Congenital Limb Overgrowth Syndromes Associated with Vascular Anomalies.

Congenital limb length discrepancy disorders are frequently associated with a variety of vascular anomalies and have unique genetic and phenotypic features. Many of these syndromes have been linked to sporadic somatic mosaicism involving mutations of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, which has an important role in tissue growth and angiogenesis. Radiologists who are aware of congenital limb length discrepancies can make specific diagnoses based on imaging findings. Although genetic confirmation is necessary for a definitive diagnosis, the radiologist serves as a central figure in the identification and treatment of these disorders. The clinical presentations, diagnostic and imaging workups, and treatment options available for patients with Klippel-Trenaunay syndrome, CLOVES (congenital lipomatous overgrowth, vascular anomalies, epidermal nevi, and scoliosis/spinal deformities) syndrome, fibroadipose vascular anomaly, phosphatase and tensin homolog mutation spectrum, Parkes-Weber syndrome, and Proteus syndrome are reviewed. ©RSNA, 2019.

The importance of prenatal 3-dimensional sonography in a case of a segmental overgrowth syndrome with unclear chromosomal microarray results.

PIK3CA-related overgrowth spectrum, caused by mosaic mutations in the PIK3CA gene, is associated with regional or generalized asymmetric overgrowth of the body or a body part in addition to other clinical findings. Three-dimensional ultrasonography (3-D US) has the capability to display structural abnormalities in soft tissues or other organs, thereby facilitating identification of segmental overgrowth lesions. We present a case suspected of having a segmental overgrowth disorder based on 3-D US, whose chromosomal microarray result was abnormal, but apparently was not the cause of the majority of the fetus's clinical features.

Lack of mutation-histopathology correlation in a patient with Proteus syndrome.

Proteus syndrome (PS) is characterized by progressive, disproportionate, segmental overgrowth, and tumor susceptibility caused by a somatic mosaic AKT1 activating mutation. Each individual has unique manifestations making this disorder extremely heterogeneous. We correlated three variables in 38 tissue samples from a patient who died with PS: the gross affection status, the microscopic affection status, and the mutation level. The AKT1 mutation was measured using a PCR-based RFLP assay. Thirteen samples were grossly normal; six had detectable mutation (2-29%) although four of these six were histopathologically normal. Of the seven grossly normal samples that had no mutation, only four were histologically normal. The mutation level in the grossly abnormal samples was 3-35% and all but the right and left kidneys, skull, and left knee bone, with mutation levels of 19%, 15%, 26%, and 17%, respectively, had abnormal histopathology. The highest mutation level was in a toe bone sample whereas the lowest levels were in the soft tissue surrounding that toe, and an omental fat nodule. We also show here that PS overgrowth can be caused by cellular proliferation or by extracellular matrix expansion. Additionally, papillary thyroid carcinoma was identified, a tumor not previously associated with PS. We conclude that gross pathology and histopathology correlate poorly with mutation levels in PS, that overgrowth can be mediated by cellular proliferation or extracellular matrix expansion, and that papillary thyroid carcinoma is part of the tumor susceptibility of PS. New methods need to be developed to facilitate genotype-phenotype correlation in mosaic disorders. © 2016 Wiley Periodicals, Inc.

Myocardial fat overgrowth in Proteus syndrome.

Proteus syndrome (PS) is a rare, mosaic disorder with asymmetric and distorting overgrowth of the skeletal system, skin, and adipose tissues. Cardiac abnormalities are rare in this syndrome and only two prior cases have been reported. Many patients with PS followed at our institution underwent transthoracic echocardiograms for preoperative evaluation or as work-up for associated pulmonary disease. Some were noted to have prominent, focal echodense areas in the myocardium. We further investigated cardiac findings in a cohort of children and adult patients with PS. Patients with abnormal echocardiograms were referred for cardiac magnetic resonance imaging, Holter monitoring, and exercise treadmill testing. Twenty children and adults with PS, age 24 months to 50 years old, underwent transthoracic echocardiograms. Seven patients (35%) had focal bright echodense areas within the myocardium suggesting fatty infiltration. The majority of patients had significant involvement of the interventricular septum. The cardiac characteristics of all patients with fatty infiltration on transthoracic echocardiograms were compared to Proteus patients without these findings. There were no significant differences in chamber sizes, mass, systolic or diastolic function. No increased risk of conduction defects or arrhythmias was found. This study shows that abnormal fat overgrowth is a common finding in the myocardium in patients with Proteus syndrome; however, it is not associated with functional derangements or arrhythmias. Further evaluation of a larger number of Proteus patients is needed in order to determine the frequency and prognosis of cardiac involvement. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Cervical canal stenosis caused by progressive fusion and enlargement of cervical vertebrae with features of Proteus syndrome and Klippel-Feil syndrome.

