendorff syndrome, limited anterior-posterior x-rays of the hands, wrists, feet, ankles, knees, and pelvis instead of a full skeletal survey. [ABSTRACT FROM AUTHOR]

Abstract: Chondrolipoma is a rare condition; especially in the oral cavity. The authors described a giant chondrolipoma of the tongue, associated with mandibular and lower lip overgrowth, in a 14-year-old boy. After tumour excision, histopathological examination showed mature cartilage within lobules of mature adipocytes. This is the first case of giant chondrolipoma associated with facial overgrowth. The aetiology and the association with a localized Proteus syndrome are discussed. [Copyright &y& Elsevier]

Abstract: Infiltrating lipomatosis of the face has been described as a congenital disorder in which mature lipocytes invade adjacent tissues in the facial region. The presentation is always unilateral with hypertrophy of hard and soft structures on the affected side of the face. We present a case of a 27-year-old female who reported with a complaint of recurrent unilateral facial swelling with history of two previous resections, the histopathology or details of these surgeries were not available. The patient underwent resection of tumour and the histopathology confirmed it to be infiltrating lipomatosis. The surgery resulted in a definite improvement in the facial asymmetry and the patient is being closely followed up with no evidence of recurrence. The pathogenesis of the condition is unclear, though it has been postulated that the condition is at one end of a spectrum of overgrowth syndromes with classic Proteus syndrome on the other extreme. Management of this condition involves resection of the tumour which in most cases is subtotal to reduce the risk of damage to facial nerve. There is a controversy regarding both timing and extent of resection in the literature and we think the subtotal resection of tumour in an adolescent or older patient can give good aesthetic outcome without compromising facial nerve function. However, the patients should be informed about high rate of recurrence and increase risk of complications with any subsequent surgery. [Copyright &y& Elsevier]

Abstract: Background: Agreement on terminology and nomenclature is fundamental and essential for effective exchange of information between clinicians and researchers. An adequate terminology to describe all patients showing vascular malformations combined with deregulated growth is at present not available. Objectives: To propose a classification of patients with vascular malformations, not restricted to the face, and growth disturbances based on simple, clinically visible characteristics, on which clinicians and researchers can comment and which should eventually lead to an internationally accepted classification. Methods: Rooted in our joint experience we established a classification of vascular malformation not limited to the face, with growth disturbances. It is based on the nature and localization of the vascular malformations; the nature, localization and timing of growth disturbances; the nature of co-localization of the vascular malformations and growth disturbances; the presence or absence of other features. Subsequently a mixed (experienced and non-experienced) group of observers evaluated 146 patients (106 from the Netherlands; 40 from the UK) with vascular malformations and disturbed growth, using the classification. Inter-observer variability was assessed by estimating the Intra-Class Correlation (ICC) coefficient and its 95% confidence interval. Results: We defined 6 subgroups within the group of entities with vascular malformation-deregulated growth. Scoring the patients using the proposed classification yielded a high inter-observer reproducibility (ICC varying between 0.747 and 0.895 for all levels of flow). Conclusions: The presently proposed classification was found to be reliable and easy to use for patients with vascular malformations with growth disturbances. We invite both clinicians and researchers to comment on the classification, in order to improve it further. This way we may obtain our final aim of an internationally accepted classification of patients, which should facilitate both clinical treatment and care of, as well as research into the molecular background of entities combining vascular malformation and deregulated growth. [Copyright &y& Elsevier]

Background: Proteus syndrome is a rare overgrowth disorder that almost always affects the skin. Objective: Our purpose was to evaluate progression of skin lesions in patients with Proteus syndrome. Methods: Skin findings were documented in 36 patients with Proteus syndrome. Progression of skin lesions in 16 of these patients was assessed by comparing photographs obtained on repeated visits for an average total duration of 53 months. Results: The skin lesion most characteristic of Proteus syndrome, the cerebriform connective tissue nevus, showed progression in 13 children but not in 3 adults. The cerebriform connective tissue nevus progressed by expansion into previously uninvolved skin, increased thickness, and development of new lesions. Lipomas increased in size, number, or both in 8 of 10 children with lipomas. In contrast, epidermal nevi and vascular malformations generally did not spread or increase in number. Limitations: Only 3 adults with Proteus syndrome were evaluated longitudinally. Conclusion: The cerebriform connective tissue nevus in Proteus syndrome grows throughout childhood but tends to remain stable in adulthood. [ABSTRACT FROM AUTHOR]

