Maffucci syndrome with the spindle cell hemangiomas in the mucosa of the lower lip: a rare case report and literature review

The presence of non‐cutaneous vascular lesions in the syndrome of multiple enchondromas and subcutaneous hemangiomas, also named Maffucci syndrome, is exceedingly rare. Until now, non‐cutaneous vascular lesions have been described in nine patients, while only three cases were present in the oral cavity; they were found in the tongue in two patients and in the lower lip in one patient. Herein, we report the second case of vascular lesions localized in the mucosa of lower lip in a patient with Maffucci syndrome. Histopathologic examination showed spindle cell hemangioma.     

Treatment of complex periorbital venolymphatic malformation in a neonate with a combination therapy of sirolimus and prednisolone

Venolymphatic malformations (VLMs) are vascular anomalies consisting of both veins and lymph vessels. A 2‐week‐old newborn presented with large VLMs on the left forehead, temple, preauricular area, and orbit. Patient was at imminent risk for permanent vision loss due to a localized mass effect. Surgical excision or debulking was contraindicated due to its complexity and proximity to the left eye, and the patient failed to respond to the sildenafil treatment and sclerotherapy. Patient was subsequently started on oral sirolimus 0.8 mg/m² twice daily in combination with prednisolone 2 mg/kg daily. The patient had an excellent therapeutic outcome for 7 months with complete preservation of vision before treatment was discontinued. However, 2 months after the medical treatments were discontinued, her VLM rebounded. She responded to the combination therapy again after a failed treatment with the mTOR inhibitor alone. This case demonstrates that the sirolimus and prednisolone combination therapy could be beneficial for treatment of complex VLM intractable to other treatments.     

Generalized lymphatic anomaly successfully treated with long‐term,low‐dose sirolimus

Generalized lymphatic anomaly is a rare, complex, lymphatic anomaly generally involving soft tissues, spleen, and bones. It can lead to focal skeletal fragility and pathologic effusions. A recent prospective trial of sirolimus for complicated vascular anomalies showed partial response in seven patients with generalized lymphatic anomaly treated with sirolimus with a target trough level of 10‐15 ng/mL for 1 year (Adams et al). We describe successful treatment of generalized lymphatic anomaly with a lower‐dose, long‐term course of sirolimus.     

Successful treatment of spindle cell hemangiomas in a patient with Maffucci syndrome and review of literatures

Maffucci syndrome is a rare genetic disease due to somatic mutation of IDH1 gene. Currently there is no medical treatment available for spindle cell hemangioma associated with this disorder. Here we report successful management of these hemangiomas using sirolimus in combination with surgery.     

Successful management of steroid‐resistant vascular tumors associated with the Kasabach–Merritt phenomenon using sirolimus

Vascular tumors associated with Kasabach–Merritt phenomenon (KMP) are life‐threatening and the mortality is as high as 10–30%. Steroids are considered the primary choice for drug therapy. However, there are many steroid‐resistant cases. In the present study, analyzed data are presented to support the use of sirolimus in clinical practise for the treatment of corticosteroid‐resistant vascular tumors with KMP in eight infants between June 2015 and April 2017 in a single hospital. The time to initial response was 6.8 ± 2.7 days. The average stabilization time for the platelet count was 19.1 ± 8.5 days. At the time of publication, the average duration of sirolimus treatment was 14.1 ± 4.0 months, and the average time for sirolimus treatment as a single agent was 12.6 ± 4.2 months. The side‐effects were tolerable and included oral ulcer, fever, pain, skin rash and transient ascension of serum transaminase and cholesterol. Our study indicated that sirolimus therapy is an effective and safe method for the treatment of corticosteroid resistant vascular tumors associated with KMP in infants.     

Preventive treatment with oral sirolimus and aspirin in a newborn with severe Sturge‐Weber syndrome

Sturge‐Weber syndrome (SWS) is characterized by facial capillary malformation, leptomeningeal capillary malformations, and choroidal and episcleral vascular malformations. These malformations produce neurologic and ophthalmological symptoms including seizures and glaucoma. A premature male newborn without prenatal diagnosis presented with severe bilateral SWS and was started on systemic sirolimus and aspirin. The patient has remained seizure‐free for 23 months and demonstrated an excellent response to pulsed dye laser treatment.     

Treatment of Infantile Hemangiomas with Sirolimus in a Patient with PHACE Syndrome

Infantile hemangiomas (IHs) are common benign tumors of childhood. IHs often regress satisfactorily without intervention, but a subset of IHs may lead to functional or cosmetic morbidity necessitating therapy. PHACE syndrome is characterized by a variety of neurocutaneous and vascular anomalies that typically include segmental hemangiomas. We present an infant with PHACE syndrome and segmental IH that failed conventional first‐line therapies. Treatment with sirolimus provided benefit with regression of the cutaneous IH. As an inhibitor of the mammalian target of rapamycin (mTOR) pathway, the effective use of sirolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of IHs.     