We report the case of a female who presented with progressive fusion and an enlargement of the cervical vertebrae. Her cervical deformity gradually progressed with age, and the abnormal bony protrusion into the spinal canal caused myelopathy. We resected the affected vertebrae to decompress the spinal cord and performed combined anterior-posterior spinal fusion. The progression of the spinal deformity and enlargement of vertebrae stopped after surgery. The enlargement of vertebrae in the present case resembled that observed in Proteus syndrome; however, autonomous vertebral fusion has not been reported previously in patients with this condition. Our report may help expand the knowledge on developmental spine disorders.

A computer-assisted diagnostic and treatment concept to increase accuracy and safety in the extracranial correction of cranial vault asymmetries.

PURPOSE: Proteus syndrome is described as a progressive, asymmetric, disproportional overgrowth of various parts of the body. The theory of somatic mosaicism is widely accepted to be the cause of this disease. Affected patients present very heterogeneous symptoms, but in about 30% craniofacial deformities are the leading clinical features. Because no causal therapy exists, treatment options are limited to surgical improvement of functional constraints. MATERIALS AND METHODS: A computer-assisted method was used to increase the accuracy and safety of bone removal in the extracranial correction of cranial vault asymmetries. Descriptions of the diagnosis, preoperative planning, and intraoperative management of craniofacial dysmorphia caused by Proteus syndrome in a 6-year-old boy are presented. After computed tomography-based generation of a virtual 3-dimensional (3D) model of the patient and a haptic stereolithographic model to display the special pathology, flow-sensitized 4-dimensional magnetic resonance imaging was performed to clarify the properties of vascular formation inside the hyperostosis. To transfer the mathematically optimized preoperative planning of a new skull shape to the patient, a surgical guide was fabricated by rapid manufacturing. Intraoperative 3D real-time navigation was installed as an additional visualization and security feature. RESULTS: The surgery could be performed safely and quickly. Postoperative imaging showed that the surgical plan was realized with high accuracy. CONCLUSION: This newly developed and validated method can be successfully implemented in the operating room environment.

Pulmonary manifestations in Proteus syndrome: pulmonary varicosities and bullous lung disease.

We report on two patients with Proteus syndrome (PS), with emphasis on its pulmonary manifestations. The first patient was a 6-year-old girl diagnosed with PS at 5 years of age. The pulmonary abnormalities first observed at age 3 years and included streaky densities with accentuated vascular markings detected by chest radiography. The patient had persistent abnormalities on follow-up chest radiographs. Chest computed tomography (CT) scans showed diffuse pulmonary venous dilatations. The second patient was a 10-year-old boy diagnosed with PS at age 4 years. Chest radiography and CT scans showed patchy and streaky densities intermixed with small bullae, which were interpreted as pneumonia with post-inflammatory pneumatoceles. The patient developed diffuse enlargement of air spaces of the lungs at age 10 years with severe respiratory compromise. Although pulmonary manifestations in PS are uncommon, recognition of pulmonary vein malformation and the presentation of enlarged air spaces in the lungs at an earlier age are important for accurate diagnosis. The plain radiograph findings of accentuated vascular markings seen in patients with PS may appear similar to interstitial or chronic pneumonia. This report emphasizes the features of lung involvement in children with PS and suggests that specific attention be paid to pulmonary manifestations using chest CT scans. © 2011 Wiley-Liss, Inc.

Maxillofacial manifestations of Proteus syndrome: a systematic review with a case report.