Proteus syndrome is a very rare, sporadic and congenital condition that is characterized by postnatal mosaic overgrowth. This disorder is thought to be caused by a somatic gene mutation, but the exact etiology is unknown. Commonly involved tissues include connective tissue, bone, skin and the central nervous system. Another less common symptom involves pulmonary emphysematous changes. This report documents a 25-year-old man with Proteus syndrome who presented with progressive exertional dyspnea and asymmetric overgrowth of his extremities. He underwent left pneumonectomy and his postoperative course was uneventful. Lung tissue showed emphysematous changes with multiple bulla formation and scattered calcification. We also review recent literature related to pulmonary manifestations and management of Proteus syndrome. [Copyright &y& Elsevier]

Abstract: The purpose of the present case study was to determine the long-term impact of partial glossectomy (using the keyhole technique) on overall speech intelligibility and articulation in a Dutch-speaking child with Beckwith–Wiedemann syndrome (BWS). Furthermore the present study is meant as a contribution to the further delineation of the phonation, resonance, articulation and language characteristics and oral behaviour in a child with BWS. Detailed information on the speech and language characteristics of children with BWS may lead to better guidance of pediatric management programs. The child''s speech was assessed 9 years after partial glossectomy with regard to ENT characteristics, overall intelligibility (perceptual consensus evaluation), articulation (phonetic and phonological errors), voice (videostroboscopy, vocal quality), resonance (perceptual, nasometric assessment), language (expressive and receptive) and oral behaviour. A class III malocclusion, an anterior open bite, diastema, overangulation of lower incisors and an enlarged but normal symmetric shaped tongue were present. The overall speech intelligibility improved from severely impaired (presurgical) to slightly impaired (5 months post-glossectomy) to normal (9 years postoperative). Comparative phonetic inventory showed a remarkable improvement of articulation. Nine years post-glossectomy three types of distortions seemed to predominate: a rhotacism and sigmatism and the substitution of the alveolar /z/. Oral behaviour, vocal characteristics and resonance were normal, but problems with expressive syntactic abilities were present. The long-term impact of partial glossectomy, using the keyhole technique (preserving the vascularity and the nervous input of the remaining intrinsic tongue muscles), on speech intelligibility, articulation, and oral behaviour in this Dutch-speaking child with congenital macroglossia can be regarded as successful. It is not clear how these expressive syntactical problems demonstrated in this child can be explained. Certainly they are not part of a more general developmental delay, hearing problems or cognitive malfunctioning. To what extent the presence of expressive syntactical problems is a possible aspect of the phenotypic spectrum of children with BWS is subject for further research. Multiple variables, both known and unknown can affect the long-term outcome after partial glossectomy in a child with BWS. The timing and type of the surgical technique, hearing and cognitive functioning are known variables in this study. But variables such as children''s motivation, the contribution of the motor-oriented speech therapy, the parental articulation input and stimulation and other family, school and community factors are unknown and are all factors which can influence speech outcome after partial glossectomy. Detailed analyses in a greater number of subjects with BWS may help further illustrate the long-term impact of partial glossectomy. [Copyright &y& Elsevier]

An ethical dilemma that is not uncommon to encounter when caring for children occurs when parental preference does not appear to be in the child''s best interest. Challenges facing the health care team are further amplified when the family''s cultural background does not match that of the team. A case study will be used to illustrate the challenges of a pediatric palliative care ethical dilemma further complicated by cultural diversity. Review of the child''s medical condition, patient/parent preferences, quality of life, and contextual features will be followed by an analysis and recommendations for resolution of this challenging situation. [Copyright &y& Elsevier]