Efficacy and safety of sirolimus in the treatment of blue rubber bleb naevus syndrome in paediatric patients

Blue rubber bleb naevus syndrome (BRBNS) is an extremely rare venous malformation that often manifests as multiple haemangioma-like lesions in the skin and gastrointestinal tract. The drug sirolimus plays a key role in the signalling pathway of angiogenesis and subsequent development of BRBNS and its use has been described in several case reports. We present a case series of four patients with BRBNS who exhibited good treatment response to sirolimus. All four patients were administered oral sirolimus at doses of 1.0–1.5 mg/m²/day with a target drug level of 5–10 ng/mL and median treatment duration of 20 months. All patients had a reduction in the size of the lesions and a normalization of coagulopathy with tolerable drug adverse reactions at follow-up. Sirolimus may be effective and safe in paediatric patients with BRBNS. Further prospective studies are suggested to evaluate the long-term effectiveness of this drug.     

西罗莫司治疗复杂性血管畸形的研究进展

血管畸形是一类良性先天性血管性病变的统称,可累及多个系统和脏器。复杂型血管畸形可以引起严重的并发症,导致毁形性损害、功能障碍甚至危及生命。西罗莫司是一种西罗莫司靶蛋白特异性抑制剂,常规应用于器官移植术后抗移植排斥反应。近年来将其用于治疗复杂性血管畸形取得良好疗效。目前报道,西罗莫司口服治疗最小年龄仅为14周龄,治疗的常用剂量为每天1.5～2 mg/m2,所有患者治疗总有效率为20%～80%。常见的生物学不良反应包括血液系统改变,代谢改变。少见且严重的不良反应为间质性肺炎和潜在性免疫抑制。目前研究显示,西罗莫司治疗复杂血管性疾病可能有非常好的前景,但尚需更多循证医学的证据支持。     

Livedoid vasculopathy and hypercoagulability in a patient with primary Sjögren's syndrome

Background A 31‐year‐old woman presented with a 5‐year history of painful ulcerations, palpable purpura, porcelain‐white atrophic scars of the malleolar region and dorsal aspect of the feet, livedo reticularis on the limbs, arthralgia, xerophthalmia, and xerostomia. Methods Skin biopsy revealed vessel wall hyalinization and thrombosis of the microvasculature with a very scarce dermal inflammatory infiltrate. Biopsy of the oral mucosa showed mononuclear infiltration of an intralobular duct of a salivary gland. Results Laboratory studies, including autoantibodies and inflammation markers, were normal, except for a positive rheumatoid factor. Coagulation screening revealed C677T methylenetetrahydrofolate reductase (MTHFR) mutation, with a normal serum homocysteine. The patient was treated with oral methylprednisolone (32 mg/day with progressive reduction) and enoxaparin (20 mg/day subcutaneously), with complete ulcer healing within 4 months. Conclusion Livedoid vasculitis or vasculopathy has not been referred to previously in association with Sjögren's syndrome, but may be associated with other autoimmune disorders and anomalies of coagulation, namely factor V Leiden mutation, protein C deficiency, and MTHFR mutation, associated or not with hyperhomocysteinemia, a condition that seems to confer an increased risk of recurrent arterial and venous thrombosis. We stress the importance of anticoagulant therapy for ulcer healing and for the prevention of other thrombotic events.     

Fibroadipose vascular anomaly treated with sirolimus: Successful outcome in two patients

Fibroadipose vascular anomaly (FAVA) is a rare, complex mesenchymal malformation combining fibrofatty replacement of the affected muscles and slow‐flow vascular malformation. The condition is characterized by localized swelling, severe pain, phlebectasia, and contracture of the affected limb. Treatment paradigms are not well established for this rare, recently recognized condition. We report two cases of FAVA in which treatment with sirolimus produced rapid, dramatic improvement in pain and quality of life.     

Recurrent Chondrosarcoma of the Right Skull Base in a Patient with Maffucci Syndrome

Maffucci syndrome is a rare, sporadic disease characterized by the development of multiple enchondromas and subcutaneous hemangiomas. Patients with Maffucci syndrome have a 23-37% risk of malignancy, with chondrosarcomas being the most common. Although the development of a chondrosarcoma in a patient with Maffucci syndrome may be expected, intracranial chondrosarcomas are rare. We present a patient with Maffucci syndrome who was diagnosed with an intracranial chondrosarcoma after presenting with hearing loss and vomiting. After three craniotomies and two recurrences of chondrosarcoma of the right skull base, the patient demonstrated a positive outcome to treatment with external radiation therapy.     