OBJECTIVES: Proteus syndrome (PS) is an extremely rare disorder with asymmetric and disproportionate bone overgrowth. Craniofacial abnormalities in PS are less frequent than skeletal abnormalities. Although there are recognized oral and maxillofacial manifestations of PS, few case reports describing these manifestations are available. Thus, the objective of this systematic review and case report is to describe oral and maxillofacial manifestations of PS and to report a PS case. METHODS: A 31-year-old male presented with restricted mouth opening and pain during mastication. A panoramic radiograph and an occlusal radiograph were obtained. Reports with relevant keywords were assessed. Data were summarized and demonstrated using a critical appraisal checklist for case reports. RESULTS: The panoramic radiograph demonstrated unilateral overgrowth of the mandible, impacted teeth, and deciduous prolonged retention. Thirteen PS case reports were identified. CONCLUSIONS: Proteus syndrome oral and maxillofacial manifestations may include dental agenesis, impacted teeth, malocclusion, asymmetric dental growth and maturation, frontal line displacement, asymmetric tongue enlargement, mandibular hemihypertrophy and asymmetry, presence of exostoses/hyperostosis, degenerative changes in the temporomandibular joint, alterations of maxillary and mandibular vertical and/or horizontal growth, and enlargement of mandibular canal and foramen. The PROSPERO systematic review registration number is CRD42019140942.

NAA10 p.(N101K) disrupts N-terminal acetyltransferase complex NatA and is associated with developmental delay and hemihypertrophy.

Nearly half of all human proteins are acetylated at their N-termini by the NatA N-terminal acetyltransferase complex. NAA10 is evolutionarily conserved as the catalytic subunit of NatA in complex with NAA15, but may also have NatA-independent functions. Several NAA10 variants are associated with genetic disorders. The phenotypic spectrum includes developmental delay, intellectual disability, and cardiac abnormalities. Here, we have identified the previously undescribed NAA10 c.303C>A and c.303C>G p.(N101K) variants in two unrelated girls. These girls have developmental delay, but they both also display hemihypertrophy a feature normally not observed or registered among these cases. Functional studies revealed that NAA10 p.(N101K) is completely impaired in its ability to bind NAA15 and to form an enzymatically active NatA complex. In contrast, the integrity of NAA10 p.(N101K) as a monomeric acetyltransferase is intact. Thus, this NAA10 variant may represent the best example of the impact of NatA mediated N-terminal acetylation, isolated from other potential NAA10-mediated cellular functions and may provide important insights into the phenotypes observed in individuals expressing pathogenic NAA10 variants.

Proteus syndrome caused by novel somatic AKT1 duplication.

Proteus syndrome (PS) is a rare overgrowth disorder that presents with asymmetrical growth of the bone and fat tissues following a mosaic pattern mutation. The estimated worldwide incidence is approximately one in one million live births. Proteus syndrome causes disfigurement and psychological impact through its effects on somatic tissue. Due to its rarity and diversity of tissues involved, it represents a significant challenge to caregivers and multidisciplinary medical teams. Here, we report a Saudi girl, with a large left cervical mass discovered antenatally. This mass was identified as a growing cystic hygroma, and she had features of overgrowth and hemangiomas. Whole exome sequencing was negative from the blood lymphocytes and affected tissue sample.  However, deletion duplication analysis from tissue shows a novel mosaic somatic mutation of the AKT1 gene. Somatic mutation remains an obstacle, and the geneticist has an essential role in its management, providing an established genetic diagnosis, prognosis, and family counselling.

[Macrodactylies of the hand and foot]. / Les macrodactylies de la main et du pied.

Macrodactyly is a rare congenital anomaly defined by an enlargement of all the structures of fingers or toes. Two forms of macrodactyly have been described. One form is static with an enlargement present at birth and growing proportionately to the other digits. The other is progressive with an enlargement beginning in early childhood and growing faster than that of the normal digits. Macrodactyly is responsible of a functional handicap and an aesthetic prejudice. Treatment may be indicated for this reason. Treatment must be individualised and depends on the proportionate size of the enlarged finger, growth rate and the patient's age when first seen. The parents and the child should be advised that multiple procedures may be required and that the result will be somewhat unsatisfactory. Surgical approaches include either reconstructive surgery or amputation. Amputation is indicated at any age for a large, unsightly and stiff digit that interferes with function of the rest of the hand. In feet with involvement of the lesser toes, proximal amputation has the best cosmetic and functional outcome. Epiphyseal arrest, bulk reduction procedures, finger shortening, lateral closing-wedge osteotomies or stripping of the nerves can be performed in the other cases.