Abstract: There is a large group of disorders characterized by non-cranial vascular malformations and a dysregulated growth, of which the prototype may be Klippel–Trenaunay syndrome (KTS). The aetiology of KTS and vascular malformations-dysregulated growth (VM-DG) syndromes resembling KTS is obscure, but polygenic paradominant inheritance involving mutations or polymorphisms in two or more genes simultaneously, of which one (or more) are involved in (lymph)angiogenesis and the other(s) in growth regulation has been proposed for KTS and related VM-DG entities. This provides an explanation for the variability of the VM-DG syndromes through the numerous possible combinations of mutated genes involved. We report on three monozygotic female twins who are discordant for a VM-DG syndrome resembling KTS. We suggest that our observation is consistent with the concept of polygenic paradominant inheritance involving two or more genes. We discuss the published observations in twins discordant for other disorders associated with disturbed growth regulation such as Beckwith–Wiedemann syndrome and Silver-Russell syndrome, and the occurrence in cousins with KTS and Beckwith–Wiedemann syndrome, which are best explained by an imprinting disturbance. We propose that, similarly, disturbed imprinting plays a role in the pathogenesis of VM-DG syndromes in general, and suggest the same may hold for KTS in sensu strictu or Proteus syndrome. Further studies to investigate imprinting status in VM-DG syndromes, including KTS and Proteus syndrome, are warranted. [Copyright &y& Elsevier]

Abstract: It is remarkable to uncover a new aspect of congenital epibulbar solid dermoids and lipodermoids. We describe a dramatic central epicorneal polypoidal lipodermoid coloboma accompanied by an upper eyelid coloboma that was not associated with Goldenhar syndrome. Histopathologically the excised lesion displayed superficial layers of epidermis and a thin dermis with eccrine glands, vestigial hair structures, and bundles of arrector pili smooth muscle that extended from the undersurface of the epidermis to the bulge area of the primitive hairs. This last feature is not present in normal eyelid skin nor in the conjunctiva, and has not been previously documented to occur in epibulbar dermoids and lipodermoids. S-100-positive dendritic melanocytes and CD1a-positive Langerhans cells were both observed intraepidermally, indicating a complete complement of normal cells in this layer. Beneath the dermis was a massive collection of lobules of mature adipose tissue that fused with the corneal stroma. A virtually identical pedunculated limbal tumor has been previously reported that was associated with Goldenhar syndrome. Review of earlier published cases of epibulbar dermoids and lipodermoids establishes that central corneal lesions are not a stigma of Goldenhar syndrome, in contrast to limbal masses. Other epibulbar choristomas that can be confused with lipodermoids are described. [Copyright &y& Elsevier]

Abstract: We report on two families in which the parental origin of duplications of the BWS imprinted regions on chromosome 11p15 influences the phenotype. In family A the transmission of a t(4; 11)(q35; p15.5) translocation results in duplication of BWSIC1 and BWSIC2. If this duplication is transmitted from the father, the extra chromosomal material has the paternal imprint. This results in overexpression of IGF2 and consequently an overgrowth phenotype. If the duplication is transmitted from the mother, the extra chromosomal material has the maternal imprint, resulting in overexpression of CDKN1C and a growth retardation phenotype. In family B an interstitial duplication of BWSIC1 results in an overgrowth phenotype when inherited from the father, similar to family A. However, no change in phenotype is observed if the duplication is transmitted through the mother suggesting that increased dosage of maternally expressed genes in the duplicated region has limited effect on the phenotype. [Copyright &y& Elsevier]

Abstract: Placental mesenchymal dysplasia (PMD) is a rare human disorder associated with stillbirth, intrauterine growth restriction (IUGR) and Beckwith–Wiedemann syndrome. Although the morphology of this condition has been described in 86 cases, the underlying cellular origin is unclear. We investigate the placental cell type involved in a case of PMD associated with a live born female infant with IUGR. In PMD intermediate villi contain cisternae, lined by non-proliferative cells. Immunostaining reveals they are not of trophoblast or vascular endothelial origin. There is positive immunostaining for lymphatic endothelium; this abnormal lymphangiogenesis is in concordance with current hypotheses regarding the aetiology of PMD. Furthermore, such observations suggest that placental villous mesenchyme may differentiate into various cell types, even those not normally found in the human placenta. [Copyright &y& Elsevier]