Pemphigus vulgaris with involvement of the cervix treated using thalidomide therapy

A 55‐year‐old White woman was first seen in July 1995 with ulceration of the oral mucosa, including the gingiva, labial mucosa, gums, palate and tongue, as well as erosions and blisters on the trunk. A biopsy showed a suprabasal blister with acantholysis. Direct immunofluorescence was positive for intercellular deposits of IgG and C3, and indirect immunofluorescence was positive for intercellular antibodies at a titer of 160. The patient was diagnosed as having pemphigus vulgaris and treated with prednisone 1–1.5 mg/kg/day from 1995 until 1998, but no response was observed (the disease continued to be active with the formation of new lesions). The patient developed a number of steroid‐induced complications including diabetes, osteoporosis, Cushing syndrome, hypertension and high‐output cardiac failure, and required repeated hospitalization. In August 1998 she was started on azathioprine 100–150 mg/day and continued on prednisone 1 mg/kg/day. One year later, in August 1999, the disease was still active with new lesion formation and persistent oral erosions and dysphagia, despite persistent therapy with azathioprine 150 mg/day and prednisone 1 mg/kg/day. Because of the disease severity and the lack of a response to treatment, in October 1999 the patient was started on thalidomide therapy 100 mg/day (1.7 mg/kg/day) and continued the prednisone treatment at 1 mg/kg/day together with azathioprine 150 mg/day (2.7 mg/kg/day). There was a good response, with clearing of all oral lesions in 20 days. The prednisone dose was gradually reduced and was discontinued in May 2000; azathioprine was gradually reduced to 50 mg 3 times/week (0.35 mg/kg/day). Thalidomide was continued at a dose of 100 mg/day. The patient was in total clinical remission, being free of both old and new lesions, for the next 14 months, when the thalidomide treatment was discontinued as a result of side‐effects, including weakness in the legs and paresthesis of the fingers. After the discontinuance of treatment with thalidomide, severe lesions returned. Thalidomide was reintroduced, at 100 mg/day. After 2 months the patient entered total clinical remission and on the last occasion on which she was seen, in May 2003, was found to have remained clear of lesions. The patient continues to take thalidomide at 100 mg/day.     

Propranolol Use in PHACE Syndrome with Cervical and Intracranial Arterial Anomalies: Collective Experience in 32 Infants

The objective of this retrospective study of patients evaluated between July 2008 and October 2011 in seven pediatric dermatology centers was to combine collective clinical experience using oral propranolol therapy in 32 infants with PHACE syndrome (Posterior fossa [brain malformations present at birth], Hemangioma [usually covering a large area of the skin of the head or neck >5 cm]; Arterial lesions [abnormalities of the blood vessels in the neck or head]; Cardiac abnormalities or aortic coarctation [abnormalities of the heart or blood vessels that are attached to the heart]; Eye abnormalities) with cervical or intracranial arterial anomalies. Patients were given an average daily dose of oral propranolol of 1.8 mg/kg divided two or three times per day for an average duration of 12.3 months. The main outcome measure was adverse neurologic events. Seven (22%) patients were categorized as being at higher risk for stroke, defined on magnetic resonance imaging as severe, long‐segment narrowing or nonvisualization of major cerebral or cervical vessels without anatomic evidence of collateral circulation, often in the presence of concomitant cardiovascular comorbidities. Only one patient developed a change in neurologic status during propranolol treatment: mild right hemiparesis that remained static and improved while propranolol was continued. An additional three patients had worsening hemangioma ulceration or tissue necrosis during therapy. This is the largest report thus far of patients with PHACE syndrome treated with propranolol. Although no catastrophic neurologic events occurred, serious complications, particularly severe ulcerations, were seen in a minority of patients, and given the sample size, we cannot exclude the possibility that propranolol could augment the risk of stroke in this population. We propose radiologic criteria that may prove useful in defining PHACE patients as being at high or standard risk for stroke. We continue to advise caution in using systemic beta‐blockers, particularly for children with vascular anomalies at higher risk for stroke. Use of the lowest possible dosage, slow dosage titration, three times per day dosing to minimize abrupt changes in blood pressure, and close follow‐up, including neurologic consultation as needed, are recommended.     

Unilateral Mosaic Cutaneous Vascular Lesions,Enchondroma, Multiple Soft Tissue Chondromas and Congenital Fibrosarcoma— A Variant of Maffucci Syndrome?