Proteus syndrome: a rare cause of hemihypertrophy and macrodactyly on bone scanning.

Proteus syndrome is a rare, sporadic genetic disorder characterized by overgrowth of multiple different tissues in a mosaic pattern. It is associated with connective tissue nevi, epidermal nevi, disproportionate overgrowth of multiple tissues, vascular malformations, characteristic tumors, and specific facial anomalies. Joseph Merrick, popularly known as the Elephant Man, is now believed to have suffered from Proteus syndrome. A case of Proteus syndrome and associated findings on bone scintigraphy are presented.

Thoracolumbar scoliosis in a patient with Proteus syndrome: a case report and literature review.

The Proteus syndrome (PS) is a complex and rare congenital hamartomatous condition with a wide range of malformations. Little is reported about spinal deformity associated with this syndrome. This study presents a case of scoliosis occurring in the setting of PS and explores the possible mechanisms between the 2 diseases. The patient is a 17-year-old Chinese female with scoliosis and hemihypertrophy of the right upper and lower extremity as well as exostosis of the right lower leg joint including the hip, knee, ankle, and toes. These manifestations were suggestive of PS. She underwent a posterior correction at thoracic 2-lumbar 4 (T5-L4) levels, using the Moss-SI spinal system. At 3-month follow-ups, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. The severity of scoliosis in PS is progressively aggravated and the correction of the extensive spinal deformities is generally difficult. Therefore, early diagnosis is required for adequate interdisciplinary treatment.

Surgical correction of kyphotic deformity in a patient with Proteus syndrome.

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.

Proteus syndrome: Report of a case with AKT1 mutation in a dental cyst.

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.

Radiologic manifestations of Proteus syndrome.

Proteus syndrome is a sporadic disorder named for its highly variable manifestations. The disease causes tissue overgrowth in a mosaic pattern and may affect tissues derived from any germinal layer. The disease process is not usually apparent at birth but develops rapidly in childhood. Common manifestations include macrodactyly, vertebral abnormalities, asymmetric limb overgrowth and length discrepancy, hyperostosis, abnormal and asymmetric fat distribution, asymmetric muscle development, connective-tissue nevi, and vascular malformations. The features of Proteus syndrome indicate that the condition may be caused by a somatic alteration in a gene, but no specific genetic mutation has yet been identified. Therefore, the diagnosis and management of the disease depend heavily on clinical evaluation and imaging. Although the manifestations of Proteus syndrome are highly variable, accurate diagnosis is possible if standard diagnostic criteria are followed and if disease features are assessed in comparison with those found in similar syndromes.

[Simultaneous use of different nuclear medical examinations in Klippel-Trenaunay syndrome--vs. Proteus syndrome]. / Simultaner Einsatz verschiedener nuklearmedizinischer Verfahren bei Klippel-Trenaunay-Syndrom--vs. Proteus-Syndrom.

A three-year-old male patient presented already at his birth a disproportion macrosomia of the left foot and a large, nodular nevus flammeus in the left hip region, which led to the tentative diagnosis of a Klippel-Trenaunay syndrome. In the following years, both changes showed a continuous progression, with distinct soft-tissue swelling as well as papillomatous and verruciform vegetations of the nevus. Additionally, large, plain subcutaneous masses developed under the right shoulder, and a macrodactyly of the first and second left toe could be observed. Although several examinations had been performed in the meantime, the tentative diagnosis could not be confirmed up to that time. On the occasion of a severe local infection in the hip region, which led to the consideration of a surgical therapy, a radionuclide lymphography, a blood pool scintigraphy including dynamic phlebography and ventriculography as well as a bone scintigraphy were performed. These examinations were done simultaneously at one day in order to avoid a longer period of immobilization. The findings led to the diagnosis of a large lymphangioma, which could be confirmed histologically after surgery. In consideration of all results, the basic disorder seems to be the rare proteus syndrome rather than a Klippel-Trenaunay syndrome.