Abstract: Wiedemann–Beckwith syndrome (WBS) is a syndrome of excessive growing with a high predisposition to developing embryologic tumours within the first years of life. This risk is evaluated between 7.5 and 10%; it varies with the mechanisms of mutations involved. These take place in two distinct domains of 11p15, which are under parental printing. Emerging techniques of cytogenetic and molecular biology now have shown correlations between genotypes and phenotypes, and can identify the 30% of WBS who are especially at risk of developing tumours. A specific follow-up, integrating the specificity of developing tumours of each 11p15 mutations involved, is now proposed to patients with WBS. [Copyright &y& Elsevier]

Summary: The authors report two cases of Brazilian children with most of the common syndromic features of Proteus syndrome, such as asymmetric overgrowth of tissues, skin abnormalities, hypotonia and mental retardation. In both patients, a refractory epilepsy, compatible with Ohtahara syndrome, as well as hemimegalencephaly, with asymmetric distribution of facial fat, were also diagnosed. [Copyright &y& Elsevier]

Abstract: A case of pancreatoblastoma (PB) in a 2 month-old male infant with incomplete Beckwith-Wiedemann syndrome is presented. Clinical examination disclosed left hemihypertrophy, macroglossia, bilateral exophthalmos, and enlargement of the left testis. Imaging with ultrasound and computed tomography scan showed a well-defined, heterogeneous, and grossly cystic mass arising from the head of the pancreas. Serum alpha-fetoprotein (AFP) level was elevated. The tumor was completely resected, and the histological analysis showed PB. The patient''s recovery was uneventful, and AFP returned to normal values after surgery. The child has been disease-free for 5 years, and his serum AFP remained within normal values. Six other examples of this association, PB, and Beckwith-Wiedemann syndrome are recorded in the literature. The risk of developing tumor in this syndrome (complete and incomplete form) increases when hemihypertrophy is present, and the need for routine screening examination is warranted. Beckwith-Wiedemann syndrome was suggested to be a favorable biological marker for survival in children who have intraabdominal tumors. [Copyright &y& Elsevier]

: PurposeTo report a patient with the Proteus syndrome who had ocular complications not previously described in the literature.: DesignSingle observational case report.: MethodsRetrospective review of the medical record and review of the literature.: ResultsThe 26-year-old man has systemic features fulfilling the diagnostic criteria for the Proteus syndrome. His ocular abnormalities are myopia, mild calcific band keratopathy, cataract, abnormal vitreous structure, vitreous hemorrhage, a large chorioretinal mass, and a resolved serous retinal detachment.: ConclusionsOcular complications are frequently reported in patients with the Proteus syndrome. Few of the patients reported in the literature have had comprehensive ocular examination by an ophthalmologist. Our patient is unique because he has been examined by ophthalmologists from childhood, and it is clear that the ocular findings may change with time. As far as we are aware, calcific band keratopathy, abnormal vitreous structure, and chorioretinal hamartoma associated with serous retinal detachment and vitreous hemorrhage have not previously been described. [Copyright &y& Elsevier]

Joseph Merrick, the Elephant Man, presented to the Royal London Hospital in 1884 with an obscure condition that puzzled his contemporaries, and fascinates clinicians to this day. Throughout the 1900s, a number of theories were advanced to explain the numerous growths that covered his body: neurofibromatosis, Proteus syndrome, and a combination of childhood injury, fibrous dysplasia, and pyarthrosis. The debate continued throughout the 20th century without resolution. Today, new consensus on the genetic and clinical diagnosis of neurofibromatosis and Proteus syndrome has allowed advancements in the Elephant Man's diagnosis. Using recent clinical diagnostic criteria it is now possible to conclude that Joseph Merrick was in all likelihood suffering from Proteus syndrome. Nevertheless, details of his genotype remain unknown. Obtaining intact DNA from the Elephant Man's skeleton is challenging, yet it is possible that sequencing Merrick's genome could provide genetic confirmation of his clinical diagnosis, and shed light on the process of tumourigenesis. [ABSTRACT FROM AUTHOR]