Abstract:  The coexistence of enchondromas and vascular lesions characterizes the principal feature of a rare congenital condition known as Maffucci syndrome. We present a 20-year-old male with a mosaic distribution of vascular malformations and atrophic overlying dermis and subcutis. Enchondroma and multiple periosteal chondromas of the ipsilateral limb led to the working diagnosis of Maffucci syndrome. Of interest, this patient also has a history of congenital fibrosarcoma with concomitant thrombocytopenia. To our knowledge this is the first report of this constellation of findings, which may represent a form of mesenchymal mosaicism analogous to the Blaschkoid distribution of other genodermatoses.     

Pediatric dermatology—Critical approach to the new treatments

The field of pediatric dermatology treatment has been rich in new developments. Several recent therapeutic advances in pediatric dermatology have been made. This review will focus on critical approach to the new treatments for several entities encountered in pediatric dermatology. The use of biologics and small molecules in children with atopic dermatitis and psoriasis, exciting advances in the use of propranolol and other beta‐blockers for the treatment of infantile hemangiomas, the use of sirolimus for vascular anomalies will be discussed.     

Maffucci综合征

报告1例Maffucci综合征.患者女,42岁.因有足、左手结节渐增多6～7年,手指结节疼痛1年就诊.患者7岁时右小腿骨折后出现畸形致跛行.左手X线摄片显示多根掌骨膨胀性改变,并有多发性钙化影.左手结节组织病理检查示海绵状血管瘤及梭形细胞血管瘤,部分可见血栓形成及静脉石.免疫组化染色示海绵状血管瘤区管腔内内皮细胞、裂隙状血管腔内皮细胞及圆形空泡细胞CD31、CD34和FVIII均阳性,而实心区波形蛋白(vimentin)阳性,余为阴性.临床表现和皮损组织病理改变符合Maffucci综合征诊断.     

An overview of interventional radiology techniques for the diagnosis and management of vascular anomalies: Part 1

Minimally invasive percutaneous and endovascular strategies performed by interventional radiologists have become the mainstays of treatment for vascular anomalies, with improved outcomes, decreased complication rates, and reduced morbidity. The aim of this article is to introduce physicians who care for patients with vascular anomalies to state-of-the-art advancements in interventional radiology (IR) for diagnosis and treatment. Part 1 of this review will focus on sclerotherapy and cryoablation. Part 2 will discuss embolization, endovenous laser ablation, and image-guided percutaneous biopsy. Select vascular anomalies will be discussed as examples to highlight IR diagnostic and/or treatment techniques.     

Sirolimus-induced onychopathy in renal transplant recipients

INTRODUCTION: A large number of drugs may be responsible for the development of nail changes. Sirolimus is an immunosuppressive drug recently developed in organ transplantation. Herein, we evaluate sirolimus-induced nail abnormalities in renal transplant recipients. PATIENTS AND METHODS: The nails of 80 consecutive renal transplant recipients receiving sirolimus have been evaluated in a systematic dermatological study in 2003. The patients were mainly men (60%) with a mean age of 48 years. The mean duration of the graft was 6 years and of sirolimus treatment 18 months. Mycophenolate mofetil and steroids were combined with sirolimus in 86% of patients. RESULTS: Fifty-seven patients (74%) complained for nail alterations. The most frequent anomalies (88%) were matrix alterations including slow growth, onychomalacia, onychorrexis, and leukonychia. Nail bed alterations (onycholysis), vascular phenomenon (erythema, splinter hemorrhages), and periungual anomalies (mainly pyogenic granulomas) were observed in 42, 42 and 19% of cases respectively. One observation of type 1 photo-onycholysis was described. DISCUSSION: This study reports a new drug-induced onychopathy. Responsibility of sirolimus is highly suggested. The main pathogenesis hypothesis to explain these nail alterations is inhibition of EGF (epidermal growth factor) pathway by sirolimus.     

Oral tacrolimus treatment for refractory eosinophilic cellulitis

A 72‐year‐old man presented with a 1‐month history of a rash. The eruption had previously been successfully treated with oral corticosteroids (prednisolone 30 mg/day) and antihistamines on two previous occasions, but recurred several days after stopping treatment. On examination, multiple, indurated, round to annular erythematous plaques were found on the trunk and limbs. Histological examination revealed interstitial oedema, a dense infiltrate of eosinophils in the dermis, and flame figure formation. These results led us to the diagnosis of eosinophilic cellulitis. Treatment with oral corticosteroids (prednisolone 15 mg/day) was unsuccessful. Four weeks after the start of oral tacrolimus 1 mg/day, the eruption completely resolved.