Abstract: Beckwith–Wiedemann syndrome (BWS) predisposes to embryonic tumors. The concomitant presence of pathologically different tumors requires patient-specific surgical care. We report a case of simultaneous occurrence of a hepatoblastoma (HB) and an infantile hepatic hemangioma (IHH). A 4-month-old girl with BWS presented with two liver masses (one in segment VI/V and the other in segment VII). Biopsy of the larger lesion confirmed the diagnosis of HB. Standard chemotherapy was started and a right hepatectomy was planned. The two masses reacted differently to chemotherapy, with a marked decrease in the size of the larger tumor, and no change in the size of the smaller one. Thus, after four chemotherapy cycles, enucleation of the smaller of the two masses was performed and intraoperative examination of the specimen revealed the presence of an IHH. Segmentectomy of the second, larger tumor was then performed, instead of the originally planned right hepatectomy. The presence of both HB and IHH in children with BWS is rare. Early recognition of the two different tumors allows for patient-specific surgical care, with resection of less liver tissue. This is important in children with BWS given the persistent lifelong risk for additional liver tumors requiring liver resections. [Copyright &y& Elsevier]

Abstract: A case of bladder hemangiomas in association with Proteus syndrome (PS) is described. PS is a rare hamartomatous disorder and comprises an association of verrucous epidermal nevi, infantile hemangiomas, lipoma-like subcutaneous hamartomas and asymmetrical overgrowth of almost any part of the body. To our knowledge, this is the second case reported of hematuria associated with bladder hemangiomas in PS. [Copyright &y& Elsevier]

Abstract: The authors report a case of fibrolipoma of the median nerve in a 6-year old boy presenting as macrodactyly with clinodactyly. The causal relationship between the nerve lesion and the deformities is discussed. The difficulties of diagnosis of the condition are presented as are the difficulties of management where a balance has to be struck between conservative treatment and amputation. [Copyright &y& Elsevier]

Abstract: We tested the sensitivity of taste after reduction of the tongue in four girls with Beckwith–Wiedemann syndrome. No patient had taste blindness, but the ability to detect salty and bitter tastes declined after reduction of the tongue. [Copyright &y& Elsevier]

The article presents a case study of 3-year-old girl who displayed rapid, progressive, postnatal macrodactyly involving four fingers and two toes and cerebriform connective tissue nevus (CCTN) on the sole of left foot. The CCTN specimens were pathologically examined and the loss of fibroblasts with variable thick collagen bundles was discovered. The authors explore the typical clinical manifestations of Proteus syndrome in the case and discuss the tumor susceptibility in the said condition.

The article presents a case study of a 15-year-old boy, born from a non-consanguineous marriage, who has sporadic gross hematuria for four months. The boy had asymmetrical and progressive lower limbs overgrowth and dilated tortuous feet veins. Moreover, results of diagnosis show that he had Proteus syndrome (PS).

Children with Beckwith-Wiedemann syndrome (BWS) are at an increased risk of developing malignancies early in life. Several malignancies have been described in this fetal overgrowth syndrome; however, to date, only one hematological malignancy developing during early childhood has been reported. We present a patient with BWS developing acute myeloid leukemia at the age of 23. Loss of genomic imprinting of growth regulatory genes is thought to be the cause of BWS. For one of those genes, IGF2, an important role in childhood overgrowth syndromes as well as in the development of adult acute leukemia has been suggested, providing a possible explanation for our presented case. [Copyright &y& Elsevier]

Background context Proteus syndrome (PS) is an extremely rare congenital disorder causing asymmetric overgrowth of different tissues. The etiology remains unclear. Limb deformities are common and often necessitate amputations. Only a few cases associated with spinal deformities have been described. Purpose The aim was to report a rare case of PS associated with spinal deformity and its surgical management. Study design A case of young boy with PS causing vertebral hypertrophy and kyphoscoliotic deformity, which was surgically corrected, is presented. Methods The patient was assessed clinically and with whole spine plain radiographs, computed tomography, and magnetic resonance imaging. Surgical correction was performed. Results Satisfactory correction of the deformity was achieved by posterior spinal fusion with instrumentation from T4–L5, five Ponte osteotomies T8–L1, and an L2 pedicle subtraction osteotomy. The kyphosis was corrected from 87° to 55°; there was improvement in all spinopelvic parameters. One year after surgery, there was maintenance of the deformity correction with no deterioration of the sagittal balance, and the patient was free of pain and had no loss of neurologic function. Conclusions Proteus syndrome can be associated with spinal stenosis and deformity. Although the syndrome can be progressive in nature, the symptomatic spinal pathology should be treated appropriately. [ABSTRACT FROM AUTHOR]